Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770

PubMed Central

Gentzsch, Martina; Ren, Hong Y.; Houck, Scott A.; Quinney, Nancy L.; Cholon, Deborah M.; Sopha, Pattarawut; Chaudhry, Imron G.; Das, Jhuma; Dokholyan, Nikolay V.; Randell, Scott H.

2016-01-01

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients. PMID:27402691

Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770.

PubMed

Gentzsch, Martina; Ren, Hong Y; Houck, Scott A; Quinney, Nancy L; Cholon, Deborah M; Sopha, Pattarawut; Chaudhry, Imron G; Das, Jhuma; Dokholyan, Nikolay V; Randell, Scott H; Cyr, Douglas M

2016-09-01

Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients. Copyright © 2016 the American Physiological Society.

Regulation and Function of TIFAB in Myelodysplastic Syndrome

DTIC Science & Technology

2013-06-01

genomic alteration in MDS is deletion of chromosome 5q (del(5q)). MDS patients with an isolated del(5q) presenting with anemia, neutropenia , and...is deletion of chromosome 5q (del(5q)). MDS patients with an isolated del(5q) presenting with anemia, neutropenia , and elevated platelets associated

Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.

PubMed

Eichner, Ruth; Heider, Michael; Fernández-Sáiz, Vanesa; van Bebber, Frauke; Garz, Anne-Kathrin; Lemeer, Simone; Rudelius, Martina; Targosz, Bianca-Sabrina; Jacobs, Laura; Knorn, Anna-Maria; Slawska, Jolanta; Platzbecker, Uwe; Germing, Ulrich; Langer, Christian; Knop, Stefan; Einsele, Herrmann; Peschel, Christian; Haass, Christian; Keller, Ulrich; Schmid, Bettina; Götze, Katharina S; Kuster, Bernhard; Bassermann, Florian

2016-07-01

Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.

Associations between uncoupling protein 2, body composition, and resting energy expenditure in lean and obese African American, white, and Asian children.

PubMed

Yanovski, J A; Diament, A L; Sovik, K N; Nguyen, T T; Li, H; Sebring, N G; Warden, C H

2000-06-01

Little is known about genes that affect childhood body weight. The objective of this study was to examine the association between alleles of the mitochondrial uncoupling protein 2 (UCP2) gene and obesity because UCP2 may influence energy expenditure. We related UCP2 genotype to body composition and resting energy expenditure in 105 children aged 6-10 y. Overweight children and nonoverweight children of overweight parents were genotyped for a 45-base pair deletion/insertion (del/ins) in 3'-untranslated region of exon 8 and for an exon 4 C to T transition. Eighty-nine children were genotyped for the exon 8 allele: 50 children had del/del, 33 had del/ins, and 6 had ins/ins. Mean (+/-SD) body mass index (BMI; in kg/m(2)) was greater for children with del/ins (24.1 +/- 5.9) than for children with del/del (20.4 +/- 4.8; P < 0.001). BMI of ins/ins children (23.7 +/- 7.8) was not significantly different from that of del/ins children. A greater BMI in del/ins children was independent of race and sex. Body composition was also different according to UCP2 genotype. All body circumferences and skinfold thicknesses examined were significantly greater in del/ins than in del/del children. Body fat mass as determined by dual-energy X-ray absorptiometry was also greater in del/ins than in del/del children (P < 0.005). For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the 3 exon 4 genotypes. Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype. The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight.

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity

PubMed Central

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127

ASSOCIATIONS BETWEEN UNCOUPLING PROTEIN 2, BODY COMPOSITION, AND RESTING ENERGY EXPENDITURE IN LEAN AND OBESE AFRICAN AMERICAN, CAUCASIAN, AND ASIAN CHILDREN

PubMed Central

Yanovski, J.A.; Diament, A.L.; Sovik, K.N.; Nguyen, T.T.; Li, H.; Sebring, N.G.; Warden, C.H.

2015-01-01

Background Little is known about genes affecting childhood body weight. Objective To examine alleles of the mitochondrial uncoupling protein-2 (UCP2) gene for association with obesity, since UCP2 may influence energy expenditure. Design We related UCP2 genotype to body composition, and to resting energy expenditure, in 105 children aged 6–10y. Overweight children and non-overweight children of overweight parents were genotyped for a 45 bp deletion/insertion (del/ins) in 3’ UTR of exon 8 and for an exon 4 C to T transition. Results 89 children were genotyped for the exon 8 allele: 50 children had del/del, 33 del/ins, and 6 ins/ins. Body mass index (BMI) was greater for del/ins (24.1 ± 5.9 kg/m2) than for del/del (20.4 ± 4.8 kg/m2, p<0.001). BMI of ins/ins (23.7 ± 7.8 kg/m2) was not different from del/ins. This effect was independent of race and gender (ANOVAs, p< 0.05). Body composition was also different according to UCP2 genotype. All body circumferences and skin fold thicknesses examined were significantly greater in del/ins than in del/del. DXA body fat mass (p<0.005) was also greater in del/ins than del/del. For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the three exon 4 genotypes. Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype. Conclusion The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight. PMID:10837279

VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

PubMed Central

Ren, Hong Yu; Grove, Diane E.; De La Rosa, Oxana; Houck, Scott A.; Sopha, Pattarawut; Van Goor, Fredrick; Hoffman, Beth J.; Cyr, Douglas M.

2013-01-01

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR. PMID:23924900

VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.

PubMed

Ren, Hong Yu; Grove, Diane E; De La Rosa, Oxana; Houck, Scott A; Sopha, Pattarawut; Van Goor, Fredrick; Hoffman, Beth J; Cyr, Douglas M

2013-10-01

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

Role of CYP1A2 polymorphisms on lung cancer risk in a prospective study.

PubMed

Pavanello, Sofia; Fedeli, Ugo; Mastrangelo, Giuseppe; Rota, Federica; Overvad, Kim; Raaschou-Nielsen, Ole; Tjønneland, Anne; Vogel, Ulla

2012-06-01

Cytochrome P4501A2 (CYP1A2) is a key enzyme for lung carcinogen activation and lung inflammation. We studied the interactions of the CYP1A2 functional variants -3860G/A(rs2069514),-2467T/delT(rs3569413),-163C/A(rs762551)] with occupational/environmental carcinogenic exposures in the development of lung cancer in a case-control study nested in the Danish prospective cohort "Diet, Cancer and Health." At enrollment (1993-1997), blood samples for genotype analyses and information on lifestyle were collected 5 (mean value) years before the onset of the disease. The study population included 425 lung cancer cases and 786 subcohort members, who were gender- and age-matched. We found that -163A carriers were at increased risk of lung cancer (P=0.035) in a multivariate COX regression model, which was adjusted for personal habits (i.e., cumulative smoking, passive smoke at home, alcohol intake, and fruit intake) and occupational exposure. Additionally, the interaction between -2467delT and smoking increases lung cancer risk in males, especially light smokers (<21.5 pack-years, P=0.004). The increased lung cancer risk found in -163C carriers, independent of smoking status, and in -2467delT male smokers, suggests that these variants could influence lung cancer development through different mechanisms (i.e. lung carcinogen activation and lung inflammation). Copyright © 2012 Elsevier Inc. All rights reserved.

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

PubMed Central

Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Stack, Jeffrey H.; Straley, Kimberly S.; Decker, Caroline J.; Miller, Mark; McCartney, Jason; Olson, Eric R.; Wine, Jeffrey J.; Frizzell, Ray A.; Ashlock, Melissa; Negulescu, Paul A.

2011-01-01

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR. PMID:21976485

Control System of a Three DOF Spacecraft Simulator by Vectorable Thrusters and Control Moment Gyros

DTIC Science & Technology

2006-12-01

1 s 1 s -K- -K- -K- -K- -K- -K- -K- -K- -K- 2 STATE 1 REF Tc urel Fx Fy Figure 42. Controller SIMULINK Model As an initial step in the...f1c a1c a1True a2c a2True f1act Thruster 1 Firing Logic [DelTrue] [a1True] [a2True] [DelTrue] Fx Fy T theta del F1c a1c F2c a2c Tcmg fcn Tc deltrue...cmgdd command CMG Steering Logic 3 theta 2 act_fb 1 uCOMMANDED Fx Fy Tc 52 to slew and fire independently, MSGCMG position is used to generate a

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation.

PubMed

De Stefano, Daniela; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; De Gregorio, Fabiola; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; De Rosa, Giuseppe; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria

2014-01-01

Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer.

PubMed

Hale, Victoria; Weischer, Maren; Park, Jong Y

2014-01-01

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2 (∗)1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23-3.18) for unselected cases and 3.39 (1.78-6.47) for familial cases, indicating that CHEK2 (∗)1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2(∗)1100delC should be considered in men with a familial history of prostate cancer.

CHEK2 ∗1100delC Mutation and Risk of Prostate Cancer

PubMed Central

Park, Jong Y.

2014-01-01

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2 ∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating that CHEK2 ∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer. PMID:25431674

An unexpected effect of TNF-α on F508del-CFTR maturation and function

PubMed Central

Bitam, Sara; Urbach, Valérie; Sermet-Gaudelus, Isabelle; Hinzpeter, Alexandre; Edelman, Aleksander

2015-01-01

Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR), which encodes a cAMP-dependent Cl - channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFα is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFα behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFα has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular. PMID:26594334

Identification of a 5‑lncRNA signature‑based risk scoring system for survival prediction in colorectal cancer.

PubMed

Gu, Liqiang; Yu, Jun; Wang, Qing; Xu, Bin; Ji, Liechen; Yu, Lin; Zhang, Xipeng; Cai, Hui

2018-05-03

The present study aimed to investigate potential prognostic long noncoding RNAs (lncRNAs) associated with colorectal cancer (CRC). An mRNA‑seq dataset obtained from The Cancer Genome Atlas was employed to identify the differentially expressed lncRNAs (DELs) between CRC patients with good and poor prognoses. Subsequently, univariate and multivariate Cox regression analyses were conducted to analyze the prognosis‑associated lncRNAs among all DELs. In addition, a risk scoring system was developed according to the expression levels of the prognostic lncRNAs, which was then applied to a training set and an independent testing set. Furthermore, the co‑expressed genes of prognostic lncRNAs were screened using a Multi‑Experiment Matrix online tool for construction of lncRNA‑gene networks. Finally, Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology (GO) function enrichment analyses were performed on genes in the lncRNA‑gene networks using KOBAS, GOATOOLS and ClusterProfiler. The present study identified 82 DELs, of which long intergenic nonprotein coding RNA 2159, RP11‑452L6.6, RP11‑894P9.1 and RP11‑69M1.6, and whey acidic protein four‑disulfide core domain 21 (WFDC21P) were reported to be independently associated with the prognosis of patients with CRC. A 5‑lncRNA signature‑based risk scoring system was developed, which may be used to classify patients into low‑ and high‑risk groups with significantly different recurrence‑free survival times in the training and testing sets (P<0.05). Co‑expressed genes of WFDC21P or RP11‑69M1.6 were utilized to construct the lncRNA‑gene networks. Genes in the networks were significantly enriched in 'tight junction', 'focal adhesion' and 'regulation of actin cytoskeleton' pathways, and numerous GO terms associated with 'reactive oxygen species metabolism' and 'nitric oxide metabolism'. The present study proposed a 5‑lncRNA signature‑based risk scoring system for predicting the prognosis of patients with CRC, and revealed the associated signaling pathways and biological processes. The results of the present study may help improve prognostic evaluation in clinical practice.

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

PubMed

Tosco, A; De Gregorio, F; Esposito, S; De Stefano, D; Sana, I; Ferrari, E; Sepe, A; Salvadori, L; Buonpensiero, P; Di Pasqua, A; Grassia, R; Leone, C A; Guido, S; De Rosa, G; Lusa, S; Bona, G; Stoll, G; Maiuri, M C; Mehta, A; Kroemer, G; Maiuri, L; Raia, V

2016-08-01

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts 'on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment.

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR

PubMed Central

Tosco, A; De Gregorio, F; Esposito, S; De Stefano, D; Sana, I; Ferrari, E; Sepe, A; Salvadori, L; Buonpensiero, P; Di Pasqua, A; Grassia, R; Leone, C A; Guido, S; De Rosa, G; Lusa, S; Bona, G; Stoll, G; Maiuri, M C; Mehta, A; Kroemer, G; Maiuri, L; Raia, V

2016-01-01

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts ‘on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment. PMID:27035618

Impact of the F508del mutation on ovine CFTR, a Cl− channel with enhanced conductance and ATP-dependent gating

PubMed Central

Cai, Zhiwei; Palmai-Pallag, Timea; Khuituan, Pissared; Mutolo, Michael J; Boinot, Clément; Liu, Beihui; Scott-Ward, Toby S; Callebaut, Isabelle; Harris, Ann; Sheppard, David N

2015-01-01

Cross-species comparative studies are a powerful approach to understanding the epithelial Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in the genetic disease cystic fibrosis (CF). Here, we investigate the single-channel behaviour of ovine CFTR and the impact of the most common CF mutation, F508del-CFTR, using excised inside-out membrane patches from transiently transfected CHO cells. Like human CFTR, ovine CFTR formed a weakly inwardly rectifying Cl− channel regulated by PKA-dependent phosphorylation, inhibited by the open-channel blocker glibenclamide. However, for three reasons, ovine CFTR was noticeably more active than human CFTR. First, single-channel conductance was increased. Second, open probability was augmented because the frequency and duration of channel openings were increased. Third, with enhanced affinity and efficacy, ATP more strongly stimulated ovine CFTR channel gating. Consistent with these data, the CFTR modulator phloxine B failed to potentiate ovine CFTR Cl− currents. Similar to its impact on human CFTR, the F508del mutation caused a temperature-sensitive folding defect, which disrupted ovine CFTR protein processing and reduced membrane stability. However, the F508del mutation had reduced impact on ovine CFTR channel gating in contrast to its marked effects on human CFTR. We conclude that ovine CFTR forms a regulated Cl− channel with enhanced conductance and ATP-dependent channel gating. This phylogenetic analysis of CFTR structure and function demonstrates that subtle changes in structure have pronounced effects on channel function and the consequences of the CF mutation F508del. Key points Malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), a gated pathway for chloride movement, causes the common life-shortening genetic disease cystic fibrosis (CF). Towards the development of a sheep model of CF, we have investigated the function of sheep CFTR. We found that sheep CFTR was noticeably more active than human CFTR, while the most common CF mutation, F508del, had reduced impact on sheep CFTR function. Our results demonstrate that subtle changes in protein structure have marked effects on CFTR function and the consequences of the CF mutation F508del. PMID:25763566

Harnessing Omics Big Data in Nine Vertebrate Species by Genome-Wide Prioritization of Sequence Variants with the Highest Predicted Deleterious Effect on Protein Function.

PubMed

Rozman, Vita; Kunej, Tanja

2018-05-10

Harnessing the genomics big data requires innovation in how we extract and interpret biologically relevant variants. Currently, there is no established catalog of prioritized missense variants associated with deleterious protein function phenotypes. We report in this study, to the best of our knowledge, the first genome-wide prioritization of sequence variants with the most deleterious effect on protein function (potentially deleterious variants [pDelVars]) in nine vertebrate species: human, cattle, horse, sheep, pig, dog, rat, mouse, and zebrafish. The analysis was conducted using the Ensembl/BioMart tool. Genes comprising pDelVars in the highest number of examined species were identified using a Python script. Multiple genomic alignments of the selected genes were built to identify interspecies orthologous potentially deleterious variants, which we defined as the "ortho-pDelVars." Genome-wide prioritization revealed that in humans, 0.12% of the known variants are predicted to be deleterious. In seven out of nine examined vertebrate species, the genes encoding the multiple PDZ domain crumbs cell polarity complex component (MPDZ) and the transforming acidic coiled-coil containing protein 2 (TACC2) comprise pDelVars. Five interspecies ortho-pDelVars were identified in three genes. These findings offer new ways to harness genomics big data by facilitating the identification of functional polymorphisms in humans and animal models and thus provide a future basis for optimization of protocols for whole genome prioritization of pDelVars and screening of orthologous sequence variants. The approach presented here can inform various postgenomic applications such as personalized medicine and multiomics study of health interventions (iatromics).

Functional characterization of a basic helix-loop-helix (bHLH) transcription factor GhDEL65 from cotton (Gossypium hirsutum).

PubMed

Shangguan, Xiao-Xia; Yang, Chang-Qing; Zhang, Xiu-Fang; Wang, Ling-Jian

2016-10-01

Cotton fiber is proposed to share some similarity with the Arabidopsis thaliana leaf trichome, which is regulated by the MYB-bHLH-WD40 transcription complex. Although several MYB transcription factors and WD40 family proteins in cotton have been characterized, little is known about the role of bHLH family proteins in cotton. Here, we report that GhDEL65, a bHLH protein from cotton (Gossypium hirsutum), is a functional homologue of Arabidopsis GLABRA3 (GL3) and ENHANCER OF GLABRA3 (EGL3) in regulating trichome development. Transcripts of GhDEL65 were detected in 0 ∼ 1 days post-anthesis (DPA) ovules and abundant in 3-DPA fibers, implying that GhDEL65 may act in early fiber development. Ectopic expression of GhDEL65 in Arabidopsis gl3 egl3 double mutant partly rescued the trichome development, and constitutive expression of GhDEL65 in wild-type plants led to increased trichome density on rosette leaves and stems, mainly by activating the transcription of two key positive regulators of trichome development, GLABRA1 (GL1) and GLABRA2 (GL2), and suppressed the expression of a R3 single-repeat MYB factor TRIPTYCHON (TRY). GhDEL65 could interact with cotton R2R3 MYB transcription factors GhMYB2 and GhMYB3, as well as the WD40 protein GhTTG3, suggesting that the MYB-bHLH-WD40 protein complex also exists in cotton fiber cell, though its function in cotton fiber development awaits further investigation. © 2016 Scandinavian Plant Physiology Society.

A Rice PECTATE LYASE-LIKE Gene Is Required for Plant Growth and Leaf Senescence1[OPEN

PubMed Central

Leng, Yujia; Yang, Yaolong; Ren, Deyong; Dai, Liping; Wang, Yuqiong; Chen, Long; Tu, Zhengjun; Gao, Yihong; Zhu, Li; Hu, Jiang; Gao, Zhenyu; Guo, Longbiao; Lin, Yongjun

2017-01-01

To better understand the molecular mechanisms behind plant growth and leaf senescence in monocot plants, we identified a mutant exhibiting dwarfism and an early-senescence leaf phenotype, termed dwarf and early-senescence leaf1 (del1). Histological analysis showed that the abnormal growth was caused by a reduction in cell number. Further investigation revealed that the decline in cell number in del1 was affected by the cell cycle. Physiological analysis, transmission electron microscopy, and TUNEL assays showed that leaf senescence was triggered by the accumulation of reactive oxygen species. The DEL1 gene was cloned using a map-based approach. It was shown to encode a pectate lyase (PEL) precursor that contains a PelC domain. DEL1 contains all the conserved residues of PEL and has strong similarity with plant PelC. DEL1 is expressed in all tissues but predominantly in elongating tissues. Functional analysis revealed that mutation of DEL1 decreased the total PEL enzymatic activity, increased the degree of methylesterified homogalacturonan, and altered the cell wall composition and structure. In addition, transcriptome assay revealed that a set of cell wall function- and senescence-related gene expression was altered in del1 plants. Our research indicates that DEL1 is involved in both the maintenance of normal cell division and the induction of leaf senescence. These findings reveal a new molecular mechanism for plant growth and leaf senescence mediated by PECTATE LYASE-LIKE genes. PMID:28455404

A Rice PECTATE LYASE-LIKE Gene Is Required for Plant Growth and Leaf Senescence.

PubMed

Leng, Yujia; Yang, Yaolong; Ren, Deyong; Huang, Lichao; Dai, Liping; Wang, Yuqiong; Chen, Long; Tu, Zhengjun; Gao, Yihong; Li, Xueyong; Zhu, Li; Hu, Jiang; Zhang, Guangheng; Gao, Zhenyu; Guo, Longbiao; Kong, Zhaosheng; Lin, Yongjun; Qian, Qian; Zeng, Dali

2017-06-01

To better understand the molecular mechanisms behind plant growth and leaf senescence in monocot plants, we identified a mutant exhibiting dwarfism and an early-senescence leaf phenotype, termed dwarf and early-senescence leaf1 ( del1 ). Histological analysis showed that the abnormal growth was caused by a reduction in cell number. Further investigation revealed that the decline in cell number in del1 was affected by the cell cycle. Physiological analysis, transmission electron microscopy, and TUNEL assays showed that leaf senescence was triggered by the accumulation of reactive oxygen species. The DEL1 gene was cloned using a map-based approach. It was shown to encode a pectate lyase (PEL) precursor that contains a PelC domain. DEL1 contains all the conserved residues of PEL and has strong similarity with plant PelC. DEL1 is expressed in all tissues but predominantly in elongating tissues. Functional analysis revealed that mutation of DEL1 decreased the total PEL enzymatic activity, increased the degree of methylesterified homogalacturonan, and altered the cell wall composition and structure. In addition, transcriptome assay revealed that a set of cell wall function- and senescence-related gene expression was altered in del1 plants. Our research indicates that DEL1 is involved in both the maintenance of normal cell division and the induction of leaf senescence. These findings reveal a new molecular mechanism for plant growth and leaf senescence mediated by PECTATE LYASE-LIKE genes. © 2017 American Society of Plant Biologists. All Rights Reserved.

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

PubMed Central

Stefano, Daniela De; Villella, Valeria R; Esposito, Speranza; Tosco, Antonella; Sepe, Angela; Gregorio, Fabiola De; Salvadori, Laura; Grassia, Rosa; Leone, Carlo A; Rosa, Giuseppe De; Maiuri, Maria C; Pettoello-Mantovani, Massimo; Guido, Stefano; Bossi, Anna; Zolin, Anna; Venerando, Andrea; Pinna, Lorenzo A; Mehta, Anil; Bona, Gianni; Kroemer, Guido; Maiuri, Luigi; Raia, Valeria

2014-01-01

Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in CftrF508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation. PMID:25350163

Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation.

PubMed

Meng, Xin; Wang, Yiting; Wang, Xiaomeng; Wrennall, Joe A; Rimington, Tracy L; Li, Hongyu; Cai, Zhiwei; Ford, Robert C; Sheppard, David N

2017-03-03

Cystic fibrosis (CF) is caused by mutations that disrupt the plasma membrane expression, stability, and function of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl - channel. Two small molecules, the CFTR corrector lumacaftor and the potentiator ivacaftor, are now used clinically to treat CF, although some studies suggest that they have counteracting effects on CFTR stability. Here, we investigated the impact of these compounds on the instability of F508del-CFTR, the most common CF mutation. To study individual CFTR Cl - channels, we performed single-channel recording, whereas to assess entire CFTR populations, we used purified CFTR proteins and macroscopic CFTR Cl - currents. At 37 °C, low temperature-rescued F508del-CFTR more rapidly lost function in cell-free membrane patches and showed altered channel gating and current flow through open channels. Compared with purified wild-type CFTR, the full-length F508del-CFTR was about 10 °C less thermostable. Lumacaftor partially stabilized purified full-length F508del-CFTR and slightly delayed deactivation of individual F508del-CFTR Cl - channels. By contrast, ivacaftor further destabilized full-length F508del-CFTR and accelerated channel deactivation. Chronic (prolonged) co-incubation of F508del-CFTR-expressing cells with lumacaftor and ivacaftor deactivated macroscopic F508del-CFTR Cl - currents. However, at the single-channel level, chronic co-incubation greatly increased F508del-CFTR channel activity and temporal stability in most, but not all, cell-free membrane patches. We conclude that chronic lumacaftor and ivacaftor co-treatment restores stability in a small subpopulation of F508del-CFTR Cl - channels but that the majority remain destabilized. A fuller understanding of these effects and the characterization of the small F508del-CFTR subpopulation might be crucial for CF therapy development. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.

PubMed

Ehrhardt, Annette; Chung, W Joon; Pyle, Louise C; Wang, Wei; Nowotarski, Krzysztof; Mulvihill, Cory M; Ramjeesingh, Mohabir; Hong, Jeong; Velu, Sadanandan E; Lewis, Hal A; Atwell, Shane; Aller, Steve; Bear, Christine E; Lukacs, Gergely L; Kirk, Kevin L; Sorscher, Eric J

2016-01-22

In this study, we present data indicating a robust and specific domain interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed that binding kinetics were not altered by the common clinical mutation F508del. Both intrinsic ATPase activity and CFTR channel gating were inhibited severely by CL1 peptide, suggesting that NBD1/CL1 binding is a crucial requirement for ATP hydrolysis and channel function. In addition to cystic fibrosis, CFTR dysregulation has been implicated in the pathogenesis of prevalent diseases such as chronic obstructive pulmonary disease, acquired rhinosinusitis, pancreatitis, and lethal secretory diarrhea (e.g. cholera). On the basis of clinical relevance of the CFTR as a therapeutic target, a cell-free drug screen was established to identify modulators of NBD1/CL1 channel activity independent of F508del CFTR and pharmacologic rescue. Our findings support a targetable mechanism of CFTR regulation in which conformational changes in the NBDs cause reorientation of transmembrane domains via interactions with CL1 and result in channel gating. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Abundance and Distribution Patterns of Thunnus albacares in Isla del Coco National Park through Predictive Habitat Suitability Models

PubMed Central

Gonzáles-Andrés, Cristina; F. M. Lopes, Priscila; Cortés, Jorge; Sánchez-Lizaso, José Luis; Pennino, Maria Grazia

2016-01-01

Information on the distribution and habitat preferences of ecologically and commercially important species is essential for their management and protection. This is especially important as climate change, pollution, and overfishing change the structure and functioning of pelagic ecosystems. In this study, we used Bayesian hierarchical spatial-temporal models to map the Essential Fish Habitats of the Yellowfin tuna (Thunnus albacares) in the waters around Isla del Coco National Park, Pacific Costa Rica, based on independent underwater observations from 1993 to 2013. We assessed if observed changes in the distribution and abundance of this species are related with habitat characteristics, fishing intensity or more extreme climatic events, including the El Niño Southern Oscillation, and changes on the average sea surface temperature. Yellowfin tuna showed a decreasing abundance trend in the sampled period, whereas higher abundances were found in shallow and warmer waters, with high concentration of chlorophyll-a, and in surrounding seamounts. In addition, El Niño Southern Oscillation events did not seem to affect Yellowfin tuna distribution and abundance. Understanding the habitat preferences of this species, using approaches as the one developed here, may help design integrated programs for more efficient management of vulnerable species. PMID:27973538

Abundance and Distribution Patterns of Thunnus albacares in Isla del Coco National Park through Predictive Habitat Suitability Models.

PubMed

Gonzáles-Andrés, Cristina; F M Lopes, Priscila; Cortés, Jorge; Sánchez-Lizaso, José Luis; Pennino, Maria Grazia

2016-01-01

Information on the distribution and habitat preferences of ecologically and commercially important species is essential for their management and protection. This is especially important as climate change, pollution, and overfishing change the structure and functioning of pelagic ecosystems. In this study, we used Bayesian hierarchical spatial-temporal models to map the Essential Fish Habitats of the Yellowfin tuna (Thunnus albacares) in the waters around Isla del Coco National Park, Pacific Costa Rica, based on independent underwater observations from 1993 to 2013. We assessed if observed changes in the distribution and abundance of this species are related with habitat characteristics, fishing intensity or more extreme climatic events, including the El Niño Southern Oscillation, and changes on the average sea surface temperature. Yellowfin tuna showed a decreasing abundance trend in the sampled period, whereas higher abundances were found in shallow and warmer waters, with high concentration of chlorophyll-a, and in surrounding seamounts. In addition, El Niño Southern Oscillation events did not seem to affect Yellowfin tuna distribution and abundance. Understanding the habitat preferences of this species, using approaches as the one developed here, may help design integrated programs for more efficient management of vulnerable species.

Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation.

PubMed

Herrera, Alex F; Mei, Matthew; Low, Lawrence; Kim, Haesook T; Griffin, Gabriel K; Song, Joo Y; Merryman, Reid W; Bedell, Victoria; Pak, Christine; Sun, Heather; Paris, Tanya; Stiller, Tracey; Brown, Jennifer R; Budde, Lihua E; Chan, Wing C; Chen, Robert; Davids, Matthew S; Freedman, Arnold S; Fisher, David C; Jacobsen, Eric D; Jacobson, Caron A; LaCasce, Ann S; Murata-Collins, Joyce; Nademanee, Auayporn P; Palmer, Joycelynne M; Pihan, German A; Pillai, Raju; Popplewell, Leslie; Siddiqi, Tanya; Sohani, Aliyah R; Zain, Jasmine; Rosen, Steven T; Kwak, Larry W; Weinstock, David M; Forman, Stephen J; Weisenburger, Dennis D; Kim, Young; Rodig, Scott J; Krishnan, Amrita; Armand, Philippe

2017-01-01

Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.

Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation

PubMed Central

Herrera, Alex F.; Mei, Matthew; Low, Lawrence; Kim, Haesook T.; Griffin, Gabriel K.; Song, Joo Y.; Merryman, Reid W.; Bedell, Victoria; Pak, Christine; Sun, Heather; Paris, Tanya; Stiller, Tracey; Brown, Jennifer R.; Budde, Lihua E.; Chan, Wing C.; Chen, Robert; Davids, Matthew S.; Freedman, Arnold S.; Fisher, David C.; Jacobsen, Eric D.; Jacobson, Caron A.; LaCasce, Ann S.; Murata-Collins, Joyce; Nademanee, Auayporn P.; Palmer, Joycelynne M.; Pihan, German A.; Pillai, Raju; Popplewell, Leslie; Siddiqi, Tanya; Sohani, Aliyah R.; Zain, Jasmine; Rosen, Steven T.; Kwak, Larry W.; Weinstock, David M.; Forman, Stephen J.; Weisenburger, Dennis D.; Kim, Young; Rodig, Scott J.; Krishnan, Amrita

2017-01-01

Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% (P = .049), and the 4-year OS was 56% versus 67% (P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% (P = .013), and 4-year OS was 25% versus 61% (P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response (v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT. PMID:28034071

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.

PubMed

Clancy, J P; Rowe, Steven M; Accurso, Frank J; Aitken, Moira L; Amin, Raouf S; Ashlock, Melissa A; Ballmann, Manfred; Boyle, Michael P; Bronsveld, Inez; Campbell, Preston W; De Boeck, Kris; Donaldson, Scott H; Dorkin, Henry L; Dunitz, Jordan M; Durie, Peter R; Jain, Manu; Leonard, Anissa; McCoy, Karen S; Moss, Richard B; Pilewski, Joseph M; Rosenbluth, Daniel B; Rubenstein, Ronald C; Schechter, Michael S; Botfield, Martyn; Ordoñez, Claudia L; Spencer-Green, George T; Vernillet, Laurent; Wisseh, Steve; Yen, Karl; Konstan, Michael W

2012-01-01

VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. NCT00865904.

Rescue of murine F508del CFTR activity in native intestine by low temperature and proteasome inhibitors.

PubMed

Wilke, Martina; Bot, Alice; Jorna, Huub; Scholte, Bob J; de Jonge, Hugo R

2012-01-01

Most patients with Cystic Fibrosis (CF) carry at least one allele with the F508del mutation, resulting in a CFTR chloride channel protein with a processing, gating and stability defect, but with substantial residual activity when correctly sorted to the apical membranes of epithelial cells. New therapies are therefore aimed at improving the folding and trafficking of F508del CFTR, (CFTR correctors) or at enhancing the open probability of the CFTR chloride channel (CFTR potentiators). Preventing premature breakdown of F508del CFTR is an alternative or additional strategy, which is investigated in this study. We established an ex vivo assay for murine F508del CFTR rescue in native intestinal epithelium that can be used as a pre-clinical test for candidate therapeutics. Overnight incubation of muscle stripped ileum in modified William's E medium at low temperature (26°C), and 4 h or 6 h incubation at 37°C with different proteasome inhibitors (PI: ALLN, MG-132, epoxomicin, PS341/bortezomib) resulted in fifty to hundred percent respectively of the wild type CFTR mediated chloride secretion (forskolin induced short-circuit current). The functional rescue was accompanied by enhanced expression of the murine F508del CFTR protein at the apical surface of intestinal crypts and a gain in the amount of complex-glycosylated CFTR (band C) up to 20% of WT levels. Sustained rescue in the presence of brefeldin A shows the involvement of a post-Golgi compartment in murine F508del CFTR degradation, as was shown earlier for its human counterpart. Our data show that proteasome inhibitors are promising candidate compounds for improving rescue of human F508del CFTR function, in combination with available correctors and potentiators.

Matrine in association with FD-2 stimulates F508del-cystic fibrosis transmembrane conductance regulator activity in the presence of corrector VX809

PubMed Central

Marengo, Barbara; Speciale, Andrea; Senatore, Lisa; Garibaldi, Silvano; Musumeci, Francesca; Nieddu, Erika; Pollarolo, Benedetta; Pronzato, Maria Adelaide; Schenone, Silvia; Mazzei, Mauro; Domenicotti, Cinzia

2017-01-01

Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and the predominant mutation is termed Phe508del (F508del). Therapy for F508del-CFTR patients is based on the use of Orkambi®, a combination of VX809 and VX770. However, though Orkambi leads to an improvement in the lung function of patients, a progressive reduction in its efficacy has been observed. In order to overcome this effect, the aim of the present study was to investigate the role of matrine and the in-house compound FD-2 in increasing the action of VX809 and VX770. Fischer rat thyroid cells overexpressing F508del-CFTR were treated with matrine, VX809 (corrector) and/or with a number of potentiators (VX770, FD-1 and FD-2). The results demonstrated that matrine was able to stimulate CFTR activity and, in association with FD-2, increased the functionality of the channel in the presence of VX809. Based on these results, it may be hypothesized that FD-2 may be a novel and more effective potentiator compared with VX770. PMID:29039559

Developing market class specific InDel markers from next generation sequence data in Phaseolus vulgaris L.

PubMed

Moghaddam, Samira Mafi; Song, Qijian; Mamidi, Sujan; Schmutz, Jeremy; Lee, Rian; Cregan, Perry; Osorno, Juan M; McClean, Phillip E

2014-01-01

Next generation sequence data provides valuable information and tools for genetic and genomic research and offers new insights useful for marker development. This data is useful for the design of accurate and user-friendly molecular tools. Common bean (Phaseolus vulgaris L.) is a diverse crop in which separate domestication events happened in each gene pool followed by race and market class diversification that has resulted in different morphological characteristics in each commercial market class. This has led to essentially independent breeding programs within each market class which in turn has resulted in limited within market class sequence variation. Sequence data from selected genotypes of five bean market classes (pinto, black, navy, and light and dark red kidney) were used to develop InDel-based markers specific to each market class. Design of the InDel markers was conducted through a combination of assembly, alignment and primer design software using 1.6× to 5.1× coverage of Illumina GAII sequence data for each of the selected genotypes. The procedure we developed for primer design is fast, accurate, less error prone, and higher throughput than when they are designed manually. All InDel markers are easy to run and score with no need for PCR optimization. A total of 2687 InDel markers distributed across the genome were developed. To highlight their usefulness, they were employed to construct a phylogenetic tree and a genetic map, showing that InDel markers are reliable, simple, and accurate.

Developing market class specific InDel markers from next generation sequence data in Phaseolus vulgaris L.

PubMed Central

Moghaddam, Samira Mafi; Song, Qijian; Mamidi, Sujan; Schmutz, Jeremy; Lee, Rian; Cregan, Perry; Osorno, Juan M.; McClean, Phillip E.

2013-01-01

Next generation sequence data provides valuable information and tools for genetic and genomic research and offers new insights useful for marker development. This data is useful for the design of accurate and user-friendly molecular tools. Common bean (Phaseolus vulgaris L.) is a diverse crop in which separate domestication events happened in each gene pool followed by race and market class diversification that has resulted in different morphological characteristics in each commercial market class. This has led to essentially independent breeding programs within each market class which in turn has resulted in limited within market class sequence variation. Sequence data from selected genotypes of five bean market classes (pinto, black, navy, and light and dark red kidney) were used to develop InDel-based markers specific to each market class. Design of the InDel markers was conducted through a combination of assembly, alignment and primer design software using 1.6× to 5.1× coverage of Illumina GAII sequence data for each of the selected genotypes. The procedure we developed for primer design is fast, accurate, less error prone, and higher throughput than when they are designed manually. All InDel markers are easy to run and score with no need for PCR optimization. A total of 2687 InDel markers distributed across the genome were developed. To highlight their usefulness, they were employed to construct a phylogenetic tree and a genetic map, showing that InDel markers are reliable, simple, and accurate. PMID:24860578

Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy.

PubMed

Ceholski, Delaine K; Trieber, Catharine A; Young, Howard S

2012-05-11

The sarco(endo)plasmic reticulum calcium ATPase (SERCA) and its regulatory partner phospholamban (PLN) are essential for myocardial contractility. Arg(9) → Cys (R9C) and Arg(14) deletion (R14del) mutations in PLN are associated with lethal dilated cardiomyopathy in humans. To better understand these mutations, we made a series of amino acid substitutions in the cytoplasmic domain of PLN and tested their ability to inhibit SERCA. R9C is a complete loss-of-function mutant of PLN, whereas R14del is a mild loss-of-function mutant. When combined with wild-type PLN to simulate heterozygous conditions, the mutants had a dominant negative effect on SERCA function. A series of targeted mutations in this region of the PLN cytoplasmic domain ((8)TRSAIRR(14)) demonstrated the importance of hydrophobic balance in proper PLN regulation of SERCA. We found that Arg(9) → Leu and Thr(8) → Cys substitutions mimicked the behavior of the R9C mutant, and an Arg(14) → Ala substitution mimicked the behavior of the R14del mutant. The results reveal that the change in hydrophobicity resulting from the R9C and R14del mutations is sufficient to explain the loss of function and persistent interaction with SERCA. Hydrophobic imbalance in the cytoplasmic domain of PLN appears to be a predictor for the development and progression of dilated cardiomyopathy.

Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation.

PubMed

Kourtzelis, Ioannis; Kotlabova, Klara; Lim, Jong-Hyung; Mitroulis, Ioannis; Ferreira, Anaisa; Chen, Lan-Sun; Gercken, Bettina; Steffen, Anja; Kemter, Elisabeth; Klotzsche-von Ameln, Anne; Waskow, Claudia; Hosur, Kavita; Chatzigeorgiou, Antonios; Ludwig, Barbara; Wolf, Eckhard; Hajishengallis, George; Chavakis, Triantafyllos

2016-04-01

Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood-islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.

Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications.

PubMed

Muranen, Taru A; Greco, Dario; Fagerholm, Rainer; Kilpivaara, Outi; Kämpjärvi, Kati; Aittomäki, Kristiina; Blomqvist, Carl; Heikkilä, Päivi; Borg, Ake; Nevanlinna, Heli

2011-09-20

Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation.

Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications

PubMed Central

2011-01-01

Introduction Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers. Methods In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method. Results We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels. Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time. Conclusions We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation. PMID:21542898

A New Interactive Method to Distance English Learning in Conceptual Age

ERIC Educational Resources Information Center

Xu, Wei

2013-01-01

Latest advance in information technology and innovative teaching confronts DEL (distance English learning) with new challenges and problems. According to the DEL analysis, the paper firstly presents cloud service's functions to the support service, which serves to distribute and store quality learning resources. Meanwhile, practice-focused…

Regulation and Function of TIFAB in Myelodysplastic Syndrome

DTIC Science & Technology

2012-06-01

neutropenia , and elevated platelets associated with dysplastic megakaryocytes are considered to have 5q- syndrome. The majority of MDS patients with del(5q... neutropenia , and elevated platelets associated with dysplastic megakaryocytes are considered to have 5q- syndrome. The majority of MDS patients with del(5q

A Little CFTR Goes a Long Way: CFTR-Dependent Sweat Secretion from G551D and R117H-5T Cystic Fibrosis Subjects Taking Ivacaftor

PubMed Central

Char, Jessica E.; Wolfe, Marlene H.; Cho, Hyung-ju; Park, Il-Ho; Jeong, Jin Hyeok; Frisbee, Eric; Dunn, Colleen; Davies, Zoe; Milla, Carlos; Moss, Richard B.; Thomas, Ewart A. C.; Wine, Jeffrey J.

2014-01-01

To determine if oral dosing with the CFTR-potentiator ivacaftor (VX-770, Kalydeco) improves CFTR-dependent sweating in CF subjects carrying G551D or R117H-5T mutations, we optically measured sweat secretion from 32–143 individually identified glands in each of 8 CF subjects; 6 F508del/G551D, one G551D/R117H-5T, and one I507del/R117H-5T. Two subjects were tested only (−) ivacaftor, 3 only (+) ivacaftor and 3 (+/−) ivacaftor (1–5 tests per condition). The total number of gland measurements was 852 (−) ivacaftor and 906 (+) ivacaftor. A healthy control was tested 4 times (51 glands). For each gland we measured both CFTR-independent (M-sweat) and CFTR-dependent (C-sweat); C-sweat was stimulated with a β-adrenergic cocktail that elevated [cAMP]i while blocking muscarinic receptors. Absent ivacaftor, almost all CF glands produced M-sweat on all tests, but only 1/593 glands produced C-sweat (10 tests, 5 subjects). By contrast, 6/6 subjects (113/342 glands) produced C-sweat in the (+) ivacaftor condition, but with large inter-subject differences; 3–74% of glands responded with C/M sweat ratios 0.04%–2.57% of the average WT ratio of 0.265. Sweat volume losses cause proportionally larger underestimates of CFTR function at lower sweat rates. The losses were reduced by measuring C/M ratios in 12 glands from each subject that had the highest M-sweat rates. Remaining losses were estimated from single channel data and used to correct the C/M ratios, giving estimates of CFTR function (+) ivacaftor  = 1.6%–7.7% of the WT average. These estimates are in accord with single channel data and transcript analysis, and suggest that significant clinical benefit can be produced by low levels of CFTR function. PMID:24520399

Introduction to Social Psychology: Administrative Manual [And] Student Manual [And] Unit Study Guide.

ERIC Educational Resources Information Center

Rankin, Robert E.

This learning package is a three-semester-hour, independent-study course in social psychology designed for postsecondary, external degree students. Keyed to the commercially published textbook "Social Psychology: Explorations in Understanding" (Del Mar, CA: CRM, 1974), the package consists of an administrator manual, a student manual, and a…

Air and Space Power Journal. Volume 20, Number 3, Fall 2006

DTIC Science & Technology

2006-01-01

ning focus to support of the Independent Electoral Commission of Iraq and election preparations. As the corps and its major sub- ordinate commands...Definición y ámbito de aplicación del Derecho Internacional Humanitario,” Revista Nacional de Derecho Aeronáutico y Espacial 3 (1989): 19. 9

A Common Mutation in DEFB126 Causes Impaired Sperm Function and Subfertility

PubMed Central

Tollner, Theodore L.; Venners, Scott A.; Hollox, Edward J.; Yudin, Ashley I.; Liu, Xue; Tang, Genfu; Xing, Houxun; Kays, Robert J.; Lau, Tsang; Overstreet, James W.; Xu, Xiping; Bevins, Charles L.; Cherr, Gary N.

2013-01-01

A glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a 2-nucleotide deletion in the open reading frame, which generates a non-stop mRNA. The allele frequency of this variant sequence is high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from the del/del donors exhibited an 84% reduction in the rate of penetration of a hyaluronic acid (HA) gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in HA gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. However, DEFB126 genotype and lectin binding were highly correlated with performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. This common sequence variation in DEFB126, and its apparent cause of impaired reproductive function, provides an opportunity to better understand, clinically evaluate, and possibly treat human infertility. PMID:21775668

Perk Ablation Ameliorates Myelination in S63del-Charcot–Marie–Tooth 1B Neuropathy

PubMed Central

Musner, Nicolò; Sidoli, Mariapaola; Zambroni, Desireè; Del Carro, Ubaldo; Ungaro, Daniela; D’Antonio, Maurizio; Feltri, Maria L.

2016-01-01

In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot–Marie–Tooth disease type 1B (CMT1B)–S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment: Perk haploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/− compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition, Perk deficiency in other cells may contribute to demyelination in a non–Schwann-cell autonomous manner. PMID:27095827

Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines

PubMed Central

2013-01-01

Background Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases. Methods To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R), the human ether-a-go-go-related gene (KCNH2, also known as hERG), and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1). We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p < 0.05). Results Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested. Conclusions Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases. PMID:23316740

Novel mutations of RPGR in Chinese retinitis pigmentosa patients and the genotype-phenotype correlation.

PubMed

Yang, Liping; Yin, Xiaobei; Feng, Lina; You, Debo; Wu, Lemeng; Chen, Ningning; Li, Aijun; Li, Genlin; Ma, Zhizhong

2014-01-01

X-linked Retinitis Pigmentosa (XLRP) accounts for 10-20% of all RP cases, and represents the most severe subtype of this disease. Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the most common causes of XLRP, accounting for over 70-75% of all XLRP cases. In this work, we analyzed all the exons of RPGR gene with Sanger sequencing in seven Chinese XLRP families, two of these with a provisional diagnosis of adRP but without male-to-male transmission. Three novel deletions (c.2233_34delAG; c.2236_37delGA and c.2403_04delAG) and two known nonsense mutations (c.851C→G and c.2260G→T) were identified in five families. Two novel deletions (c.2233_34delAG and c.2236_37delGA) resulted in the same frame shift (p.E746RfsX22), created similar phenotype in Family 3 and 4. The novel deletion (c.2403_04delAG; p.E802GfsX31) resulted in both XLRP and x-linked cone-rod dystrophy within the male patients of family 5, which suggested the presence of either genetic or environmental modifiers, or both, play a substantial role in disease expression. Genotype-phenotype correlation analysis suggested that (1) both patients and female carriers with mutation in Exon 8 (Family 1) manifest more severe disease than did those with ORF15 mutations (Family 2&3&4); (2) mutation close to downstream of ORF15 (Family 5) demonstrate the early preferential loss of cone function with moderate loss of rod function.

Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2).

PubMed

Beneyto, M M; Cuevas, J M; Millán, J M; Espinós, C; Mateu, E; González-Cabo, P; Baiget, M; Doménech, M; Bernal, S; Ayuso, C; García-Sandoval, B; Trujillo, M J; Borrego, S; Antiñolo, G; Carballo, M; Nájera, C

2000-06-01

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

Biological soil crusts in Chile along the precipitation gradient

NASA Astrophysics Data System (ADS)

Samolov, Elena; Glaser, Karin; Baumann, Karen; Leinweber, Peter; Jung, Patrick; Büdel, Burkhard; Mikhailyuk, Tatiana; Karsten, Ulf

2017-04-01

Biological soil crusts in Chile along a precipitation gradient Elena Samolov* (1), Karin Glaser (1), Karen Baumann (2), Peter Leinweber (2), Patrick Jung (3), Burkhard Büdel (3), Tatiana Mikhailyuk (4) and Ulf Karsten (1) (1) Institute of Biological Sciences - Applied Ecology and Phycology, University of Rostock, Rostock, Germany, (2) Faculty of Agricultural and Environmental Sciences - Soil Sciences, University of Rostock, Rostock, Germany (3) University of Kaiserslautern, Kaiserslautern, Germany (4) M.H. Kholodny Institute of Botany, National Academy of Science of Ukraine, Kyiv, Ukraine * elena.samolov@uni-rostock.de Biological soil crusts (BSCs) are an association of different microorganisms and soil particles in the top millimeters of the soil. They are formed by algae, cyanobacteria, microfungi, bacteria, bryophytes and lichens in various compositions; together with their by-products they create a micro-ecosystem that performs important ecological functions, e.g. primary production, nitrogen fixation, mineralization and stabilization of soils. These top-soil assemblages are almost unstudied in South America (Büdel et al. 2016). Therefore, our aim is to investigate for the first time biodiversity of the key photosynthetic organisms, green algae and cyanobacteria following a precipitation gradient along the west coast of Chile. We are applying polyphasic approach - a combination of microscopy, culture dependent (16S and 18S rRNA, ITS) and culture independent molecular techniques (NGS). First results, based on culturing and light microscopy, showed high diversity of eukaryotic algae in biocrusts from humid regions, followed by semi-arid regions. Lichen dominated biocrusts from arid regions were characterized by a high diversity of green algae, while cyanobacteria were scarcely present. The functional role of the BSCs in the biogeochemical cycle of phosphorous (P) was evaluated using state of the art analytical methods including 31P-NMR (nuclear magnetic resonance) spectroscopy and P K-edge XANES (x-ray absorbance near edge structures). Total P as well as P fractions were quantified in all BSCs, adjacent soil underneath and comparable nearby soil of BSC-free areas, revealing a slight accumulation of total phosphorous and a distinct pattern of P fractions in the crust. Our study describes for the first time the diversity of photosynthetic organisms in BSCs along a precipitation gradient in South America and their functional role in biogeochemical cycle of phosphorus as an important macronutrient. Reference: Büdel et al. "Cyanobacteria and Algae of Biological soil crusts". In B. Weber et al. (eds.), Biological Soli Crusts: An Organizing Principle in Drylands, Ecological Studies 226, Springer International Publishing Switzerland: 2016. (pp. 55-80).

CHEK2 1100delC, IVS2+1G>A and I157T mutations are not present in colorectal cancer cases from Turkish population.

PubMed

Bayram, Süleyman; Topaktaş, Mehmet; Akkız, Hikmet; Bekar, Aynur; Akgöllü, Ersin

2012-10-01

The cell cycle checkpoint kinase 2 (CHEK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHEK2 (1100delC, IVS2+1G>A and I157T) have been impaired serine/threonine kinase activity and associated with a range of cancer types. This hospital-based case-control study aimed to investigate whether CHEK2 1100delC, IVS2+1G>A and I157T mutations play an important role in the development of colorectal cancer (CRC) in Turkish population. A total of 210 CRC cases and 446 cancer-free controls were genotyped for CHEK2 mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific-polymerase chain reaction (AS-PCR) methods. We did not find the CHEK2 1100delC, IVS2+1G>A and I157T mutations in any of the Turkish subjects. Our result demonstrate for the first time that CHEK2 1100delC, IVS2+1G>A and I157T mutations have not been agenetic susceptibility factor for CRC in the Turkish population. Overall, our data suggest that genotyping of CHEK2 mutations in clinical settings in the Turkish population should not be recommended. However, independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins. Copyright © 2012 Elsevier Ltd. All rights reserved.

CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women.

PubMed

Adank, Muriel A; Jonker, Marianne A; Kluijt, Irma; van Mil, Saskia E; Oldenburg, Rogier A; Mooi, Wolter J; Hogervorst, Frans B L; van den Ouweland, Ans M W; Gille, Johan J P; Schmidt, Marjanka K; van der Vaart, Aad W; Meijers-Heijboer, Hanne; Waisfisz, Quinten

2011-12-01

Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk. Homozygosity for the CHEK2*1100delC allele was identified in 8/2554 Dutch independent familial non-BRCA1/2 breast cancer cases. The genotype relative risk for breast cancer of homozygous and heterozygous familial breast cancer cases was 101.34 (95% CI 4.47 to 121 000) and 4.04 (95% CI 0.88 to 21.0), respectively. Female homozygotes appeared to have a greater than twofold increased breast cancer risk compared to familial CHEK2*1100delC heterozygotes (p=0.044). These results and the occurrence of multiple primary tumours in 7/10 homozygotes indicate a high cancer risk in homozygous women from non-BRCA1/2 families. Intensive breast surveillance is therefore justified in these homozygous women. It is concluded that diagnostic testing for biallelic mutations in CHEK2 is indicated in non-BRCA1/2 breast cancer families, especially in populations with a relatively high prevalence of deleterious mutations in CHEK2.

Nature and Recurrence of AVPR2 Mutations in X-linked Nephrogenic Diabetes Insipidus

PubMed Central

Bichet, Daniel G.; Birnbaumer, Mariel; Lonergan, Michèle; Arthus, Marie-Françoise; Rosenthal, Walter; Goodyer, Paul; Nivet, Hubert; Benoit, Stéphane; Giampietro, Philip; Simonetti, Simonetta; Fish, Alfred; Whitley, Chester B.; Jaeger, Philippe; Gertner, Joseph; New, Maria; DiBona, Francis J.; Kaplan, Bernard S.; Robertson, Gary L.; Hendy, Geoffrey N.; Fujiwara, T. Mary; Morgan, Kenneth

1994-01-01

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with defective renal and extrarenal arginine-vasopressin V2 receptor responses due to mutations in the AVPR2 gene in Xq28. We analyzed 31 independent NDI families to determine the nature and recurrence of AVPR2 mutations. Twenty-one new putative disease-causing mutations were identified: 113delCT, 253del35, 255del9, 274insG, V88M, R106C, 402delCT, C112R, Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mutations—R113W, Y128S, R137H, R181C, and R202C—that previously had been reported in other families were detected. There was evidence for recurrent mutation for four mutations (R113W, R137H, S167L, and R337X). Eight de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one), grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported by us, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletions and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methylcytosine deamination at a CpG dinucleotide. Most of the small deletions and insertions could be attributed to slipped mispairing during DNA replication. PMID:8037205

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.

PubMed

Stephen, Joshi; Nampoothiri, Sheela; Vinayan, K P; Yesodharan, Dhanya; Remesh, Preetha; Gahl, William A; Malicdan, May Christine V

2018-05-16

Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy. The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy. Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.

Quantum Phases at the Nanoscale

DTIC Science & Technology

2002-07-20

Sapienza" Roma. (Ital)y and Consejo perpendicular magnetic field, independent Nacional de Investigaciones Cientificas y electrons occupy Landau levels...Electromodulation of charge transfer and Departamento de Fisica Teorica de la the breathing mode of C60 on graphite Materia Condensada, Spain Miriam del...Instituto de Ciencia de Materiales de Madrid- epitaxial ferromagnetic metal [4], exhibiting CSIC. Spain coherent dynamics that persist over time scales

Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition

PubMed Central

Arbogast, Thomas; Iacono, Giovanni; Chevalier, Claire; Afinowi, Nurudeen O.; Houbaert, Xander; Laliberte, Christine; Birling, Marie-Christine; Linda, Katrin; Meziane, Hamid; Selloum, Mohammed; Sorg, Tania; Koolen, David A.; Stunnenberg, Henk G.; Kopanitsa, Maksym; Humeau, Yann; De Vries, Bert B. A.

2017-01-01

Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches. PMID:28704368

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice.

PubMed

D'Antonio, Maurizio; Musner, Nicolò; Scapin, Cristina; Ungaro, Daniela; Del Carro, Ubaldo; Ron, David; Feltri, M Laura; Wrabetz, Lawrence

2013-04-08

P0 glycoprotein is an abundant product of terminal differentiation in myelinating Schwann cells. The mutant P0S63del causes Charcot-Marie-Tooth 1B neuropathy in humans, and a very similar demyelinating neuropathy in transgenic mice. P0S63del is retained in the endoplasmic reticulum of Schwann cells, where it promotes unfolded protein stress and elicits an unfolded protein response (UPR) associated with translational attenuation. Ablation of Chop, a UPR mediator, from S63del mice completely rescues their motor deficit and reduces active demyelination by half. Here, we show that Gadd34 is a detrimental effector of CHOP that reactivates translation too aggressively in myelinating Schwann cells. Genetic or pharmacological limitation of Gadd34 function moderates translational reactivation, improves myelination in S63del nerves, and reduces accumulation of P0S63del in the ER. Resetting translational homeostasis may provide a therapeutic strategy in tissues impaired by misfolded proteins that are synthesized during terminal differentiation.

Expression of exon-8-skipped kindlin-1 does not compensate for defects of Kindler syndrome.

PubMed

Natsuga, Ken; Nishie, Wataru; Shinkuma, Satoru; Nakamura, Hideki; Matsushima, Yoichiro; Tatsuta, Aya; Komine, Mayumi; Shimizu, Hiroshi

2011-01-01

Kindler syndrome (KS) is a rare, inherited skin disease characterized by blister formation and generalized poikiloderma. Mutations in KIND1, which encodes kindlin-1, are responsible for KS. c.1089del/1089+1del is a recurrent splice-site deletion mutation in KS patients. To elucidate the effects of c.1089del/1089+1del at the mRNA and protein level. Two KS patients with c.1089del/1089+1del were included in this study. Immunofluorescence analysis of KS skin samples using antibodies against the dermo-epidermal junction proteins was performed. Exon-trapping experiments were performed to isolate the mRNA sequences transcribed from genomic DNA harbouring c.1089del/1089+1del. β1 integrin activation in HeLa cells transfected with truncated KIND1 cDNA was analyzed. Immunofluorescence study showed positive expression of kindlin-1 in KS skin with c.1089del/1089+1del mutation. We identified the exon-8-skipped in-frame transcript as the main product among multiple splicing variants derived from that mutation. HeLa cells transfected with KIND1 cDNA without exon 8 showed impaired β1 integrin activation. Exon-8-coding amino acids are located in the FERM F2 domain, which is conserved among species, and the unstructured region between F2 and the pleckstrin homology domain. This study suggests that exon-8-skipped truncated kindlin-1 is functionally defective and does not compensate for the defects of KS, even though kindlin-1 expression in skin is positive. Copyright © 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Lack of effect of the alpha2C-adrenoceptor Del322-325 polymorphism on inhibition of cyclic AMP production in HEK293 cells.

PubMed

Montgomery, M D; Bylund, D B

2010-02-01

The alpha(2C)-adrenoceptor has multiple functions, including inhibiting release of noradrenaline from presynaptic nerve terminals. A human alpha(2C) polymorphism, Del322-325, a potential risk factor for heart failure, has been reported to exhibit reduced signalling in CHO cells. To further understand the role of the Del322-325 polymorphism on receptor signalling, we attempted to replicate and further study the reduced signalling in HEK293 cells. Human alpha(2C) wild-type (WT) and Del322-325 adrenoceptors were stably transfected into HEK293 cells. Radioligand binding was performed to determine affinities for both receptors. In intact cells, inhibition of forskolin-stimulated cyclic AMP production by WT and Del322-325 clones with a range of receptor densities (200-2320 fmol.mg(-1) protein) was measured following agonist treatment. Noradrenaline, brimonidine and clonidine exhibited similar binding affinities for WT and Del322-325. Brimonidine and clonidine also had similar efficacies and potencies for both receptors for the inhibition of cyclic AMP production at all receptor densities tested. A linear regression analysis comparing efficacy and potency with receptor expression levels showed no differences in slopes between WT and Del322-325. The alpha(2C) WT and Del322-325 adrenoceptors exhibited similar binding properties. Additionally, inhibition of cyclic AMP production by Del322-325 was similar to that of WT over a range of receptor densities. Therefore, in intact HEK293 cells, the alpha(2C)-Del322-325 polymorphism does not exhibit reduced signalling to adenylyl cyclase and may not represent a clinically important phenotype.

Thermal Smearing of the Magneto-Kohn Anomaly for Dirac materials and comparison with the Two-dimensional electron Liquid

NASA Astrophysics Data System (ADS)

Dahal, Dipendra; Balassis, Antonios; Gumbs, Godfrey; Glasser, M. L.; graphene projects Collaboration

We compute and compare the effects due to a uniform perpendicular magnetic field and the temperature on the static polarization functions for monolayer graphene (MLG) associated with the Dirac point with that for the two-dimensional electron liquid (2DEL). Previous results for the 2DEL are discussed and we point out a flaw in reported analytic derivation to exhibit the smearing of the Fermi surface for 2DEL. The relevance of our study to the Kohn anomaly in low-dimensional structures and the Friedel oscillations for the screening of the potential for a dilute distribution of impurities is reported.

Deleterious CHEK2 1100delC and L303X mutants identified among 38 human breast cancer cell lines.

PubMed

Wasielewski, Marijke; Hanifi-Moghaddam, Pejman; Hollestelle, Antoinette; Merajver, Sofia D; van den Ouweland, Ans; Klijn, Jan G M; Ethier, Stephen P; Schutte, Mieke

2009-01-01

The CHEK2 protein plays a major role in the regulation of DNA damage response pathways. Mutations in the CHEK2 gene, in particular 1100delC, have been associated with increased cancer risks, but the precise function of CHEK2 mutations in carcinogenesis is not known. Human cancer cell lines with CHEK2 mutations are therefore of main interest. Here, we have sequenced 38 breast cancer cell lines for mutations in the CHEK2 gene and identified two cell lines with deleterious CHEK2 mutations. Cell line UACC812 has a nonsense truncating mutation in the CHEK2 kinase domain (L303X) and cell line SUM102PT has the well-known oncogenic CHEK2 1100delC founder mutation. Immunohistochemical analysis revealed that the two CHEK2 mutant cell lines expressed neither CHEK2 nor P-Thr(68) CHEK2 proteins, implying abrogation of normal CHEK2 DNA repair functions. Cell lines UACC812 and SUM102PT thus are the first human CHEK2 null cell lines reported and should therefore be a major help in further unraveling the function of CHEK2 mutations in carcinogenesis.

Politica Nacional sobre Discapacidad: Un Informe del Progreso, Diciembre 2000-Diciembre 2001 (National Disability Policy: A Progress Report, December 2000-December 2001).

ERIC Educational Resources Information Center

National Council on Disability, Washington, DC.

This report (written in Spanish) of the National Council on Disability (NCD) describes the nation's progress in advancing public policies to increase the inclusion, empowerment, and independence of people with disabilities in light of the Americans with Disabilities Act of 1990. The report covers December 2000 through December 2001. It reviews…

CCR5 gene polymorphism is a genetic risk factor for radiographic severity of rheumatoid arthritis.

PubMed

Han, S W; Sa, K H; Kim, S I; Lee, S I; Park, Y W; Lee, S S; Yoo, W H; Soe, J S; Nam, E J; Lee, J; Park, J Y; Kang, Y M

2012-11-01

The chemokine receptor [C-C chemokine receptor 5 (CCR5)] is expressed on diverse immune effecter cells and has been implicated in the pathogenesis of rheumatoid arthritis (RA). This study sought to determine whether single-nucleotide polymorphisms (SNPs) in the CCR5 gene and their haplotypes were associated with susceptibility to and severity of RA. Three hundred fifty-seven patients with RA and 383 healthy unrelated controls were recruited. Using a pyrosequencing assay, we examined four polymorphisms -1118 CTAT(ins) (/del) (rs10577983), 303 A>G (rs1799987), 927 C>T (rs1800024), and 4838 G>T (rs1800874) of the CCR5 gene, which were distributed over the promoter region as well as the 5' and 3' untranslated regions. No significant difference in the genotype, allele, and haplotype frequencies of the four selected SNPs was observed between RA patients and controls. CCR5 polymorphisms of -1118 CTAT(del) (P = 0.012; corrected P = 0.048) and 303 A>G (P = 0.012; corrected P = 0.048) showed a significant association with radiographic severity in a recessive model, and, as a result of multivariate logistic regression analysis, were found to be an independent predictor of radiographic severity. When we separated the erosion score from the total Sharp score, the statistical significance of CCR5 polymorphisms showed an increase; -1118 CTAT(ins) (/del) (P = 0.007; corrected P = 0.028) and 303 A>G (P = 0.007; corrected P = 0.028). Neither SNPs nor haplotypes of the CCR5 gene showed a significant association with joint space narrowing score. These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA. © 2012 John Wiley & Sons A/S.

Fatty Acid Cysteamine Conjugates as Novel and Potent Autophagy Activators That Enhance the Correction of Misfolded F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

PubMed

Vu, Chi B; Bridges, Robert J; Pena-Rasgado, Cecilia; Lacerda, Antonio E; Bordwell, Curtis; Sewell, Abby; Nichols, Andrew J; Chandran, Sachin; Lonkar, Pallavi; Picarella, Dominic; Ting, Amal; Wensley, Allison; Yeager, Maisy; Liu, Feng

2017-01-12

A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.

Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q).

PubMed

Fenaux, Pierre; Giagounidis, Aristoteles; Selleslag, Dominik; Beyne-Rauzy, Odile; Mittelman, Moshe; Muus, Petra; Nimer, Stephen D; Hellström-Lindberg, Eva; Powell, Bayard L; Guerci-Bresler, Agnes; Sekeres, Mikkael A; Deeg, H Joachim; Del Cañizo, Consuelo; Greenberg, Peter L; Shammo, Jamile M; Skikne, Barry; Yu, Xujie; List, Alan F

2017-06-26

Particularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed. We assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials. A total of 33.9, 34.3, and 31.8% patients were aged <65 years, ≥65 to <75 years, and ≥75 years, respectively. Age <65 years was associated with less favorable International Prognostic Scoring System (IPSS) risk and additional cytopenias at baseline versus older age groups, significantly lower cytogenetic response rates (p = 0.022 vs. ≥65 to <75 years; p = 0.047 vs. ≥75 years), and higher rates of acute myeloid leukemia (AML) progression (Gray's test, p = 0.013). Lenalidomide was equally well tolerated across age groups, producing consistently high rates of red blood cell transfusion independence ≥26 weeks. Baseline disease characteristics and AML progression appear to be more severe in younger lower-risk MDS patients with del(5q), whereas older age does not seem to compromise the response to lenalidomide. ClinicalTrials.gov NCT00065156 and NCT00179621.

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL

PubMed Central

Brown, J R; Hillmen, P; O’Brien, S; Barrientos, J C; Reddy, N M; Coutre, S E; Tam, C S; Mulligan, S P; Jaeger, U; Barr, P M; Furman, R R; Kipps, T J; Cymbalista, F; Thornton, P; Caligaris-Cappio, F; Delgado, J; Montillo, M; DeVos, S; Moreno, C; Pagel, J M; Munir, T; Burger, J A; Chung, D; Lin, J; Gau, L; Chang, B; Cole, G; Hsu, E; James, D F; Byrd, J C

2018-01-01

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations. PMID:28592889

A High-Resolution InDel (Insertion–Deletion) Markers-Anchored Consensus Genetic Map Identifies Major QTLs Governing Pod Number and Seed Yield in Chickpea

PubMed Central

Srivastava, Rishi; Singh, Mohar; Bajaj, Deepak; Parida, Swarup K.

2016-01-01

Development and large-scale genotyping of user-friendly informative genome/gene-derived InDel markers in natural and mapping populations is vital for accelerating genomics-assisted breeding applications of chickpea with minimal resource expenses. The present investigation employed a high-throughput whole genome next-generation resequencing strategy in low and high pod number parental accessions and homozygous individuals constituting the bulks from each of two inter-specific mapping populations [(Pusa 1103 × ILWC 46) and (Pusa 256 × ILWC 46)] to develop non-erroneous InDel markers at a genome-wide scale. Comparing these high-quality genomic sequences, 82,360 InDel markers with reference to kabuli genome and 13,891 InDel markers exhibiting differentiation between low and high pod number parental accessions and bulks of aforementioned mapping populations were developed. These informative markers were structurally and functionally annotated in diverse coding and non-coding sequence components of genome/genes of kabuli chickpea. The functional significance of regulatory and coding (frameshift and large-effect mutations) InDel markers for establishing marker-trait linkages through association/genetic mapping was apparent. The markers detected a greater amplification (97%) and intra-specific polymorphic potential (58–87%) among a diverse panel of cultivated desi, kabuli, and wild accessions even by using a simpler cost-efficient agarose gel-based assay implicating their utility in large-scale genetic analysis especially in domesticated chickpea with narrow genetic base. Two high-density inter-specific genetic linkage maps generated using aforesaid mapping populations were integrated to construct a consensus 1479 InDel markers-anchored high-resolution (inter-marker distance: 0.66 cM) genetic map for efficient molecular mapping of major QTLs governing pod number and seed yield per plant in chickpea. Utilizing these high-density genetic maps as anchors, three major genomic regions harboring each of pod number and seed yield robust QTLs (15–28% phenotypic variation explained) were identified on chromosomes 2, 4, and 6. The integration of genetic and physical maps at these QTLs mapped on chromosomes scaled-down the long major QTL intervals into high-resolution short pod number and seed yield robust QTL physical intervals (0.89–2.94 Mb) which were essentially got validated in multiple genetic backgrounds of two chickpea mapping populations. The genome-wide InDel markers including natural allelic variants and genomic loci/genes delineated at major six especially in one colocalized novel congruent robust pod number and seed yield robust QTLs mapped on a high-density consensus genetic map were found most promising in chickpea. These functionally relevant molecular tags can drive marker-assisted genetic enhancement to develop high-yielding cultivars with increased seed/pod number and yield in chickpea. PMID:27695461

A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice.

PubMed

Zhu, Xiaoquan; Wang, Fengchao; Zhao, Yanyang; Yang, Peng; Chen, Jun; Sun, Hanzi; Liu, Lei; Li, Wenjun; Pan, Lin; Guo, Yanru; Kou, Zhaohui; Zhang, Yu; Zhou, Cheng; He, Jiang; Zhang, Xue; Li, Jianxin; Han, Weitian; Li, Jian; Liu, Guanghui; Gao, Shaorong; Yang, Ze

2014-10-01

Distal arthrogryposis type 2B (DA2B) is an important genetic disorder in humans. However, the mechanisms governing this disease are not clearly understood. In this study, we generated knock-in mice carrying a DA2B mutation (K175del) in troponin I type 2 (skeletal, fast) (TNNI2), which encodes a fast-twitch skeletal muscle protein. Tnni2K175del mice (referred to as DA2B mice) showed typical DA2B phenotypes, including limb abnormality and small body size. However, the current knowledge concerning TNNI2 could not explain the small body phenotype of DA2B mice. We found that Tnni2 was expressed in the osteoblasts and chondrocytes of long bone growth plates. Expression profile analysis using radii and ulnae demonstrated that Hif3a expression was significantly increased in the Tnni2K175del mice. Chromatin immunoprecipitation assays indicated that both wild-type and mutant tnni2 protein can bind to the Hif3a promoter using mouse primary osteoblasts. Moreover, we showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein. The increased amount of hif3a resulted in impairment of angiogenesis, delay in endochondral ossification, and decrease in chondrocyte differentiation and osteoblast proliferation, suggesting that hif3a counteracted hif1a-induced Vegf expression in DA2B mice. Together, our data indicated that Tnni2K175del mutation led to abnormally increased hif3a and decreased vegf in bone, which explain, at least in part, the small body size of Tnni2K175del mice. Furthermore, our findings revealed a new function of tnni2 in the regulation of bone development, and the study of gain-of-function mutation in Tnni2 in transgenic mice opens a new avenue to understand the pathological mechanism of human DA2B disorder.

The relationship between motor function, cognition, independence and quality of life in myelomeningocele patients.

PubMed

Luz, Carolina Lundberg; Moura, Maria Clara Drummond Soares de; Becker, Karine Kyomi; Teixeira, Rosani Aparecida Antunes; Voos, Mariana Callil; Hasue, Renata Hydee

2017-08-01

Motor function, cognition, functional independence and quality of life have been described in myelomeningocele patients, but no study has investigated their relationships. We aimed to investigate the relationships between motor function, cognition, functional independence, quality of life, age, and lesion level in myelomeningocele patients, and investigate the influence of hydrocephalus on these variables. We assessed 47 patients with the Gross Motor Function Measure (motor function), Raven's Colored Progressive Matrices (cognition), Pediatric Evaluation of Disability Inventory (functional independence) and the Autoquestionnaire Qualité de vie Enfant Imagé (quality of life). Spearman's correlation tests determined relationships between the variables. The Friedman ANOVAs determined the influence of hydrocephalus. Motor function was strongly related to mobility and lesion level, and moderately related to cognition, self-care and social function. Cognition and quality of life were moderately related to functional independence. Age correlated moderately with functional independence and quality of life. Hydrocephalus resulted in poorer motor/cognitive outcomes and lower functional independence.

Effect of the F508del genotype on outcomes of endoscopic sinus surgery in children with cystic fibrosis.

PubMed

Do, Bao Anh Julie; Lands, Larry C; Saint-Martin, Christine; Mascarella, Marco A; Manoukian, John J; Daniel, Sam J; Nguyen, Lily H P

2014-07-01

Numerous authors have sought to describe genotype-phenotype correlations in cystic fibrosis (CF), notably to pancreatic insufficiency and lung disease. However, few studies have focused on the association between the F508del genotype and response to sinus surgery. The objective of this study is to assess the effect of the F508del genotype on sinonasal disease severity and outcomes following functional endoscopic sinus surgery (FESS) in a pediatric population. A retrospective chart review of 153 children with CF seen at a tertiary care pediatric hospital from 1995 to 2008 was performed. Patients were classified into one of three groups according to F508del genotype, either as homozygous, heterozygous or not carrying a F508del mutation. The sinonasal disease phenotype of the three groups was compared based on clinical and radiological findings, extent of endoscopic sinus surgery and rate of revision surgery. The relationship between the F508del genotype and pancreatic insufficiency was confirmed (p<0.05). There was no association between the F508del genotype and increased need for FESS (p=0.75). Moreover, no association was established between F508del homozygosity and presence of nasal polyps, Lund-Mackay score, extent of surgery or length of postoperative hospitalization. The rates of revision surgery did not differ significantly among the three genotypes analyzed (p=0.59). There is no clear association between the F508del genotype and an increased need for FESS, extent of surgery, or revision surgery. Given the phenotypic variability of sinonasal disease in patients with CF, a prospective study is needed to better understand outcomes following FESS and the contribution of gene modifiers to this effect. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Estructura y Funcionamiento del Cuerpo Humano. Prontuario. Guia del Maestro. Documento de Trabajo (Structure and Function of the Human Body. Handbook and Teacher's Guide. Working Document).

ERIC Educational Resources Information Center

Puerto Rico State Dept. of Education, Hato Rey. Area for Vocational and Technical Education.

This handbook and teacher's guide are for a 37-week course on the human body, intended for secondary or postsecondary students in allied health occupations. The syllabus lists general objectives and the number of hours and weeks devoted to each unit. A course outline is provided for five units: anatomy and physiology terminology; general…

La Aplicacion de las Bases de Datos al Estudio Historico del Espanol (The Application of Databases to the Historical Study of Spanish).

ERIC Educational Resources Information Center

Nadal, Gloria Claveria; Lancis, Carlos Sanchez

1997-01-01

Notes that the employment of databases to the study of the history of a language is a method that allows for substantial improvement in investigative quality. Illustrates this with the example of the application of this method to two studies of the history of Spanish developed in the Language and Information Seminary of the Independent University…

Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies.

PubMed

Komrokji, Rami; Swern, Arlene S; Grinblatt, David; Lyons, Roger M; Tobiasson, Magnus; Silverman, Lewis R; Sayar, Hamid; Vij, Ravi; Fliss, Albert; Tu, Nora; Sugrue, Mary M

2018-02-01

After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response. Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by anemia. After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta-analysis of 233 azacitidine-treated red blood cell (RBC) transfusion-dependent patients with LR-MDS (92.3% non-del[5q]) from 7 studies showed 38.9% became RBC transfusion-independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non-del(5q) LR-MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR-MDS patients. © AlphaMed Press 2017.

Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study.

PubMed

Näslund-Koch, Charlotte; Nordestgaard, Børge G; Bojesen, Stig E

2016-04-10

CHEK2 is a cell cycle checkpoint regulator, and the CHEK2*1100delC germline mutation leads to loss of function and increased breast cancer risk. It seems plausible that this mutation could also predispose to other cancers. Therefore, we tested the hypothesis that CHEK2*1100delC heterozygosity is associated with increased risk for other cancers in addition to breast cancer in the general population. We examined 86,975 individuals from the Copenhagen General Population Study, recruited from 2003 through 2010. The participants completed a questionnaire on health and lifestyle, were examined physically, had blood drawn for DNA extraction, were tested for presence of CHEK2*1100delC using Taqman assays and sequencing, and were linked over 1943 through 2011 to the Danish Cancer Registry. Incidences and risks of individual cancer types, including breast cancer, were calculated using Kaplan-Meier estimates, Fine and Gray competing-risks regressions, and stratified analyses with interaction tests. Among 86,975 individuals, 670 (0.8%) were CHEK2*1100delC heterozygous, 2,442 developed breast cancer, and 6,635 developed other cancers. The age- and sex-adjusted hazard ratio for CHEK2*1100delC heterozygotes compared with noncarriers was 2.08 (95% CI, 1.51 to 2.85) for breast cancer and 1.45 (95% CI, 1.15 to 1.82) for other cancers. When stratifying for sex, the age-adjusted hazard ratios for other cancers were 1.54 (95% CI, 1.08 to 2.18) for women and 1.37 (95% CI, 1.01 to 1.85) for men (sex difference: P = .63). For CHEK2*1100delC heterozygotes compared with noncarriers, the age- and sex-adjusted hazard ratios were 5.76 (95% CI, 2.12 to 15.6) for stomach cancer, 3.61 (95% CI, 1.33 to 9.79) for kidney cancer, 3.45 (95% CI, 1.09 to 10.9) for sarcoma, and 1.60 (95% CI, 1.00 to 2.56) for prostate cancer. CHEK2*1100delC heterozygosity is associated with 15% to 82% increased risk for at least some cancers in addition to breast cancer. This information may be useful in clinical counseling of patients with this loss-of-function mutation. © 2016 by American Society of Clinical Oncology.

QOL in caregivers of Japanese patients with Prader-Willi syndrome with reference to age and genotype.

PubMed

Ihara, Hiroshi; Ogata, Hiroyuki; Sayama, Masayuki; Kato, Aya; Gito, Masao; Murakami, Nobuyuki; Kido, Yasuhiro; Nagai, Toshiro

2014-09-01

This study aimed to measure quality of life (QOL) of the primary family caregivers for patients with Prader-Willi syndrome (PWS). Comparisons were made between caregivers' QOL in regard to their dependents' genotype and age group. The participants with PWS consisted of 22 children (aged from 6 to 12 years) and 23 adolescents (aged from 13 to 19 years), including 6 children and 7 adolescents with maternal uniparental disomy (mUPD) and 16 children and 16 adolescents with deletion (DEL). The QOL of the primary family caregiver for each patient was assessed using the Japanese version of the WHOQOL-BREF. To examine the effect that age (children vs. adolescents) and genotype (DEL vs. mUPD) have on the QOL of caregivers, a two-way ANOVA was conducted, followed by the Bonferroni procedure to test the simple main effects. The two age groups and the two genotypes of PWS were used as independent variables and the total QOL of caregivers as a dependent variable. The two-way ANOVA (F(1, 41) = 6.98, P < 0.05), followed by the Bonferroni procedure, showed the following: the total QOL of caregivers of DEL adolescents showed little difference from that with DEL children, but the QOL of caregivers for mUPD adolescents was shown to be lower than that with mUPD children along with that of caregivers with DEL adolescents. There is hence a growing tendency for the deterioration in the QOL of caregivers to manifest itself later in the patients' adolescence, found mainly with mUPD patients. © 2014 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis.

PubMed

Esposito, Speranza; Tosco, Antonella; Villella, Valeria R; Raia, Valeria; Kroemer, Guido; Maiuri, Luigi

2016-12-01

Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient's nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation.

Natural Variation in the Promoter of GSE5 Contributes to Grain Size Diversity in Rice.

PubMed

Duan, Penggen; Xu, Jinsong; Zeng, Dali; Zhang, Baolan; Geng, Mufan; Zhang, Guozheng; Huang, Ke; Huang, Luojiang; Xu, Ran; Ge, Song; Qian, Qian; Li, Yunhai

2017-05-01

The utilization of natural genetic variation greatly contributes to improvement of important agronomic traits in crops. Understanding the genetic basis for natural variation of grain size can help breeders develop high-yield rice varieties. In this study, we identify a previously unrecognized gene, named GSE5, in the qSW5/GW5 locus controlling rice grain size by combining the genome-wide association study with functional analyses. GSE5 encodes a plasma membrane-associated protein with IQ domains, which interacts with the rice calmodulin protein, OsCaM1-1. We found that loss of GSE5 function caused wide and heavy grains, while overexpression of GSE5 resulted in narrow grains. We showed that GSE5 regulates grain size predominantly by influencing cell proliferation in spikelet hulls. Three major haplotypes of GSE5 (GSE5, GSE5 DEL1+IN1 , and GSE5 DEL2 ) in cultivated rice were identified based on the deletion/insertion type in its promoter region. We demonstrated that a 950-bp deletion (DEL1) in indica varieties carrying the GSE5 DEL1+IN1 haplotype and a 1212-bp deletion (DEL2) in japonica varieties carrying the GSE5 DEL2 haplotype associated with decreased expression of GSE5, resulting in wide grains. Further analyses indicate that wild rice accessions contain all three haplotypes of GSE5, suggesting that the GSE5 haplotypes present in cultivated rice are likely to have originated from different wild rice accessions during rice domestication. Taken together, our results indicate that the previously unrecognized GSE5 gene in the qSW5/GW5 locus, which is widely utilized by rice breeders, controls grain size, and reveal that natural variation in the promoter region of GSE5 contributes to grain size diversity in rice. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

A chemical corrector modifies the channel function of F508del-CFTR.

PubMed

Kim Chiaw, Patrick; Wellhauser, Leigh; Huan, Ling Jun; Ramjeesingh, Mohabir; Bear, Christine E

2010-09-01

The deletion of Phe-508 (F508del) constitutes the most prevalent cystic fibrosis-causing mutation. This mutation leads to cystic fibrosis transmembrane conductance regulator (CFTR) misfolding and retention in the endoplasmic reticulum and altered channel activity in mammalian cells. This folding defect can however be partially overcome by growing cells expressing this mutant protein at low (27 degrees C) temperature. Chemical "correctors" have been identified that are also effective in rescuing the biosynthetic defect in F508del-CFTR, thereby permitting its functional expression at the cell surface. The mechanism of action of chemical correctors remains unclear, but it has been suggested that certain correctors [including 4-cyclohexyloxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-325)] may act to promote trafficking by interacting directly with the mutant protein. To test this hypothesis, we assessed the effect of VRT-325 addition on the channel activity of F508del-CFTR after its surface expression had been "rescued" by low temperature. It is noteworthy that short-term pretreatment with VRT-325 [but not with an inactive analog, 4-hydroxy-2-(1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl)-quinazoline (VRT-186)], caused a modest but significant inhibition of cAMP-mediated halide flux. Furthermore, VRT-325 decreased the apparent ATP affinity of purified and reconstituted F508del-CFTR in our ATPase activity assay, an effect that may account for the decrease in channel activity by temperature-rescued F508del-CFTR. These findings suggest that biosynthetic rescue mediated by VRT-325 may be conferred (at least in part) by direct modification of the structure of the mutant protein, leading to a decrease in its ATP-dependent conformational dynamics. Therefore, the challenge for therapy discovery will be the design of small molecules that bind to promote biosynthetic maturation of the major mutant without compromising its activity in vivo.

Cystic fibrosis transmembrane conductance regulator modulators: precision medicine in cystic fibrosis.

PubMed

Burgener, Elizabeth B; Moss, Richard B

2018-06-01

The aim of this study was to describe the newest development in cystic fibrosis (CF) care, CF transmembrane conductance regulator (CFTR) modulator therapies. Phase II results showing CFTR modulator triple therapies are more effective than current CFTR modulators. CFTR modulator therapy targets the protein defective in CF and boosts its function, but the drug must match mutation pathobiology. Ivacaftor, a CFTR potentiator, was the first modulator approved in 2012, with impressive improvement in lung function and other measures of disease in patients with gating and other residual function mutations (∼10% of CF patients). In 2015, the combination of lumacaftor, a CFTR corrector, and ivacaftor was approved for patients homozygous for the F508del mutation (∼40-50% of the CF population) with positive but less impressive clinical response and 10-20% incidence of intolerance. A next-generation CFTR corrector, tezacaftor, with ivacaftor equally effective and better tolerated than lumacaftor, has also received US Food and Drug Administration approval. Novel CFTR correctors, entering Phase 3 trials in triple modulator combination with tezacaftor-ivacaftor, appear substantially more effective for patients who are homozygous for the F508del mutation and can provide benefit for patients with a single F508del mutation. This offers promise of effective CFTR modulator therapy for nearly 90% of CF patients.

CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis.

PubMed

Weischer, Maren; Heerfordt, Ida M; Bojesen, Stig E; Eigentler, Thomas; Garbe, Claus; Röcken, Martin; Hölmich, Lisbet Rosenkrantz; Schmidt, Henrik; Klyver, Helle; Bastholt, Lars; Nordestgaard, Børge G

2012-02-01

It is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1.07-3.05). Stratifications did not alter these results. CHEK2*1100delC heterozygotes have a twofold risk of malignant melanoma compared with noncarriers.

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

PubMed

Strug, Lisa J; Gonska, Tanja; He, Gengming; Keenan, Katherine; Ip, Wan; Boëlle, Pierre-Yves; Lin, Fan; Panjwani, Naim; Gong, Jiafen; Li, Weili; Soave, David; Xiao, Bowei; Tullis, Elizabeth; Rabin, Harvey; Parkins, Michael D; Price, April; Zuberbuhler, Peter C; Corvol, Harriet; Ratjen, Felix; Sun, Lei; Bear, Christine E; Rommens, Johanna M

2016-10-15

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

Breakthrough Therapies: Cystic Fibrosis (CF) Potentiators and Correctors

PubMed Central

Solomon, George M.; Marshall, Susan G.; Ramsey, Bonnie W.; Rowe, Steven M.

2015-01-01

Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene resulting in abnormal protein function. Recent advances of targeted molecular therapies and high throughput screening have resulted in multiple drug therapies that target many important mutations in the CFTR protein. In this review, we provide the latest results and current progress of CFTR modulators for the treatment of cystic fibrosis, focusing on potentiators of CFTR channel gating and Phe508del processing correctors for the Phe508del CFTR mutation. Special emphasis is placed on the molecular basis underlying these new therapies and emerging results from the latest clinical trials. The future directions for augmenting the rescue of Phe508del with CFTR modulators is also emphasized. PMID:26097168

Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTR.

PubMed

Farinha, Carlos M; Sousa, Marisa; Canato, Sara; Schmidt, André; Uliyakina, Inna; Amaral, Margarida D

2015-08-01

Cystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del-CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors (VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del-CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del-CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue.

Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTR

PubMed Central

Farinha, Carlos M; Sousa, Marisa; Canato, Sara; Schmidt, André; Uliyakina, Inna; Amaral, Margarida D

2015-01-01

Cystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del-CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors (VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del-CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del-CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue. PMID:26171232

Probing Conformational Rescue Induced by a Chemical Corrector of F508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutant*

PubMed Central

Yu, Wilson; Chiaw, Patrick Kim; Bear, Christine E.

2011-01-01

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that cause loss of function of the CFTR channel on the apical surface of epithelial cells. The major CF-causing mutation, F508del-CFTR, is misfolded, retained in the endoplasmic reticulum, and degraded. Small molecule corrector compounds have been identified using high throughput screens, which partially rescue the trafficking defect of F508del-CFTR, allowing a fraction of the mutant protein to escape endoplasmic reticulum retention and traffic to the plasma membrane, where it exhibits partial function as a cAMP-regulated chloride channel. A subset of such corrector compounds binds directly to the mutant protein, prompting the hypothesis that they rescue the biosynthetic defect by inducing improved protein conformation. We tested this hypothesis directly by evaluating the consequences of a corrector compound on the conformation of each nucleotide binding domain (NBD) in the context of the full-length mutant protein in limited proteolytic digest studies. Interestingly, we found that VRT-325 was capable of partially restoring compactness in NBD1. However, VRT-325 had no detectable effect on the conformation of the second half of the molecule. In comparison, ablation of the di-arginine sequence, R553XR555 (F508del-KXK-CFTR), modified protease susceptibility of NBD1, NBD2, and the full-length protein. Singly, each intervention led to a partial correction of the processing defect. Together, these interventions restored processing of F508del-CFTR to near wild type. Importantly, however, a defect in NBD1 conformation persisted, as did a defect in channel activation after the combined interventions. Importantly, this defect in channel activation can be fully corrected by the addition of the potentiator, VX-770. PMID:21602569

PUP: An Architecture to Exploit Parallel Unification in Prolog

DTIC Science & Technology

1988-03-01

environment stacking mo del similar to the Warren Abstract Machine [23] since it has been shown to be super ior to other known models (see [21]). The storage...execute in groups of independent operations. Unifications belonging to different group s may not overlap. Also unification operations belonging to the...since all parallel operations on the unification units must complete before any of the units can star t executing the next group of parallel

Interaction between CYP1A2-T2467DELT polymorphism and smoking in adenocarcinoma and squamous cell carcinoma of the lung.

PubMed

Pavanello, Sofia; B'chir, Fatma; Pulliero, Alessandra; Saguem, Saâd; Ben Fraj, Radhia; El Aziz Hayouni, Abed; Clonfero, Erminio; Mastrangelo, Giuseppe

2007-09-01

This study aimed to identify new genetic characteristics contributing to individual susceptibility to smoke-induced lung cancer. Despite functional evidence of a possible role of cytochrome P450 1A2 (CYP1A2) in lung cancer susceptibility, no studies have evaluated the influence of CYP1A2 genotypes on lung cancer risk. We investigated the interaction between CYP1A2-T2467delT (allele*1D) polymorphism and smoking in Tunisian lung cancer cases (n=101 male smokers) separately for the histological types squamous cell carcinoma (SCC) (n=60) and adenocarcinoma (n=41), and in controls (n=98 male smokers) using a case-only study design. A significant interaction between CYP1A2-T/delT or delT/delT genotypes and tobacco consumption (pack-years) adjusted for age was evident (OR (95% CI) 7.78 (1.52-42.8)) in the SCC cases who smoked relatively less (< or =33 pack-years, I quartile value), but not in adenocarcinoma and controls. Our results suggest that CYP1A2-T2467delT polymorphism has an important role in lung carcinogenesis, especially SCC, among smokers.

DelPhiPKa web server: predicting pKa of proteins, RNAs and DNAs.

PubMed

Wang, Lin; Zhang, Min; Alexov, Emil

2016-02-15

A new pKa prediction web server is released, which implements DelPhi Gaussian dielectric function to calculate electrostatic potentials generated by charges of biomolecules. Topology parameters are extended to include atomic information of nucleotides of RNA and DNA, which extends the capability of pKa calculations beyond proteins. The web server allows the end-user to protonate the biomolecule at particular pH based on calculated pKa values and provides the downloadable file in PQR format. Several tests are performed to benchmark the accuracy and speed of the protocol. The web server follows a client-server architecture built on PHP and HTML and utilizes DelPhiPKa program. The computation is performed on the Palmetto supercomputer cluster and results/download links are given back to the end-user via http protocol. The web server takes advantage of MPI parallel implementation in DelPhiPKa and can run a single job on up to 24 CPUs. The DelPhiPKa web server is available at http://compbio.clemson.edu/pka_webserver. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Pulmonary Function in a Diving Population Aged Over 40 Years Old: A Cross-Sectional Study

DTIC Science & Technology

2000-08-01

ADIVP -2 ALLIED GUIDE TO DIVING Fisiologia del ejercicio . la edicion. Madrid. MEDICAL DISORDERS. Publicacion Editorial Medica Panamericana S.A. 1995...activity. 13-5 12. LUCIA MULAS A. La ventilaci6n REFERENCES.- pulmonar durante el ejercicio . En L6pez Chicharro J. Fern-ndez Vaquero AX(eds.). 1...las pruebas de funci6n KK. Relation of alveolar size to forced vital pulmonar a la medicina del deporte. Tesis capacity in professional divers. Doctoral

Older Workers in the Market for Part-Time Employment. Appendices to PP 396.

DTIC Science & Technology

1983-09-01

Ehrenberg, R.G., Fringe Benefits and Overtime Behavior. Lexington, 1971. Levis, H. G., "Interes del Employeador en las Horas de Tobajo del Empleado...34 "The Employer Interest in Employees’ Hours of Work," Cuadernos de Economia , 18 (1969), pp. 38-54, summarized in Rosen, Harvey, reference below. Owen...just tangential to the g(h) function. The next question is: Which factors shift the optimum combination of h and c? C-I D * .k=* ~ .... LA A U..~..’ 4 g

Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia: Clinical and biologic correlations.

PubMed

Rigolin, Gian Matteo; del Giudice, Ilaria; Formigaro, Luca; Saccenti, Elena; Martinelli, Sara; Cavallari, Maurizio; Lista, Enrico; Tammiso, Elisa; Volta, Eleonora; Lupini, Laura; Bassi, Cristian; Bardi, Antonella; Sofritti, Olga; Daghia, Giulia; Cavazzini, Francesco; Marinelli, Marilisa; Tavolaro, Simona; Guarini, Anna; Negrini, Massimo; Foà, Robin; Cuneo, Antonio

2015-12-01

To clarify whether karyotype aberrations (KA) involving regions not covered by the standard fluorescence in situ hybridization (FISH) panel have independent prognostic relevance, we evaluated KA by conventional cytogenetics in a learning cohort (LC; n = 166) and a validation cohort (VC; n = 250) of untreated chronic lymphocytic leukemia (CLL) patients. In the VC, novel mitogens were used to improve metaphase generation and TP53, NOTCH1, and SF3B1 mutations were assessed. KA undetected by FISH were found in 35 and 35% of the cases in the LC and VC, respectively. In addition to FISH, KA allowed reclassification of 23 and 26% of cases in the LC and VC, respectively, into a higher cytogenetic risk group. By multivariate analysis, both in the LC and VC, KA other than isolated 13q deletion correlated with a shorter time to first treatment (TFT; P < 0.001 and 0.003, respectively), while a complex karyotype predicted a worse overall survival (OS, P = 0.015 and 0.010, respectively). In the VC, where a comprehensive biologic assessment was performed, a shorter TFT was also predicted by stage (P < 0.001), IGHV mutational status (P = 0.05), and del(17p)/TP53 mutations (P = 0.033) while stage (P = 0.023) and del(17p)/TP53 mutations (P = 0.024) independently predicted a shorter OS. FISH results did not independently impact on TFT and OS, in the LC and VC cohorts; this was also the case for NOTCH1 and SF3B1 mutations in the VC. We suggest that in CLL, conventional karyotyping with novel mitogens could be more effective than FISH for the detection of KA allowing for a more precise refinement of prognosis. © 2015 Wiley Periodicals, Inc.

Gap junction- and hemichannel-independent actions of connexins.

PubMed

Jiang, Jean X; Gu, Sumin

2005-06-10

Connexins have been known to be the protein building blocks of gap junctions and mediate cell-cell communication. In contrast to the conventional dogma, recent evidence suggests that in addition to forming gap junction channels, connexins possess gap junction-independent functions. One important gap junction-independent function for connexins is to serve as the major functional component for hemichannels, the un-apposed halves of gap junctions. Hemichannels, as independent functional units, play roles that are different from that of gap junctions in the cell. The other functions of connexins appear to be gap junction- and hemichannel-independent. Published studies implicate the latter functions of connexins in cell growth, differentiation, tumorigenicity, injury, and apoptosis, although the mechanistic aspects of these actions remain largely unknown. In this review, gap junction- and hemichannel-independent functions of connexins are summarized, and the molecular mechanisms underlying these connexin functions are speculated and discussed.

Tezacaftor/Ivacaftor in Subjects with Cystic Fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR.

PubMed

Donaldson, Scott H; Pilewski, Joseph M; Griese, Matthias; Cooke, Jon; Viswanathan, Lakshmi; Tullis, Elizabeth; Davies, Jane C; Lekstrom-Himes, Julie A; Wang, Linda T

2018-01-15

Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D. This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day). Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV 1 (ppFEV 1 ) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV 1 in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV 1 in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all). These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).

Polymorphism of the NFKB1 affects the serum inflammatory levels of IL-6 in Hashimoto thyroiditis in a Turkish population.

PubMed

Koc, Arzuhan; Batar, Bahadir; Celik, Ozlem; Onaran, Ilhan; Tasan, Ertugrul; Sultuybek, Gonul Kanigur

2014-07-01

Hashimoto thyroiditis (HT) is a chronic inflammatory autoimmune disease of thyroid gland affected by interaction of multiple genes and various cytokines. Variants in the genes coding for the NFKB and IKB proteins can be potentially involved in the development of the inflammatory diseases. NFKB, a key transcription factor of the regulation of immune responses, is interesting candidate for association studies about autoimmune disorder. The aim of the present study was to investigate the relationship between NFKB1 and NFKBIA (NFKB1 inhibitor gene) polymorphisms, and the risk of HT in a Turkish Population in the context of IL-6 serum levels which may contribute to susceptibility to the disease. We analyzed the distribution of NFKB1-94ins/del ATTG and NFKBIA 3'UTR A→G polymorphisms using PCR-RFLP method and IL-6 serum levels using ELISA method in 120 HT patients and 190 healthy controls in Turkish population. Although, there was no statistical significant difference in distribution of the genotypes and alleles of NFKB1-94ins/del ATTG or NFKBIA 3'UTR A→G polymorphisms in patients and control subjects as single, ins/ins/GG combined genotype had protective effect on the disease when compared to ins/ins/AG combined genotype as combined genotypes of both polymorphisms. In addition to this finding, IL-6 serum levels in HT patients with del/del genotype were significantly higher than in patients with del/ins genotype (p<0.001). According to the combined genotype analysis of NFKB1-94ins/del ATTG and NFKBIA 3'UTR A→G polymorphisms, IL-6 levels were also higher in patients with del/del genotype when at least one G allele existing (p=0.007). Therefore, our findings suggest that the functional promoter NFKB1-94ins/del ATTG polymorphism was significantly associated with population HT disease through acting by directly modulating IL-6 serum levels. Copyright © 2014 Elsevier GmbH. All rights reserved.

Command and Control of Guerrilla Groups in the Philippines, 1941-1945

DTIC Science & Technology

2017-05-25

However, the phasing concept in this case seems ex post facto , rather than descriptive of any initial design. Especially in its early days, the trajectory... post -independence era. They apply a framework that examines the environment, organization, tactics, doctrine, and technology of each phase of history...defenses on Mindanao and destroyed the bulk of Sharp’s force, though the command post at Del Monte remained intact.33 On May 9, Sharp met with a

Receiver Function Analyses of Uturuncu Volcano, Bolivia and Lastarria/Cordon Del Azufre Volcanoes, Chile

NASA Astrophysics Data System (ADS)

Mcfarlin, H. L.; Christensen, D. H.; Thompson, G.; McNutt, S. R.; Ryan, J. C.; Ward, K. M.; Zandt, G.; West, M. E.

2014-12-01

Uturuncu Volcano and a zone between Lastarria and Cordon del Azufre Volcanoes (also calledLazufre), have seen much attention lately because of significant and rapid inflation of one to twocentimeters per year over large areas. Uturuncu is located near the Bolivian-Chilean border, andLazufre is located near the Chilean-Argentine border. The PLUTONS Project deployed 28broadband seismic stations around Uturuncu Volcano, from April 2009 to Octobor 2012, and alsodeployed 9 stations around Lastarria and Cordon del Azufre volcanoes, from November, 2011 toApril 2013. Teleseismic receiver functions were generated using the time-domain iterativedeconvolution algorithm of Ligorria and Ammon (1999) for each volcanic area. These receiverfunctions were used to better constrain the depths of magma bodies under Uturuncu and Lazufre,as well as the ultra low velocity layer within the Altiplano-Puna Magma Body (APMB). Thelow velocity zone under Uturuncu is shown to have a top around 10 km depth b.s.l and isgenerally around 20 km thick with regional variations. Tomographic inversion shows a well resolved,near vertical, high Vp/Vs anomaly directly beneath Uturuncu that correlates well with adisruption in the receiver function results; which is inferred to be a magmatic intrusion causing alocal thickening of the APMB. Preliminary results at Lazufre show the top of a low velocityzone around 5-10 km b.s.l with a thickness of 15-30 km.

Whole Genome Re-Sequencing and Characterization of Powdery Mildew Disease-Associated Allelic Variation in Melon.

PubMed

Natarajan, Sathishkumar; Kim, Hoy-Taek; Thamilarasan, Senthil Kumar; Veerappan, Karpagam; Park, Jong-In; Nou, Ill-Sup

2016-01-01

Powdery mildew is one of the most common fungal diseases in the world. This disease frequently affects melon (Cucumis melo L.) and other Cucurbitaceous family crops in both open field and greenhouse cultivation. One of the goals of genomics is to identify the polymorphic loci responsible for variation in phenotypic traits. In this study, powdery mildew disease assessment scores were calculated for four melon accessions, 'SCNU1154', 'Edisto47', 'MR-1', and 'PMR5'. To investigate the genetic variation of these accessions, whole genome re-sequencing using the Illumina HiSeq 2000 platform was performed. A total of 754,759,704 quality-filtered reads were generated, with an average of 82.64% coverage relative to the reference genome. Comparisons of the sequences for the melon accessions revealed around 7.4 million single nucleotide polymorphisms (SNPs), 1.9 million InDels, and 182,398 putative structural variations (SVs). Functional enrichment analysis of detected variations classified them into biological process, cellular component and molecular function categories. Further, a disease-associated QTL map was constructed for 390 SNPs and 45 InDels identified as related to defense-response genes. Among them 112 SNPs and 12 InDels were observed in powdery mildew responsive chromosomes. Accordingly, this whole genome re-sequencing study identified SNPs and InDels associated with defense genes that will serve as candidate polymorphisms in the search for sources of resistance against powdery mildew disease and could accelerate marker-assisted breeding in melon.

[Independent ethics committees for clinical research in Argentina. An evaluation and a system to guarantee their independence].

PubMed

Gonorazky, Sergio E

2008-01-01

The Administración Nacional de Medicamentos, Alimentos y Tecnología Médica de la República Argentina (ANMAT) requires that an independent ethics committee of sponsors and/or researchers must previously evaluate and approve all the new pharmacological research protocols carried out on human beings. However, due to the lucrative nature of the evaluation, and because the selection of the Independent Ethics Committee is carried out by the sponsors and/or researchers, the assumed autonomy of the former can be reduced to merely a relationship of "service provider-customer". The Institutional Review Board of the Mar del Plata s Community Hospital has evaluated, between 2005 and 2006, thirty three research protocols (with their corresponding information sheets for patients and informed consent forms) previously approved by a non-institutional Independent Ethics Committee. The median number of objections made by the Institutional Review Board, which prompted the previously mentioned protocols to be modified in order to be approved, was of three per protocol. In other words, the accreditation of an Independent Ethics Committee requires a system that guarantees actual independence from the sponsors and/or researchers, as well as management control mechanisms that may lead them into an eventual loss of accreditation. Several measures are proposed in order to correct the deficiencies of the present system.

Factors associated with poor sleep quality in women with cancer.

PubMed

Mansano-Schlosser, Thalyta Cristina; Ceolim, Maria Filomena

2017-03-02

to analyze the factors associated with poor sleep quality, its characteristics and components in women with breast cancer prior to surgery for removing the tumor and throughout the follow-up. longitudinal study in a teaching hospital, with a sample of 102 women. The following were used: a questionnaire for sociodemographic and clinical characterization, the Pittsburgh Sleep Quality Index; the Beck Depression Inventory; and the Herth Hope Scale. Data collection covered from prior to the surgery for removal of the tumor (T0) to T1, on average 3.2 months; T2, on average 6.1 months; and T3, on average 12.4 months. Descriptive statistics and the Generalized Estimating Equations model were used. depression and pain contributed to the increase in the score of the Pittsburgh Sleep Quality Index, and hope, to the reduction of the score - independently - throughout follow-up. Sleep disturbances were the component with the highest score throughout follow-up. the presence of depression and pain, prior to the surgery, contributed to the increase in the global score of the Pittsburgh Sleep Quality Index, which indicates worse quality of sleep throughout follow-up; greater hope, in its turn, influenced the reduction of the score of the Pittsburgh Sleep Quality Index. analizar los factores asociados a la mala calidad del sueño, sus características y componentes en mujeres con cáncer de mama, antes de la cirugía de retirada del tumor y a lo largo del seguimiento. estudio longitudinal, en hospital universitario con muestra de 102 mujeres. Fueron utilizados: un cuestionario de caracterización sociodemográfica y clínica; el Índice de Calidad del Sueño de Pittsburgh; el Inventario de Depresión de Beck; y la Escala de Esperanza de Herth. La recolección comprendió los momentos: antes de la cirugía de retirada del tumor (T0), en (T1) en promedio 3,2 meses, en (T2) en promedio 6,1 meses y en (T3) en promedio 12,4 meses. Se utilizó estadística descriptiva y el modelo de Ecuaciones de Estimación Generalizada. la depresión y el dolor contribuyeron para el aumento del puntaje del Índice de Calidad del Sueño de Pittsburgh y la esperanza para la reducción del puntaje, de manera independiente, a lo largo del seguimiento. Los trastornos del sueño fueron el componente con puntuación más elevada, a lo largo del seguimiento. la presencia de la depresión y del dolor, previos a la cirugía, contribuyeron para el aumento del puntaje global del Índice de Calidad del Sueño de Pittsburgh, lo que indica peor calidad del sueño, a lo largo del seguimiento y, la mayor esperanza, a su vez, influenció en la reducción del puntaje del Índice de Calidad del Sueño de Pittsburgh. analisar os fatores associados à má qualidade do sono, suas características e componentes em mulheres com câncer de mama antes da cirurgia de retirada do tumor e ao longo do seguimento. estudo longitudinal, em hospital universitário com amostra de 102 mulheres. Foram utilizados: questionário de caracterização sociodemográfica e clínica, Índice de Qualidade do Sono de Pittsburgh; Inventário de Depressão de Beck; Escala de Esperança de Herth. Coleta compreendeu antes da cirurgia de retirada do tumor (T0) em T1, em média 3,2 meses; T2, em média 6,1 meses; T3, em média 12,4 meses. Utilizou-se estatística descritiva e o modelo de Equações de Estimação Generalizada. a depressão e a dor contribuíram para o aumento do escore do Índice de Qualidade de Sono de Pittsburgh, e a esperança, para a redução do escore, de maneira independente, ao longo do seguimento. Os transtornos do sono foram o componente com pontuação mais elevada, ao longo do seguimento. a presença de depressão e de dor, previamente à cirurgia, contribuiu para o aumento do escore global do Índice de Qualidade do Sono de Pittsburgh, o que indica pior qualidade do sono, ao longo do seguimento e, a maior esperança, por sua vez, influenciou na redução do escore do Índice de Qualidade do Sono de Pittsburgh.

Potential forensic use of a 33 X-InDel panel in the Argentinean population.

PubMed

Caputo, Mariela; Amador, M A; Santos, S; Corach, D

2017-01-01

Polymorphic genetic markers located on the X chromosome might become a complement in particular forensic identification when the biological kinship are deficient. We analyzed forensic statistical parameters of 33 X-chromosome InDel polymorphisms in a sample of 320 individuals from Argentina. The X-chromosome InDel polymorphism (X-InDel) panel was amplified in a single multiplex PCR reaction. Hardy-Weinberg Equilibrium was determined in the female cohort, whereas the male cohort was used to calculate linkage disequilibrium (LD) tested by an extension of Fisher's exact test, D', and Chi-square values. Regarding LD, 15 markers were organized and grouped into six blocks containing two or three linked loci each, namely block I (MID356-MID357), block II (MID448804-MID3703-MID218), block III (MID3705-MID3706-MID304737), block IV (MID197147-MID3754), block V (MID3664-MID284601-MID103547), and block VI (MID3763-MID3728). The haplotype diversity was higher than 0.99 in all cases. Blocks III and VI showed the highest match probability in the studied population, whereas block II showed the lowest. The accumulated power of discrimination was 99.9999991 % in women and 99.9992925 % in men. The mean exclusion chance in trios and duos were 99.9891736 and 99.6099391 %, respectively. Since 15 markers are associated as haplotypic blocks, for a conservative treatment of the data, statistical evaluation should consider their haplotypic frequencies and the remaining 18 markers can be evaluated as independent loci.

Developmental validation of an X-Insertion/Deletion polymorphism panel and application in HAN population of China.

PubMed

Zhang, Suhua; Sun, Kuan; Bian, Yingnan; Zhao, Qi; Wang, Zheng; Ji, Chaoneng; Li, Chengtao

2015-12-14

InDels are short-length polymorphisms characterized by low mutation rates, high inter-population diversity, short amplicon strategy and simplicity of laboratory analysis. This work describes the developmental validation of an X-InDels panel amplifying 18 bi-allelic markers and Amelogenin in one single PCR system. Developmental validation indicated that this novel panel was reproducible, accurate, sensitive and robust for forensic application. Sensitivity testing of the panel was such that a full profile was obtainable even with 125 pg of human DNA with intra-locus balance above 70%. Specificity testing was demonstrated by the lack of cross-reactivity with a variety of commonly encountered animal species and microorganisms. For the stability testing in cases of PCR inhibition, full profiles have been obtained with hematin (≤1000 μM) and humic acid (≤150 ng/μL). For the forensic investigation of the 18 X-InDels in the HAN population of China, no locus deviated from the Hardy-Weinberg equilibrium and linkage disequilibrium. Since they are independent from each other, the CDPfemale was 0.999999726 and CDPmale was 0.999934223. The forensic parameters suggested that this X-Indel panel is polymorphic and informative, which provides valuable X-linked information for deficient relationship cases where autosomal markers are uninformative.

Developmental validation of an X-Insertion/Deletion polymorphism panel and application in HAN population of China

PubMed Central

Zhang, Suhua; Sun, Kuan; Bian, Yingnan; Zhao, Qi; Wang, Zheng; Ji, Chaoneng; Li, Chengtao

2015-01-01

InDels are short-length polymorphisms characterized by low mutation rates, high inter-population diversity, short amplicon strategy and simplicity of laboratory analysis. This work describes the developmental validation of an X-InDels panel amplifying 18 bi-allelic markers and Amelogenin in one single PCR system. Developmental validation indicated that this novel panel was reproducible, accurate, sensitive and robust for forensic application. Sensitivity testing of the panel was such that a full profile was obtainable even with 125 pg of human DNA with intra-locus balance above 70%. Specificity testing was demonstrated by the lack of cross-reactivity with a variety of commonly encountered animal species and microorganisms. For the stability testing in cases of PCR inhibition, full profiles have been obtained with hematin (≤1000 μM) and humic acid (≤150 ng/μL). For the forensic investigation of the 18 X-InDels in the HAN population of China, no locus deviated from the Hardy–Weinberg equilibrium and linkage disequilibrium. Since they are independent from each other, the CDPfemale was 0.999999726 and CDPmale was 0.999934223. The forensic parameters suggested that this X-Indel panel is polymorphic and informative, which provides valuable X-linked information for deficient relationship cases where autosomal markers are uninformative. PMID:26655948

A DFT study on surface-enhanced Raman spectroscopy of aromatic dithiol derivatives adsorbed on gold nanojunctions

NASA Astrophysics Data System (ADS)

You, Tingting; Lang, Xiufeng; Huang, Anping; Yin, Penggang

2018-01-01

A computational study on aromatic dithiol derivatives (HS-Ar-X-Ar-SH, X = O, S, Se, NH, CH2, Ndbnd N, CHdbnd CH, Ctbnd C) interacting with gold cluster(s) was presented to investigate the chemical enhancement mechanism related to surface-enhanced Raman spectroscopy (SERS) for molecular junctions. Density functional theory (DFT) were performed on derivatives molecules as well as their single-end-linked (SEL) or double-end-linked (DEL) complexes for geometric, spectra, electronic and excitation properties, leading to discussions on dominant factor during SERS process. The resulted enhancement factors of SEL and DEL complexes exhibited specific dependency on linking atom or functional group between two phenyls, which was in accordance with the variation of polarizabilities and molecule-cluster transition energy.

Educacion Bilingue: Una Declaraccion del Plan y Accion que Proponen los Regentes de la Universidad del Estado de Nueva York. Bilingual Education: A Statement of Policy and Proposed Action by the Regents of the University of the State of New York. Position Paper No. 16.

ERIC Educational Resources Information Center

New York State Education Dept., Albany.

Large numbers of Puerto Rican and other non-English-speaking students live in school districts throughout New York State. To enable these students to function in an English-speaking society while retaining their own culture, a policy to promote bilingual program planning was established by the Board of Regents of New York State in 1972. In this…

Targeting the Kinase-Independent Pro-survival Function of EGFR in Prostate Cancer

DTIC Science & Technology

2013-06-01

AD AWARD NUMBER: W81XWH-09-1-0343 TITLE: Targeting the Kinase-Independent Pro -survival Function of EGFR in Prostate Cancer...SUBTITLE Targeting the Kinase-Independent, Pro -survival Function of EGFR in Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-09-1...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The proposed study, targeting the kinase independent pro -survival function of EGFR in prostate

Small heat shock proteins target mutant cystic fibrosis transmembrane conductance regulator for degradation via a small ubiquitin-like modifier–dependent pathway

PubMed Central

Ahner, Annette; Gong, Xiaoyan; Schmidt, Bela Z.; Peters, Kathryn W.; Rabeh, Wael M.; Thibodeau, Patrick H.; Lukacs, Gergely L.; Frizzell, Raymond A.

2013-01-01

Small heat shock proteins (sHsps) bind destabilized proteins during cell stress and disease, but their physiological functions are less clear. We evaluated the impact of Hsp27, an sHsp expressed in airway epithelial cells, on the common protein misfolding mutant that is responsible for most cystic fibrosis. F508del cystic fibrosis transmembrane conductance regulator (CFTR), a well-studied protein that is subject to cytosolic quality control, selectively associated with Hsp27, whose overexpression preferentially targeted mutant CFTR to proteasomal degradation. Hsp27 interacted physically with Ubc9, the small ubiquitin-like modifier (SUMO) E2 conjugating enzyme, implying that F508del SUMOylation leads to its sHsp-mediated degradation. Enhancing or disabling the SUMO pathway increased or blocked Hsp27’s ability to degrade mutant CFTR. Hsp27 promoted selective SUMOylation of F508del NBD1 in vitro and of full-length F508del CFTR in vivo, which preferred endogenous SUMO-2/3 paralogues that form poly-chains. The SUMO-targeted ubiquitin ligase (STUbL) RNF4 recognizes poly-SUMO chains to facilitate nuclear protein degradation. RNF4 overexpression elicited F508del degradation, whereas Hsp27 knockdown blocked RNF4’s impact on mutant CFTR. Similarly, the ability of Hsp27 to degrade F508del CFTR was lost during overexpression of dominant-negative RNF4. These findings link sHsp-mediated F508del CFTR degradation to its SUMOylation and to STUbL-mediated targeting to the ubiquitin–proteasome system and thereby implicate this pathway in the disposal of an integral membrane protein. PMID:23155000

A Framework for Improving Integrative Factors in C3I Systems of the Argentine Army

DTIC Science & Technology

1991-03-01

and installed without regard to system integration or interoperability. The SIIFE Project (Sistema Informdtico Integrado de la Fuerza Ej~rcito) was the...de la Fuerza Ej~rcito). At the same time, a secure and independent system for the intelligence area was also developed. In the 1980s, the development...Comando v Control Para las Tropas del Ei~rcito, Buenos Aires, September 1989. 38. Levine, Judith, "Networking for Desert Shield," Communica tions Week

Low free drug concentration prevents inhibition of F508del CFTR functional expression by the potentiator VX-770 (ivacaftor).

PubMed

Matthes, Elizabeth; Goepp, Julie; Carlile, Graeme W; Luo, Yishan; Dejgaard, Kurt; Billet, Arnaud; Robert, Renaud; Thomas, David Y; Hanrahan, John W

2016-02-01

The most common cystic fibrosis (CF) mutation F508del inhibits the gating and surface expression of CFTR, a plasma membrane anion channel. Optimal pharmacotherapies will probably require both a 'potentiator' to increase channel open probability and a 'corrector' that improves folding and trafficking of the mutant protein and its stability at the cell surface. Interaction between CF drugs has been reported but remains poorly understood. CF bronchial epithelial cells were exposed to the corrector VX-809 (lumacaftor) and potentiator VX-770 (ivacaftor) individually or in combination. Functional expression of CFTR was assayed as the forskolin-stimulated short-circuit current (Isc ) across airway epithelial monolayers expressing F508del CFTR. The potentiated Isc response during forskolin stimulation was increased sixfold after pretreatment with VX-809 alone and reached ~11% that measured across non-CF monolayers. VX-770 (100 nM) and genistein (50 μM) caused similar levels of potentiation, which were not additive and were abolished by the CFTR inhibitor CFTRinh -172. The unbound fraction of VX-770 in plasma was 0.13 ± 0.04%, which together with previous measurements in patients given 250 mg p.o. twice daily, suggests a peak free plasma concentration of 1.5-8.5 nM. Chronic exposure to high VX-770 concentrations (>1 μM) inhibited functional correction by VX-809 but not in the presence of physiological protein levels (20-40 mg·mL(-1) ). Chronic exposure to a low concentration of VX-770 (100 nM) together with VX-809 (1 μM) also did not reduce the forskolin-stimulated Isc , relative to cells chronically exposed to VX-809 alone, provided it was assayed acutely using the same, clinically relevant concentration of potentiator. Chronic exposure to clinically relevant concentrations of VX-770 did not reduce F508del CFTR function. Therapeutic benefit of VX-770 + VX-809 (Orkambi) is probably limited by the efficacy of VX-809 rather than by inhibition by VX-770. © 2015 The British Pharmacological Society.

[Mutation analysis of seven patients with Waardenburg syndrome].

PubMed

Hao, Ziqi; Zhou, Yongan; Li, Pengli; Zhang, Quanbin; Li, Jiao; Wang, Pengfei; Li, Xiangshao; Feng, Yong

2016-06-01

To perform genetic analysis for 7 patients with Waardenburg syndrome. Potential mutation of MITF, PAX3, SOX10 and SNAI2 genes was screened by polymerase chain reaction and direct sequencing. Functions of non-synonymous polymorphisms were predicted with PolyPhen2 software. Seven mutations, including c.649-651delAGA (p.R217del), c.72delG (p.G24fs), c.185T>C (p.M62T), c.118C>T (p.Q40X), c.422T>C (p.L141P), c.640C>T (p.R214X) and c.28G>T(p.G43V), were detected in the patients. Among these, four mutations of the PAX3 gene (c.72delG, c.185T>C, c.118C>T and c.128G>T) and one SOX10 gene mutation (c.422T>C) were not reported previously. Three non-synonymous SNPs (c.185T>C, c.128G>T and c.422T>C) were predicted as harmful. Genetic mutations have been detected in all patients with Waardenburg syndrome.

Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese.

PubMed

Huang, Dongsheng; Yang, Lei; Liu, Yehua; Zhou, Yumin; Guo, Yuan; Pan, Mingan; Wang, Yunnan; Tan, Yigang; Zhong, Haibo; Hu, Min; Lu, Wenju; Ji, Weidong; Wang, Jian; Ran, Pixin; Zhong, Nanshan; Zhou, Yifeng; Lu, Jiachun

2013-04-01

Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: -94del>insATTG; NFκB2: -2966G>A; IκBα: -826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the -94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95% CI 1.06-1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95% CI 1.30-1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the -94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for -2966G>A and -826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (-94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.

Pío del Río Hortega and the discovery of the oligodendrocytes

PubMed Central

Pérez-Cerdá, Fernando; Sánchez-Gómez, María Victoria; Matute, Carlos

2015-01-01

Pío del Río Hortega (1882–1945) discovered microglia and oligodendrocytes (OLGs), and after Ramón y Cajal, was the most prominent figure of the Spanish school of neurology. He began his scientific career with Nicolás Achúcarro from whom he learned the use of metallic impregnation techniques suitable to study non-neuronal cells. Later on, he joined Cajal’s laboratory. and Subsequently, he created his own group, where he continued to develop other innovative modifications of silver staining methods that revolutionized the study of glial cells a century ago. He was also interested in neuropathology and became a leading authority on Central Nervous System (CNS) tumors. In parallel to this clinical activity, del Río Hortega rendered the first systematic description of a major polymorphism present in a subtype of macroglial cells that he named as oligodendroglia and later OLGs. He established their ectodermal origin and suggested that they built the myelin sheath of CNS axons, just as Schwann cells did in the periphery. Notably, he also suggested the trophic role of OLGs for neuronal functionality, an idea that has been substantiated in the last few years. Del Río Hortega became internationally recognized and established an important neurohistological school with outstanding pupils from Spain and abroad, which nearly disappeared after his exile due to the Spanish civil war. Yet, the difficulty of metal impregnation methods and their variability in results, delayed for some decades the confirmation of his great insights into oligodendrocyte biology until the development of electron microscopy and immunohistochemistry. This review aims at summarizing the pioneer and essential contributions of del Río Hortega to the current knowledge of oligodendrocyte structure and function, and to provide a hint of the scientific personality of this extraordinary and insufficiently recognized man. PMID:26217196

Using evidence on violence and injury prevention for policy development and decision making in Ciudad Juarez, Mexico.

PubMed

Gutiérrez, Luis Alberto; Pacheco, Sergio; Juárez, Alethia Yurithzi; Palacios, Luis Alexandro; Cerqueira, Maria Teresa

2012-05-01

This report describes the implementation process and functional structure of the Observatory of Security and Citizen Conviviality of the Juarez Municipality (Observatorio de Seguridad y Convivencia Ciudadanas del Municipio de Juárez) in Chihuahua, Mexico, and discusses the most relevant lessons learned and main challenges in the near future. The Observatory, created in 2008, is a joint effort of the Juarez Municipal Government, Autonomous University of Ciudad Juarez (Universidad Autónoma de Ciudad Juárez), and the Pan American Health Organization. The Observatory's main objective is to propose strategies and public policy recommendations to prevent and control violence and injuries in the Juarez Municipality. Most key federal, state, and local agencies have joined this independent autonomous citizen-based initiative, feed the databases, and benefit from the information produced by a multisectoral, multidisciplinary approach. The Observatory contributes far more than the technical data provided and its facilitating functions. The clear results obtained in such a short time-as seen in the preliminary results of the case study on road injuries from January 2009 to July 2011-demonstrate the appropriateness of this course of action and should stimulate the creation of new observatories whenever and wherever needed. Lessons learned, as discussed here, can open the way to new endeavors, and current challenges show how much work remains to be done.

How Disabling Are Pediatric Burns? Functional Independence in Dutch Pediatric Patients with Burns

ERIC Educational Resources Information Center

Disseldorp, Laurien M.; Niemeijer, Anuschka S.; Van Baar, Margriet E.; Reinders-Messelink, Heleen A.; Mouton, Leonora J.; Nieuwenhuis, Marianne K.

2013-01-01

Although the attention for functional outcomes after burn injury has grown over the past decades, little is known about functional independence in performing activities of daily living in children after burn injury. Therefore, in this prospective cohort study functional independence was measured by burn care professionals with the WeeFIM[R]…

First results from the DarkSide-50 dark matter experiment at Laboratori Nazionali del Gran Sasso

NASA Astrophysics Data System (ADS)

Agnes, P.; Alexander, T.; Alton, A.; Arisaka, K.; Back, H. O.; Baldin, B.; Biery, K.; Bonfini, G.; Bossa, M.; Brigatti, A.; Brodsky, J.; Budano, F.; Cadonati, L.; Calaprice, F.; Canci, N.; Candela, A.; Cao, H.; Cariello, M.; Cavalcante, P.; Chavarria, A.; Chepurnov, A.; Cocco, A. G.; Crippa, L.; D'Angelo, D.; D'Incecco, M.; Davini, S.; De Deo, M.; Derbin, A.; Devoto, A.; Di Eusanio, F.; Di Pietro, G.; Edkins, E.; Empl, A.; Fan, A.; Fiorillo, G.; Fomenko, K.; Forster, G.; Franco, D.; Gabriele, F.; Galbiati, C.; Goretti, A.; Grandi, L.; Gromov, M.; Guan, M. Y.; Guardincerri, Y.; Hackett, B.; Herner, K.; Hungerford, E. V.; Ianni, Al.; Ianni, An.; Jollet, C.; Keeter, K.; Kendziora, C.; Kidner, S.; Kobychev, V.; Koh, G.; Korablev, D.; Korga, G.; Kurlej, A.; Li, P. X.; Loer, B.; Lombardi, P.; Love, C.; Ludhova, L.; Luitz, S.; Ma, Y. Q.; Machulin, I.; Mandarano, A.; Mari, S.; Maricic, J.; Marini, L.; Martoff, C. J.; Meregaglia, A.; Meroni, E.; Meyers, P. D.; Milincic, R.; Montanari, D.; Monte, A.; Montuschi, M.; Monzani, M. E.; Mosteiro, P.; Mount, B.; Muratova, V.; Musico, P.; Nelson, A.; Odrowski, S.; Okounkova, M.; Orsini, M.; Ortica, F.; Pagani, L.; Pallavicini, M.; Pantic, E.; Papp, L.; Parmeggiano, S.; Parsells, R.; Pelczar, K.; Pelliccia, N.; Perasso, S.; Pocar, A.; Pordes, S.; Pugachev, D.; Qian, H.; Randle, K.; Ranucci, G.; Razeto, A.; Reinhold, B.; Renshaw, A.; Romani, A.; Rossi, B.; Rossi, N.; Rountree, S. D.; Sablone, D.; Saggese, P.; Saldanha, R.; Sands, W.; Sangiorgio, S.; Segreto, E.; Semenov, D.; Shields, E.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Stanford, C.; Suvorov, Y.; Tartaglia, R.; Tatarowicz, J.; Testera, G.; Tonazzo, A.; Unzhakov, E.; Vogelaar, R. B.; Wada, M.; Walker, S.; Wang, H.; Wang, Y.; Watson, A.; Westerdale, S.; Wojcik, M.; Wright, A.; Xiang, X.; Xu, J.; Yang, C. G.; Yoo, J.; Zavatarelli, S.; Zec, A.; Zhu, C.; Zuzel, G.

2015-04-01

We report the first results of DarkSide-50, a direct search for dark matter operating in the underground Laboratori Nazionali del Gran Sasso (LNGS) and searching for the rare nuclear recoils possibly induced by weakly interacting massive particles (WIMPs). The dark matter detector is a Liquid Argon Time Projection Chamber with a (46.4 ± 0.7) kg active mass, operated inside a 30 t organic liquid scintillator neutron veto, which is in turn installed at the center of a 1 kt water Cherenkov veto for the residual flux of cosmic rays. We report here the null results of a dark matter search for a (1422 ± 67) kgd exposure with an atmospheric argon fill. This is the most sensitive dark matter search performed with an argon target, corresponding to a 90% CL upper limit on the WIMP-nucleon spin-independent cross section of 6.1 ×10-44 cm2 for a WIMP mass of 100 Gev /c2.

Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer.

PubMed

Chen, Ina; Mathews-Greiner, Lesley; Li, Dandan; Abisoye-Ogunniyan, Abisola; Ray, Satyajit; Bian, Yansong; Shukla, Vivek; Zhang, Xiaohu; Guha, Raj; Thomas, Craig; Gryder, Berkley; Zacharia, Athina; Beane, Joal D; Ravichandran, Sarangan; Ferrer, Marc; Rudloff, Udo

2017-05-01

Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease. In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells. Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function. Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.

Vitamin K status in cystic fibrosis patients with liver cirrhosis.

PubMed

Krzyżanowska, Patrycja; Drzymała-Czyż, Sławomira; Pogorzelski, Andrzej; Duś-Żuchowska, Monika; Skorupa, Wojciech; Bober, Lyudmyla; Sapiejka, Ewa; Oralewska, Beata; Rohovyk, Nataliya; Moczko, Jerzy; Nowak, Jan; Wenska-Chyży, Ewa; Rachel, Marta; Lisowska, Aleksandra; Walkowiak, Jarosław

2017-06-01

The available data on the influence of liver cirrhosis on vitamin K status in CF patients is scarce. Therefore, the aims of the present study were to assess the prevalence of vitamin K deficiency in cirrhotic CF subjects and to determine whether it correlates with liver cirrhosis. The study group comprised of 27 CF patients with and 63 without liver cirrhosis. Vitamin K status was assessed using prothrombin induced by vitamin K absence (PIVKA-II) and the percentage of undercarboxylated osteocalcin (u-OC). PIVKA-II concentrations were higher in cirrhotic than in non-cirrhotic CF patients (median [1st-3rd quartile]: 3.2ng/ml [1.0-10.0] vs. 1.3ng/ml [0.2-2.6], p=0.0029). However, the differences in u-OC percentages between the studied groups did not reach the level of significance (49.4% [7.0-73.8] vs. 8.0% [2.6-59.1], p=0.0501). Based on multiple linear regression analysis the dose of vitamin K and F508del mutation were potentially defined as determinants of vitamin K deficiency. Liver cirrhosis was not documented to be an independent risk factor. In CF patients with liver cirrhosis vitamin K deficiency is not only more frequent, but also more severe. However, not liver cirrhosis, but the presence of a F508del CFTR mutation constitutes an independent risk factor for vitamin K deficiency. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

PDK4 Deficiency Induces Intrinsic Apoptosis in Response to Starvation in Fibroblasts from Doberman Pinschers with Dilated Cardiomyopathy.

PubMed

Taggart, Kathryn; Estrada, Amara; Thompson, Patrick; Lourenco, Francisco; Kirmani, Sara; Suzuki-Hatano, Silveli; Pacak, Christina A

2017-01-01

The Doberman pinscher (DP) canine breed displays a high incidence of idiopathic, nonischemic dilated cardiomyopathy (DCM) with increased mortality. A common mutation in DPs is a splice site deletion in the pyruvate dehydrogenase kinase 4 (PDK4) gene that shows a positive correlation with DCM development. PDK4, a vital mitochondrial protein, controls the switch between glycolysis and oxidative phosphorylation based upon nutrient availability. It is likely, although unproven, that DPs with the PDK4 mutation are unable to switch to oxidative phosphorylation during periods of low nutrient availability, and thus are highly susceptible to mitochondrial-mediated apoptosis. This study investigated cell viability, mitochondrial stress, and activation of the intrinsic (mitochondrial mediated) apoptotic pathway in dermal fibroblasts from DPs that were healthy (PDK4 wt/wt ), heterozygous (PDK4 wt/del ), and homozygous (PDK4 del/del ) for the PDK4 mutation under conditions of high (unstarved) and low (starved) nutrient availability in vitro . As hypothesized, PDK4 wt/del and PDK4 del/del cells showed evidence of mitochondrial stress and activation of the intrinsic apoptotic pathway following starvation, while the PDK4 wt/wt cells remained healthy and viable under these conditions. Adeno-associated virus (AAV) PDK4-mediated gene replacement experiments confirmed cause-effect relationships between PDK4 deficiency and apoptosis activation. The restoration of function observed following administration of AAV-PDK4 provides strong support for the translation of this gene therapy approach into the clinical realm for PDK4-affected Dobermans.

Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo.

PubMed

Woll, Petter S; Kjällquist, Una; Chowdhury, Onima; Doolittle, Helen; Wedge, David C; Thongjuea, Supat; Erlandsson, Rikard; Ngara, Mtakai; Anderson, Kristina; Deng, Qiaolin; Mead, Adam J; Stenson, Laura; Giustacchini, Alice; Duarte, Sara; Giannoulatou, Eleni; Taylor, Stephen; Karimi, Mohsen; Scharenberg, Christian; Mortera-Blanco, Teresa; Macaulay, Iain C; Clark, Sally-Ann; Dybedal, Ingunn; Josefsen, Dag; Fenaux, Pierre; Hokland, Peter; Holm, Mette S; Cazzola, Mario; Malcovati, Luca; Tauro, Sudhir; Bowen, David; Boultwood, Jacqueline; Pellagatti, Andrea; Pimanda, John E; Unnikrishnan, Ashwin; Vyas, Paresh; Göhring, Gudrun; Schlegelberger, Brigitte; Tobiasson, Magnus; Kvalheim, Gunnar; Constantinescu, Stefan N; Nerlov, Claus; Nilsson, Lars; Campbell, Peter J; Sandberg, Rickard; Papaemmanuil, Elli; Hellström-Lindberg, Eva; Linnarsson, Sten; Jacobsen, Sten Eirik W

2014-06-16

Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation. Copyright © 2014 Elsevier Inc. All rights reserved.

Tuning the Two-Dimensional Electron Liquid at Oxide Interfaces by Buffer-Layer-Engineered Redox Reactions.

PubMed

Chen, Yunzhong; Green, Robert J; Sutarto, Ronny; He, Feizhou; Linderoth, Søren; Sawatzky, George A; Pryds, Nini

2017-11-08

Polar discontinuities and redox reactions provide alternative paths to create two-dimensional electron liquids (2DELs) at oxide interfaces. Herein, we report high mobility 2DELs at interfaces involving SrTiO 3 (STO) achieved using polar La 7/8 Sr 1/8 MnO 3 (LSMO) buffer layers to manipulate both polarities and redox reactions from disordered overlayers grown at room temperature. Using resonant X-ray reflectometry experiments, we quantify redox reactions from oxide overlayers on STO as well as polarity induced electronic reconstruction at epitaxial LSMO/STO interfaces. The analysis reveals how these effects can be combined in a STO/LSMO/disordered film trilayer system to yield high mobility modulation doped 2DELs, where the buffer layer undergoes a partial transformation from perovskite to brownmillerite structure. This uncovered interplay between polar discontinuities and redox reactions via buffer layers provides a new approach for the design of functional oxide interfaces.

Characterization of nasal potential difference in cftr knockout and F508del-CFTR mice.

PubMed

Saussereau, Emilie Lyne; Roussel, Delphine; Diallo, Siradiou; Debarbieux, Laurent; Edelman, Aleksander; Sermet-Gaudelus, Isabelle

2013-01-01

Treatments designed to correct cystic fibrosis transmembrane conductance regulator (CFTR) defects must first be evaluated in preclinical experiments in the mouse model of cystic fibrosis (CF). Mice nasal mucosa mimics the bioelectric defect seen in humans. The use of nasal potential difference (V(TE)) to assess ionic transport is a powerful test evaluating the restoration of CFTR function. Nasal V(TE) in CF mice must be well characterized for correct interpretation. We performed V(TE) measurements in large-scale studies of two mouse models of CF--B6;129 cftr knockout and FVB F508del-CFTR--and their respective wild-type (WT) littermates. We assessed the repeatability of the test for cftr knockout mice and defined cutoff points distinguishing between WT and F508del-CFTR mice. We determined the typical V(TE) values for CF and WT mice and demonstrated the existence of residual CFTR activity in F508del-CFTR mice. We characterized intra-animal variability in B6;129 mice and defined the cutoff points for F508del-CFTR chloride secretion rescue. Hyperpolarization of more than -2.15 mV after perfusion with a low-concentration Cl(-) solution was considered to indicate a normal response. These data will make it possible to interpret changes in nasal V(TE) in mouse models of CF, in future preclinical studies.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schürpf, Thomas; Chen, Qiang; Liu, Jin-huan

Developmental endothelial cell locus-1 (Del-1) glycoprotein is secreted by endothelial cells and a subset of macrophages. Del-1 plays a regulatory role in vascular remodeling and functions in innate immunity through interaction with integrin {alpha}{sub V}{beta}{sub 3}. Del-1 contains 3 epidermal growth factor (EGF)-like repeats and 2 discoidin-like domains. An Arg-Gly-Asp (RGD) motif in the second EGF domain (EGF2) mediates adhesion by endothelial cells and phagocytes. We report the crystal structure of its 3 EGF domains. The RGD motif of EGF2 forms a type II' {beta} turn at the tip of a long protruding loop, dubbed the RGD finger. Whereas EGF2more » and EGF3 constitute a rigid rod via an interdomain calcium ion binding site, the long linker between EGF1 and EGF2 lends considerable flexibility to EGF1. Two unique O-linked glycans and 1 N-linked glycan locate to the opposite side of EGF2 from the RGD motif. These structural features favor integrin binding of the RGD finger. Mutagenesis data confirm the importance of having the RGD motif at the tip of the RGD finger. A database search for EGF domain sequences shows that this RGD finger is likely an evolutionary insertion and unique to the EGF domain of Del-1 and its homologue milk fat globule-EGF 8. The RGD finger of Del-1 is a unique structural feature critical for integrin binding.« less

Association between a promoter dopamine D2 receptor gene variant and the personality trait detachment.

PubMed

Jönsson, Erik G; Cichon, Sven; Gustavsson, J Petter; Grünhage, Frank; Forslund, Kaj; Mattila-Evenden, Marja; Rylander, Gunnar; Asberg, Marie; Farde, Lars; Propping, Peter; Nöthen, Markus M

2003-04-01

Personality traits have shown considerable heritable components. Striatal dopamine D(2) receptor density, as determined by positron-emission tomography, has been associated with detached personality, as assessed by the Karolinska Scales of Personality. A putative functional promoter polymorphism in the dopamine D(2) receptor gene (DRD2), -141C ins/del, has been associated with dopamine D(2) receptor density. In this study healthy subjects (n = 235) who filled in at least one of several personality questionnaires (Karolinska Scales of Personality, Swedish Universities Scales of Personality, Health-relevant Five-factor Personality Inventory, and Temperament and Character Inventory) were analyzed with regard to the DRD2 -141C ins/del variant. There was an association (p =.001) between the DRD2 -141C ins/del variant and Karolinska Scales of Personality Detachment scale, indicating higher scores in subjects with the -141C del variant. There were also associations between the DRD2 -141C ins/del variant and a number of Karolinska Scales of Personality and Swedish Universities Scales of Personality Neuroticism-related scales, but of these only Swedish Universities Scales of Personality Lack of Assertiveness scale (p =.001) survived correction for multiple testing. These results add further support for the involvement of dopamine D(2) receptor in certain personality traits. The results should be treated with caution until replicated.

Short communication: novel truncating mutations in the CFTR gene causing a severe form of cystic fibrosis in Italian patients.

PubMed

Lenarduzzi, S; Morgutti, M; Crovella, S; Coiana, A; Rosatelli, M C

2014-11-14

Cystic fibrosis (CF) is a common recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. More than 1800 different mutations have been described to date. Here, we report 3 novel mutations in CFTR in 3 Italian CF patients. To detect and identify 36 frequent mutations in Caucasians, we used the INNO-LiPA CFTR19 and INNO-LiPA CFTR17+Tn Update kits (Innogenetics; Ghent, Belgium). Our first analysis did not reveal both of the responsible mutations; thus, direct sequencing of the CFTR gene coding region was performed. The 3 patients were compound heterozygous. In one allele, the F508del (c.1521_1523delCTT, p.PHE508del) mutation in exon 11 was observed in each case. For the second allele, in patient No.1, direct sequencing revealed an 11-base pair deletion (GAGGCGATACT) in exon 14 (c.2236_2246del; pGlu746Alafs*29). In patient No. 2, direct sequencing revealed a nonsense mutation at nucleotide 3892 (c.3892G>T) in exon 24. In patient No. 3, direct sequencing revealed a deletion of cytosine in exon 27 (c.4296delC; p.Asn1432Lysfs*16). These 3 novel mutations indicate the production of a truncated protein, which consequently results in a non-functional polypeptide.

M-Estimation for Discrete Data. Asymptotic Distribution Theory and Implications.

DTIC Science & Technology

1985-10-01

outlying data points, can be specified in a direct way since the influence function of an IM-estimator is proportional to its score function; see HamDel...consistently estimates - when the model is correct. Suppose now that ac RI. The influence function at F of an M-estimator for 3 has the form 2(x,S) = d/ P ("e... influence function at F . This is assuming, of course, that the estimator is asymototically normal at Fe. The truncation point c(f) determines the bounds

Towards a prevention program for β-thalassemia. The molecular spectrum in East Java, Indonesia.

PubMed

Hernanda, Pratika Yuhyi; Tursilowati, Luluk; Arkesteijn, Sandra G J; Ugrasena, I Dewa Gede; Larasati, Marian C Shanty; Soeatmadji, Sentot Mustajab; Giordano, Piero C; Harteveld, Cornelis L

2012-01-01

Defining the spectrum of specific thalassemia mutations is an important issue when planning prevention programs in large multi ethnic countries as is Indonesia. In a first attempt to define the prevalence of the common mutations in East Java we selected a cohort of 17 transfusion-dependent patients attending the Dr. Soetomo Hospital, Surabaya, Indonesia. After basic diagnostics we performed direct DNA sequencing for all β-globin genes. The results obtained on 34 independent chromosomes revealed the following prevalence rates: c.79 G>A p. Glu27Lys (Hb E) 47.0%; c.92+5G>C (IVS-I-5 G>C) 20.6%; c.109_110 delC p.Pro37Leu fs X7 [codon 35 (-C)] 17.6%; c.46del T p.Trp16Gly fsX4 [codon 15 (-T)] 5.9%; c.126_129delCTTT p. Phe42Leu fs X19 (codons 41/42) 2.9%; c.316-197 C>T [IVS-II-654 (C>T)] 2.9%; c*112 A>G (PolyA) 2.9%. Our preliminary results show that the distribution of the prevalent mutations in our cohort is quite homogeneous but with different forms than previously reported. This indicates that more studies on a larger scale and in different geographical areas are needed to refine our provisional results and to characterize the molecular background of the disease in the whole country.

Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene.

PubMed

Orrico, A; Galli, L; Faivre, L; Clayton-Smith, J; Azzarello-Burri, S M; Hertz, J M; Jacquemont, S; Taurisano, R; Arroyo Carrera, I; Tarantino, E; Devriendt, K; Melis, D; Thelle, T; Meinhardt, U; Sorrentino, V

2010-02-01

Mutations in the FGD1 gene have been shown to cause Aarskog-Scott syndrome (AAS), or facio-digito-genital dysplasia (OMIM#305400), an X-linked disorder characterized by distinctive genital and skeletal developmental abnormalities with a broad spectrum of clinical phenotypes. To date, 20 distinct mutations have been reported, but little phenotypic data are available on patients with molecularly confirmed AAS. In the present study, we report on our experience of screening for mutations in the FGD1 gene in a cohort of 60 European patients with a clinically suspected diagnosis of AAS. We identified nine novel mutations in 11 patients (detection rate of 18.33%), including three missense mutations (p.R402Q; p.S558W; p.K748E), four truncating mutations (p.Y530X; p.R656X; c.806delC; c.1620delC), one in-frame deletion (c.2020_2022delGAG) and the first reported splice site mutation (c.1935+3A>C). A recurrent mutation (p.R656X) was detected in three independent families. We did not find any evidence for phenotype-genotype correlations between type and position of mutations and clinical features. In addition to the well-established phenotypic features of AAS, other clinical features are also reported and discussed. Copyright 2010 Wiley-Liss, Inc.

Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study.

PubMed

Stilgenbauer, Stephan; Eichhorst, Barbara; Schetelig, Johannes; Coutre, Steven; Seymour, John F; Munir, Talha; Puvvada, Soham D; Wendtner, Clemens-Martin; Roberts, Andrew W; Jurczak, Wojciech; Mulligan, Stephen P; Böttcher, Sebastian; Mobasher, Mehrdad; Zhu, Ming; Desai, Monali; Chyla, Brenda; Verdugo, Maria; Enschede, Sari Heitner; Cerri, Elisa; Humerickhouse, Rod; Gordon, Gary; Hallek, Michael; Wierda, William G

2016-06-01

Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. AbbVie and Genentech. Copyright © 2016 Elsevier Ltd. All rights reserved.

Simple image-based no-wash method for quantitative detection of surface expressed CFTR

PubMed Central

Larsen, Mads Breum; Hu, Jennifer; Frizzell, Raymond A.; Watkins, Simon C.

2016-01-01

Cystic fibrosis (CF) is the most common lethal genetic disease among Caucasians. It is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, which encodes an apical membrane anion channel that is required for regulating the volume and composition of epithelial secretions. The most common CFTR mutation, present on at least one allele in >90% of CF patients, deletes phenylalanine at position 508 (F508del), which causes the protein to misfold. Endoplasmic reticulum (ER) quality control elicits the degradation of mutant CFTR, compromising its trafficking to the epithelial cell apical membrane. The absence of functional CFTR leads to depletion of airway surface liquid, impaired clearance of mucus and bacteria from the lung, and predisposes to recurrent infections. Ultimately, respiratory failure results from inflammation and bronchiectasis. Although high throughput screening has identified small molecules that can restore the anion transport function of F508del CFTR, they correct less than 15% of WT CFTR activity, yielding insufficient clinical benefit. To date, most primary CF drug discovery assays have employed measurements of CFTR’s anion transport function, a method that depends on the recruitment of a functional CFTR to the cell surface, involves multiple wash steps, and relies on a signal that saturates rapidly. Screening efforts have also included assays for detection of extracellularly HA-tagged or HRP-tagged CFTR, which require multiple washing steps. We have recently developed tools and cell lines that report the correction of mutant CFTR trafficking by currently available small molecules, and have extended this assay to the 96-well format. This new and simple no-wash assay of F508del CFTR at the cell surface may permit the discovery of more efficacious drugs, and hopefully thereby prevent the catastrophic effects of this disease. In addition, the modular design of this platform should make it useful for other diseases where loss-of-function results from folding and/or trafficking defects in membrane proteins. PMID:26361332

Experimental design and multiple response optimization. Using the desirability function in analytical methods development.

PubMed

Candioti, Luciana Vera; De Zan, María M; Cámara, María S; Goicoechea, Héctor C

2014-06-01

A review about the application of response surface methodology (RSM) when several responses have to be simultaneously optimized in the field of analytical methods development is presented. Several critical issues like response transformation, multiple response optimization and modeling with least squares and artificial neural networks are discussed. Most recent analytical applications are presented in the context of analytLaboratorio de Control de Calidad de Medicamentos (LCCM), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, C.C. 242, S3000ZAA Santa Fe, ArgentinaLaboratorio de Control de Calidad de Medicamentos (LCCM), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, C.C. 242, S3000ZAA Santa Fe, Argentinaical methods development, especially in multiple response optimization procedures using the desirability function. Copyright © 2014 Elsevier B.V. All rights reserved.

Genetic and Functional Dissection of HTRA1 and LOC387715 in Age-Related Macular Degeneration

PubMed Central

Zeng, Jiexi; Lu, Fang; Sun, Xufang; Zhao, Chao; Wang, Kevin; Davey, Lisa; Chen, Haoyu; London, Nyall; Muramatsu, Daisuke; Salasar, Francesca; Carmona, Ruben; Kasuga, Daniel; Wang, Xiaolei; Bedell, Matthew; Dixie, Manjuxia; Zhao, Peiquan; Yang, Ruifu; Gibbs, Daniel; Liu, Xiaoqi; Li, Yan; Li, Cai; Li, Yuanfeng; Campochiaro, Betsy; Constantine, Ryan; Zack, Donald J.; Campochiaro, Peter; Fu, Yinbin; Li, Dean Y.; Katsanis, Nicholas; Zhang, Kang

2010-01-01

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits. PMID:20140183

Evaluation of functional independence after discharge from the intensive care unit

PubMed Central

Curzel, Juliane; Forgiarini Junior, Luiz Alberto; Rieder, Marcelo de Mello

2013-01-01

Objective 1) To evaluate the functional independence measures immediately after discharge from an intensive care unit and to compare these values with the FIMs 30 days after that period. 2) To evaluate the possible associated risk factors. Methods The present investigation was a prospective cohort study that included individuals who were discharged from the intensive care unit and underwent physiotherapy in the unit. Functional independence was evaluated using the functional independence measure immediately upon discharge from the intensive care unit and 30 days thereafter via a phone call. The patients were admitted to the Hospital Santa Clara intensive care unit during the period from May 2011 to August 2011. Results During the predetermined period of data collection, 44 patients met the criteria for inclusion in the study. The mean age of the patients was 55.4±10.5 years. Twenty-seven of the subjects were female, and 15 patients were admitted due to pulmonary disease. The patients exhibited an functional independence measure of 84.1±24.2. When this measure was compared to the measure at 30 days after discharge, there was improvement across the functional independence variables except for that concerned with sphincter control. There were no significant differences when comparing the gender, age, clinical diagnosis, length of stay in the intensive care unit, duration of mechanical ventilation, and the presence of sepsis during this period. Conclusion Functional independence, as evaluated by the functional independence measure scale, was improved at 30 days after discharge from the intensive care unit, but it was not possible to define the potentially related factors. PMID:23917973

Highly efficient and exact method for parallelization of grid-based algorithms and its implementation in DelPhi

PubMed Central

Li, Chuan; Li, Lin; Zhang, Jie; Alexov, Emil

2012-01-01

The Gauss-Seidel method is a standard iterative numerical method widely used to solve a system of equations and, in general, is more efficient comparing to other iterative methods, such as the Jacobi method. However, standard implementation of the Gauss-Seidel method restricts its utilization in parallel computing due to its requirement of using updated neighboring values (i.e., in current iteration) as soon as they are available. Here we report an efficient and exact (not requiring assumptions) method to parallelize iterations and to reduce the computational time as a linear/nearly linear function of the number of CPUs. In contrast to other existing solutions, our method does not require any assumptions and is equally applicable for solving linear and nonlinear equations. This approach is implemented in the DelPhi program, which is a finite difference Poisson-Boltzmann equation solver to model electrostatics in molecular biology. This development makes the iterative procedure on obtaining the electrostatic potential distribution in the parallelized DelPhi several folds faster than that in the serial code. Further we demonstrate the advantages of the new parallelized DelPhi by computing the electrostatic potential and the corresponding energies of large supramolecular structures. PMID:22674480

The HLA-G Genetic Contribution to Bipolar Disorder: A Trans-Ethnic Replication.

PubMed

Sundaresh, Aparna; Wu, Ching-Lien; Chinnadurai, Raj Kumar; Rajkumar, Ravi Philip; Mariaselvam, Christina Mary; LeMaoult, Joël; Krishnamoorthy, Rajagopal; Leboyer, Marion; Negi, Vir Singh; Tamouza, Ryad

2018-05-08

Bipolar disorder (BD) is frequently associated with immune dysfunctions. Studying the genetic diversity of the immuno-modulatory human leukocyte antigen (HLA)-G locus in a French BD cohort, we previously reported an association between a functionally relevant 14 bp Ins/Del polymorphism and BD risk. The present study investigated the genetic and expression diversities of HLA-G in a geographically distinct South Indian population-group BD patients, as well as the influence of exposure to the neurotropic Toxoplasma gondii pathogen. Three functionally relevant HLA-G polymorphisms, i.e. HLA-G 14 bp Ins/Del (rs66554220), +3142G>C (rs1063320) and +3187A>G (rs9380142) were genotyped by polymerase chain reaction (PCR) and real-time PCR. Sub-samples of BD patients and healthy controls (HC) were investigated for plasma levels of soluble HLA-G (sHLA-G) isoforms, as well as circulating stigma of T. gondii infection. Findings indicate: (i) the frequency of the HLA-G 14 bp Del/Del genotype was higher in BD cases, as compared to HC; (ii) the HLA-G + 3142 C allele and CC genotype were more prevalent in BD patients than in HC; (iii) sHLA-G levels were significantly higher in BD cases, especially in females and in the early onset sub-group; and (iv) the InsGA haplotype was more prevalent in HC. Our findings further support the genetic contribution of HLA-G to BD risk, as well as indicate relevant expression profiles. Such data may also indicate a potential developmental role in BD etiology, given that HLA-G is an important immune regulator from the intrauterine period and across development.

Involvement of delta and mu opioid receptors in the acute and sensitized locomotor action of cocaine in mice.

PubMed

Kotlinska, J H; Gibula-Bruzda, E; Witkowska, E; Izdebski, J

2013-10-01

Analogs of deltorphins, such as cyclo(Nδ, Nδ-carbonyl-d-Orn2, Orn4)deltorphin (DEL-6) and deltorphin II N-(ureidoethyl)amide (DK-4) are functional agonists predominantly for the delta opioid receptors (DOR) in the guinea-pig ileum and mouse vas deferens bioassays. The purpose of this study was to examine an influence of these peptides (5, 10 or 20 nmol, i.c.v.) on the acute cocaine-induced (10mg/kg, i.p.) locomotor activity and the expression of sensitization to cocaine locomotor effect. Sensitization to locomotor effect of cocaine was developed by five injections of cocaine at the dose of 10mg/kg, i.p. every 3 days. Our results indicated that DK-4 and DEL-6 differently affected the acute and sensitized cocaine locomotion. Co-administration of DEL-6 with cocaine enhanced acute cocaine locomotion only at the dose of 10 nmol, with minimal effects at the doses 5 and 20 nmol, whereas co-administration of DK-4 with cocaine enhanced acute cocaine-induced locomotion in a dose-dependent manner. Similarly to the acute effects, DEL-6 only at the dose of 10 nmol but DK-4 dose-dependently enhanced the expression of cocaine sensitization. Pre-treatment with DOR antagonist - naltrindole (5 nmol, i.c.v.) and mu opioid receptor (MOR) antagonist, β-funaltrexamine abolished the ability of both peptides to potentiate the effects of cocaine. Our study suggests that MOR and DOR are involved in the interactions between cocaine and both deltorphins analogs. A distinct dose-response effects of these peptides on cocaine locomotion probably arise from differential functional activation (targeting) of the DOR and MOR by both deltorphins analogs. Copyright © 2013 Elsevier Inc. All rights reserved.

Independent component model for cognitive functions of multiple subjects using [15O]H2O PET images.

PubMed

Park, Hae-Jeong; Kim, Jae-Jin; Youn, Tak; Lee, Dong Soo; Lee, Myung Chul; Kwon, Jun Soo

2003-04-01

An independent component model of multiple subjects' positron emission tomography (PET) images is proposed to explore the overall functional components involved in a task and to explain subject specific variations of metabolic activities under altered experimental conditions utilizing the Independent component analysis (ICA) concept. As PET images represent time-compressed activities of several cognitive components, we derived a mathematical model to decompose functional components from cross-sectional images based on two fundamental hypotheses: (1) all subjects share basic functional components that are common to subjects and spatially independent of each other in relation to the given experimental task, and (2) all subjects share common functional components throughout tasks which are also spatially independent. The variations of hemodynamic activities according to subjects or tasks can be explained by the variations in the usage weight of the functional components. We investigated the plausibility of the model using serial cognitive experiments of simple object perception, object recognition, two-back working memory, and divided attention of a syntactic process. We found that the independent component model satisfactorily explained the functional components involved in the task and discuss here the application of ICA in multiple subjects' PET images to explore the functional association of brain activations. Copyright 2003 Wiley-Liss, Inc.

Evaluation of HLA-G 14-bp ins/del and +3142G>C polymorphisms with susceptibility to recurrent spontaneous abortion.

PubMed

Hashemi, Mohammad; Mokhtari, Mojgan; Khazaeian, Safura; Bahari, Gholamreza; Rezaei, Maryam; Nakhaee, Alireza; Taheri, Mohsen

2017-06-01

HLA-G is critically important for successful implantation during pregnancy. Increasing evidence supposed that HLA-G plays a key role in tolerance of the semi-allogeneic graft in pregnancy by inhibiting the cytotoxic functions of T and NK cells. The present study aimed to evaluate the impact of HLA-G rs1063320 (+3142G>C) and 14-bp insertion (ins)/deletion (del) polymorphisms on recurrent spontaneous abortion (RSA). Genomic DNA from 93 RSA patients and 93 normal fertile women was isolated using the salting out method. Genotyping of HLA-G +3142G>C and 14-bp ins/del variants was done by polymerase chain reaction restriction fragment length polymorphism (PCR-RFP) and PCR method, respectively. The HLA-G +3142G>C polymorphism increased the risk of RSA in codominant (OR = 2.39, 95%CI = 1.27-4.49, p = 0.010, GC vs GG; OR = 3.28, 95%CI = 1.16-9.72, p = 0.040, CC vs GG) and dominant (OR = 2.52, 95%CI = 1.37-4.64, p = 0.004, GC + CC vs GG) tested inheritance models. HLA-G rs1063320 C allele was associated with increased risk of RSA (OR = 1.84, 95%CI = 1.20-2.83, p = 0.007). The del/del genotype as well as del allele of 14-bp ins/del variant increased that risk of RSA (OR = 3.02, 95%CI = 1.23-7.41, p = 0.025 and OR = 1.65, 95%CI = 1.09-2.50, p = 0.022, respectively). In summary, our results showed that HLA-G gene polymorphisms significantly increased the risk of RSA in a sample of the Iranian population. Copyright © 2017. Published by Elsevier B.V.

Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers.

PubMed

Pavanello, Sofia; Pulliero, Alessandra; Lupi, Silvia; Gregorio, Pasquale; Clonfero, Erminio

2005-11-10

The functional significance of genetic polymorphisms on tobacco smoke-induced CYP1A2 activity was examined. The influence of three polymorphisms of the cytochrome P450 1A2 gene (CYP1A2) (-3860 G-->A (allele *1C), -2467 T-->delT (allele *1D), -163C-->A (allele *1F)), located in the 5'-noncoding promoter region of the gene, on CYP1A2 activity (measured as caffeine metabolic ratio, CMR), was studied in Caucasian current smokers (n=95). Tobacco smoke intake was calculated from the number of cigarettes/day. Also, studied was the influence of these CYP1A2 genotypes on smoking-associated urinary mutagenicity, detected in Salmonella typhimurium strain YG1024 with S9 mix, considering the urinary excretion of nicotine plus its metabolites as an internal indicator of tobacco smoke exposure. Smokers with at least one of the variant alleles CYP1A2 -3860A and -2467 delT showed a significantly increased CYP1A2 CMR (-3860 G/A versus G/G, p<0.05; -2467 delT/delT versus T/delT and T/T, p<0.01). Multiple regression analysis showed that the increase in CYP1A2 CMR (ln values) was again significantly related to the presence of CYP1A2 variants -2467delT and also to variant -163A (p<0.05), but moderately to -3860A (p=0.084). No influence of the number of cigarettes smoked per day by each subject was found. Heavy smokers (n=48, with urinary nicotine plus its metabolites>or=0.69 mg/mmol creatinine) with variant allele -2467delT or -163A had significantly increased urinary mutagenicity (p<0.01 and <0.05). CYP1A2 genetic polymorphisms are shown to influence the CYP1A2 phenotype in smokers, -2467 T-->delT having the main effect. This information is of interest for future studies assessing the possible role of tobacco smoke-inducible CYP1A2 genotypes as individual susceptibility factors in exposure to carcinogens.

Adequate proverb interpretation is associated with performance on the independent living scales.

PubMed

Ahmed, Fayeza S; Miller, L Stephen

2015-01-01

The purpose of this study was to examine proverb interpretation performance and functional independence in older adults. From the limited literature on proverb interpretation in aging and its conceptualization as an executive function, it was hypothesized that proverb interpretation would be related to functional independence similar to other executive functions. Tests of proverb interpretation, additional executive functions, and functional ability were administered to nondemented older adults. Results showed that proverb interpretation accounted for a significant amount of unique variance of functional ability scores. This supports including a measure of proverb interpretation to the assessment of older adults.

NF-κB1 Rs28362491 Mutant Allele Frequencies along the Silk Road and Beyond.

PubMed

Pordel, Safoora; Nemati, Kazem; Karimi, Mohammad Hossein; Doroudchi, Mehrnoosh

2018-03-01

In the human evolutionary history, Single Nucleotide Polymorphism (SNP) frequencies are valuable in terms of finding connections between different populations. Due to the pronounced role of the immune system in combating pathogens and environmental stressors, polymorphisms in the immune genes are subject to selection pressure of the diseases as well. The functional polymorphisms in NF-κB1 promoter (-94 ins/del) are associated with different diseases; therefore, we aimed to establish the frequencies of NF-κB1 rs28362491 alleles in a population of Southwestern Iranians in comparison with the world populations. We assessed the polymorphism of -94 ATTG ins/del (rs28362491) in 201 Iranian healthy blood donors from Fars Province, central Iran in a one year period between 2015 and 2016 by PCR-RFLP method using DNA extracted from peripheral blood mononuclear cells. The frequency of ins/ins homozygote genotype was found to be 46.97%. The frequency of heterozygote individuals was 42.42% and the percentage of del/del homozygote genotype was 10.61%. We observed a genetic similarity based on the genotype frequencies of NF-κB1 -94 ins/del ATTG polymorphism between our sample of Iranians with American Jewish, Turkish, American non-Jewish, Chinese-Uyghurs and Germans. The results confirmed genetic interrelation of Iranians with some ancient neighbors and their admixture with countries along the Silk Road. We suggest that mapping the distribution of NF-κB1-94 ATTG ins/del along with HLA genes may help to better define the relations between human populations and design population-specific vaccines for pathogens with a high rate of variation.

Comparison of the sensitivity to change of the Functional Independence Measure with the Assessment of Motor and Process Skills within different rehabilitation populations.

PubMed

Choo, Silvana X; Stratford, Paul; Richardson, Julie; Bosch, Jackie; Pettit, Susan M; Ansley, Barbara J; Harris, Jocelyn E

2017-09-10

To determine whether there was a difference in the sensitivity to change of the subscales of the Functional Independence Measure and the Assessment of Motor and Process Skills within three different post-acute inpatient rehabilitation populations. We conducted retrospective chart review of patients consecutively admitted to inpatient rehabilitation units, with both admission and discharge Functional Independence Measure and Assessment of Motor and Process Skills scores. A total of 276 participants were included and categorized into diagnostic groups (orthopedic, oncology, and geriatric). Within group, sensitivity to change was evaluated for the subscales of each measure by calculating the difference in standardized response means (SRM) and 95% confidence intervals (CI). The Functional Independence Measure motor subscale was more sensitive to change than the Assessment of Motor and Process Skills in the orthopedic and geriatric groups (SRM difference  = 1.53 [95% CI 0.93, 2.3] and 0.65 [95% CI 0.3, 1.02], respectively) but not in the oncology group (SRM difference  = 0.42 [95% CI -0.2, 1.04]). For the cognitive subscales, the Assessment of Motor and Process Skills was more sensitive to change than the Functional Independence Measure in all three groups (SRM difference  = 0.38 [95% CI 004, 0.74], 0.65 [95% CI 0.45, 0.90], and 1.15 [95% CI 0.77, 1.69] for orthopedic, geriatric, and oncology, respectively). The Functional Independence Measure is a mandated measure for all rehabilitation units in Canada. As the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change than the Functional Independence Measure, we recommend also administering the Assessment of Motor and Process Skills to better detect changes in the cognitive aspect of function. Implications for rehabilitation When deciding between the Functional Independence Measure or the Assessment of Motor and Process Skills, it is important to consider whether patients' functional status is expected to change similarly or differently. The difference in sensitivity to change between the subscales of the two outcome measures varies with the characteristics of change (similar or different) in patients' functional status. We recommend using the Assessment of Motor and Process Skills, along with the Functional Independence Measure, for patients who are expected to make similar amounts of change in functional status, as the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change and can better detect changes in the cognitive aspect of functioning. For patients whose functional status are expected to change differently (diverse diagnoses), the Functional Independence Measure may be more useful as the motor subscale was more sensitive to change when comparing between rehabilitation populations.

Physical function and independence 1 year after myocardial infarction: observations from the Translational Research Investigating Underlying disparities in recovery from acute Myocardial infarction: Patients' Health status registry.

PubMed

Dodson, John A; Arnold, Suzanne V; Reid, Kimberly J; Gill, Thomas M; Rich, Michael W; Masoudi, Frederick A; Spertus, John A; Krumholz, Harlan M; Alexander, Karen P

2012-05-01

Acute myocardial infarction (AMI) may contribute to health status declines including "independence loss" and "physical function decline." Despite the importance of these outcomes for prognosis and quality of life, their incidence and predictors have not been well described. We studied 2,002 patients with AMI enrolled across 24 sites in the TRIUMPH registry who completed assessments of independence and physical function at the time of AMI and 1 year later. Independence was evaluated by the EuroQol-5D (mobility, self-care, and usual activities), and physical function was assessed with the Short Form-12 physical component score. Declines in ≥1 level on EuroQol-5D and >5 points in PCS were considered clinically significant changes. Hierarchical, multivariable, modified Poisson regression models accounting for within-site variability were used to identify predictors of independence loss and physical function decline. One-year post AMI, 43.0% of patients experienced health status declines: 12.8% independence loss alone, 15.2% physical function decline alone, and 15.0% both. After adjustment, variables that predicted independence loss included female sex, nonwhite race, unmarried status, uninsured status, end-stage renal disease, and depression. Variables that predicted physical function decline were uninsured status, lack of cardiac rehabilitation referral, and absence of pre-AMI angina. Age was not predictive of either outcome after adjustment. >40% of patients experience independence loss or physical function decline 1 year after AMI. These changes are distinct but can occur simultaneously. Although some risk factors are not modifiable, others suggest potential targets for strategies to preserve patients' health status. Copyright © 2012 Mosby, Inc. All rights reserved.

Rupture of a non-traumatic anterior communicating artery aneurysm: Does location of aneurysm associate with functional independence following post-acute in-patient neurorehabilitation?

PubMed

Stabel, Henriette Holm; Pedersen, Asger Roer; Johnsen, Søren Paaske; Nielsen, Jørgen Feldbæk

2017-12-01

Patients with non-traumatic rupture of an aneurysm located at the anterior communicating artery (ACoA) often experience cognitive disabilities. It is unknown whether location of aneurysm also affects the possibility for improvement in functional independence compared to patients with an aneurysmal subarachnoid hemorrhage (a-SAH) located elsewhere. The aim was to explore the association between location of aneurysm (ACoA versus other) and level of functional independence, measured by Functional Independence Measure (FIM), at discharge from rehabilitation. Additionally, age and FIM at admission were explored. Historical cohort study among 107 patients with a-SAH based on data from a clinical database and a population-based register. Data were analyzed using multivariable logistic regression. Patients with ACoA were admitted with poorer cognitive FIM (median 6 (IQR 5-14) compared to patients with aneurysms located elsewhere (median 12 (IQR 6-23) (p = 0.0129); no difference at discharge. No association between aneurysm location and functional independence was observed. Higher age was associated with poorer outcome in bowel management OR 0.54 (95% CI 0.31-0.92), bladder management OR 0.59 (95% CI 0.35-0.98), comprehension OR 0.53 (95% CI 0.30-0.94), and memory OR 0.48 (95% CI 0.25-0.93). Overall, FIM at admission was associated with functional independence at discharge with the exception of stair walking and bladder management which did not reach statistical significance. ACoA was not associated with poorer level of functional independence compared to patients with a-SAH located elsewhere. Higher age was associated with poorer outcome in continence, comprehension, and memory, whereas higher FIM was associated with better functional independence across items at discharge.

Measure of functional independence dominates discharge outcome prediction after inpatient rehabilitation for stroke.

PubMed

Brown, Allen W; Therneau, Terry M; Schultz, Billie A; Niewczyk, Paulette M; Granger, Carl V

2015-04-01

Identifying clinical data acquired at inpatient rehabilitation admission for stroke that accurately predict key outcomes at discharge could inform the development of customized plans of care to achieve favorable outcomes. The purpose of this analysis was to use a large comprehensive national data set to consider a wide range of clinical elements known at admission to identify those that predict key outcomes at rehabilitation discharge. Sample data were obtained from the Uniform Data System for Medical Rehabilitation data set with the diagnosis of stroke for the years 2005 through 2007. This data set includes demographic, administrative, and medical variables collected at admission and discharge and uses the FIM (functional independence measure) instrument to assess functional independence. Primary outcomes of interest were functional independence measure gain, length of stay, and discharge to home. The sample included 148,367 people (75% white; mean age, 70.6±13.1 years; 97% with ischemic stroke) admitted to inpatient rehabilitation a mean of 8.2±12 days after symptom onset. The total functional independence measure score, the functional independence measure motor subscore, and the case-mix group were equally the strongest predictors for any of the primary outcomes. The most clinically relevant 3-variable model used the functional independence measure motor subscore, age, and walking distance at admission (r(2)=0.107). No important additional effect for any other variable was detected when added to this model. This analysis shows that a measure of functional independence in motor performance and age at rehabilitation hospital admission for stroke are predominant predictors of outcome at discharge in a uniquely large US national data set. © 2015 American Heart Association, Inc.

Non-invasive prenatal diagnosis (NIPD) of cystic fibrosis: an optimized protocol using MEMO fluorescent PCR to detect the p.Phe508del mutation.

PubMed

Guissart, C; Dubucs, C; Raynal, C; Girardet, A; Tran Mau Them, F; Debant, V; Rouzier, C; Boureau-Wirth, A; Haquet, E; Puechberty, J; Bieth, E; Dupin Deguine, D; Khau Van Kien, P; Brechard, M P; Pritchard, V; Koenig, M; Claustres, M; Vincent, M C

2017-03-01

Analysis of cell-free foetal DNA (cff-DNA) in maternal plasma is very promising for early diagnosis of monogenic diseases; in particular, cystic fibrosis (CF). However, NIPD of single-gene disorders has been limited by the availability of suitable technical platforms and the need to set up patient or disease-specific custom-made approaches. To make research applications more readily accessible to the clinic, we offer a simple assay combining two independent methods to determine the presence or absence of paternally inherited foetal allele p.Phe508del (the most frequent mutation in CF patients worldwide). The first method detects the presence or absence of a p.Phe508del allele by Mutant Enrichment with 3'-Modified Oligonucleotide PCR coupled to Fragment Length Analysis (MEMO-PCR-FLA). The second method detects the p.Phe508del allele with classical Multiplex Fluorescent PCR including five intragenic and extragenic STR markers of the CFTR locus and a specific SRY sequence. We collected 24 plasma samples from 23 women carrying foetuses at risk for CF and tested each sample using both methods. Our new procedures were successfully applied to 10 couples where fathers carried the p.Phe508del mutation and mothers were carrying a different mutation in the CFTR gene. These simple tests provided clear positive or negative results from the maternal plasma of the pregnant women. We confirmed the presence of cff-DNA in the studied samples by the identification of a tri-allelic DNA profile using a miniSTR kit. All results were correlated with chorionic villus sampling or amniocentesis analyses. This NIPD approach, easily set up in any clinical laboratory where prenatal diagnosis is routinely performed, offers many advantages over current methods: it is simple, rapid, and cost-effective. It opens up the possibility for testing a large number of couples with offspring at risk for CF. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

The English as a Foreign Language/Lingua Franca Debate: Sensitising Teachers of English as a Foreign Language towards Teaching English as a Lingua Franca (El debate del inglés como lengua extranjera o como lengua franca: sensibilización de docentes de inglés como lengua extranjera hacia la enseñanza del inglés como lengua franca)

ERIC Educational Resources Information Center

Mansfield, Gillian; Poppi, Franca

2012-01-01

The function of English as a lingua franca for communication needs rethinking in the teaching of English as a foreign language classroom as a consequence of globalisation. The present contribution is an empirical study carried out in an Italian university environment which aims to show how teachers should take on board awareness raising activities…

Thermal smearing and screening in a strong magnetic field for Dirac materials in comparison with the two dimensional electron liquid

NASA Astrophysics Data System (ADS)

Gumbs, Godfrey; Balassis, Antonios; Dahal, Dipendra; Lawrence Glasser, M.

2016-10-01

We compute and compare the effects due to a uniform perpendicular magnetic field as well as temperature on the static polarization functions for monolayer graphene (MLG), associated with the Dirac point, with that for the two-dimensional electron liquid (2DEL) with the use of comprehensive numerical calculations. The relevance of our study to the Friedel oscillations for the screening of the potential for a dilute distribution of impurities is reported too. Our results show substantial differences due to screening for the 2DEL and MLG which have not been given adequate attention previously.

Functional mental capacity is not independent of the severity of psychosis.

PubMed

Rutledge, Emer; Kennedy, Miriam; O'Neill, Helen; Kennedy, Harry G

2008-01-01

Function-specific mental capacities are the legal criteria for competence. These are regarded as superior to clinical assessments of mental state and general function. To determine whether tests of fitness to plead and capacity to consent are independent of each other and independent of mental state and global function in psychosis. The MacCAT-T and MacCAT-FP, PANSS and GAF were administered to 102 compulsorily detained forensic patients with psychosis. Criteria for incompetence were inability to express a preference concerning treatment, and independent rating as unfit to plead. MacCAT-T, MacCAT-FP totals and sub-scales correlated with each other and with PANSS and GAF. Those independently rated unfit to plead or who were incapable of making a treatment choice scored significantly worse on all rating scales. No test had satisfactory sensitivity or specificity. Legal definitions of mind and of functional capacity offer a basis for structured clinical judgement regarding decision-making capacity. However, function-specific measures of understanding, reasoning and appreciation generate much the same results as measures of mental state and global functioning.

Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells

DTIC Science & Technology

2005-03-01

Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL INVESTIGATOR: Dr. Dean Tang...SUBTITLE 5a. CONTRACT NUMBER Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells 5b. GRANT NUMBER DAMD17-03-1...Unlimited 13. SUPPLEMENTARY NOTES Original contains colored plates: ALL DTIC reproductions will be in black and white. 14. ABSTRACT

Chronic lymphocytic leukemia: A prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI.

PubMed

Delgado, Julio; Doubek, Michael; Baumann, Tycho; Kotaskova, Jana; Molica, Stefano; Mozas, Pablo; Rivas-Delgado, Alfredo; Morabito, Fortunato; Pospisilova, Sarka; Montserrat, Emili

2017-04-01

Rai and Binet staging systems are important to predict the outcome of patients with chronic lymphocytic leukemia (CLL) but do not reflect the biologic diversity of the disease nor predict response to therapy, which ultimately shape patients' outcome. We devised a biomarkers-only CLL prognostic system based on the two most important prognostic parameters in CLL (i.e., IGHV mutational status and fluorescence in situ hybridization [FISH] cytogenetics), separating three different risk groups: (1) low-risk (mutated IGHV + no adverse FISH cytogenetics [del(17p), del(11q)]); (2) intermediate-risk (either unmutated IGHV or adverse FISH cytogenetics) and (3) high-risk (unmutated IGHV + adverse FISH cytogenetics). In 524 unselected subjects with CLL, the 10-year overall survival was 82% (95% CI 76%-88%), 52% (45%-62%), and 27% (17%-42%) for the low-, intermediate-, and high-risk groups, respectively. Patients with low-risk comprised around 50% of the series and had a life expectancy comparable to the general population. The prognostic model was fully validated in two independent cohorts, including 417 patients representative of general CLL population and 337 patients with Binet stage A CLL. The model had a similar discriminatory value as the CLL-IPI. Moreover, it applied to all patients with CLL independently of age, and separated patients with different risk within Rai or Binet clinical stages. The biomarkers-only CLL prognostic system presented here simplifies the CLL-IPI and could be useful in daily practice and to stratify patients in clinical trials. © 2017 Wiley Periodicals, Inc.

Mutation in lamin A/C sensitizes the myocardium to exercise-induced mechanical stress but has no effect on skeletal muscles in mouse.

PubMed

Cattin, Marie-Elodie; Ferry, Arnaud; Vignaud, Alban; Mougenot, Nathalie; Jacquet, Adeline; Wahbi, Karim; Bertrand, Anne T; Bonne, Gisèle

2016-08-01

LMNA gene encodes lamin A/C, ubiquitous proteins of the nuclear envelope. They play crucial role in maintaining nuclear shape and stiffness. When mutated, they essentially lead to dilated cardiomyopathy with conduction defects, associated or not with muscular diseases. Excessive mechanical stress sensitivity has been involved in the pathophysiology. We have previously reported the phenotype of Lmna(delK32) mice, reproducing a mutation found in LMNA-related congenital muscular dystrophy patients. Heterozygous Lmna(delK32/+) (Het) mice develop a progressive dilated cardiomyopathy leading to death between 35 and 70 weeks of age. To investigate the sensitivity of the skeletal muscles and myocardium to chronic exercise-induced stress, Het and wild-type (Wt) mice were subjected to strenuous running treadmill exercise for 5 weeks. Before exercise, the cardiac function of Het mice was similar to Wt-littermates. After the exercise-period, Het mice showed cardiac dysfunction and dilation without visible changes in cardiac morphology, molecular remodelling or nuclear structure compared to Wt exercised and Het sedentary mice. Contrary to myocardium, skeletal muscle ex vivo contractile function remained unaffected in Het exercised mice. In conclusion, the expression of the Lmna(delK32) mutation increased the susceptibility of the myocardium to cardiac stress and led to an earlier onset of the cardiac phenotype in Het mice. Copyright © 2016 Elsevier B.V. All rights reserved.

Unilateral spatial neglect in the acute phase of ischemic stroke can predict long-term disability and functional capacity.

PubMed

Luvizutto, Gustavo José; Moliga, Augusta Fabiana; Rizzatti, Gabriela Rizzo Soares; Fogaroli, Marcelo Ortolani; Moura Neto, Eduardo de; Nunes, Hélio Rubens de Carvalho; Resende, Luiz Antônio de Lima; Bazan, Rodrigo

2018-05-21

The aim of this study was to assess the relationship between the degree of unilateral spatial neglect during the acute phase of stroke and long-term functional independence. This was a prospective study of right ischemic stroke patients in which the independent variable was the degree of spatial neglect and the outcome that was measured was functional independence. The potential confounding factors included sex, age, stroke severity, topography of the lesion, risk factors, glycemia and the treatment received. Unilateral spatial neglect was measured using the line cancellation test, the star cancellation test and the line bisection test within 48 hours of the onset of symptoms. Functional independence was measured using the modified Rankin and Barthel scales at 90 days after discharge. The relationship between unilateral spatial neglect and functional independence was analyzed using multiple logistic regression that was corrected for confounding factors. We studied 60 patients with a median age of 68 (34-89) years, 52% of whom were male and 74% of whom were Caucasian. The risk for moderate to severe disability increased with increasing star cancellation test scores (OR=1.14 [1.03-1.26], p=0.01) corrected for the stroke severity, which was a confounding factor that had a statistically positive association with disability (OR=1.63 [1.13-2.65], p=0.01). The best chance of functional independence decreased with increasing star cancellation test scores (OR=0.86 [0.78-0.96], p=0.006) corrected for the stroke severity, which was a confounding factor that had a statistically negative association with independence (OR=0.66 [0.48-0.92], p=0.017). The severity of unilateral spatial neglect in acute stroke worsens the degree of long-term disability and functional independence.

Cryptic within cryptic: genetics, morphometrics, and bioacoustics delimitate a new species of Eleutherodactylus (Anura: Eleutherodactylidae) from Eastern Cuba.

PubMed

Rodríguez, Ariel; Dugo-Cota, Álvaro; Montero-Mendieta, Santiago; Gonzalez-Voyer, Alejandro; Bosch, Roberto Alonso; Vences, Miguel; Vilà, Carles

2017-01-20

We studied the variation in genetics, bioacustics, and morphology in Eleutherodactylus glamyrus, a regionally endemic frog species restricted to high elevations in the Sierra Maestra Massif, Western Cuba that was originally described as a cryptic species hidden under the name E. auriculatus. Genetic analysis of mtDNA sequences of the 16S and cob genes identify two allopatric and strongly supported mitochondrial clades (phylogroups) which also showed no haplotype sharing in the nuclear Rag-1 gene. Bioacustic, and morphological comparisons concordantly identify these two phylogroups as independent evolutionary lineages. Therefore, we herein restrict the name Eleutherodactylus glamyrus Estrada and Hedges to populations represented in our analyses as the western phylogroup (Cordillera del Turquino to Pico La Bayamesa) and consider specimens from the eastern phylogroup (Sierra del Cobre) to represent a new species described and named as Eleutherodactylus cattus. Our results add to the growing list of Eleutherodactylus species endemic to Cuba and highlight the importance of combining different sources of evidence for obtaining robust assessments of species limits in amphibians.

First results from the DarkSide-50 dark matter experiment at Laboratori Nazionali del Gran Sasso

DOE PAGES

Agnes, P.

2015-03-11

We report the first results of DarkSide-50, a direct search for dark matter operating in the underground Laboratori Nazionali del Gran Sasso (LNGS) and searching for the rare nuclear recoils possibly induced by weakly interacting massive particles (WIMPs). The dark matter detector is a Liquid Argon Time Projection Chamber with a (46.4 ± 0.7) kg active mass, operated inside a 30 t organic liquid scintillator neutron veto, which is in turn installed at the center of a 1 kt water Cherenkov veto for the residual flux of cosmic rays. We report here the null results of a dark matter searchmore » for a (1422 ± 67) kg d exposure with an atmospheric argon fill. As a result, this is the most sensitive dark matter search performed with an argon target, corresponding to a 90% CL upper limit on the WIMP-nucleon spin-independent cross section of 6.1×10 -44 cm 2 for a WIMP mass of 100 Gev/c 2.« less

Relationship between theory of mind and functional independence is mediated by executive function.

PubMed

Ahmed, Fayeza S; Miller, L Stephen

2013-06-01

Theory of mind (ToM) is the ability to comprehend another person's perspective. Although there is much literature of ToM in children, there is a limited and somewhat inconclusive amount of studies examining ToM in a geriatric population. This study examined ToM's relationship to functional independence. Two tests of ToM, tests of executive function, and a measure of functional ability were administered to cognitively intact older adults. Results showed that 1 test of ToM (Strange Stories test) significantly accounted for variance in functional ability, whereas the other did not (Faux Pas test). In addition, Strange Stories test performance was partially driven by a verbal abstraction-based executive function: proverb interpretation. A multiple mediation model was employed to examine whether executive functions explained the relationship between the Strange Stories test and functional ability. Results showed that both the combined and individual indirect effects of the executive function measures mediated the relationship. We argue that, although components of ToM are associated with functional independence, ToM does not appear to account for additional variance in functional independence beyond executive function measures. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Functional ecology of soil microbial communities along a glacier forefield in Tierra del Fuego (Chile).

PubMed

Fernández-Martínez, Miguel A; Pointing, Stephen B; Pérez-Ortega, Sergio; Arróniz-Crespo, María; Green, T G Allan; Rozzi, Ricardo; Sancho, Leopoldo G; de Los Ríos, Asunción

2016-09-01

A previously established chronosequence from Pia Glacier forefield in Tierra del Fuego (Chile) containing soils of different ages (from bare soils to forest ones) is analyzed. We used this chronosequence as framework to postulate that microbial successional development would be accompanied by changes in functionality. To test this, the GeoChip functional microarray was used to identify diversity of genes involved in microbial carbon and nitrogen metabolism, as well as other genes related to microbial stress response and biotic interactions. Changes in putative functionality generally reflected succession-related taxonomic composition of soil microbiota. Major shifts in carbon fixation and catabolism were observed, as well as major changes in nitrogen metabolism. At initial microbial dominated succession stages, microorganisms could be mainly involved in pathways that help to increase nutrient availability, while more complex microbial transformations such as denitrification and methanogenesis, and later degradation of complex organic substrates, could be more prevalent at vegetated successional states. Shifts in virus populations broadly reflected changes in microbial diversity. Conversely, stress response pathways appeared relatively well conserved for communities along the entire chronosequence. We conclude that nutrient utilization is likely the major driver of microbial succession in these soils. [Int Microbiol 19(3):161-173 (2016)]. Copyright© by the Spanish Society for Microbiology and Institute for Catalan Studies.

Exome Sequencing Identifies a REEP1 Mutation Involved in Distal Hereditary Motor Neuropathy Type V

PubMed Central

Beetz, Christian; Pieber, Thomas R.; Hertel, Nicole; Schabhüttl, Maria; Fischer, Carina; Trajanoski, Slave; Graf, Elisabeth; Keiner, Silke; Kurth, Ingo; Wieland, Thomas; Varga, Rita-Eva; Timmerman, Vincent; Reilly, Mary M.; Strom, Tim M.; Auer-Grumbach, Michaela

2012-01-01

The distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of neurodegenerative disorders affecting the lower motoneuron. In a family with both autosomal-dominant dHMN and dHMN type V (dHMN/dHMN-V) present in three generations, we excluded mutations in all genes known to be associated with a dHMN phenotype through Sanger sequencing and defined three potential loci through linkage analysis. Whole-exome sequencing of two affected individuals revealed a single candidate variant within the linking regions, i.e., a splice-site alteration in REEP1 (c.304-2A>G). A minigene assay confirmed complete loss of splice-acceptor functionality and skipping of the in-frame exon 5. The resulting mRNA is predicted to be expressed at normal levels and to encode an internally shortened protein (p.102_139del). Loss-of-function REEP1 mutations have previously been identified in dominant hereditary spastic paraplegia (HSP), a disease associated with upper-motoneuron pathology. Consistent with our clinical-genetic data, we show that REEP1 is strongly expressed in the lower motoneurons as well. Upon exogeneous overexpression in cell lines we observe a subcellular localization defect for p.102_139del that differs from that observed for the known HSP-associated missense mutation c.59C>A (p.Ala20Glu). Moreover, we show that p.102_139del, but not p.Ala20Glu, recruits atlastin-1, i.e., one of the REEP1 binding partners, to the altered sites of localization. These data corroborate the loss-of-function nature of REEP1 mutations in HSP and suggest that a different mechanism applies in REEP1-associated dHMN. PMID:22703882

Long-range Receiver Function Profile of Crustal and Mantle Discontinuities From the Aleutian Arc to Tierra del Fuego

NASA Astrophysics Data System (ADS)

Spieker, Kathrin; Rondenay, Stéphane; Sawade, Lucas

2016-04-01

The Circum-Pacific belt, also called the Pacific Ring of Fire, is the most seismically active region on Earth. Multiple plate boundaries form a zone characterized by frequent volcanic eruptions and seismicity. While convergent plate boundaries such as the Peru-Chile trench dominate the Circum-Pacific belt, divergent and transform boundaries are present as well. The eastern section of the Circum-Pacific belt extends from the Aleutian arc, through the Cascadia subduction zone, San Andreas Fault, middle America trench and the Andean margin down to Tierra del Fuego. Due to the significant hazards posed by this tectonic activity, the region has been densely instrumented by thousands of seismic stations deployed across fifteen countries, over a distance of more than 15000 km. Various seismological studies, including receiver function analyses, have been carried out to investigate the crustal and mantle structure beneath local segments of the eastern Circum-Pacific belt (i.e., at ~100-500 km scale). However, to the best of our knowledge, no study to date has ever attempted to combine all available seismic data from the eastern Circum-Pacific belt to generate a continuous profile of seismic discontinuities extending from the Aleutians to Tierra del Fuego. Here, we use results from the "Global Imaging using Earthquake Records" (GLImER) P-wave receiver function database to create a long-range profile of crustal and upper mantle discontinuities across the entire eastern portion of the Circum-Pacific belt. We image intermittent crustal and mantle discontinuities along the profile, and examine them with regard to their behaviour and properties across transitions between different tectonic regimes.

Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy.

PubMed

Corbett, Mark A; Bellows, Susannah T; Li, Melody; Carroll, Renée; Micallef, Silvana; Carvill, Gemma L; Myers, Candace T; Howell, Katherine B; Maljevic, Snezana; Lerche, Holger; Gazina, Elena V; Mefford, Heather C; Bahlo, Melanie; Berkovic, Samuel F; Petrou, Steven; Scheffer, Ingrid E; Gecz, Jozef

2016-11-08

To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations. A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes. The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G>A; p.Arg297Gln) in a girl with EE, ataxia, and tremor. A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders. © 2016 American Academy of Neurology.

Quorum Sensing Down-Regulation Counteracts the Negative Impact of Pseudomonas aeruginosa on CFTR Channel Expression, Function and Rescue in Human Airway Epithelial Cells

PubMed Central

Maillé, Émilie; Ruffin, Manon; Adam, Damien; Messaoud, Hatem; Lafayette, Shantelle L.; McKay, Geoffrey; Nguyen, Dao; Brochiero, Emmanuelle

2017-01-01

The function of cystic fibrosis transmembrane conductance regulator (CFTR) channels is crucial in human airways. However unfortunately, chronic Pseudomonas aeruginosa infection has been shown to impair CFTR proteins in non-CF airway epithelial cells (AEC) and to alter the efficiency of new treatments with CFTR modulators designed to correct the basic CFTR default in AEC from cystic fibrosis (CF) patients carrying the F508del mutation. Our aim was first to compare the effect of laboratory strains, clinical isolates, engineered and natural mutants to determine the role of the LasR quorum sensing system in CFTR impairment, and second, to test the efficiency of a quorum sensing inhibitor to counteract the deleterious impact of P. aeruginosa both on wt-CFTR and on the rescue of F508del-CFTR by correctors. We first report that exoproducts from either the laboratory PAO1 strain or a clinical ≪Early≫ isolate (from an early stage of infection) altered CFTR expression, localization and function in AEC expressing wt-CFTR. Genetic inactivation of the quorum-sensing LasR in PAO1 (PAO1ΔlasR) or in a natural clinical mutant (≪Late≫ CF-adapted clinical isolate) abolished wt-CFTR impairment. PAO1 exoproducts also dampened F508del-CFTR rescue by VRT-325 or Vx-809 correctors in CF cells, whereas PAO1ΔlasR had no impact. Importantly, treatment of P. aeruginosa cultures with a quorum sensing inhibitor (HDMF) prevented the negative effect of P. aeruginosa exoproducts on wt-CFTR and preserved CFTR rescue by correctors in CF AEC. These findings indicate that LasR-interfering strategies could be of benefits to counteract the deleterious effect of P. aeruginosa in infected patients. PMID:29177135

Paracellular transport through healthy and cystic fibrosis bronchial epithelial cell lines--do we have a proper model?

PubMed

Molenda, Natalia; Urbanova, Katarina; Weiser, Nelly; Kusche-Vihrog, Kristina; Günzel, Dorothee; Schillers, Hermann

2014-01-01

It has been reported recently that the cystic fibrosis transmembrane conductance regulator (CFTR) besides transcellular chloride transport, also controls the paracellular permeability of bronchial epithelium. The aim of this study was to test whether overexpressing wtCFTR solely regulates paracellular permeability of cell monolayers. To answer this question we used a CFBE41o- cell line transfected with wtCFTR or mutant F508del-CFTR and compered them with parental line and healthy 16HBE14o- cells. Transepithelial electrical resistance (TER) and paracellular fluorescein flux were measured under control and CFTR-stimulating conditions. CFTR stimulation significant decreased TER in 16HBE14o- and also in CFBE41o- cells transfected with wtCFTR. In contrast, TER increased upon stimulation in CFBE41o- cells and CFBE41o- cells transfected with F508del-CFTR. Under non-stimulated conditions, all four cell lines had similar paracellular fluorescein flux. Stimulation increased only the paracellular permeability of the 16HBE14o- cell monolayers. We observed that 16HBE14o- cells were significantly smaller and showed a different structure of cell-cell contacts than CFBE41o- and its overexpressing clones. Consequently, 16HBE14o- cells have about 80% more cell-cell contacts through which electrical current and solutes can leak. Also tight junction protein composition is different in 'healthy' 16HBE14o- cells compared to 'cystic fibrosis' CFBE41o- cells. We found that claudin-3 expression was considerably stronger in 16HBE14o- cells than in the three CFBE41o- cell clones and thus independent of the presence of functional CFTR. Together, CFBE41o- cell line transfection with wtCFTR modifies transcellular conductance, but not the paracellular permeability. We conclude that CFTR overexpression is not sufficient to fully reconstitute transport in CF bronchial epithelium. Hence, it is not recommended to use those cell lines to study CFTR-dependent epithelial transport.

ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2).

PubMed

Jiang, Y; Chen, H-C; Su, X; Thompson, P A; Liu, X; Do, K-A; Wierda, W; Keating, M J; Plunkett, W

2016-09-02

Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22-23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

Inhibition of Protease-Epithelial Sodium Channel Signaling Improves Mucociliary Function in Cystic Fibrosis Airways.

PubMed

Reihill, James A; Walker, Brian; Hamilton, Robert A; Ferguson, Timothy E G; Elborn, J Stuart; Stutts, M Jackson; Harvey, Brian J; Saint-Criq, Vinciane; Hendrick, Siobhan M; Martin, S Lorraine

2016-09-15

In cystic fibrosis (CF) a reduction in airway surface liquid (ASL) height compromises mucociliary clearance, favoring mucus plugging and chronic bacterial infection. Inhibitors of the epithelial sodium channel (ENaC) have therapeutic potential in CF airways to reduce hyperstimulated sodium and fluid absorption to levels that can restore airway hydration. To determine whether a novel compound (QUB-TL1) designed to inhibit protease/ENaC signaling in CF airways restores ASL volume and mucociliary function. Protease activity was measured using fluorogenic activity assays. Differentiated primary airway epithelial cell cultures (F508del homozygotes) were used to determined ENaC activity (Ussing chamber recordings), ASL height (confocal microscopy), and mucociliary function (by tracking the surface flow of apically applied microbeads). Cell toxicity was measured using a lactate dehydrogenase assay. QUB-TL1 inhibits extracellularly located channel activating proteases (CAPs), including prostasin, matriptase, and furin, the activities of which are observed at excessive levels at the apical surface of CF airway epithelial cells. QUB-TL1-mediated CAP inhibition results in diminished ENaC-mediated Na(+) absorption in CF airway epithelial cells caused by internalization of a prominent pool of cleaved (active) ENaCγ from the cell surface. Importantly, diminished ENaC activity correlates with improved airway hydration status and mucociliary clearance. We further demonstrate QUB-TL1-mediated furin inhibition, which is in contrast to other serine protease inhibitors (camostat mesylate and aprotinin), affords protection against neutrophil elastase-mediated ENaC activation and Pseudomonas aeruginosa exotoxin A-induced cell death. QUB-TL1 corrects aberrant CAP activities, providing a mechanism to delay or prevent the development of CF lung disease in a manner independent of CF transmembrane conductance regulator mutation.

A preliminary candidate genotype-intermediate phenotype study of satiation and gastric motor function in obesity.

PubMed

Papathanasopoulos, Athanasios; Camilleri, Michael; Carlson, Paula J; Vella, Adrian; Nord, Sara J Linker; Burton, Duane D; Odunsi, Suwebatu T; Zinsmeister, Alan R

2010-06-01

Stomach motility contributes significantly to fullness sensation while eating and cessation of food intake in humans. Genes controlling adrenergic and serotonergic mechanisms (ADRA2A, GNB3, and SLC6A4) affect gastric emptying (GE), volume (GV), and satiation. Fat mass and obesity-associated gene (FTO) is linked with satiety. Our aim was to examine the association of these candidate genes with stomach functions that signal postprandial fullness: GE, GV, and maximum tolerated volume (MTV). These biomarkers constitute a component of the intermediate phenotype of satiation. A total of 62 overweight or obese participants underwent genotyping of the candidate genes, and validated measurements of GE of solids and liquids by scintigraphy, fasting and postprandial change in GV by SPECT (single photon emission computed tomography), and MTV by nutrient drink test. These markers of satiation were compared for 38 genetic variants in ADRA2A, ADR2C, ADRB3, uncoupling protein (UCP)-2 and -3, GNB3, FTO, and SLC6A4 using a recessive model of inheritance. ADRA2A, ADR2C, UCP-3, GNB3, and FTO loci were significantly associated with the intermediate phenotype markers of satiation: ADR2C (Ins-Del322_325) with accelerated GE; GNB3 (rs1047776) with delayed GE; ADRA2A (rs491589 and rs553668) and GNB3 (rs2269355, rs10849527, and rs3759348) with decreased postprandial GV; ADRA2A (rs3750625) and GNB3 (rs4963517 and rs1129649) with increased postprandial GV; UCP-3 (rs1685356) with increased MTV, and FTO (rs9939609) decreased MTV. Genetic susceptibility to postprandial satiation can be identified through intermediate phenotype markers. With independent validation, these markers may guide patient selection of weight-loss therapies directed at gastric motor functions.

Nitrogen and 15N in the Mer Bleue peatland

NASA Astrophysics Data System (ADS)

Moore, Tim

2017-04-01

Although much of our attention in peatlands has focussed on carbon, as CO2, CH4 and DOC processing and fluxes, N plays an important role in the functioning of these ecosystems. Here, I present information on the distribution of N and 15N in plant and peat tissues and relate them to the cycling of N. N concentration in foliar tissues, ranged from 0.67 to 1.3% in evergreen shrubs and trees and mosses with little seasonal variation, and with a strong seasonal variation from 0.5 to 3.5% in the deciduous forbs, shrubs and trees, with a strong overall relationship to [chlorophyll]. Although the proportion of shrubs and mosses varied with microtopography the spatial foliar mass of N varied little with water table position, resulting in minor spatial variations in photosynthetic potential. Decomposition of plant tissues through litter to peat resulted in a decrease in the C:N ratio from about 50:1 to about 30:1 at the base of the profile, representing peat about 8000 yr old. This marginally larger loss of N through decomposition (mainly as TDN, 0.4 g N m-2 yr-1) compared to C produced a long-term N accumulation rate of 0.9 g N m-2 yr-1, being smaller in the bog phase, 0.6 N m-2 yr-1, and over past 150 yr, 0.8 g N m-2 yr-1. Although N is 'hard won' through N2 fixation, northern peatlands are significant global sinks of N and have limited N availability. del15N in foliar tissues ranged from -4 to -9 ‰ in evergreen and deciduous shrubs and trees, from -4 to -5 ‰ in mosses and from -1 to +1 ‰ in sedges and forbs. This appears to be a function of the mycorhizzal infection of the shrubs and trees, compared to sedges and forbs and the values for mosses may partially reflect the signature of atmospheric N deposition. There was no strong correlation between foliar [N] and del15N. In peat profiles from bog and fen sections of Mer Bleue, del15N values in peat fell from -5 to -2 ‰ in the top 10 cm to values of -1 to +1 ‰ at a depth of 40 cm and remained close to 0 ‰ below this. In 30-cm thick beaver pond sediments, the del15N values remained between 0 and +2 ‰. A number of processes may account for the increase in the del15N with depth in the peat profile: more rapid decomposition of tissues with larger del15N values than the slowly decomposing mosses; fractionation of N during decomposition, leaving the heavier 15N enriched in the peat; fractionation during denitrification (though denitrification potentials and emissions are small). An intriguing possibility is that methane oxidation at and just above the water table would lead to an increase in del15N, assuming the fixed N2 has a del15N close to 0.

Covariance Method of the Tunneling Radiation from High Dimensional Rotating Black Holes

NASA Astrophysics Data System (ADS)

Li, Hui-Ling; Han, Yi-Wen; Chen, Shuai-Ru; Ding, Cong

2018-04-01

In this paper, Angheben-Nadalini-Vanzo-Zerbini (ANVZ) covariance method is used to study the tunneling radiation from the Kerr-Gödel black hole and Myers-Perry black hole with two independent angular momentum. By solving the Hamilton-Jacobi equation and separating the variables, the radial motion equation of a tunneling particle is obtained. Using near horizon approximation and the distance of the proper pure space, we calculate the tunneling rate and the temperature of Hawking radiation. Thus, the method of ANVZ covariance is extended to the research of high dimensional black hole tunneling radiation.

Novel genetic risk variants for pediatric celiac disease.

PubMed

Balasopoulou, Angeliki; Stanković, Biljana; Panagiotara, Angeliki; Nikčevic, Gordana; Peters, Brock A; John, Anne; Mendrinou, Effrosyni; Stratopoulos, Apostolos; Legaki, Aigli Ioanna; Stathakopoulou, Vasiliki; Tsolia, Aristoniki; Govaris, Nikolaos; Govari, Sofia; Zagoriti, Zoi; Poulas, Konstantinos; Kanariou, Maria; Constantinidou, Nikki; Krini, Maro; Spanou, Kleopatra; Radlovic, Nedeljko; Ali, Bassam R; Borg, Joseph; Drmanac, Radoje; Chrousos, George; Pavlovic, Sonja; Roma, Eleftheria; Zukic, Branka; Patrinos, George P; Katsila, Theodora

2016-10-24

Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c.4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n = 109) and Serbian (n = 73) descent and their healthy counterparts (n = 111 and n = 32, respectively) indicated that HoxD12 c.418G>A is more prevalent in celiac disease patients in the Serbian population (P < 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0.03). SLC9A4 c.1919G>A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance. The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology.

The USH2A c.2299delG mutation: dating its common origin in a Southern European population

PubMed Central

Aller, Elena; Larrieu, Lise; Jaijo, Teresa; Baux, David; Espinós, Carmen; González-Candelas, Fernando; Nájera, Carmen; Palau, Francesc; Claustres, Mireille; Roux, Anne-Françoise; Millán, José M

2010-01-01

Usher syndrome type II is the most common form of Usher syndrome. USH2A is the main responsible gene of the three known to be disease causing. It encodes two isoforms of the protein usherin. This protein is part of an interactome that has an essential role in the development and function of inner ear hair cells and photoreceptors. The gene contains 72 exons spanning over a region of 800 kb. Although numerous mutations have been described, the c.2299delG mutation is the most prevalent in several populations. Its ancestral origin was previously suggested after the identification of a common core haplotype restricted to 250 kb in the 5′ region that encodes the short usherin isoform. By extending the haplotype analysis over the 800 kb region of the USH2A gene with a total of 14 intragenic single nucleotide polymorphisms, we have been able to define 10 different c.2299delG haplotypes, showing high variability but preserving the previously described core haplotype. An exhaustive c.2299delG/control haplotype study suggests that the major source of variability in the USH2A gene is recombination. Furthermore, we have evidenced twice the amount of recombination hotspots located in the 500 kb region that covers the 3′ end of the gene, explaining the higher variability observed in this region when compared with the 250 kb of the 5′ region. Our data confirm the common ancestral origin of the c.2299delG mutation. PMID:20145675

Lenalidomide: a review of its use in patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndrome associated with 5q chromosome deletion.

PubMed

Syed, Yahiya Y; Scott, Lesley J

2013-07-01

Lenalidomide (Revlimid(®)), a thalidomide analogue, is an orally administered second generation immunomodulator with anti-angiogenic, antineoplastic, anti-inflammatory and pro-erythropoietic properties. It is approved for the treatment of patients with transfusion-dependent anaemia due to International Prognostic Scoring System low- or intermediate-1-risk myelodysplastic syndrome (MDS) associated with either chromosome 5q deletion [del(5q)] with or without additional cytogenetic abnormalities (US, Japan and Switzerland etc.), or with an isolated del(5q) cytogenetic abnormality when other therapeutic options are insufficient or inadequate (EU) [featured indication]. In a randomized, double-blind, multicentre, registrational trial (MDS-004; n = 205) in this patient population, a significantly higher proportion of lenalidomide recipients than placebo recipients achieved red blood cell transfusion independence for ≥26 consecutive weeks (primary endpoint for efficacy) and cytogenetic responses. The erythroid response to lenalidomide was accompanied by an increase in the haemoglobin levels. These efficacy outcomes are generally consistent with those seen in an earlier noncomparative registrational trial (MDS-003; n = 148). In MDS-004, lenalidomide also significantly improved health-related quality of life compared with placebo at 12 weeks. Retrospective analyses that compared outcomes between lenalidomide-treated patients with low- or intermediate-1-risk del(5q) MDS and multicentre registry cohorts showed that lenalidomide treatment did not appear to increase the risk of progression to acute myeloid leukaemia. Lenalidomide had a manageable safety profile in the registrational trials, with ≤20 % of patients discontinuing treatment because of adverse events. The most common adverse events (incidence ≥20 %) occurring in lenalidomide recipients were thrombocytopenia and neutropenia, which were generally managed by dosage reductions and/or interruptions, and/or pharmacotherapy. Thus, lenalidomide is a useful option for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk del(5q) MDS, with or without additional cytogenetic abnormalities.

Functional Independence in Late-Life: Maintaining Physical Functioning in Older Adulthood Predicts Daily Life Function after Age 80

PubMed Central

Leng, Xiaoyan; La Monte, Michael J.; Tindle, Hilary A.; Cochrane, Barbara B.; Shumaker, Sally A.

2016-01-01

Abstract Background. We examined physical functioning (PF) trajectories (maintaining, slowly declining, and rapidly declining) spanning 15 years in older women aged 65–80 and protective factors that predicted better current levels and less decline in functional independence outcomes after age 80. Methods. Women’s Health Initiative extension participants who met criteria (enrolled in either the clinical trial or observational study cohort, >80 years at the data release cutoff, PF survey data from initial enrollment to age 80, and functional independence survey data after age 80) were included in these analyses (mean [ SD ] age = 84.0 [1.4] years; N = 10,478). PF was measured with the SF-36 (mean = 4.9 occasions). Functional independence was measured by self-reported level of dependence in basic and instrumental activities of daily living (ADLs and IADLs) (mean = 3.4 and 3.3 occasions). Results. Maintaining consistent PF in older adulthood extends functional independence in ADL and IADL in late-life. Protective factors shared by ADL and IADL include maintaining PF over time, self-reported excellent or very good health, no history of hip fracture after age 55, and no history of cardiovascular disease. Better IADL function is uniquely predicted by a body mass index less than 25 and no depression. Less ADL and IADL decline is predicted by better self-reported health, and less IADL decline is uniquely predicted by having no history of hip fracture after age 55. Conclusions. Maintaining or improving PF and preventing injury and disease in older adulthood (ages 65–80) has far-reaching implications for improving late-life (after age 80) functional independence. PMID:26858328

Functional Independence in Late-Life: Maintaining Physical Functioning in Older Adulthood Predicts Daily Life Function after Age 80.

PubMed

Vaughan, Leslie; Leng, Xiaoyan; La Monte, Michael J; Tindle, Hilary A; Cochrane, Barbara B; Shumaker, Sally A

2016-03-01

We examined physical functioning (PF) trajectories (maintaining, slowly declining, and rapidly declining) spanning 15 years in older women aged 65-80 and protective factors that predicted better current levels and less decline in functional independence outcomes after age 80. Women's Health Initiative extension participants who met criteria (enrolled in either the clinical trial or observational study cohort, >80 years at the data release cutoff, PF survey data from initial enrollment to age 80, and functional independence survey data after age 80) were included in these analyses (mean [SD] age = 84.0 [1.4] years; N = 10,478). PF was measured with the SF-36 (mean = 4.9 occasions). Functional independence was measured by self-reported level of dependence in basic and instrumental activities of daily living (ADLs and IADLs) (mean = 3.4 and 3.3 occasions). Maintaining consistent PF in older adulthood extends functional independence in ADL and IADL in late-life. Protective factors shared by ADL and IADL include maintaining PF over time, self-reported excellent or very good health, no history of hip fracture after age 55, and no history of cardiovascular disease. Better IADL function is uniquely predicted by a body mass index less than 25 and no depression. Less ADL and IADL decline is predicted by better self-reported health, and less IADL decline is uniquely predicted by having no history of hip fracture after age 55. Maintaining or improving PF and preventing injury and disease in older adulthood (ages 65-80) has far-reaching implications for improving late-life (after age 80) functional independence. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Apoptosis-Dependent and Apoptosis-Independent Functions Bim in Prostate Cancer Cells

DTIC Science & Technology

2004-03-01

AD_ Award Number: DAMD17-03-1-0146 TITLE: Apoptosis-Dependent and Apoptosis-Independent Functions of Bim in Prostate Cancer Cells PRINCIPAL...FUNDING NUMBERS Apoptosis-Dependent and Apoptosis-Independent Functions of DAMD17-03-1-0146 Bim in Prostate Cancer Cells 6. A UTHORs) Junwei Liu, M.D...extended cell survival have been implicated in prostate cancer (PCa) development and progression. We recently found that Bim , a BH3-only pro

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Potentiator VX-770 (Ivacaftor) Opens the Defective Channel Gate of Mutant CFTR in a Phosphorylation-dependent but ATP-independent Manner* ♦

PubMed Central

Eckford, Paul D. W.; Li, Canhui; Ramjeesingh, Mohabir; Bear, Christine E.

2012-01-01

The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe. PMID:22942289

Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner.

PubMed

Eckford, Paul D W; Li, Canhui; Ramjeesingh, Mohabir; Bear, Christine E

2012-10-26

The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe.

Deletion of P399{sub E}401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flueck, Christa E., E-mail: christa.flueck@dkf.unibe.ch; Mallet, Delphine; Hofer, Gaby

2011-09-09

Highlights: {yields} Mutations in human POR cause congenital adrenal hyperplasia. {yields} We are reporting a novel 3 amino acid deletion mutation in POR P399{sub E}401del. {yields} POR mutation P399{sub E}401del decreased P450 activities by 60-85%. {yields} Impairment of steroid metabolism may be caused by multiple hits. {yields} Severity of aromatase inhibition is related to degree of in utero virilization. -- Abstract: P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399{sub E}401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant PORmore » proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399{sub E}401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17{alpha}-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399{sub E}401 revealed reduced stability and flexibility of the mutant. In conclusion, P399{sub E}401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399{sub E}401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.« less

Development of a smartphone application for the objective detection of attentional deficits in delirium.

PubMed

Tieges, Zoë; Stíobhairt, Antaine; Scott, Katie; Suchorab, Klaudia; Weir, Alexander; Parks, Stuart; Shenkin, Susan; MacLullich, Alasdair

2015-08-01

Delirium is an acute, severe deterioration in mental functioning. Inattention is the core feature, yet there are few objective methods for assessing attentional deficits in delirium. We previously developed a novel, graded test for objectively detecting inattention in delirium, implemented on a computerized device (Edinburgh Delirium Test Box (EDTB)). Although the EDTB is effective, tests on universally available devices have potential for greater impact. Here we assessed feasibility and validity of the DelApp, a smartphone application based on the EDTB. This was a preliminary case-control study in hospital inpatients (aged 60-96 years) with delirium (N = 50), dementia (N = 52), or no cognitive impairment (N = 54) who performed the DelApp assessment, which comprises an arousal assessment followed by counting of lights presented serially. Delirium was assessed using the Confusion Assessment Method and Delirium Rating Scale-Revised-98 (DRS-R98), and cognition with conventional tests of attention (e.g. digit span) and the short Orientation-Memory-Concentration Test (OMCT). DelApp scores (maximum score = 10) were lower in delirium (scores (median(IQR)): 6 (4-7)) compared to dementia (10 (9-10)) and control groups (10 (10-10), p-values < 0.001). Receiver operating characteristic (ROC) analyses revealed excellent accuracy of the DelApp for discriminating delirium from dementia (AUC = 0.93), and delirium from controls (AUC = 0.99, p-values < 0.001). DelApp and DRS-R98 severity scores were moderately well correlated (Kendall's tau = -0.60, p < 0.001). OMCT scores did not differ between delirium and dementia. The DelApp test showed good performance, supporting the utility of objectively measuring attention in delirium assessment. This study provides evidence of the feasibility of using a smartphone test for attentional assessment in hospital inpatients with possible delirium, with potential applications in research and clinical practice.

The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9.

PubMed

Bertrand, Carol A; Mitra, Shalini; Mishra, Sanjay K; Wang, Xiaohui; Zhao, Yu; Pilewski, Joseph M; Madden, Dean R; Frizzell, Raymond A

2017-06-01

Several members of the SLC26A family of anion transporters associate with CFTR, forming complexes in which CFTR and SLC26A functions are reciprocally regulated. These associations are thought to be facilitated by PDZ scaffolding interactions. CFTR has been shown to be positively regulated by NHERF-1, and negatively regulated by CAL in airway epithelia. However, it is unclear which PDZ-domain protein(s) interact with SLC26A9, a SLC26A family member found in airway epithelia. We have previously shown that primary, human bronchial epithelia (HBE) from non-CF donors exhibit constitutive anion secretion attributable to SLC26A9. However, constitutive anion secretion is absent in HBE from CF donors. We examined whether changes in SLC26A9 constitutive activity could be attributed to a loss of CFTR trafficking, and what role PDZ interactions played. HEK293 coexpressing SLC26A9 with the trafficking mutant F508del CFTR exhibited a significant reduction in constitutive current compared with cells coexpressing SLC26A9 and wt CFTR. We found that SLC26A9 exhibits complex glycosylation when coexpressed with F508del CFTR, but its expression at the plasma membrane is decreased. SLC26A9 interacted with both NHERF-1 and CAL, and its interaction with both significantly increased with coexpression of wt CFTR. However, coexpression with F508del CFTR only increased SLC26A9's interaction with CAL. Mutation of SLC26A9's PDZ motif decreased this association with CAL, and restored its constitutive activity. Correcting aberrant F508del CFTR trafficking in CF HBE with corrector VX-809 also restored SLC26A9 activity. We conclude that when SLC26A9 is coexpressed with F508del CFTR, its trafficking defect leads to a PDZ motif-sensitive intracellular retention of SLC26A9. Copyright © 2017 the American Physiological Society.

Community-Based Instruction and Differences in Functional Independence of Young Adults with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Johnson, Temperance L.

2014-01-01

Students with significant developmental disabilities who engage in activities outside the classroom appear to have better post-school outcomes in the areas of employability, living skills, and independence. No research has examined whether functional independence was significantly different in graduates with autism spectrum disorder (ASD) who have…

Independent Living Functions for the Elderly (IN-LIFE): Supporting Communication in Dementia.

PubMed

Smith, Sarah K; Astell, Arlene J

2017-01-01

Independent Living Functions for the Elderly (IN-LIFE) is a 3 year multidisciplinary, multisite European project that aims to prolong and support independent living for people with cognitive impairments, through (ICT) services. Sheffield is one of six research sites and is focused on enhancing communication and conversations using touch screen computers.

Independent functions and the geometry of Banach spaces

NASA Astrophysics Data System (ADS)

Astashkin, Sergey V.; Sukochev, Fedor A.

2010-12-01

The main objective of this survey is to present the `state of the art' of those parts of the theory of independent functions which are related to the geometry of function spaces. The `size' of a sum of independent functions is estimated in terms of classical moments and also in terms of general symmetric function norms. The exposition is centred on the Rosenthal inequalities and their various generalizations and sharp conditions under which the latter hold. The crucial tool here is the recently developed construction of the Kruglov operator. The survey also provides a number of applications to the geometry of Banach spaces. In particular, variants of the classical Khintchine-Maurey inequalities, isomorphisms between symmetric spaces on a finite interval and on the semi-axis, and a description of the class of symmetric spaces with any sequence of symmetrically and identically distributed independent random variables spanning a Hilbert subspace are considered. Bibliography: 87 titles.

The personal receiving document management and the realization of email function in OAS

NASA Astrophysics Data System (ADS)

Li, Biqing; Li, Zhao

2017-05-01

This software is an independent software system, suitable for small and medium enterprises, contains personal office, scientific research project management and system management functions, independently run in relevant environment, and to solve practical needs. This software is an independent software system, using the current popular B/S (browser/server) structure and ASP.NET technology development, using the Windows 7 operating system, Microsoft SQL Server2005 Visual2008 and database as a development platform, suitable for small and medium enterprises, contains personal office, scientific research project management and system management functions, independently run in relevant environment, and to solve practical needs.

Determinants of Occupational and Residential Functioning in Bipolar Disorder

PubMed Central

Depp, Colin A; Mausbach, Brent T; Bowie, Christopher; Wolyniec, Paula; Thornquist, Mary H.; Luke, James R.; McGrath, John A.; Pulver, Ann E.; Harvey, Philip D.; Patterson, Thomas L

2013-01-01

Background Bipolar disorder is associated with reduced rates of employment and residential independence. The influence of cognitive impairment and affective symptoms on these functional attainments has received little previous attention and is the focus of this study. Method A total of 229 adult outpatients with bipolar disorder without active substance use disorders and with an average of mild severity of affective symptoms were included in the analyses. After adjusting for sociodemographic and illness history covariates, univariate and multivariate analyses were used to evaluate the independent and interactive associations of neurocognitive ability, performance-based functional capacity, and affective symptom severity with residential independence, occupational status and number of hours worked. Results A total of 30% of the sample was unemployed and 18% were not independently residing. Neurocognitive ability was the strongest predictor of any employment, but depressive symptom severity was the only variable significantly related to hours worked. The strongest predictor of residential independence was performance-based functional capacity. Affective symptoms and neurocognitive ability were independent (non-interactive) predictors of occupational and residential status. Limitations This is a cross-sectional study and thus causal direction among variables is unknown. The sample was ethnically homogeneous and thus the results may not generalize to ethnically diverse samples. Conclusions This study confirmed elevated rates of unemployment and residential non-independence in adults with bipolar disorder. Interventions targeting cognitive deficits and functional capacity may increase the likelihood of any employment or residential independence, respectively. Interventions targeting depressive symptoms may be most influential on work outcomes among those already employed. PMID:22129770

Sociologia del linguaggio ed insegnamento delle lingue (Language Sociology and Language Teaching).

ERIC Educational Resources Information Center

Braga, Giorgio

1980-01-01

Discusses the fundamental aspects of verbal communication and analyzes its functions in terms of social needs. Takes an historical perspective to distinguish different levels of social development characterized by different communication requirements and stages of language evolution. From these premises, it argues for a sociocultural approach to…

Accurate quantification of chromosomal lesions via short tandem repeat analysis using minimal amounts of DNA

PubMed Central

Jann, Johann-Christoph; Nowak, Daniel; Nolte, Florian; Fey, Stephanie; Nowak, Verena; Obländer, Julia; Pressler, Jovita; Palme, Iris; Xanthopoulos, Christina; Fabarius, Alice; Platzbecker, Uwe; Giagounidis, Aristoteles; Götze, Katharina; Letsch, Anne; Haase, Detlef; Schlenk, Richard; Bug, Gesine; Lübbert, Michael; Ganser, Arnold; Germing, Ulrich; Haferlach, Claudia; Hofmann, Wolf-Karsten; Mossner, Maximilian

2017-01-01

Background Cytogenetic aberrations such as deletion of chromosome 5q (del(5q)) represent key elements in routine clinical diagnostics of haematological malignancies. Currently established methods such as metaphase cytogenetics, FISH or array-based approaches have limitations due to their dependency on viable cells, high costs or semi-quantitative nature. Importantly, they cannot be used on low abundance DNA. We therefore aimed to establish a robust and quantitative technique that overcomes these shortcomings. Methods For precise determination of del(5q) cell fractions, we developed an inexpensive multiplex-PCR assay requiring only nanograms of DNA that simultaneously measures allelic imbalances of 12 independent short tandem repeat markers. Results Application of this method to n=1142 samples from n=260 individuals revealed strong intermarker concordance (R²=0.77–0.97) and reproducibility (mean SD: 1.7%). Notably, the assay showed accurate quantification via standard curve assessment (R²>0.99) and high concordance with paired FISH measurements (R²=0.92) even with subnanogram amounts of DNA. Moreover, cytogenetic response was reliably confirmed in del(5q) patients with myelodysplastic syndromes treated with lenalidomide. While the assay demonstrated good diagnostic accuracy in receiver operating characteristic analysis (area under the curve: 0.97), we further observed robust correlation between bone marrow and peripheral blood samples (R²=0.79), suggesting its potential suitability for less-invasive clonal monitoring. Conclusions In conclusion, we present an adaptable tool for quantification of chromosomal aberrations, particularly in problematic samples, which should be easily applicable to further tumour entities. PMID:28600436

Autism spectrum disorder in Prader-Willi syndrome: A systematic review.

PubMed

Bennett, Jeffrey A; Germani, Tamara; Haqq, Andrea M; Zwaigenbaum, Lonnie

2015-12-01

Prader-Willi syndrome (PWS) is a rare genetic disorder that results from lack of expression of paternally-derived genes on chromosome 15q11-13; caused by a deletion (DEL), uniparental disomy (UPD), or a rare imprinting center defect. PWS is associated with a distinct behavioral phenotype that in some respects overlaps with autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by restricted or repetitive behaviors (RRBs) and social-communication impairment. The goal of this review was to (i) review published literature investigating core ASD symptoms in PWS and (ii) provide a prevalence estimate of ASD in PWS. Two independent reviewers searched Medline, CINAHL, PsychINFO, Embase, and Web of Science to find studies that answered the research questions. Individuals with PWS demonstrate significant levels of RRBs and social-communication impairment, in some reports reaching similar levels to those of non-PWS ASD comparison groups. Individuals with UPD had more social-communication impairment than those with DEL. Of 786 PWS participants, 210 (26.7%) were reported as meeting criteria for ASD, either based on clinical diagnosis or by exceeding clinical cut-points on relevant ASD symptom measures. In studies that distinguished genetic subtypes, rates of ASD were higher in individuals with PWS with UPD (67 of 190; 35.3%) than those with DEL (47 of 254; 18.5%). Published data on the association of PWS and ASD to date are limited to sample means of 8 years of age and older. Further research is needed to identify early markers of ASD in PWS children, to support earlier diagnosis and intervention for this important comorbidity. © 2015 Wiley Periodicals, Inc.

The Functional Independence of Mands and Tacts: Has It Been Demonstrated Empirically?

ERIC Educational Resources Information Center

Gamba, Jonas; Goyos, Celso; Petursdottir, Anna Ingeborg

2015-01-01

Recently, there has been a proliferation of research on the functional independence of two of Skinner's (1957) verbal operants, the mand, and the tact. This research has produced highly variable results. In this article, we provide a critical review of the literature on mand-tact independence, a literature that has implications for both theory and…

Sea level oscillations in coastal waters of the Buenos Aires province, Argentina

NASA Astrophysics Data System (ADS)

Dragani, W. C.; Mazio, C. A.; Nuñez, M. N.

2002-03-01

Sea level oscillations, with periods ranging from a few minutes to almost 2 h, have been observed at various tide stations located on the coast of Buenos Aires. Simultaneous records of sea level elevation measured in Mar de Ajó, Pinamar and Mar del Plata during 1982 have been spectrally analyzed. Significant spectral energy has been detected between 0.85 and 4.69 cycles per hour (cph) and the most energetic peaks have frequencies between 1.17 and 1.49 cph. Spectra, coherence, and phase difference have been analyzed for the most energetic event of the year. During that event, the most intensive spectral peak is at 1.17 cph for Mar de Ajó and Pinamar, and at 1.49 cph for Mar del Plata. Simultaneous total energy peaks at Mar de Ajó, Pinamar and Mar del Plata, and the coherence function estimated between Mar de Ajó and Pinamar suggests that sea level oscillations could be a regional phenomenon. The analyzed data suggest that sea level oscillations could be forced by atmospheric gravity waves associated with frontal passages.

Variable pathogenicity of exon 43del (FAA) in four Fanconi anaemia patients within a consanguineous family.

PubMed

Koc, A; Pronk, J C; Alikasifoglu, M; Joenje, H; Altay, C

1999-01-01

Four Fanconi anaemia group A (FAA) patients within two related consanguineous families are presented: the propositus (male, 13 years, transplanted at age 10), and his three cousins (one male, 8 years, and two female newborns). Assignment of the patients to FAA was based on the functional complementation analysis by somatic cell hybridization and confirmed by mutation screening showing a homozygous deletion of exon 43 (4267-4404del) in the FAA gene to be present in all four patients. The newborn patients had been diagnosed prenatally by DNA analysis. In spite of identical molecular pathology and close familial relationship the clinical phenotypes of the four patients were not concordant. Discordant symptoms included birthweight, pigmentation abnormalities, skeletal, renal and genital abnormalities, whereas microcephaly and possibly the haematological course were concordant. Differences in environmental conditions and/or genetic make-up along with chance effects during development may explain discordant phenotypes despite identical molecular pathology in these patients. However, our results do not rule out the possibility that the exon 43del mutation may have prognostic value for the haematological course of the disease.

Asymptotic-preserving Lagrangian approach for modeling anisotropic transport in magnetized plasmas for arbitrary magnetic fields

NASA Astrophysics Data System (ADS)

Chacon, Luis; Del-Castillo-Negrete, Diego; Hauck, Cory

2012-10-01

Modeling electron transport in magnetized plasmas is extremely challenging due to the extreme anisotropy between parallel (to the magnetic field) and perpendicular directions (χ/χ˜10^10 in fusion plasmas). Recently, a Lagrangian Green's function approach, developed for the purely parallel transport case,footnotetextD. del-Castillo-Negrete, L. Chac'on, PRL, 106, 195004 (2011)^,footnotetextD. del-Castillo-Negrete, L. Chac'on, Phys. Plasmas, 19, 056112 (2012) has been extended to the anisotropic transport case in the tokamak-ordering limit with constant density.footnotetextL. Chac'on, D. del-Castillo-Negrete, C. Hauck, JCP, submitted (2012) An operator-split algorithm is proposed that allows one to treat Eulerian and Lagrangian components separately. The approach is shown to feature bounded numerical errors for arbitrary χ/χ ratios, which renders it asymptotic-preserving. In this poster, we will present the generalization of the Lagrangian approach to arbitrary magnetic fields. We will demonstrate the potential of the approach with various challenging configurations, including the case of transport across a magnetic island in cylindrical geometry.

Molecular Genetic and Functional Characterization Implicate Muscle-Restricted Coiled-Coil Gene (MURC) as a Causal Gene for Familial Dilated Cardiomyopathy

PubMed Central

Rodriguez, Gabriela; Ueyama, Tomomi; Ogata, Takehiro; Czernuszewicz', Grazyna; Tan, Yanli; Dorn, Gerald W.; Bogaev, Roberta; Amano, Katsuya; Oh, Hidemasa; Matsubara, Hiroaki; Willerson, James T.; Marian, Ali J.

2011-01-01

Background Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. Methods and Results We sequenced MURC in 1,199 individuals including 383 probands with DCM, 307 with HCM and 509 healthy controls. We found six heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L and p.S364L) in eight unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ2=8.5, p=0.003). Variants p.N128K, p.R140W, p.L153P and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in three independent probands, including one proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in three unrelated HCM probands but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L970V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in four patients, conduction defects and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared to wild type MURC. Conclusions MURC mutations impart loss-of-function effects on MURC functions and are likely causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain. PMID:21642240

Molecular genetic and functional characterization implicate muscle-restricted coiled-coil gene (MURC) as a causal gene for familial dilated cardiomyopathy.

PubMed

Rodriguez, Gabriela; Ueyama, Tomomi; Ogata, Takehiro; Czernuszewicz, Grazyna; Tan, Yanli; Dorn, Gerald W; Bogaev, Roberta; Amano, Katsuya; Oh, Hidemasa; Matsubara, Hiroaki; Willerson, James T; Marian, Ali J

2011-08-01

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. We sequenced MURC in 1199 individuals, including 383 probands with DCM, 307 with HCM, and 509 healthy control subjects. We found 6 heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L, and p.S364L) in 8 unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ(2)=8.5, P=0.003). Variants p.N128K, p.R140W, p.L153P, and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in 3 independent probands, including 1 proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in 3 unrelated HCM probands, but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L907V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in 4 patients, conduction defects, and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared with wild-type MURC. MURC mutations impart loss-of-function effects on MURC functions and probably are causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain.

Mutations in MAB21L2 result in ocular Coloboma, microcornea and cataracts.

PubMed

Deml, Brett; Kariminejad, Ariana; Borujerdi, Razieh H R; Muheisen, Sanaa; Reis, Linda M; Semina, Elena V

2015-01-01

Ocular coloboma results from abnormal embryonic development and is often associated with additional ocular and systemic features. Coloboma is a highly heterogeneous disorder with many cases remaining unexplained. Whole exome sequencing from two cousins affected with dominant coloboma with microcornea, cataracts, and skeletal dysplasia identified a novel heterozygous allele in MAB21L2, c.151 C>G, p.(Arg51Gly); the mutation was present in all five family members with the disease and appeared de novo in the first affected generation of the three-generational pedigree. MAB21L2 encodes a protein similar to C. elegans mab-21 cell fate-determining factor; the molecular function of MAB21L2 is largely unknown. To further evaluate the role of MAB21L2, zebrafish mutants carrying a p.(Gln48Serfs*5) frameshift truncation (mab21l2Q48Sfs*5) and a p.(Arg51_Phe52del) in-frame deletion (mab21l2R51_F52del) were developed with TALEN technology. Homozygous zebrafish embryos from both lines developed variable lens and coloboma phenotypes: mab21l2Q48Sfs*5 embryos demonstrated severe lens and retinal defects with complete lethality while mab21l2R51_F52del mutants displayed a milder lens phenotype and severe coloboma with a small number of fish surviving to adulthood. Protein studies showed decreased stability for the human p.(Arg51Gly) and zebrafish p.(Arg51_Phe52del) mutant proteins and predicted a complete loss-of-function for the zebrafish p.(Gln48Serfs*5) frameshift truncation. Additionally, in contrast to wild-type human MAB21L2 transcript, mutant p.(Arg51Gly) mRNA failed to efficiently rescue the ocular phenotype when injected into mab21l2Q48Sfs*5 embryos, suggesting this allele is functionally deficient. Histology, immunohistochemistry, and in situ hybridization experiments identified retinal invagination defects, an increase in cell death, abnormal proliferation patterns, and altered expression of several ocular markers in the mab21l2 mutants. These findings support the identification of MAB21L2 as a novel factor involved in human coloboma and highlight the power of genome editing manipulation in model organisms for analysis of the effects of whole exome variation in humans.

Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

PubMed Central

Van Goor, Fredrick; Hadida, Sabine; Grootenhuis, Peter D. J.; Burton, Bill; Cao, Dong; Neuberger, Tim; Turnbull, Amanda; Singh, Ashvani; Joubran, John; Hazlewood, Anna; Zhou, Jinglan; McCartney, Jason; Arumugam, Vijayalaksmi; Decker, Caroline; Yang, Jennifer; Young, Chris; Olson, Eric R.; Wine, Jeffery J.; Frizzell, Raymond A.; Ashlock, Melissa; Negulescu, Paul

2009-01-01

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (Po) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl− secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by ≈10-fold, to ≈50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na+ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway. PMID:19846789

A case report: a heterozygous deletion (2791_2805 del) in exon 18 of the filamin C gene causing filamin C-related myofibrillar myopathies in a Chinese family.

PubMed

Miao, Jing; Su, Fei-Fei; Liu, Xue-Mei; Wei, Xiao-Jing; Yuan, Yun; Yu, Xue-Fan

2018-06-04

Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient's serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient's father, sister, brother, three paternal aunts, one paternal uncle, and the uncle's son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness.

Constitutional del(19)(q12q13.1) in a three-year-old girl with severe phenotypic abnormalities affecting multiple organ systems.

PubMed

Kulharya, A S; Michaelis, R C; Norris, K S; Taylor, H A; Garcia-Heras, J

1998-06-05

We present the clinical, cytogenetic, and molecular studies on a constitutional deletion of 19q ascertained prenatally due to decreased fetal activity and IUGR. Chromosome analysis by GTG banding on amniocytes suggested a del(19)(q13.1q13.3), but the analysis of microsatellites by PCR demonstrated that the deletion involved the distal segment of q12 and the proximal segment of q13.1 (15 cM). The severely affected female infant born at 38 weeks has clinical findings that may be related to haploinsufficiency of specific genes within 19q12.1-->q13.1 that control important processes of normal development and cell function.

The Independent Associations of Physical Activity and Sleep with Cognitive Function in Older Adults.

PubMed

Falck, Ryan S; Best, John R; Davis, Jennifer C; Liu-Ambrose, Teresa

2018-01-01

Current evidence suggests physical activity (PA) and sleep are important for cognitive health; however, few studies examining the role of PA and sleep for cognitive health have measured these behaviors objectively. We cross-sectionally examined whether 1) higher PA is associated with better cognitive performance independently of sleep quality; 2) higher sleep quality is associated with better cognitive performance independently of PA; and 3) whether higher PA is associated with better sleep quality. We measured PA, subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep quality (i.e., fragmentation, efficiency, duration, and latency) using the MotionWatch8© in community-dwelling adults (N = 137; aged 55+). Cognitive function was indexed using the Alzheimer's Disease Assessment Scale-Plus. Correlation analyses were performed to determine relationships between PA, sleep quality, and cognitive function. We then used latent variable modelling to examine the relationships of PA with cognitive function independently of sleep quality, sleep quality with cognitive function independently of PA, and PA with sleep quality. We found greater PA was associated with better cognitive performance independently of 1) PSQI (β= -0.03; p < 0.01); 2) sleep fragmentation (β= -0.02; p < 0.01); 3) sleep duration (β= -0.02; p < 0.01); and 4) sleep latency (β= -0.02; p < 0.01). In addition, better sleep efficiency was associated with better cognitive performance independently of PA (β= -0.01; p = 0.04). We did not find any associations between PA and sleep quality. PA is associated with better cognitive performance independently of sleep quality, and sleep efficiency is associated with better cognitive performance independently of PA. However, PA is not associated with sleep quality and thus PA and sleep quality may be related to cognitive performance through independent mechanisms.

[Health status of the elderly in primary health care practices using an integral geriatric assessment].

PubMed

Cervantes Becerra, Roxana Gisela; Villarreal Ríos, Enrique; Galicia Rodríguez, Liliana; Vargas Daza, Emma Rosa; Martínez González, Lidia

2015-01-01

To determine the health status of patients 60 years of age or over in Primary Health Care practices using an integral geriatric assessment. Descriptive cross-sectional study. Five primary care units, Instituto Mexicano del Seguro Social; México. Elderly patient aged 60 years of age or over, who were seen in primary health care practices. Previously signed informed consent was given, with exclusion criteria being non-completion of the integral geriatric assessment. A technical sample of conglomerates and quota was used. Medical dimension variables: visual, hearing (Hearing Handicap Inventory for the Elderly), urinary incontinence (Consultation in Incontinence Questionnaire), nutritional condition (Mini Nutritional Assessment), personal clinical history, polypharmacy; mental impairment (Mini Mental State Examination), depression (Yesavaje); functional: basic (Katz) and instrumental (Lawton and Brody) activities of daily living, mobility (Up and go) and social (Social sources scale). The analysis included percentages and confidence intervals. In the medical dimensions; 42.3% with visual impairment, 27.7% hearing, 68.3% urinary incontinence, 37.0% malnutrition, and 54.7% polypharmacy. In the mental dimension: 4.0% severe mental impairment, and 11% depression: functional dimension: 2.0% total dependence of activities of daily living; 14.3% instrumental activities impairment; 29.0% mobility impairment, and 48.0% had moderately deteriorated social resources. The health status of the elderly seen in primary health care practices is characterized by independent patients with different levels of alterations in the medical dimensions, low levels in mental alteration, and moderately deteriorated social resources. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Limit on Neutrinoless Double Beta Decay of 76Ge by GERDA

NASA Astrophysics Data System (ADS)

Agostini, M.; Allardt, M.; Andreotti, E.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Heider, M. Barabè; Barros, N.; Baudis, L.; Bauer, C.; Becerici-Schmidt, N.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Brudanin, V.; Brugnera, R.; Budjáš, D.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; Cossavella, F.; Demidova, E. V.; Domula, A.; Egorov, V.; Falkenstein, R.; Ferella, A.; Freund, K.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Gotti, C.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Guthikonda, K. K.; Hampel, W.; Hegai, A.; Heisel, M.; Hemmer, S.; Heusser, G.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Csáthy, J. Janicskó; Jochum, J.; Junker, M.; Kihm, T.; Kirpichnikov, I. V.; Kirsch, A.; Klimenko, A.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V. V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Liao, H. Y.; Lindner, M.; Lippi, I.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Machado, A. A.; Macolino, C.; Majorovits, B.; Maneschg, W.; Misiaszek, M.; Nemchenok, I.; Nisi, S.; Shaughnessy, C. O.'.; Pandola, L.; Pelczar, K.; Pessina, G.; Pullia, A.; Riboldi, S.; Rumyantseva, N.; Sada, C.; Salathe, M.; Schmitt, C.; Schreiner, J.; Schulz, O.; Schwingenheuer, B.; Schönert, S.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Strecker, H.; Tarka, M.; Ur, C. A.; Vasenko, A. A.; Volynets, O.; von Sturm, K.; Wagner, V.; Walter, M.; Wegmann, A.; Wester, T.; Wojcik, M.; Yanovich, E.; Zavarise, P.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

The Gerda experiment at the Laboratori Nazionali del Gran Sasso in Italy uses germanium detectors made from material with an enriched 76Ge isotope fraction to search for neutrinoless double beta decay of this nucleus. Applying a blind analysis we find no signal after an exposure of 21.6 kg·yr and a background of about 0.01 cts/(keV·kg·yr). A half-life limit of Tov1/2> 2.1 · 1025 yr (90% C.L.) is extracted. The previous claim of a signal for 76Ge is excluded with 99% probability in a model independent way.

With simple gasoline stripping devices, a problem of gas transportation by pipeline is resolved (in Spanish)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Couto, J.A.

1975-06-01

Liquid hydrocarbons contained in Argentina's Pico Truncade natural gas caused a number of serious pipeline transmission and gas processing problems. Gas del Estado has installed a series of efficient liquid removal devices at the producing fields. A flow chart of the gasoline stripping process is illustrated, as are 2 types of heat exchangers. This process of gasoline stripping (gas condensate recovery) integrates various operations which normally are performed independently: separation of the poor condensate in the gas, stabilization of the same, and incorporation of the light components (products of the stabilization) in the main gas flow.

Cyclic Mario worlds — color-decomposition for one-loop QCD

NASA Astrophysics Data System (ADS)

Kälin, Gregor

2018-04-01

We present a new color decomposition for QCD amplitudes at one-loop level as a generalization of the Del Duca-Dixon-Maltoni and Johansson-Ochirov decomposition at tree level. Starting from a minimal basis of planar primitive amplitudes we write down a color decomposition that is free of linear dependencies among appearing primitive amplitudes or color factors. The conjectured decomposition applies to any number of quark flavors and is independent of the choice of gauge group and matter representation. The results also hold for higher-dimensional or supersymmetric extensions of QCD. We provide expressions for any number of external quark-antiquark pairs and gluons. [Figure not available: see fulltext.

Asymptotic-preserving Lagrangian approach for modeling anisotropic transport in magnetized plasmas

NASA Astrophysics Data System (ADS)

Chacon, Luis; Del-Castillo-Negrete, Diego

2011-10-01

Modeling electron transport in magnetized plasmas is extremely challenging due to the extreme anisotropy introduced by the presence of the magnetic field (χ∥ /χ⊥ ~1010 in fusion plasmas). Recently, a novel Lagrangian method has been proposed to solve the local and non-local purely parallel transport equation in general 3D magnetic fields. The approach avoids numerical pollution (in fact, it respects transport barriers -flux surfaces- exactly by construction), is inherently positivity-preserving, and is scalable algorithmically (i.e., work per degree-of-freedom is grid-independent). In this poster, we discuss the extension of the Lagrangian approach to include perpendicular transport and sources. We present an asymptotic-preserving numerical formulation that ensures a consistent numerical discretization temporally and spatially for arbitrary χ∥ /χ⊥ ratios. This is of importance because parallel and perpendicular transport terms in the transport equation may become comparable in regions of the plasma (e.g., at incipient islands), while remaining disparate elsewhere. We will demonstrate the potential of the approach with various challenging configurations, including the case of transport across a magnetic island in cylindrical geometry. D. del-Castillo-Negrete, L. Chacón, PRL, 106, 195004 (2011); DPP11 invited talk by del-Castillo-Negrete.

The association between atrial fibrillation and cognitive function in patients with heart failure.

PubMed

Yang, Huifeng; Niu, Weihua; Zang, Xiaoying; Lin, Mei; Zhao, Yue

2017-02-01

Atrial fibrillation (AF) is associated with cognitive impairment in heart failure (HF). The purpose of this study was to examine whether AF independently predicted cognitive function in HF patients after controlling for more demographic, medical and psychological characteristics, and whether the timing of AF onset in relation to HF diagnosis independently contributed to cognitive function in HF patients with AF. A total of 188 hospitalized HF patients (62.8% male, age 66.3±10.6 years) completed cognitive function assessment with the Montreal Cognitive Assessment (MoCA). A history of AF, along with other medical characteristics, was ascertained through a review of participants' medical charts. The timing of AF onset in relation to HF diagnosis was categorized into AF occurring prior to HF diagnosis (i.e. prior AF) and AF developing after HF diagnosis (i.e. incident AF). Altogether 72 participants had a positive diagnostic history of AF. Specifically, 41 had prior AF, and 31 developed AF subsequently. In HF patients, AF was associated with poorer performance on cognitive function after controlling for more confounders (β=-0.112, ΔR 2 =0.010, p=0.046). Among HF patients with AF, incident AF independently predicted poorer cognitive function (β=-0.238, ΔR 2 =0.027, p=0.047). AF independently contributes to cognitive function in HF patients after adjusting for more confounding variables. The timing of AF onset in relation to HF diagnosis independently predicts cognitive function in HF patients with AF. Prospective studies are needed to elucidate possible mechanisms for the association between AF and cognitive function in HF populations.

A method for measuring quality of life through subjective weighting of functional status.

PubMed

Stineman, Margaret G; Wechsler, Barbara; Ross, Richard; Maislin, Greg

2003-04-01

To apply a new tool to understand the quality of life (QOL) implications of patients' functional status. Results from the Features-Resource Trade-Off Game were used to form utility weights by ranking functional activities by the relative value of achieving independence in each activity compared with all other component activities. The utility weights were combined with patients' actual levels of performance across the same activities to produce QOL-weighted functional status scores and to form "value rulers" to order activities by perceived importance. Persons with severe disabilities living in the community and clinicians practicing in various rehabilitation disciplines. Two panels of 5 consumers with disabilities and 2 panels of 5 rehabilitation clinicians. The 4 panels played the Features Resource Trade-Off Game by using the FIMT(TM) instrument definitions. Utility weights for each of the 18 FIM items, QOL-weighted FIM scores, and value rulers. All 4 panels valued the achievement of independence in cognitive and communication activities more than independence in physical activities. Consequently, the unweighted FIM scores of patients who have severe physical disabilities but relatively intact cognitive skills will underestimate QOL, while inflating QOL in those with low levels of independence in cognition and communication but higher physical function. Independence in some activities is more valued than in others; thus, 2 people with the same numeric functional status score could experience very different QOL. QOL-weighted functional status scores translate objectively measured functional status into its subjective meaning. This new technology for measuring subjective function-related QOL has a variety of applications to clinical, educational, and research practices.

First Chance Outreach. Del Rio First Chance Early Childhood Program.

ERIC Educational Resources Information Center

Hanna, Cornelia B.; Levermann, D.

In order to help handicapped children function in regular school programs by the time they enter first grade, the First Chance Early Childhood Program provides precise intervention into the development of children aged 3 to 5 with clearly identified handicapping conditions. Using English and/or Spanish, program staff test and measure the referred…

SIGMA Final Report. Volume V, Part 1-3. Introduction, Functional Description and Evaluation.

DTIC Science & Technology

1982-05-01

AD-AlSb 359 UNIVERSITY OF SOUTHERN CALIFORNIA MARINA DEL REY INFO-ETC F/6 17/2 SIGMA FINAL REPORT . VOLUME V. PART 1-3. INTRODUCTION. FUNCTIONA-ETC(U...EIIIIIIIIIIIIE IIIEIIIIEIIIII 111111111111flfflfflEllllllEEllEE H ~28 ",2,5 11111 ..25 .411111 ii1.6 MICROCOPY RESOLUTION TEST CHAFT N W MME Final Report ...Volume V, Parts 1, 2, and 3 ISI/FiR-82-94 SIGMA Final Report : Introduction, Functional Description, and Evaluation Robert Stotz David Wilczynski

Lack of Spartin Protein in Troyer Syndrome

PubMed Central

Bakowska, Joanna C.; Wang, Heng; Xin, Baozhong; Sumner, Charlotte J.; Blackstone, Craig

2017-01-01

Background Hereditary spastic paraplegias (SPG1-SPG33) are characterized by progressive spastic weakness of the lower limbs. A nucleotide deletion (1110delA) in the (SPG20; OMIM 275900) spartin gene is the origin of autosomal recessive Troyer syndrome. This mutation is predicted to cause premature termination of the spartin protein. However, it remains unknown whether this truncated spartin protein is absent or is present and partially functional in patients. Objective To determine whether the truncated spartin protein is present or absent in cells derived from patients with Troyer syndrome. Design Case report. Setting Academic research. Patients We describe a new family with Troyer syndrome due to the 1110delA mutation. Main Outcome Measures We cultured primary fibroblasts and generated lymphoblasts from affected individuals, carriers, and control subjects and subjected these cells to immunoblot analyses. Results Spartin protein is undetectable in several cell lines derived from patients with Troyer syndrome. Conclusions Our data suggest that Troyer syndrome results from complete loss of spartin protein rather than from the predicted partly functional fragment. This may reflect increased protein degradation or impaired translation. PMID:18413476

Genome wide linkage disequilibrium and genetic structure in Sicilian dairy sheep breeds.

PubMed

Mastrangelo, Salvatore; Di Gerlando, Rosalia; Tolone, Marco; Tortorici, Lina; Sardina, Maria Teresa; Portolano, Baldassare

2014-10-10

The recent availability of sheep genome-wide SNP panels allows providing background information concerning genome structure in domestic animals. The aim of this work was to investigate the patterns of linkage disequilibrium (LD), the genetic diversity and population structure in Valle del Belice, Comisana, and Pinzirita dairy sheep breeds using the Illumina Ovine SNP50K Genotyping array. Average r (2) between adjacent SNPs across all chromosomes was 0.155 ± 0.204 for Valle del Belice, 0.156 ± 0.208 for Comisana, and 0.128 ± 0.188 for Pinzirita breeds, and some variations in LD value across chromosomes were observed, in particular for Valle del Belice and Comisana breeds. Average values of r (2) estimated for all pairwise combinations of SNPs pooled over all autosomes were 0.058 ± 0.023 for Valle del Belice, 0.056 ± 0.021 for Comisana, and 0.037 ± 0.017 for Pinzirita breeds. The LD declined as a function of distance and average r (2) was lower than the values observed in other sheep breeds. Consistency of results among the several used approaches (Principal component analysis, Bayesian clustering, F ST, Neighbor networks) showed that while Valle del Belice and Pinzirita breeds formed a unique cluster, Comisana breed showed the presence of substructure. In Valle del Belice breed, the high level of genetic differentiation within breed, the heterogeneous cluster in Admixture analysis, but at the same time the highest inbreeding coefficient, suggested that the breed had a wide genetic base with inbred individuals belonging to the same flock. The Sicilian breeds were characterized by low genetic differentiation and high level of admixture. Pinzirita breed displayed the highest genetic diversity (He, Ne) whereas the lowest value was found in Valle del Belice breed. This study has reported for the first time estimates of LD and genetic diversity from a genome-wide perspective in Sicilian dairy sheep breeds. Our results indicate that breeds formed non-overlapping clusters and are clearly separated populations and that Comisana sheep breed does not constitute a homogenous population. The information generated from this study has important implications for the design and applications of association studies as well as for development of conservation and/or selection breeding programs.

BRCA1 And BRCA2 analysis of Argentinean breast/ovarian cancer patients selected for age and family history highlights a role for novel mutations of putative south-American origin.

PubMed

Solano, Angela Rosaria; Aceto, Gitana Maria; Delettieres, Dreanina; Veschi, Serena; Neuman, Maria Isabel; Alonso, Eduardo; Chialina, Sergio; Chacón, Reinaldo Daniel; Renato, Mariani-Costantini; Podestá, Ernesto Jorge

2012-01-01

The spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history. The study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2). We found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component. This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews.

Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study

PubMed Central

Zhou, Kaixin; Donnelly, Louise A.; Kimber, Charlotte H.; Donnan, Peter T.; Doney, Alex S.F.; Leese, Graham; Hattersley, Andrew T.; McCarthy, Mark I.; Morris, Andrew D.; Palmer, Colin N.A.; Pearson, Ewan R.

2009-01-01

OBJECTIVE Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C <7% was achieved. Sustained metformin effect on A1C between 6 and 42 months was also assessed, as was the time to metformin monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence, and creatinine clearance. RESULTS A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56). CONCLUSIONS The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes. PMID:19336679

Electrostatic potential calculation for biomolecules--creating a database of pre-calculated values reported on a per residue basis for all PDB protein structures.

PubMed

Rocchia, W; Neshich, G

2007-10-05

STING and Java Protein Dossier provide a collection of physical-chemical parameters, describing protein structure, stability, function, and interaction, considered one of the most comprehensive among the available protein databases of similar type. Particular attention in STING is paid to the electrostatic potential. It makes use of DelPhi, a well-known tool that calculates this physical-chemical quantity for biomolecules by solving the Poisson Boltzmann equation. In this paper, we describe a modification to the DelPhi program aimed at integrating it within the STING environment. We also outline how the "amino acid electrostatic potential" and the "surface amino acid electrostatic potential" are calculated (over all Protein Data Bank (PDB) content) and how the corresponding values are made searchable in STING_DB. In addition, we show that the STING and Java Protein Dossier are also capable of providing these particular parameter values for the analysis of protein structures modeled in computers or being experimentally solved, but not yet deposited in the PDB. Furthermore, we compare the calculated electrostatic potential values obtained by using the earlier version of DelPhi and those by STING, for the biologically relevant case of lysozyme-antibody interaction. Finally, we describe the STING capacity to make queries (at both residue and atomic levels) across the whole PDB, by looking at a specific case where the electrostatic potential parameter plays a crucial role in terms of a particular protein function, such as ligand binding. BlueStar STING is available at http://www.cbi.cnptia.embrapa.br.

Terrestrial Responses to Variability in the Southern Westerlies Inferred from Deep Holocene Peat Archives

NASA Astrophysics Data System (ADS)

Hughes, P. D. M.; Mauquoy, D.; van Bellen, S.; Roland, T. P.; Loader, N.; Street-Perrott, F. A.; Daley, T.

2017-12-01

The deep ombrotrophic peat bogs of Chile are located throughout the latitudes dominated by the southern westerly wind belt. The domed surfaces of these peatlands make them sensitive to variability in summer atmospheric moisture balance and the near-continuous accumulation of deep peat strata throughout the Holocene to the present day means that these sites provide undisturbed archives of palaeoclimatic change. We have reconstructed late-Holocene bog water table depths - which can be related to changes in the regional balance of precipitation to evaporation (P-E) - from a suite of peat bogs located in three areas of Tierra del Feugo, Chile, under the main path of the SWWB. Water-table depths were reconstructed from sub-fossil testate amoebae assemblages using a conventional transfer function to infer past water-table depths, based on taxonomic classification of tests but also an innovative trait-based transfer function to infer the same parameter. Water table reconstructions derived from the two methods were consistent within sites. They show that mire water tables have been relatively stable in the last 2000 years across Tierra del Feugo. Higher water table levels, most probably indicating increased effective precipitation, were found between c. 1400 and 900 cal. BP., whereas a consistent drying trend was reconstructed across the region in the most recent peat strata. This shift may represent a pronounced regional decrease in precipitation and/or a change to warmer conditions linked to strengthening of the SWWB. However, other factors such as recent thinning of the ozone layer over Tierra del Fuego could have contributed to recent shifts in some testate amoebae species.

Nitrogen cycling in ombrotrophic peat bogs in the Czech Republic: Is microbial N-fixation occurring at atmospheric depositions of reactive N higher than 10 kg/ha/yr?

NASA Astrophysics Data System (ADS)

Novak, Martin; Jackova, Ivana; Cejkova, Bohuslava; Buzek, Frantisek; Curik, Jan; Stepanova, Marketa; Prechova, Eva; Veselovsky, Frantisek; Komarek, Arnost

2017-04-01

Biogeochemical cycling of carbon (C) and nitrogen (N) in peat bogs are coupled. Whereas at low pollution levels, reactive nitrogen (Nr, mainly nitrate- and ammonium-N) inputs may positively affect C storage, high Nr deposition may have a detrimental effect on C storage. We have previously reported N isotope systematics at two ombrotrophic peat bogs in the Czech Republic, receiving medium levels of Nr of about 10 kg/ha/yr via atmospheric deposition. Nitrogen of living Sphagnum was systematically heavier than N of the atmospheric input (p < 0.001), and close to the N isotope signature of atmospheric N2 (del15N-N2 of 0.0 per mil). We argued that even at medium Nr pollution, such as that in the Czech Republic, the amount of Nr in rainfall becomes minute toward the end of major precipitation events, possible triggering off microbial N-fixation. This process may be responsible for the del15N shift in Sphagnum from negative values of atmospheric deposition to the zero value of N2. In 2016, we conducted a laboratory study in which living Sphagnum from sites receiving annually slightly over 10 kg Nr/ha/yr via atmospheric deposition was incubated in an atmosphere enriched in 15N-N2. At the end of the incubation, we detected a 1 to 3 per mil increase in del15N of Sphagnum. Rinsing Sphagnum capitula in deionized water prior to the 15N-N2 incubation has led to a slight further increase in del15N of Sphagnum. Also in 2016, we monitored del15N of atmospheric deposition at three medium Nr-polluted peat bogs. Open-area precipitation had the following mean del 15N values: Uhlirska -6.1 per mil (NH4) and -6.2 per mil (NO3); Brumiste -1.7 per mil (NH4) and -3.4 per mil (NO3); Male Mechove Jezirko -3.3 per mil (NH4) and -3.9 per mil (NO3). At all sites, atmospheric Nr deposition was made up by NO3-N and NH4-N in a roughly 1.1 ratio. We found that N of winter-time deposition became isotopically extremely light (less than -10.0 per mil). During the growing season, del15N of total atmospheric input was higher, closer to 0.0 per mil, but still slightly lower than del15N of living Sphagnum. These data thus confirm a N isotope discrepancy between the N isotope signature of deposition and Sphagnum. In the paper, we will also discuss a mass balance discrepancy in long-term atmospheric N input and N storage at the Czech sites, determined for replicated, lead-210 dated peat cores. We took into consideration a 30 % contribution of horizontal deposition (mainly fog interception), which we had directly measured, to total Nr deposition. Still, the dated peat cores appeared to accumulate 30 to 60 % more N than the maximum estimated atmospheric Nr input (both estimates for the period 1900-2015). Preliminarily, we conclude that three independent lines of evidence indicate intermittent N-fixation even at medium Nr-polluted peat bogs in Central Europe.

The novel complex allele [A238V;F508del] of the CFTR gene: clinical phenotype and possible implications for cystic fibrosis etiological therapies.

PubMed

Diana, Anna; Polizzi, Angela Maria; Santostasi, Teresa; Ratclif, Luigi; Pantaleo, Maria Giuseppina; Leonetti, Giuseppina; Iusco, Danila Rosa; Gallo, Crescenzio; Conese, Massimo; Manca, Antonio

2016-06-01

Few mutations in cis have been annotated for F508del homozygous patients. Southern Italy patients who at a first analysis appeared homozygous for the F508del mutation (n=63) or compound heterozygous for the F508del and another mutation in the cystic fibrosis transmembrane conductance regulator gene (n=155) were searched for the A238V mutation in exon 6. The allelic frequency of the complex allele [A238V;F508del] was 0.04. When the whole data set was used (comprised also of 56 F508del/F508del and 34 F508del/other mutation controls), no differences reached the statistical significance in the clinical parameters, except chloride concentrations which were lower in [A238V;F508del]/other mutation compared with F508del/other mutation (P=0.03). The two study groups presented less complications than the control groups. Within the minimal data set (34 F508del/F508del, 27 F508del/other mutation, 4 [A238V;F508del]/F508del cases and 5 [A238V;F508del]/other mutation cases); that is, presenting all the variables in each patient, forced expiratory volume in 1 s and forced vital capacity presented a trend to lower levels in the study groups in comparison with the F508del/F508del group, and C-reactive protein approximated statistically significant higher levels in the [A238V;F508del]/other mutation as compared with F508del/F508del patients (P=0.09). The analysis of statistical dependence among the variables showed a significant anticorrelation between chloride and body mass index in the [A238V;F508del]/other mutation group. In conclusion, the complex allele [A238V;F508del] seems to be associated with less general complications than in the control groups, on the other hand possibly giving a worse pulmonary phenotype and higher systemic/local inflammatory response. These findings have implications for the correct recruitment and clinical response of F508del patients in the clinical trials testing the new etiological drugs for cystic fibrosis.

Predictive abilities of cardiovascular biomarkers to rapid decline of renal function in Chinese community-dwelling population: a 5-year prospective analysis.

PubMed

Fu, Shihui; Liu, Chunling; Luo, Leiming; Ye, Ping

2017-11-09

Predictive abilities of cardiovascular biomarkers to renal function decline are more significant in Chinese community-dwelling population without glomerular filtration rate (GFR) below 60 ml/min/1.73m 2 , and long-term prospective study is an optimal choice to explore this problem. Aim of this analysis was to observe this problem during the follow-up of 5 years. In a large medical check-up program in Beijing, there were 948 participants with renal function evaluated at baseline and follow-up of 5 years. Physical examinations were performed by well-trained physicians. Blood samples were analyzed by qualified technicians in central laboratory. Median rate of renal function decline was 1.46 (0.42-2.91) mL/min/1.73m 2 /year. Rapid decline of renal function had a prevalence of 23.5% (223 participants). Multivariate linear and Logistic regression analyses confirmed that age, sex, baseline GFR, homocysteine and N-terminal pro B-type natriuretic peptide (NT-proBNP) had independently predictive abilities to renal function decline rate and rapid decline of renal function (p < 0.05 for all). High-sensitivity cardiac troponin T (hs-cTnT), carotid femoral pulse wave velocity and central augmentation index had no statistically independent association with renal function decline rate and rapid decline of renal function (p > 0.05 for all). Homocysteine and NT-proBNP rather than hs-cTnT had independently predictive abilities to rapid decline of renal function in Chinese community-dwelling population without GFR below 60 ml/min/1.73m 2 . Baseline GFR was an independent factor predicting the rapid decline of renal function. Arterial stiffness and compliance had no independent effect on rapid decline of renal function. This analysis has a significant implication for public health, and changing the homocysteine and NT-proBNP levels might slow the rapid decline of renal function.

Association Between Perceived Physical Activity and Cognitive Function in Older Adults.

PubMed

Loprinzi, Paul D; Frith, Emily

2018-01-01

There is irrefutable evidence that regular participation in physical activity is favorably associated with numerous positive health outcomes, including cognitive function. Emerging work suggests that perceived physical activity, independent of actual physical activity behavior, is inversely associated with mortality risk. In this study, we evaluate whether perceived physical activity, independent of actual physical activity, is associated with cognitive function, a robust indicator of mortality risk. Data from the cross-sectional 1999-2002 National Health and Nutrition Examination Survey were employed ( N = 2352; 60+ years of age). Actual physical activity was assessed via a validated survey. Perceived physical activity was assessed using the following question: "Compared with others of the same age, would you say that you are: more active, less active, or about the same?" Cognitive function was assessed from the Digit Symbol Substitution Test. When examined in separate models, both actual and perceived physical activity were positively and statistically significantly associated with cognitive function. However, when considered in the same model, actual physical activity was no longer statistically significantly associated with cognitive function, but perceived physical activity was. Perceived physical activity, independent of actual physical activity, is independently associated with cognitive function. If these findings are replicated, future work should consider evaluating perceived physical activity when examining the effects of actual physical activity behavior on cognitive function.

Requirements of transcription factor Smad-dependent and -independent TGF-β signaling to control discrete T-cell functions.

PubMed

Gu, Ai-Di; Wang, Yunqi; Lin, Lin; Zhang, Song S; Wan, Yisong Y

2012-01-17

TGF-β modulates immune response by suppressing non-regulatory T (Treg) function and promoting Treg function. The question of whether TGF-β achieves distinct effects on non-Treg and Treg cells through discrete signaling pathways remains outstanding. In this study, we investigated the requirements of Smad-dependent and -independent TGF-β signaling for T-cell function. Smad2 and Smad3 double deficiency in T cells led to lethal inflammatory disorder in mice. Non-Treg cells were spontaneously activated and produced effector cytokines in vivo on deletion of both Smad2 and Smad3. In addition, TGF-β failed to suppress T helper differentiation efficiently and to promote induced Treg generation of non-Treg cells lacking both Smad2 and Smad3, suggesting that Smad-dependent signaling is obligatory to mediate TGF-β function in non-Treg cells. Unexpectedly, however, the development, homeostasis, and function of Treg cells remained intact in the absence of Smad2 and Smad3, suggesting that the Smad-independent pathway is important for Treg function. Indeed, Treg-specific deletion of TGF-β-activated kinase 1 led to failed Treg homeostasis and lethal immune disorder in mice. Therefore, Smad-dependent and -independent TGF-β signaling discretely controls non-Treg and Treg function to modulate immune tolerance and immune homeostasis.

Time to First Cigarette, Physical Activity, and Pulmonary Function in Middle-aged to Older Adult Smokers.

PubMed

Nye, Russell T; Mercincavage, Melissa; Branstetter, Steven A

2017-08-01

How addiction severity relates to physical activity (PA), and if PA moderates the relation between PA and lung function among smokers, is unknown. This study explored the independent and interactive associations of nicotine addiction severity and PA with lung function. The study used cross-sectional data from 343 adult smokers aged 40 to 79 participating in the 2009-10 and 2011-12 National Health and Nutrition Examination Survey. Assessed were the independent relations of nicotine addiction severity, as measured by the time to first cigarette (TTFC), and average daily minutes of moderate and vigorous PA with lung function ratio (FEV1/FVC). Additional analysis examined whether PA moderated the relationship between addiction severity and lung function. Greater lung function was independently associated with moderate PA and later TTFC, but not vigorous PA, when controlling for cigarettes per day (CPD), past month smoking, ethnicity, years smoked, and gender (P-values < .05). PA did not moderate the association between addiction severity (TTFC) and lung function (P = .441). Among middle-aged to older smokers, increased PA and lower addiction severity were associated with greater lung function, independent of CPD. This may inform research into the protective role of PA and identification of risk factors for interventions.

Development of a RAD-Seq Based DNA Polymorphism Identification Software, AgroMarker Finder, and Its Application in Rice Marker-Assisted Breeding

PubMed Central

Luo, Zhijing; Chen, Mingjiao; Zhao, Xiangxiang; Zhang, Dabing; Qi, Yiping; Yuan, Zheng

2016-01-01

Rapid and accurate genome-wide marker detection is essential to the marker-assisted breeding and functional genomics studies. In this work, we developed an integrated software, AgroMarker Finder (AMF: http://erp.novelbio.com/AMF), for providing graphical user interface (GUI) to facilitate the recently developed restriction-site associated DNA (RAD) sequencing data analysis in rice. By application of AMF, a total of 90,743 high-quality markers (82,878 SNPs and 7,865 InDels) were detected between rice varieties JP69 and Jiaoyuan5A. The density of the identified markers is 0.2 per Kb for SNP markers, and 0.02 per Kb for InDel markers. Sequencing validation revealed that the accuracy of genome-wide marker detection by AMF is 93%. In addition, a validated subset of 82 SNPs and 31 InDels were found to be closely linked to 117 important agronomic trait genes, providing a basis for subsequent marker-assisted selection (MAS) and variety identification. Furthermore, we selected 12 markers from 31 validated InDel markers to identify seed authenticity of variety Jiaoyuanyou69, and we also identified 10 markers closely linked to the fragrant gene BADH2 to minimize linkage drag for Wuxiang075 (BADH2 donor)/Jiachang1 recombinants selection. Therefore, this software provides an efficient approach for marker identification from RAD-seq data, and it would be a valuable tool for plant MAS and variety protection. PMID:26799713

A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rossi, Daniela; Palmio, Johanna; Evilä, Anni

A novel FLNC c.5161delG (p.Gly1722ValfsTer61) mutation was identified in two members of a French family affected by distal myopathy and in one healthy relative. This FLNC c.5161delG mutation is one nucleotide away from a previously reported FLNC mutation (c.5160delC) that was identified in patients and in asymptomatic carriers of three Bulgarian families with distal muscular dystrophy, indicating a low penetrance of the FLNC frameshift mutations. Given these similarities, we believe that the two FLNC mutations alone can be causative of distal myopathy without full penetrance. Moreover, comparative analysis of the clinical manifestations indicates that patients of the French family showmore » an earlier onset and a complete segregation of the disease. As a possible explanation of this, the two French patients also carry a OBSCN c.13330C>T (p.Arg4444Trp) mutation. The p.Arg4444Trp variant is localized within the OBSCN Ig59 domain that, together with Ig58, binds to the ZIg9/ZIg10 domains of titin at Z-disks. Structural and functional studies indicate that this OBSCN p.Arg4444Trp mutation decreases titin binding by ~15-fold. On this line, we suggest that the combination of the OBSCN p.Arg4444Trp variant and of the FLNC c.5161delG mutation, can cooperatively affect myofibril stability and increase the penetrance of muscular dystrophy in the French family.« less

Development of a RAD-Seq Based DNA Polymorphism Identification Software, AgroMarker Finder, and Its Application in Rice Marker-Assisted Breeding.

PubMed

Fan, Wei; Zong, Jie; Luo, Zhijing; Chen, Mingjiao; Zhao, Xiangxiang; Zhang, Dabing; Qi, Yiping; Yuan, Zheng

2016-01-01

Rapid and accurate genome-wide marker detection is essential to the marker-assisted breeding and functional genomics studies. In this work, we developed an integrated software, AgroMarker Finder (AMF: http://erp.novelbio.com/AMF), for providing graphical user interface (GUI) to facilitate the recently developed restriction-site associated DNA (RAD) sequencing data analysis in rice. By application of AMF, a total of 90,743 high-quality markers (82,878 SNPs and 7,865 InDels) were detected between rice varieties JP69 and Jiaoyuan5A. The density of the identified markers is 0.2 per Kb for SNP markers, and 0.02 per Kb for InDel markers. Sequencing validation revealed that the accuracy of genome-wide marker detection by AMF is 93%. In addition, a validated subset of 82 SNPs and 31 InDels were found to be closely linked to 117 important agronomic trait genes, providing a basis for subsequent marker-assisted selection (MAS) and variety identification. Furthermore, we selected 12 markers from 31 validated InDel markers to identify seed authenticity of variety Jiaoyuanyou69, and we also identified 10 markers closely linked to the fragrant gene BADH2 to minimize linkage drag for Wuxiang075 (BADH2 donor)/Jiachang1 recombinants selection. Therefore, this software provides an efficient approach for marker identification from RAD-seq data, and it would be a valuable tool for plant MAS and variety protection.

Functional capacities of Polish adults of 60-87 years and risk of losing functional independence.

PubMed

Ignasiak, Zofia; Sławinska, Teresa; Skrzek, Anna; Rożek, Krystyna; Kozieł, Sławomir; Posłuszny, Pawel; Malina, Robert M

2017-09-01

To characterise the functional capacities of Polish men and women aged 60-87 years and evaluate their status relative to criteria for functional independence. Four hundred and thirty-one women and 125 men, aged 60-87 years, who were residents of Wrocław, southwestern Poland, were recruited. Height and weight were measured and BMI was calculated. The Fullerton Functional Fitness Test was administered to test upper and lower body strength, upper and lower body flexibility, agility-dynamic balance and aerobic endurance. The Paffenbarger physical activity questionnaire was completed. Characteristics of individuals classified by the number of tests which equalled or exceeded criterion-referenced standards for functional independence (excluding flexibility) were compared. Polish older adults compared favourably to American reference values. Percentages meeting the criteria for all four, for two or three and for one or no tests were, respectively, 21%, 54% and 25% in women and 37%, 45% and 18% in men. Adults meeting the criteria for all four tests were lighter, with a lower BMI and more physically active than those meeting the criteria on two or three tests and on one or no tests. The majority of Polish older adults were not at risk for loss of physical independence. The most functionally independent adults of both sexes had a lower BMI and less obesity, and were physically more active; the converse was true for those not meeting the criteria.

On the Association between Adolescent Autonomy and Psychosocial Functioning: Examining Decisional Independence from a Self-Determination Theory Perspective

ERIC Educational Resources Information Center

Van Petegem, Stijn; Beyers, Wim; Vansteenkiste, Maarten; Soenens, Bart

2012-01-01

In the present study, we focus on the concept of adolescent autonomy and its relation with psychosocial functioning. Specifically, we aim to differentiate between 2 prevailing conceptualizations of autonomy, that is, (a) autonomy defined as independence versus dependence and (b) autonomy defined as self-endorsed versus controlled functioning. A…

"Estudio tribologico de aceros para moldes. Aplicacion al moldeo por inyeccion de polibutilentereftalato reforzado con fibra de vidrio"

NASA Astrophysics Data System (ADS)

Martinez Mateo, Isidoro Jose

Mould materials for injection moulding of polymers and polymer-matrix composites represent a relevant industrial economic sector due to the large quantity of pieces and components processed. The material selection for mould manufacturing, its composition and heat treatment, the hardening procedures and machining and finishing processes determine the service performance and life of the mould. In the first part of the present study, the relationship between the hardness and microstructure and the wear resistance of mould steels from large blocks has been studied by pin-on-disc tests, studying the main wear mechanisms. In order to determine the surface damage on mould steels under real injection conditions, different commercial steels have been studied by measuring the variation of surface roughness with the number of injected pieces with different reinforcement percentages and different mould geometries, by using optical profilometry and scanning electron microscopy techniques. It was important to determine the variation of surface roughness of the moulded pieces with the number of injection operations. The materials used were polybutyleneterephthalate pure and reinforced with either 20% or 50% glass fibre. For the different mould designs, the evolution of the glass fibre orientation with injection flow has been determined by image analysis and related to roughness changes and surface damage, both of the composite parts and of the mould steel surface. Finally, the abrasion resistance of the composite parts has been studied by scratch tests as a function of the number of injected parts and of the scratch direction with respect to injection flow and glass fibre orientation. Los materiales para moldes de inyeccion de polimeros y materiales compuestos representan un sector economicamente muy relevante debido al gran aumento del numero de componentes fabricados a partir de materiales polimericos obtenidos mediante moldeo por inyeccion. La seleccion del material para la fabricacion del molde, tienen una gran influencia sobre su comportamiento en servicio a lo largo de la vida util del molde. En la primera parte del presente estudio, a partir de ensayos punzon sobre disco, se ha determinado la relacion entre la resistencia al desgaste y la dureza de aceros para moldes obtenidos a partir de bloques de gran espesor, estudiando los principales mecanismos de desgaste que tienen lugar. A continuacion, con el fin de determinar el dano superficial que sufren los aceros para moldes en condiciones reales de inyeccion, se han estudiado distintos tipos de aceros utilizados comercialmente en moldes de inyeccion de polimeros y materiales compuestos, seleccionando las condiciones de operacion para determinar la variacion de la rugosidad superficial del acero en funcion del material inyectado, del numero de operaciones sucesivas de inyeccion y de la orientacion del flujo de inyeccion, mediante tecnicas de perfilometria optica y microscopia electronica de barrido. Ademas del dano superficial sufrido por el acero con el numero de piezas inyectadas, tambien se ha determinado la evolucion de la rugosidad superficial de los materiales inyectados, polibutilentereftalato (PBT) puro y materiales compuestos derivados de PBT por adicion de un 20 o un 50% en peso de fibra de vidrio. En el caso de las piezas inyectadas, se ha caracterizado su microestructura en funcion del flujo de inyeccion y de la densidad de fibra, se han determinado sus propiedades termicas y dinamico-mecanicas, asi como la variacion de la rugosidad superficial de las piezas inyectadas con el numero de operaciones de inyeccion y con la geometria de las distintas secciones de las piezas. Finalmente, se ha evaluado la resistencia a la abrasion de PBT reforzado con un 50% de fibra, en funcion del numero de piezas inyectadas y de la direccion de rayado con respecto a la orientacion del flujo de inyeccion.

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

PubMed

Davies, Gail; Lam, Max; Harris, Sarah E; Trampush, Joey W; Luciano, Michelle; Hill, W David; Hagenaars, Saskia P; Ritchie, Stuart J; Marioni, Riccardo E; Fawns-Ritchie, Chloe; Liewald, David C M; Okely, Judith A; Ahola-Olli, Ari V; Barnes, Catriona L K; Bertram, Lars; Bis, Joshua C; Burdick, Katherine E; Christoforou, Andrea; DeRosse, Pamela; Djurovic, Srdjan; Espeseth, Thomas; Giakoumaki, Stella; Giddaluru, Sudheer; Gustavson, Daniel E; Hayward, Caroline; Hofer, Edith; Ikram, M Arfan; Karlsson, Robert; Knowles, Emma; Lahti, Jari; Leber, Markus; Li, Shuo; Mather, Karen A; Melle, Ingrid; Morris, Derek; Oldmeadow, Christopher; Palviainen, Teemu; Payton, Antony; Pazoki, Raha; Petrovic, Katja; Reynolds, Chandra A; Sargurupremraj, Muralidharan; Scholz, Markus; Smith, Jennifer A; Smith, Albert V; Terzikhan, Natalie; Thalamuthu, Anbupalam; Trompet, Stella; van der Lee, Sven J; Ware, Erin B; Windham, B Gwen; Wright, Margaret J; Yang, Jingyun; Yu, Jin; Ames, David; Amin, Najaf; Amouyel, Philippe; Andreassen, Ole A; Armstrong, Nicola J; Assareh, Amelia A; Attia, John R; Attix, Deborah; Avramopoulos, Dimitrios; Bennett, David A; Böhmer, Anne C; Boyle, Patricia A; Brodaty, Henry; Campbell, Harry; Cannon, Tyrone D; Cirulli, Elizabeth T; Congdon, Eliza; Conley, Emily Drabant; Corley, Janie; Cox, Simon R; Dale, Anders M; Dehghan, Abbas; Dick, Danielle; Dickinson, Dwight; Eriksson, Johan G; Evangelou, Evangelos; Faul, Jessica D; Ford, Ian; Freimer, Nelson A; Gao, He; Giegling, Ina; Gillespie, Nathan A; Gordon, Scott D; Gottesman, Rebecca F; Griswold, Michael E; Gudnason, Vilmundur; Harris, Tamara B; Hartmann, Annette M; Hatzimanolis, Alex; Heiss, Gerardo; Holliday, Elizabeth G; Joshi, Peter K; Kähönen, Mika; Kardia, Sharon L R; Karlsson, Ida; Kleineidam, Luca; Knopman, David S; Kochan, Nicole A; Konte, Bettina; Kwok, John B; Le Hellard, Stephanie; Lee, Teresa; Lehtimäki, Terho; Li, Shu-Chen; Liu, Tian; Koini, Marisa; London, Edythe; Longstreth, Will T; Lopez, Oscar L; Loukola, Anu; Luck, Tobias; Lundervold, Astri J; Lundquist, Anders; Lyytikäinen, Leo-Pekka; Martin, Nicholas G; Montgomery, Grant W; Murray, Alison D; Need, Anna C; Noordam, Raymond; Nyberg, Lars; Ollier, William; Papenberg, Goran; Pattie, Alison; Polasek, Ozren; Poldrack, Russell A; Psaty, Bruce M; Reppermund, Simone; Riedel-Heller, Steffi G; Rose, Richard J; Rotter, Jerome I; Roussos, Panos; Rovio, Suvi P; Saba, Yasaman; Sabb, Fred W; Sachdev, Perminder S; Satizabal, Claudia L; Schmid, Matthias; Scott, Rodney J; Scult, Matthew A; Simino, Jeannette; Slagboom, P Eline; Smyrnis, Nikolaos; Soumaré, Aïcha; Stefanis, Nikos C; Stott, David J; Straub, Richard E; Sundet, Kjetil; Taylor, Adele M; Taylor, Kent D; Tzoulaki, Ioanna; Tzourio, Christophe; Uitterlinden, André; Vitart, Veronique; Voineskos, Aristotle N; Kaprio, Jaakko; Wagner, Michael; Wagner, Holger; Weinhold, Leonie; Wen, K Hoyan; Widen, Elisabeth; Yang, Qiong; Zhao, Wei; Adams, Hieab H H; Arking, Dan E; Bilder, Robert M; Bitsios, Panos; Boerwinkle, Eric; Chiba-Falek, Ornit; Corvin, Aiden; De Jager, Philip L; Debette, Stéphanie; Donohoe, Gary; Elliott, Paul; Fitzpatrick, Annette L; Gill, Michael; Glahn, David C; Hägg, Sara; Hansell, Narelle K; Hariri, Ahmad R; Ikram, M Kamran; Jukema, J Wouter; Vuoksimaa, Eero; Keller, Matthew C; Kremen, William S; Launer, Lenore; Lindenberger, Ulman; Palotie, Aarno; Pedersen, Nancy L; Pendleton, Neil; Porteous, David J; Räikkönen, Katri; Raitakari, Olli T; Ramirez, Alfredo; Reinvang, Ivar; Rudan, Igor; Dan Rujescu; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter W; Schofield, Peter R; Starr, John M; Steen, Vidar M; Trollor, Julian N; Turner, Steven T; Van Duijn, Cornelia M; Villringer, Arno; Weinberger, Daniel R; Weir, David R; Wilson, James F; Malhotra, Anil; McIntosh, Andrew M; Gale, Catharine R; Seshadri, Sudha; Mosley, Thomas H; Bressler, Jan; Lencz, Todd; Deary, Ian J

2018-05-29

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10 -8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Polymorphism of TS 3'-UTR predicts survival of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel.

PubMed

Gao, J; He, Q; Hua, D; Mao, Y; Li, Y; Shen, L

2013-08-01

Capecitabine-containing chemotherapy was widely used in clinic medication. We investigated the association of the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD) polymorphisms with the clinical outcome of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. Blood samples were collected prior to treatment from 125 patients with advanced gastric cancer and the TS (two or three repeats of a 28 bp sequence in 5'-untranslated region and 6 bp insertion or deletion in 3'-untranslated region), MTHFR (C677T) and DPD (IVS14+1G > A) polymorphisms were determined using PCR amplification and Sanger sequencing. The median age of 125 patients was 58 years (range, 23-76) with female 42 and male 83, and the response rate, median progression-free survival and overall survival (OS) were 43.2 %, 5.2 and 11.0 months. The median OS in patients with TS ins6/ins6 genotype (6.8 months) was significantly shorter than those in patients with ins6/del6 (11.0 months, P = 0.016) and del6/del6 (11.5 months, P = 0.039) genotypes. Cox multivariate analysis also showed that TS ins6/ins6 genotype was the independent poor OS predictor (P = 0.001, HR = 3.182). No significant associations were found between the polymorphisms of TS 5'-UTR/MTHFR and clinical outcome, and no IVS14+1G > A polymorphism of DPD was found in this study. We first reported that TS 3'-UTR ins6/ins6 genotype could predict the poor survival of advanced gastric cancer patients treated with capecitabine plus paclitaxel, which would be further verified in a large multicenter study.

Accurate quantification of chromosomal lesions via short tandem repeat analysis using minimal amounts of DNA.

PubMed

Jann, Johann-Christoph; Nowak, Daniel; Nolte, Florian; Fey, Stephanie; Nowak, Verena; Obländer, Julia; Pressler, Jovita; Palme, Iris; Xanthopoulos, Christina; Fabarius, Alice; Platzbecker, Uwe; Giagounidis, Aristoteles; Götze, Katharina; Letsch, Anne; Haase, Detlef; Schlenk, Richard; Bug, Gesine; Lübbert, Michael; Ganser, Arnold; Germing, Ulrich; Haferlach, Claudia; Hofmann, Wolf-Karsten; Mossner, Maximilian

2017-09-01

Cytogenetic aberrations such as deletion of chromosome 5q (del(5q)) represent key elements in routine clinical diagnostics of haematological malignancies. Currently established methods such as metaphase cytogenetics, FISH or array-based approaches have limitations due to their dependency on viable cells, high costs or semi-quantitative nature. Importantly, they cannot be used on low abundance DNA. We therefore aimed to establish a robust and quantitative technique that overcomes these shortcomings. For precise determination of del(5q) cell fractions, we developed an inexpensive multiplex-PCR assay requiring only nanograms of DNA that simultaneously measures allelic imbalances of 12 independent short tandem repeat markers. Application of this method to n=1142 samples from n=260 individuals revealed strong intermarker concordance (R²=0.77-0.97) and reproducibility (mean SD: 1.7%). Notably, the assay showed accurate quantification via standard curve assessment (R²>0.99) and high concordance with paired FISH measurements (R²=0.92) even with subnanogram amounts of DNA. Moreover, cytogenetic response was reliably confirmed in del(5q) patients with myelodysplastic syndromes treated with lenalidomide. While the assay demonstrated good diagnostic accuracy in receiver operating characteristic analysis (area under the curve: 0.97), we further observed robust correlation between bone marrow and peripheral blood samples (R²=0.79), suggesting its potential suitability for less-invasive clonal monitoring. In conclusion, we present an adaptable tool for quantification of chromosomal aberrations, particularly in problematic samples, which should be easily applicable to further tumour entities. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Impaired Heme Binding and Aggregation of Mutant Cystathionine β-Synthase Subunits in Homocystinuria

PubMed Central

Janošík, Miroslav; Oliveriusová, Jana; Janošíková, Bohumila; Sokolová, Jitka; Kraus, Eva; Kraus, Jan P.; Kožich, Viktor

2001-01-01

During the past 20 years, cystathionine β-synthase (CBS) deficiency has been detected in the former Czechoslovakia with a calculated frequency of 1:349,000. The clinical manifestation was typical of homocystinuria, and about half of the 21 patients were not responsive to pyridoxine. Twelve distinct mutations were detected in 30 independent homocystinuric alleles. One half of the alleles carried either the c.833 T→C or the IVS11−2A→C mutation; the remaining alleles contained private mutations. The abundance of five mutant mRNAs with premature stop codons was analyzed by PCR-RFLP. Two mRNAs, c.828_931ins104 (IVS7+1G→A) and c.1226 G→A, were severely reduced in the cytoplasm as a result of nonsense-mediated decay. In contrast, the other three mRNAs—c.19_20insC, c.28_29delG, and c.210_235del26 (IVS1−1G→C)—were stable. Native western blot analysis of 14 mutant fibroblast lines showed a paucity of CBS antigen, which was detectable only in aggregates. Five mutations—A114V (c.341C→T), A155T (c.463G→A), E176K (c.526G→A), I278T (c.833T→C), and W409_G453del (IVS11−2A→C)—were expressed in Escherichia coli. All five mutant proteins formed substantially more aggregates than did the wild-type CBS, and no aggregates contained heme. These data suggest that abnormal folding, impaired heme binding, and aggregation of mutant CBS polypeptides may be common pathogenic mechanisms in CBS deficiency. PMID:11359213

A precise mass function in the excursion set approach

NASA Astrophysics Data System (ADS)

Del Popolo, Antonino

2017-04-01

In the present paper, using previous results from Del Popolo papers, we show how the mass function evolution can be obtained in the framework of a spherical collapse model, which has been modified to take account of dynamical friction, the cosmological constant, and angular momentum which proto-structures acquire through tidal interaction with neighbouring ones. We found an improved barrier which is in excellent agreement with simulations. The quoted barrier is used to calculated the mass function. In the case of the ΛCDM paradigm, our mass function is in good agreement (within some %) with the mass function of Klypin's Bolshoi simulation for the virial mass range 5 × 109 - 5 × 1014h-1M⊙, and 0 ≾ z ≿ 10. Similar agreement is obtained with Tinker's mass function, and Castorina's simulations.

Insulin resistance-associated decreases in left ventricular diastolic function are strongly modified by the extent of concentric remodeling in a community sample.

PubMed

Peterson, Vernice; Norton, Gavin R; Raymond, Andrew; Libhaber, Carlos D; Millen, Aletta M E; Majane, Olebogeng H I; Maseko, Muzi J; Woodiwiss, Angela J

2016-10-01

Whether excess adiposity, associated metabolic abnormalities or alternative risk factors for left ventricular (LV) diastolic function are modified rather than mediated by geometric LV remodeling, is uncertain. Echocardiographic LV mass index (LVMI), relative wall thickness (RWT) and diastolic function (lateral and septal wall myocardial tissue lengthening at the level of the mitral annulus [e'] [n=430], ratio of early-to-late transmitral blood flow velocity (E/A), and E/e' [n=430]) were determined in 737 randomly recruited participants of a community-based study (43% obese). Independent of LVMI and confounders, indexes of adiposity and the homeostasis model of insulin resistance (HOMA-IR) were independently associated with LV diastolic function (p<0.05). In addition, RWT was independently associated with LV diastolic function (p<0.002). Importantly, an independent interaction between HOMA-IR and RWT, but not between blood pressure or age and RWT, was related to LV diastolic function (p<0.05). This translated into an independent relationship between HOMA-IR and lateral e' (partial r=-0.17, p<0.02), septal e' (partial r=-0.14, p=0.05), E/A (partial r=-0.17, p<0.005) and E/e' (partial r=0.19, p<0.01) in those with RWT above, but a lack of relationship between HOMA-IR and LV diastolic function (p>0.59) in those with RWT below the median for the sample. Similarly, HOMA-IR was independently associated with LV diastolic dysfunction in those with RWT above (p<0.05) but not below (p>0.19) the median for the sample. The relationship between insulin resistance, but not alternative risk factors and LV diastolic function is markedly modified by the presence of a more concentrically remodeled LV. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Relationship of cognitive and perceptual abilities to functional independence in adults who have had a stroke.

PubMed

Brown, Ted; Mapleston, Jennifer; Nairn, Allison; Molloy, Andrew

2013-03-01

Most individuals who have had a stroke present with some degree of residual cognitive and/or perceptual impairment. Occupational therapists often utilize standardized cognitive and perceptual assessments with clients to establish a baseline of skill performance as well as to inform goal setting and intervention planning. Being able to predict the functional independence of individuals who have had a stroke based on cognitive and perceptual impairments would assist with appropriate discharge planning and follow-up resource allocation. The study objective was to investigate the ability of the Developmental Test of Visual Perception - Adolescents and Adults (DTVP-A) and the Neurobehavioural Cognitive Status Exam (Cognistat) to predict the functional performance as measured by the Barthel Index of individuals who have had a stroke. Data was collected using the DTVP-A, Cognistat and the Barthal Index from 32 adults recovering from stroke. Two standard multiple regression models were used to determine predictive variables of the functional independence dependent variable. Both the Cognistat and DTVP-A had a statistically significant ability to predict functional performance (as measured by the Barthel Index) accounting for 64.4% and 27.9% of each regression model, respectively. Two Cognistat subscales (Comprehension [beta = 0.48; p < 0.001)] and Repetition [beta = 0.45; p < 0.004]) and one DTVP-A subscale (Copying [beta = 0.46; p < 0.014]) made statistically significant contributions to the regression models as independent variables. On the basis of the regression model findings, it appears that DTVP-A's Copying and the Cognistat's Comprehension and Repetition subscales are useful in predicting the functional independence (as measured by the Barthel Index) in those individuals who have had a stroke. Given the fundamental importance that cognition and perception has for one's ability to function independently, further investigation is warranted to determine other predictors of functional performance of individuals with a stroke. Copyright © 2012 John Wiley & Sons, Ltd.

Exploring the association between insecure attachment styles and adolescent autonomy in family decision making: a differentiated approach.

PubMed

Van Petegem, Stijn; Beyers, Wim; Brenning, Katrijn; Vansteenkiste, Maarten

2013-12-01

The present investigation focuses on the associations between adolescents' insecure attachment styles (i.e., anxiety and avoidance) and their autonomous functioning in family decision making. In line with recent insights in the construct of adolescent autonomy, we combined two perspectives on autonomy, differentiating between the degree of independent versus dependent functioning and the self-endorsed and pressuring motives underlying (in)dependent functioning. A longitudinal sample of 327 adolescents (age range = 13-20 years; 64 % girls) completed questionnaires on attachment to the mother and father and on both autonomy operationalisations on two measurement moments spanning a 1-year interval. Structural equation modeling showed that attachment avoidance generally was unrelated to the degree of independent decision making and the motives underlying independent decision making, but related to more pressuring motives for dependent decision making. Anxiety, on the other hand, was associated with a lower degree of independent decision making as well as with more pressuring motives for both independent and dependent decision making. Cross-lagged paths were generally in line with these findings. Theoretical implications are outlined in the discussion.

Comparison of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Ciliary Beat Frequency Activation by the CFTR Modulators Genistein, VRT-532, and UCCF-152 in Primary Sinonasal Epithelial Cultures

PubMed Central

Conger, Bryant T.; Zhang, Shaoyan; Skinner, Daniel; Hicks, Stephen B.; Sorscher, Eric J.; Rowe, Steven M.; Woodworth, Bradford A.

2014-01-01

IMPORTANCE Pharmacologic activation of mucociliary clearance (MCC) represents an emerging therapeutic strategy for patients with chronic rhinosinusitis, even in the absence of congenital mutations of the CFTR gene. Drug discovery efforts have identified small molecules that activate the cystic fibrosis transmembrane conductance regulator (CFTR), including potentiators under development for treatment of cystic fibrosis. OBJECTIVE To evaluate the properties of CFTR modulators and their effects on ciliary beat frequency (CBF) in human sinonasal epithelium (HSNE). DESIGN Primary HSNE cultures (wild type and F508del/F508del) were used to compare stimulation of CFTR-mediated Cl− conductance and CBF by the CFTR modulators genistein, VRT-532, and UCCF-152. MAIN OUTCOMES AND MEASURES Increase in CFTR-dependent anion transport and CBF. RESULTS HSNE cultures were analyzed using pharmacologic manipulation of ion transport (change in short-circuit current [ΔISC]) and high-speed digital imaging (CBF). Activation of CFTR-dependent anion transport was significantly different among agonists (P < .001), with genistein exerting the greatest effect (mean [SD] ΔISC, genistein, 23.1 [1.8] µA/cm2 > VRT-532, 8.1 [1.0] µA/cm2 > UCCF-152, 3.4 [1.4] µA/cm2 > control, 0.7 [0.2] µA/cm2; Tukey-Kramer P < .05) in the absence of forskolin. Genistein and UCCF-152 augmented CBF (under submerged conditions) significantly better (Tukey-Kramer P < .05) than cells treated with VRT-532 or dimethyl sulfoxide vehicle control (mean [SD] fold change over baseline, genistein, 1.63 [0.06]; UCCF-152, 1.56 [0.06]; VRT-532, 1.38 [0.08]; control, 1.27 [0.02]). Activation of CBF was blunted in F508del/F508del HSNE cultures. CONCLUSIONS AND RELEVANCE The degree of CBF stimulation was not dependent on the magnitude of Cl− secretion, suggesting that different mechanisms of action may underlie MCC activation by these small molecule potentiators. Agents that activate both CFTR-dependent ISC and CBF are particularly attractive as therapeutics because they may address 2 independent pathways that contribute to deficient MCC in chronic rhinosinusitis. PMID:23949358

Comparison of cystic fibrosis transmembrane conductance regulator (CFTR) and ciliary beat frequency activation by the CFTR Modulators Genistein, VRT-532, and UCCF-152 in primary sinonasal epithelial cultures.

PubMed

Conger, Bryant T; Zhang, Shaoyan; Skinner, Daniel; Hicks, Stephen B; Sorscher, Eric J; Rowe, Steven M; Woodworth, Bradford A

2013-08-01

Pharmacologic activation of mucociliary clearance (MCC) represents an emerging therapeutic strategy for patients with chronic rhinosinusitis, even in the absence of congenital mutations of the CFTR gene. Drug discovery efforts have identified small molecules that activate the cystic fibrosis transmembrane conductance regulator (CFTR), including potentiators under development for treatment of cystic fibrosis. To evaluate the properties of CFTR modulators and their effects on ciliary beat frequency (CBF) in human sinonasal epithelium (HSNE). Primary HSNE cultures (wild type and F508del/F508del) were used to compare stimulation of CFTR-mediated Cl- conductance and CBF by the CFTR modulators genistein, VRT-532, and UCCF-152. Increase in CFTR-dependent anion transport and CBF. HSNE cultures were analyzed using pharmacologic manipulation of ion transport (change in short-circuit current [∆ISC]) and high-speed digital imaging (CBF). Activation of CFTR-dependent anion transport was significantly different among agonists (P < .001), with genistein exerting the greatest effect (mean [SD] ∆ISC, genistein, 23.1 [1.8] μA/cm2² > VRT-532, 8.1 [1.0] μA/cm² > UCCF-152, 3.4 [1.4] μA/cm² > control, 0.7 [0.2] μA/cm²; Tukey-Kramer P < .05) in the absence of forskolin. Genistein and UCCF-152 augmented CBF (under submerged conditions) significantly better (Tukey-Kramer P < .05) than cells treated with VRT-532 or dimethyl sulfoxide vehicle control (mean [SD] fold change over baseline, genistein, 1.63 [0.06]; UCCF-152, 1.56 [0.06]; VRT-532, 1.38 [0.08]; control, 1.27 [0.02]). Activation of CBF was blunted in F508del/F508del HSNE cultures. The degree of CBF stimulation was not dependent on the magnitude of Cl- secretion, suggesting that different mechanisms of action may underlie MCC activation by these small molecule potentiators. Agents that activate both CFTR-dependent ISC and CBF are particularly attractive as therapeutics because they may address 2 independent pathways that contribute to deficient MCC in chronic rhinosinusitis.

DelPhi webserver: Comprehensive suite for electrostatic calculations of biological macromolecules and their complexes

NASA Astrophysics Data System (ADS)

Witham, Shawn; Boylen, Brett; Owesen, Barr; Rocchia, Walter; Alexov, Emil

2011-03-01

Electrostatic forces and energies are two of the major components that contribute to the stability, function and interaction of biological macromolecules. The calculations of the electrostatic potential distribution in such systems, which are comprised of irregularly shaped objects immersed in a water phase, is not a trivial task. In addition, an accurate model requires any missing hydrogen atoms of the corresponding structural files (Protein Data Bank, or, PDB files) to be generated in silico and, if necessary, missing atoms or residues to be predicted as well. Here we report a comprehensive suite, an academic DelPhi webserver, which allows the users to upload their structural file, calculate the components of the electrostatic energy, generate the corresponding potential (and/or concentration/dielectric constant) distribution map, and choose the appropriate force field. The webserver utilizes modern technology to take user input and construct an algorithm that suits the users specific needs. The webserver uses Clemson University's Palmetto Supercomputer Cluster to handle the DelPhi calculations, which can range anywhere from small and short computation times, to extensive and computationally demanding runtimes. The work was supported by a grant from NIGMS, NIH, grant number 1R01GM093937-01.

Nuclear Tubulin: A Novel Target for Breast Cancer Chemotherapy

DTIC Science & Technology

2001-05-01

A. Castillo1, R.F. Luduena 3, and I. Meza 2 ’Departamentos de Biologia Celular and 2 Biomedicina Molecular, CINVESTA V del /PN, M6xico, D. F...resistance. J Biol Chem 270: 31269-31275. Hyams JS, Lloyd CW. 1994.-.The role of multiple tubulin isoforms in celular microtubule function. In: Raff E editor

Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK.

PubMed

Park, Sung-Jun; Ahmad, Faiyaz; Um, Jee-Hyun; Brown, Alexandra L; Xu, Xihui; Kang, Hyeog; Ke, Hengming; Feng, Xuesong; Ryall, James; Philp, Andrew; Schenk, Simon; Kim, Myung K; Sartorelli, Vittorio; Chung, Jay H

2017-04-01

The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Inhibiting the cAMP effector protein Epac prevents SRT1720 from activating AMPK or Sirt1 in myotubes. Moreover, SRT1720 does not increase mitochondrial function or improve glucose tolerance in AMPKα2 knockout mice. Interestingly, weight loss induced by SRT1720 is not sufficient to improve glucose tolerance. Therefore, contrary to current belief, the metabolic effects produced by SRT1720 require AMPK, which can be activated independently of Sirt1. Published by Elsevier B.V.

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium.

PubMed

Muranen, Taru A; Blomqvist, Carl; Dörk, Thilo; Jakubowska, Anna; Heikkilä, Päivi; Fagerholm, Rainer; Greco, Dario; Aittomäki, Kristiina; Bojesen, Stig E; Shah, Mitul; Dunning, Alison M; Rhenius, Valerie; Hall, Per; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Chang-Claude, Jenny; Rudolph, Anja; Nordestgaard, Børge G; Couch, Fergus J; Hart, Steven N; Figueroa, Jonine; García-Closas, Montserrat; Fasching, Peter A; Beckmann, Matthias W; Li, Jingmei; Liu, Jianjun; Andrulis, Irene L; Winqvist, Robert; Pylkäs, Katri; Mannermaa, Arto; Kataja, Vesa; Lindblom, Annika; Margolin, Sara; Lubinski, Jan; Dubrowinskaja, Natalia; Bolla, Manjeet K; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Easton, Douglas F; Pharoah, Paul D P; Schmidt, Marjanka K; Nevanlinna, Heli

2016-10-03

P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.

77 FR 31032 - National Institute on Aging; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-24

... applications. Place: Marina del Rey Hotel, 13534 Bali Way, Marina del Rey, CA 90292. Contact Person: Bita... applications. Place: Marina del Rey Hotel, 13534 Bali Way, Marina del Rey, CA 90292. Contact Person: Ramesh... and evaluate grant applications. Place: Marina del Rey Hotel, 13534 Bali Way, Marina del Rey, CA 90292...

Rough-pipe flows and the existence of fully developed turbulence

NASA Astrophysics Data System (ADS)

Gioia, G.; Chakraborty, Pinaki; Bombardelli, Fabián A.

2006-03-01

It is widely believed that at high Reynolds number (Re) all turbulent flows approach a limiting state of "fully developed turbulence" in which the statistics of the velocity fluctuations are independent of Re. Nevertheless, direct measurements of the velocity fluctuations have failed to yield firm empirical evidence that even the second-order structure function becomes independent of Re at high Re, let alone structure functions of higher order. Here we relate the friction coefficient (f) of rough-pipe flows to the second-order structure function. Then we show that in light of experimental measurements of f our results yield unequivocal evidence that the second-order structure function becomes independent of Re at high Re, compatible with the existence of fully developed turbulence.

Discriminant analysis of resting-state functional connectivity patterns on the Grassmann manifold

NASA Astrophysics Data System (ADS)

Fan, Yong; Liu, Yong; Jiang, Tianzi; Liu, Zhening; Hao, Yihui; Liu, Haihong

2010-03-01

The functional networks, extracted from fMRI images using independent component analysis, have been demonstrated informative for distinguishing brain states of cognitive functions and neurological diseases. In this paper, we propose a novel algorithm for discriminant analysis of functional networks encoded by spatial independent components. The functional networks of each individual are used as bases for a linear subspace, referred to as a functional connectivity pattern, which facilitates a comprehensive characterization of temporal signals of fMRI data. The functional connectivity patterns of different individuals are analyzed on the Grassmann manifold by adopting a principal angle based subspace distance. In conjunction with a support vector machine classifier, a forward component selection technique is proposed to select independent components for constructing the most discriminative functional connectivity pattern. The discriminant analysis method has been applied to an fMRI based schizophrenia study with 31 schizophrenia patients and 31 healthy individuals. The experimental results demonstrate that the proposed method not only achieves a promising classification performance for distinguishing schizophrenia patients from healthy controls, but also identifies discriminative functional networks that are informative for schizophrenia diagnosis.

Relationship between Grooming Performance and Motor and Cognitive Functions in Stroke Patients with Receiver Operating Characteristic Analysis.

PubMed

Fujita, Takaaki; Sato, Atsushi; Tsuchiya, Kenji; Ohashi, Takuro; Yamane, Kazuhiro; Yamamoto, Yuichi; Iokawa, Kazuaki; Ohira, Yoko; Otsuki, Koji; Tozato, Fusae

2017-12-01

This study aimed to elucidate the relationship between grooming performance of stroke patients and various motor and cognitive functions and to examine the cognitive and physical functional standards required for grooming independence. We retrospectively analyzed the data of 96 hospitalized patients with first stroke in a rehabilitation hospital ward. Logistic regression analysis and receiver operating characteristic curves were used to investigate the related cognitive and motor functions with grooming performance and to calculate the cutoff values for independence and supervision levels in grooming. For analysis between the independent and supervision-dependent groups, the only item with an area under the curve (AUC) of .9 or higher was the Berg Balance Scale, and the calculated cutoff value was 41/40 (sensitivity, 83.6%; specificity, 87.8%). For analysis between the independent-supervision and dependent groups, the items with an AUC of .9 or higher were the Simple Test for Evaluating Hand Function (STEF) on the nonaffected side, Vitality Index (VI), and FIM ® cognition. The cutoff values were 68/67 for the STEF (sensitivity, 100%; specificity, 72.2%), 9/8 points for the VI (sensitivity, 92.3%; specificity, 88.9%), and 23/22 points for FIM ® cognition (sensitivity, 91.0%; specificity, 88.9%). Our results suggest that upper-extremity functions on the nonaffected side, motivation, and cognitive functions are particularly important to achieve the supervision level and that balance is important to reach the independence level. The effective improvement of grooming performance is possible by performing therapeutic or compensatory intervention on functions that have not achieved these cutoff values. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Slimmer women's waist is associated with better erectile function in men independent of age.

PubMed

Brody, Stuart; Weiss, Petr

2013-10-01

Previous research has indicated that men generally rate slimmer women as more sexually attractive, consistent with the increased morbidity risks associated with even mild abdominal adiposity. To assess the association of women's waist size with a more tangible measure of perceived sexual attractiveness (as well as reward value for both sexes), we examined the association of women's age and waist circumference with an index of men's erectile function (IIEF-5 scores), frequency of penile-vaginal intercourse (PVI), and sexual satisfaction in a representative sample of Czechs (699 men and 715 women) aged 35-65 years. Multivariate analyses indicated that better erectile function scores were independently associated with younger age of self and partner and women's slimmer waist. PVI frequency was independently associated with women's younger age and women's slimmer waist. Sexual satisfaction was independently associated with men's younger age and slimmer waist for both sexes. Better erectile function, greater PVI frequency, and greater sexual satisfaction were associated with women's slimmer waist, independently of both sexes' ages. Possible reasons for the waist effects were discussed, including women's abdominal body fat decreasing their own desire through neurohormonal mechanisms and decreasing their partner's desire through evolutionarily-related decreased sexual attractiveness.

Microwave moisture sensing through use of a piecewise density-independent function

USDA-ARS?s Scientific Manuscript database

Microwave moisture sensing provides a means to determine nondestructively the amount of water in materials. This is accomplished through the correlation of dielectric properties with moisture in the material. In this study, linear relationships between a density-independent function of the dielectri...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2010 CFR

2010-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2012 CFR

2012-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2013 CFR

2013-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2011 CFR

2011-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Marina Del Rey, CA. 80.1118...

33 CFR 80.1118 - Marina Del Rey, CA.

Code of Federal Regulations, 2014 CFR

2014-07-01

... NAVIGATION RULES COLREGS DEMARCATION LINES Pacific Coast § 80.1118 Marina Del Rey, CA. (a) A line drawn from Marina Del Rey Breakwater South Light 1 to Marina Del Rey Light 4. (b) A line drawn from Marina Del Rey... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Marina Del Rey, CA. 80.1118...

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

PubMed

Sehrawat, Archana; Gao, Lina; Wang, Yuliang; Bankhead, Armand; McWeeney, Shannon K; King, Carly J; Schwartzman, Jacob; Urrutia, Joshua; Bisson, William H; Coleman, Daniel J; Joshi, Sunil K; Kim, Dae-Hwan; Sampson, David A; Weinmann, Sheila; Kallakury, Bhaskar V S; Berry, Deborah L; Haque, Reina; Van Den Eeden, Stephen K; Sharma, Sunil; Bearss, Jared; Beer, Tomasz M; Thomas, George V; Heiser, Laura M; Alumkal, Joshi J

2018-05-01

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

A Comparative Analysis of the Safety, Efficacy, and Cost of Islet Versus Pancreas Transplantation in Nonuremic Patients With Type 1 Diabetes

PubMed Central

Moassesfar, S.; Masharani, U.; Frassetto, L. A.; Szot, G. L.; Tavakol, M.; Stock, P. G.; Posselt, A. M.

2017-01-01

Few current studies compare the outcomes of islet transplantation alone (ITA) and pancreas transplantation alone (PTA) for type 1 diabetes (T1D). We examined these two beta cell replacement therapies in nonuremic patients with T1D with respect to safety, graft function and cost. Sequential patients received PTA (n = 15) or ITA (n = 10) at our institution. Assessments of graft function included duration of insulin independence; glycemic control, as measured by hemoglobin A1c; and elimination of severe hypoglycemia. Cost analysis included all normalized costs associated with transplantation and inpatient management. ITA patients received one (n = 6) or two (n = 4) islet transplants. Mean duration of insulin independence in this group was 35 mo; 90% were independent at 1 year, and 70% were independent at 3 years. Mean duration of insulin independence in PTA was 55 mo; 93% were insulin independent at 1 year, and 64% were independent at 3 years. Glycemic control was comparable in all patients with functioning grafts, as were overall costs ($138 872 for ITA, $134 748 for PTA). We conclude that with advances in islet isolation and posttransplant management, ITA can produce outcomes similar to PTA and represents a clinically viable option to achieve long-term insulin independence in selected patients with T1D. PMID:26595767

8th Argentinean Bioengineering Society Conference (SABI 2011) and 7th Clinical Engineering Meeting

NASA Astrophysics Data System (ADS)

Meschino, Gustavo Javier; Ballarin, Virginia L.

2011-12-01

In September 2011, the Eighteenth Edition of the Argentinean Bioengineering Society Conference (SABI 2011) and Seventh Clinical Engineering Meeting were held in Mar del Plata, Argetina. The Mar del Plata SABI Regional and the School of Engineering of the Universidad Nacional de Mar del Plata invited All bioengineers, engineers, physicists, mathematicians, biologists, physicians and health professionals working in the field of Bioengineering to participate in this event. The overall objectives of the Conference were: To provide discussion of scientific research results in Bioengineering and Clinical Engineering. To promote technological development experiences. To strengthen the institutional and scientific communication links in the area of Bioengineering, mainly between Universities of Latin America. To encourage students, teachers, researchers and professionals to establish exchanges of experiences and knowledge. To provide biomedical engineering technology solutions to the society and contributing ideas for low cost care. Conference photograph Conference photograph Conference photograph Conference photograph EXECUTIVE COMMITTEE SABI 2011 Chair Dra Virginia L Ballarin Universidad Nacional de Mar del Plata Co-Chair Dra Teresita R Cuadrado Universidad Nacional de Mar del Plata - CONICET Local Comittee Dr Gustavo Abraham Universidad Nacional de Mar del Plata - CONICET Dra Josefina Ballarre Universidad Nacional de Mar del Plata - CONICET Dr Eduardo Blotta Universidad Nacional de Mar del Plata Dra Agustina Bouchet Universidad Nacional de Mar del Plata Dr Marcel Brun Universidad Nacional de Mar del Plata Dra Silvia Ceré Universidad Nacional de Mar del Plata - CONICET Dra Mariela Azul Gonzalez Universidad Nacional de Mar del Plata - CONICET Dra Lucia Isabel Passoni Universidad Nacional de Mar del Plata Dr Juan Ignacio Pastore Universidad Nacional de Mar del Plata - CONICET Dra Adriana Scandurra Universidad Nacional de Mar del Plata SCIENTIFIC ADVISORY COMMITTEE President Dr Gustavo Meschino Universidad Nacional de Mar del Plata Comittee Dr Gustavo Abraham Universidad Nacional de Mar del Plata - CONICET Mg Rubén Acevedo Universidad Nacional de Entre Ríos Ing Pablo Agüero Universidad Nacional de Mar del Plata Ing Mariela Ambrustolo Universidad Nacional de Mar del Plata Dr Ricardo Armentano Universidad Favaloro Dra Virginia L Ballarin Universidad Nacional de Mar del Plata Dra Josefina Ballarre Universidad Nacional de Mar del Plata - CONICET Dr Eduardo Blotta Universidad Nacional de Mar del Plata Ing Marco Benalcázar Universidad Nacional de Mar del Plata Mg Freddy Geovanny Benalcázar Palacios Escuela Superior Politécnica de Chimborazo, Ecuador Dr Roberto Boeri Universidad Nacional de Mar del Plata - CONICET - INTEMA Dra Agustina Bouchet Universidad Nacional de Mar del Plata Dr Ariel Braidot Universidad Nacional de Entre Ríos Dr Marcel Brun Universidad Nacional de Mar del Plata Dra Silvia Ceré Universidad Nacional de Mar del Plata - CONICET Ing Fernando Clara Universidad Nacional de Mar del Plata Dr Raúl Correa Prado Universidad Nacional de San Juan Bioing Pablo Cortez Universidad Nacional de Mar del Plata Dra Teresita R Cuadrado Universidad Nacional de Mar del Plata - CONICET Ing Eduardo De Forteza Universidad Favaloro Dra Mariana Del Fresno Universidad Nacional del Centro de la Provincia de Buenos Aires Dr Martín Diaz Informática Médica Hospital Aleman de Buenos Aires - GIBBA Ing Julio César Doumecq Universidad Nacional de Mar del Plata Mg Ana María Echenique Universidad Nacional de San Juan Bioing Pedro Escobar Universidad Nacional del Centro, Olavarría, Pcia de Buenos Aires Dr Fernando Daniel Farfán Universidad Nacional de Tucumán Dr Carmelo Felice Universidad Nacional de Tucumán - CONICET Dr Elmer Fernández Universidad Católica de Córdoba - CONICET Ing José Flores Universidad Nacional de Entre Ríos Dr Arturo Gayoso Universidad Nacional de Mar del Plata Dra Bioing Agustina Garcés Universidad Nacional de San Juan ¬- CONICET Bioing Luciano Gentile Universidad Favaloro Mg María Eugenia Gómez Universidad Nacional de San Juan Dr Claudio González Universidad Nacional de Mar del Plata Mg Esteban González Universidad Nacional de Mar del Plata Dra Mariela A Gonzalez Universidad Nacional de Mar del Plata - CONICET Dr Juan Pablo Graffigna Universidad Nacional de San Juan Dra Myriam Herrera Universidad Nacional de Tucumán - CONICET Dr Roberto Hidalgo Universidad Nacional de Mar del Plata Dr Roberto Isoardi Fundación Escuela de Medicina Nuclear de Mendoza - CNEA Dra Susana Jerez Universidad Nacional de Tucumán Dr Eric Laciar Universidad Nacional de San Juan - CONICET Bioing Roberto Leonarduzzi Universidad Nacional de Entre Ríos Mg Norberto Lerendegui Instituto Tecnológico de Buenos Aires Dra Natalia López Universidad Nacional de San Juan - CONICET Dra Rossana Madrid Universidad Nacional de Tucuman - CONICET Ing Florencia Montini Ballarin Universidad Nacional de Mar del Plata - CONICET Dra Emilce Moler Universidad Nacional de Mar del Plata Dr Jorge Castiñieira Moreira Universidad Nacional de Mar del Plata Dr Silvia Murialdo Universidad Nacional de Mar del Plata - CIC Dr Juan Manuel Olivera Universidad Nacional de Tucumán Dra Lucia Isabel Passoni Universidad Nacional de Mar del Plata Dr Juan Ignacio Pastore Universidad Nacional de Mar del Plata - CONICET Dra María Elisa Pérez Universidad Nacional de San Juan Mg Franco M Pessana Universidad Favaloro Dr Julio Politti Universidad Nacional de Tucumán Dr Marcelo Risk Universidad Nacional de Buenos Aires - CONICET Ing Raúl Rivera Universidad Nacional de Mar del Plata Mg Luis Rocha Universidad Nacional de Tucumán - SIPROSA Dra Silvia Rodrigo Universidad Nacional de San Juan Dra Viviana Rotger Universidad Nacional de Tucumán Dr Leonardo Rufiner Universidad Nacional de Entre Rios - CONICET Dra Estela Ruiz Universidad Nacional de Tucumán Dr Martín Santiago Universidad Nacional del Centro de la Provincia de Buenos Aires Dra Adriana Scandurra Universidad Nacional de Mar del Plata Ing Graciela Secreto Universidad Favaloro Mg Pablo Solarz Universidad Nacional de Tucumán Mg Carolina Tabernig Universidad Nacional de Entre Ríos Ing Ricardo Taborda Universidad Nacional de Córdoba Dra María Eugenia Torres Universidad Nacional de Entre Ríos - CONICET Ing Juan Carlos Tulli Universidad Nacional de Mar del Plata Dr Gerardo Tusman Hospital Privado de Comunidad, Mar del Plata Dr Santiago Urquiza Universidad Nacional de Mar del Plata Mg Andrés Valdez Universidad Nacional de San Juan Dr Máximo Valentinuzzi INSIBIO - CONICET - Universidad Nacional de Tucumán

Mutant DD genotype of NFKB1 gene is associated with the susceptibility and severity of coronary artery disease.

PubMed

Luo, Jun-Yi; Li, Xiao-Mei; Zhou, Yun; Zhao, Qiang; Chen, Bang-Dang; Liu, Fen; Chen, Xiao-Cui; Zheng, Hong; Ma, Yi-Tong; Gao, Xiao-Ming; Yang, Yi-Ning

2017-02-01

Nuclear factor κappa B (NF-κB) is an important transcription factor in the development and progression of coronary artery disease (CAD). Recent evidence suggests that -94 ATTG ins/del mutant in the promoter of NFKB1 gene is an essential functional mutant. The present study demonstrated the frequencies of the del/del (DD) genotype and del (D) allele were significantly higher in CAD patients than in controls. CAD patients carrying mutant DD genotype had worse stenosis of diseased coronary arteries compared to those carrying ins/ins (II) or ins/del (ID) genotype. Plasma levels of endothelial nitric oxide synthase (eNOS) were lower, while inflammatory cytokine incnterlukin-6 (IL-6) was higher in CAD patients with DD genotype than those with II or ID genotype (both P<0.05). In vitro study showed that mutant human umbilical vein endothelial cells (DD genotype HUVECs) were more susceptible to H 2 O 2 -induced apoptosis, which was accompanied with a decreased Bcl-2 expression. Further, mutant HUVECs had lower eNOS but higher IL-6 mRNA levels and decreased phosphorylation of eNOS under H 2 O 2 -stimulation (both P<0.05). Compared to wild type cells (II genotype), significantly downregulated protein expression of total NF-κB p50 subunit were observed in mutant HUVECs with or without oxidative stress, and a lower expression of unclear p50 was associated with a decreased p50 nuclear translocation in mutant HUVECs versus wild type cells under H 2 O 2 -stimulation (both P<0.05). In conclusion, mutant DD genotype of NFKB1 gene is associated with the risk and severity of CAD. Dwonregulation of NF-κB p50 subunit leads to exacerbated endothelial dysfunction and apoptosis and enhanced inflammatory response that is the potential underlying mechanism. Copyright © 2017 Elsevier Ltd. All rights reserved.

MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del

PubMed Central

Zhao, Dejian; Lin, Mingyan; Chen, Jian; Pedrosa, Erika; Hrabovsky, Anastasia; Fourcade, H. Matthew; Zheng, Deyou; Lachman, Herbert M.

2015-01-01

We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher). Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05), including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p). Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis. PMID:26173148

Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation.

PubMed

Ferrari, Eleonora; Monzani, Romina; Villella, Valeria R; Esposito, Speranza; Saluzzo, Francesca; Rossin, Federica; D'Eletto, Manuela; Tosco, Antonella; De Gregorio, Fabiola; Izzo, Valentina; Maiuri, Maria C; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi

2017-01-12

Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF.

Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation

PubMed Central

Ferrari, Eleonora; Monzani, Romina; Villella, Valeria R; Esposito, Speranza; Saluzzo, Francesca; Rossin, Federica; D'Eletto, Manuela; Tosco, Antonella; De Gregorio, Fabiola; Izzo, Valentina; Maiuri, Maria C; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi

2017-01-01

Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF. PMID:28079883

[What is the Institutional Teaching Career?].

PubMed

Aguilar-Mejía, Estela

2006-01-01

The Instituto Mexicano del Seguro Social carries out a project of enormous relevance: to train health attention staff, which is its main function. The emergence and progress of a different concept and practice of teaching made possible the creation of the Institutional Teaching Career at the end of 2004. This achievement represents the acknowledgement of teaching practice, making possible the permanence, self-improvement and promotion of those professors truly committed to a teaching practice of greater importance at IMSS. The theoretical perspective that conceptually frames this career as well as the different categories of career professor implies an idea of education, as well as a teaching and improvement practice concept of health assistance that outlines a way in search of the perfection of both occupations (teaching and assistance) at the Instituto Mexicano del Seguro Social, with growing repercussions in its influence sphere.

Gelsolin functions as a metastasis suppressor in B16-BL6 mouse melanoma cells and requirement of the carboxyl-terminus for its effect.

PubMed

Fujita, H; Okada, F; Hamada , J; Hosokawa, M; Moriuchi, T; Koya, R C; Kuzumaki, N

2001-09-01

Gelsolin, an actin-binding protein, is implicated as a critical regulator in cell motility. In addition, we have reported that cellular levels of gelsolin are decreased in various tumor cells, and overexpression of gelsolin by gene transfer suppresses tumorigenicity. We sought to assess the effects of gelsolin overexpression on metastasis and to determine the importance of a carboxyl-terminus that confers Ca(2+) dependency on gelsolin for effects of its overexpression. Expression vectors with cDNA encoding either full-length wild-type or His321 mutant form, isolated from a flat revertant of Ras-transformed cells and a carboxyl-terminal truncate, C-del of gelsolin, were transfected into a highly metastatic murine melanoma cell line, B16-BL6. Expression of introduced cDNA in transfectants was confirmed using Western blotting, 2-dimensional gel electrophoresis and reverse transcription-polymerase chain reaction (RT-PCR). We characterized phenotypes of transfectants, such as growth rate, colony formation in soft agar, cell motility and metastasis formation in vivo. Transfectants expressing the wild-type, His321 mutant and C-del gelsolin exhibited reduced growth ability in soft agar. Although expression of integrin beta1 or alpha4 on the cell surface of transfectants was not changed, wild-type and His321 mutant gelsolin, except for C-del gelsolin, exhibited retardation of cell spreading, reduced chemotatic migration to fibronectin and suppressed lung colonization in spontaneous metastasis assay. Gelsolin may function as a metastasis suppressor as well as a tumor suppressor gene. The carboxyl-terminus of gelsolin is important for retardation of cell spreading, reduced chemotasis and metastasis suppression. Copyright 2001 Wiley-Liss, Inc.

Calf muscle density is independently associated with physical function in overweight and obese older adults.

PubMed

Scott, David; Shore-Lorenti, Catherine; McMillan, Lachlan B; Mesinovic, Jakub; Clark, Ross A; Hayes, Alan; Sanders, Kerrie M; Duque, Gustavo; Ebeling, Peter R

2018-03-01

To determine whether associations of calf muscle density with physical function are independent of other determinants of functional decline in overweight and obese older adults. This was a secondary analysis of a cross-sectional study of 85 community-dwelling overweight and obese adults (mean±SD age 62.8±7.9 years; BMI 32.3±6.1 kg/m2; 58% women). Peripheral quantitative computed tomography assessed mid-calf muscle density (66% tibial length) and dual-energy X-ray absorptiometry determined visceral fat area. Fasting glucose, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) were analysed. Physical function assessments included hand grip and knee extension strength, balance path length (computerised posturography), stair climb test, Short Physical Performance Battery (SPPB) and self-reported falls efficacy (Modified Falls Efficacy Scale; M-FES). Visceral fat area, not muscle density, was independently associated with CRP and fasting glucose (B=0.025; 95% CI 0.009-0.042 and B=0.009; 0.001-0.017, respectively). Nevertheless, higher muscle density was independently associated with lower path length and stair climb time, and higher SPPB and M-FES scores (all P⟨0.05). Visceral fat area, fasting glucose and CRP did not mediate these associations. Higher calf muscle density predicts better physical function in overweight and obese older adults independent of insulin resistance, visceral adiposity or inflammation.

Adaptation of multidimensional group particle tracking and particle wall-boundary condition model to the FDNS code

NASA Technical Reports Server (NTRS)

Chen, Y. S.; Farmer, R. C.

1992-01-01

A particulate two-phase flow CFD model was developed based on the FDNS code which is a pressure based predictor plus multi-corrector Navier-Stokes flow solver. Turbulence models with compressibility correction and the wall function models were employed as submodels. A finite-rate chemistry model was used for reacting flow simulation. For particulate two-phase flow simulations, a Eulerian-Lagrangian solution method using an efficient implicit particle trajectory integration scheme was developed in this study. Effects of particle-gas reaction and particle size change to agglomeration or fragmentation were not considered in this investigation. At the onset of the present study, a two-dimensional version of FDNS which had been modified to treat Lagrangian tracking of particles (FDNS-2DEL) had already been written and was operational. The FDNS-2DEL code was too slow for practical use, mainly because it had not been written in a form amenable to vectorization on the Cray, nor was the full three-dimensional form of FDNS utilized. The specific objective of this study was to reorder to calculations into long single arrays for automatic vectorization on the Cray and to implement the full three-dimensional version of FDNS to produce the FDNS-3DEL code. Since the FDNS-2DEL code was slow, a very limited number of test cases had been run with it. This study was also intended to increase the number of cases simulated to verify and improve, as necessary, the particle tracking methodology coded in FDNS.

Single nucleotide variants and InDels identified from whole-genome re-sequencing of Guzerat, Gyr, Girolando and Holstein cattle breeds.

PubMed

Stafuzza, Nedenia Bonvino; Zerlotini, Adhemar; Lobo, Francisco Pereira; Yamagishi, Michel Eduardo Beleza; Chud, Tatiane Cristina Seleguim; Caetano, Alexandre Rodrigues; Munari, Danísio Prado; Garrick, Dorian J; Machado, Marco Antonio; Martins, Marta Fonseca; Carvalho, Maria Raquel; Cole, John Bruce; Barbosa da Silva, Marcos Vinicius Gualberto

2017-01-01

Whole-genome re-sequencing, alignment and annotation analyses were undertaken for 12 sires representing four important cattle breeds in Brazil: Guzerat (multi-purpose), Gyr, Girolando and Holstein (dairy production). A total of approximately 4.3 billion reads from an Illumina HiSeq 2000 sequencer generated for each animal 10.7 to 16.4-fold genome coverage. A total of 27,441,279 single nucleotide variations (SNVs) and 3,828,041 insertions/deletions (InDels) were detected in the samples, of which 2,557,670 SNVs and 883,219 InDels were novel. The submission of these genetic variants to the dbSNP database significantly increased the number of known variants, particularly for the indicine genome. The concordance rate between genotypes obtained using the Bovine HD BeadChip array and the same variants identified by sequencing was about 99.05%. The annotation of variants identified numerous non-synonymous SNVs and frameshift InDels which could affect phenotypic variation. Functional enrichment analysis was performed and revealed that variants in the olfactory transduction pathway was over represented in all four cattle breeds, while the ECM-receptor interaction pathway was over represented in Girolando and Guzerat breeds, the ABC transporters pathway was over represented only in Holstein breed, and the metabolic pathways was over represented only in Gyr breed. The genetic variants discovered here provide a rich resource to help identify potential genomic markers and their associated molecular mechanisms that impact economically important traits for Gyr, Girolando, Guzerat and Holstein breeding programs.

Single nucleotide variants and InDels identified from whole-genome re-sequencing of Guzerat, Gyr, Girolando and Holstein cattle breeds

PubMed Central

Lobo, Francisco Pereira; Yamagishi, Michel Eduardo Beleza; Chud, Tatiane Cristina Seleguim; Caetano, Alexandre Rodrigues; Munari, Danísio Prado; Garrick, Dorian J.; Machado, Marco Antonio; Martins, Marta Fonseca; Carvalho, Maria Raquel; Cole, John Bruce; Barbosa da Silva, Marcos Vinicius Gualberto

2017-01-01

Whole-genome re-sequencing, alignment and annotation analyses were undertaken for 12 sires representing four important cattle breeds in Brazil: Guzerat (multi-purpose), Gyr, Girolando and Holstein (dairy production). A total of approximately 4.3 billion reads from an Illumina HiSeq 2000 sequencer generated for each animal 10.7 to 16.4-fold genome coverage. A total of 27,441,279 single nucleotide variations (SNVs) and 3,828,041 insertions/deletions (InDels) were detected in the samples, of which 2,557,670 SNVs and 883,219 InDels were novel. The submission of these genetic variants to the dbSNP database significantly increased the number of known variants, particularly for the indicine genome. The concordance rate between genotypes obtained using the Bovine HD BeadChip array and the same variants identified by sequencing was about 99.05%. The annotation of variants identified numerous non-synonymous SNVs and frameshift InDels which could affect phenotypic variation. Functional enrichment analysis was performed and revealed that variants in the olfactory transduction pathway was over represented in all four cattle breeds, while the ECM-receptor interaction pathway was over represented in Girolando and Guzerat breeds, the ABC transporters pathway was over represented only in Holstein breed, and the metabolic pathways was over represented only in Gyr breed. The genetic variants discovered here provide a rich resource to help identify potential genomic markers and their associated molecular mechanisms that impact economically important traits for Gyr, Girolando, Guzerat and Holstein breeding programs. PMID:28323836

Attenuation of Ultraviolet Radiation by Dust in Interstellar Clouds

NASA Astrophysics Data System (ADS)

Escalante, V.

1994-07-01

Se han obtenido soluciones de la ecuación de transporte para la dispersión coherente, no conservativa y anisotrópica para estimar la precisión de métodos aproximados, usados en modelos de nubes en que la luz es atenuada principalmente por el polvo. En los cálculos se ha aplicado el metodo de armónicos esféricos para distintos parámetros del polvo. Se ha explorado la posibilidad de descubrir cambios en las caracterísiticas del polvo mediante observaciones de regiones fotodisociadas. Se muestra que para altos valores del albedo de dispersión simple y del parametro de asimetria de Ia función de fase que son adecuados para el polvo galáctico, no es posible determinar variaciones de más de un factor de 2 en el cociente de gas a polvo. Solutions to the transfer equation for coherent, non-conservative, anisotropic scattering have been obtained in order to estimate the accuracy of approximate methods used in models of clouds where light is attenuated mostly by dust. In the calculations the spherical harmonic method has been applied for different grain parameters. The possibility of discovering changes of dust characteristics through observations of photodissociation regions has been considered. It is shown that for the high values of the single scattering albedo and the asymmetry parameter of the phase function for redistribution that appear to be appropriate for galactic dust, it is not possible to determine variations of more than a factor of 2 in the gas to dust ratio.

Assessing groundwater recharge in an Andean closed basin using isotopic characterization and a rainfall-runoff model: Salar del Huasco basin, Chile

NASA Astrophysics Data System (ADS)

Uribe, Javier; Muñoz, José F.; Gironás, Jorge; Oyarzún, Ricardo; Aguirre, Evelyn; Aravena, Ramón

2015-11-01

Closed basins are catchments whose drainage networks converge to lakes, salt flats or alluvial plains. Salt flats in the closed basins in arid northern Chile are extremely important ecological niches. The Salar del Huasco, one of these salt flats located in the high plateau (Altiplano), is a Ramsar site located in a national park and is composed of a wetland ecosystem rich in biodiversity. The proper management of the groundwater, which is essential for the wetland function, requires accurate estimates of recharge in the Salar del Huasco basin. This study quantifies the spatio-temporal distribution of the recharge, through combined use of isotopic characterization of the different components of the water cycle and a rainfall-runoff model. The use of both methodologies aids the understanding of hydrological behavior of the basin and enabled estimation of a long-term average recharge of 22 mm/yr (i.e., 15 % of the annual rainfall). Recharge has a high spatial variability, controlled by the geological and hydrometeorological characteristics of the basin, and a high interannual variability, with values ranging from 18 to 26 mm/yr. The isotopic approach allowed not only the definition of the conceptual model used in the hydrological model, but also eliminated the possibility of a hydrogeological connection between the aquifer of the Salar del Huasco basin and the aquifer that feeds the springs of the nearby town of Pica. This potential connection has been an issue of great interest to agriculture and tourism activities in the region.

F508del-CFTR rescue: a matter of cell stress response.

PubMed

Nieddu, Erika; Pollarolo, Benedetta; Merello, Luisa; Schenone, Silvia; Mazzei, Mauro

2013-01-01

Cystic fibrosis (CF) is a common inherited fatal disease affecting 70,000 people worldwide, with a median predicted age of survival of approximately 38 years. The deletion of Phenylalanine in position 508 of the Cystic Fibrosis Transmembrane conductance Regulator (F508del-CFTR) is the most common mutation in CF patients: the deleted protein, not properly folded, is degraded. To date no commercial drugs are available. Low temperature, some osmolytes and conditions able to induce heat shock protein 70 (Hsp70) expression and heat shock cognate 70 (Hsc70) inhibition result in F508del-CFTR rescue, hence restoring its physiological function: this review sheds light on the correlation between these several evidences. Interestingly, all these approaches have a role in the cell stress response (CSR), a set of cell reactions to stress. In addition, unpredictably, F508del-CFTR rescue has to be considered in the frame of CSR: entities that induce - or are induced during - the CSR are, in general, also able to correct trafficking defect of CFTR. Specifically, the low temperature induces, by definition, a CSR; osmolytes, such as glycerol and trimethylamine N-oxide (TMAO), are products of the CSR; pharmacological correctors, such as Matrine and 4-phenylbutirric acid (4PBA), down-regulate the constitutive Hsc70 in favor of an up-regulation of the inducible chaperone Hsp70, another component of the CSR. The identification of a common mechanism of action for different types of correctors could drive the discovery of new active molecules in CF, overcoming methods clinically inapplicable, such as the low temperature.

Evolution of Nucleotide Punctuation Marks: From Structural to Linear Signals.

PubMed

El Houmami, Nawal; Seligmann, Hervé

2017-01-01

We present an evolutionary hypothesis assuming that signals marking nucleotide synthesis (DNA replication and RNA transcription) evolved from multi- to unidimensional structures, and were carried over from transcription to translation. This evolutionary scenario presumes that signals combining secondary and primary nucleotide structures are evolutionary transitions. Mitochondrial replication initiation fits this scenario. Some observations reported in the literature corroborate that several signals for nucleotide synthesis function in translation, and vice versa. (a) Polymerase-induced frameshift mutations occur preferentially at translational termination signals (nucleotide deletion is interpreted as termination of nucleotide polymerization, paralleling the role of stop codons in translation). (b) Stem-loop hairpin presence/absence modulates codon-amino acid assignments, showing that translational signals sometimes combine primary and secondary nucleotide structures (here codon and stem-loop). (c) Homopolymer nucleotide triplets (AAA, CCC, GGG, TTT) cause transcriptional and ribosomal frameshifts. Here we find in recently described human mitochondrial RNAs that systematically lack mono-, dinucleotides after each trinucleotide (delRNAs) that delRNA triplets include 2x more homopolymers than mitogenome regions not covered by delRNA. Further analyses of delRNAs show that the natural circular code X (a little-known group of 20 translational signals enabling ribosomal frame retrieval consisting of 20 codons {AAC, AAT, ACC, ATC, ATT, CAG, CTC, CTG, GAA, GAC, GAG, GAT, GCC, GGC, GGT, GTA, GTC, GTT, TAC, TTC} universally overrepresented in coding versus other frames of gene sequences), regulates frameshift in transcription and translation. This dual transcription and translation role confirms for X the hypothesis that translational signals were carried over from transcriptional signals.

Velafrons coahuilensis, a new labeosaurine haddrosaurid (Dinosauria: Ornithopoda) from the Late Campanian Cerro del Pueblo formation, Coahuila, Mexico

USGS Publications Warehouse

Gates, Terry A.; Sampson, Scott D.; de Jesus, Carlos R. Delgado; Zanno, Lindsay E.; Eberth, David; Hernandez-Rivera, Rene; Aguillon-Martinez, Martha C.; Kirkland, James I.

2007-01-01

A new lambeosaurine hadrosaurid, Velafrons coahuilensis, is described as the first lambeosaurine from the Cerro del Pueblo Formation of Coahuila, Mexico, and the first lambeosaurine genus to be named from North America in more than 70 years. Although the holotype specimen is a juvenile individual—as evidenced by its incomplete crest development and relative size compared to other North American lambeosaurines—ontogeny independent autapomor-phies have been identified including quadrate with narrow quadratojugal notch and a postorbital with well developed, dorsally positioned squamosal process. Additionally, this taxon is unique in that the prefrontal is not dorsally deflected and anteroposteriorly expanded as in other lambeosaurine taxa of its size, but rather retains the frontal-prefrontal “clamp” present in smaller individuals of other taxa. Phylogenetic analysis places Velafrons in a polytomy with numerous other fan-crested lambeosaurines. The crest structure of Velafrons more closely resembles that of Corythosaurus and Hypacrosaurus because it possesses an anteriorly projecting nasal process over the dorsal premaxilla process. Biogeo-graphically, Velafrons is one of three distinct hadrosaurids known from approximately 73.5 Ma—two lambeosaurines and one hadrosaurine—all restricted to the southern region of the Western Interior Basin of North America.

General topology meets model theory, on and

PubMed Central

Malliaris, Maryanthe; Shelah, Saharon

2013-01-01

Cantor proved in 1874 [Cantor G (1874) J Reine Angew Math 77:258–262] that the continuum is uncountable, and Hilbert’s first problem asks whether it is the smallest uncountable cardinal. A program arose to study cardinal invariants of the continuum, which measure the size of the continuum in various ways. By Gödel [Gödel K (1939) Proc Natl Acad Sci USA 25(4):220–224] and Cohen [Cohen P (1963) Proc Natl Acad Sci USA 50(6):1143–1148], Hilbert’s first problem is independent of ZFC (Zermelo-Fraenkel set theory with the axiom of choice). Much work both before and since has been done on inequalities between these cardinal invariants, but some basic questions have remained open despite Cohen’s introduction of forcing. The oldest and perhaps most famous of these is whether “,” which was proved in a special case by Rothberger [Rothberger F (1948) Fund Math 35:29–46], building on Hausdorff [Hausdorff (1936) Fund Math 26:241–255]. In this paper we explain how our work on the structure of Keisler’s order, a large-scale classification problem in model theory, led to the solution of this problem in ZFC as well as of an a priori unrelated open question in model theory. PMID:23836659

Search for Muon Neutrino Disappearance in the Booster Neutrino Beam of Fermilab; Busqueda de Desaparicion de Neutrinos del Muon en el Haz de Neutrinos del Booster de Fermilab (in Spanish)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mendez Mendez, Diana Patricia

In this work we carried out the disappearance analysis of muon neutrinos produced in the Fermilab Booster Neutrino Beam, using the data released to the public by the collaborations of the MiniBooNE and SciBooNE experiments. The calculations were made with programs in C and C++, implementing the ROOT libraries. From the analysis, using both the classical Pearson method and the Feldman and Cousins frequentist corrections, we obtained the 90\\% C.L. limit for the oscillation parameters sin 22θ and Δm 2 in the region 0.1 ≤ Δm 2 ≤ 10 eV 2 using a two neutrino model. The result presented inmore » this work is consistent with the official one, with small deviations ascribed to round-off errors in the format of the used data, as well as statistical fluctuations in the generation of fake experiments used in the Feldman and Cousins method. As the official one, our result is consistent with the null oscillation hypothesis. This work was carried out independently to the MiniBooNE and SciBooNE collaborations and its results are not official.« less

Hand Strength, Handwriting, and Functional Skills in Children With Autism.

PubMed

Alaniz, Michele L; Galit, Eleanor; Necesito, Corina Isabel; Rosario, Emily R

2015-01-01

To establish hand strength development trends in children with autism and to investigate correlations between grip and pinch strength, components of handwriting, and functional activities in children with and without autism. Fifty-one children were divided into two groups: typically developing children and children on the autism spectrum. Each child completed testing for pinch and grip strength, handwriting legibility, pencil control, and independence in functional activities. The children with autism followed the same strength development trends as the typically developing children. Grip strength correlated with pencil control in both groups and with handwriting legibility in the typically developing children but not in the children with autism. Grip and pinch strength correlated with independence with functional activities in both groups. This study provides evidence that grip and pinch strength are important components in developing pencil control, handwriting legibility, and independence with functional fine motor tasks. Copyright © 2015 by the American Occupational Therapy Association, Inc.

Nutrient cycling in Nothofagus pumilio forests along an altitudinal gradient in Tierra del Fuego, Argentina

Treesearch

Jorge L. Frangi; Marcelo D. Barrera; Laura L. Richter; Ariel E. Lugo

2005-01-01

Nothofagus pumilio (lenga) forests form monocultures from sea level to timberline in Tierra de Fuego, Argentina. Past studies suggested that the life form change from erect forest to krummholz had advantages to forest function. Aboveground net primary productivity (NPP) and organic matter production per unit leaf area and growing season day were higher in krummholz...

Dynamic human landscapes of the Rio del Oso: Restoration and the simulation of past ecological conditions in the Upper Rio Grande Basin

Treesearch

Richard D. Periman

1999-01-01

The successful restoration of riparian ecosystems to sustainable conditions requires that we understand the dynamic historical relationships between humans and the environment. Research is needed that measures the continuing effects of past human activities on contemporary ecosystem structure and function. An interdisciplinary approach is needed that incorporates...

The Integration of Delta Prime (f)in a Multidimensional Space

NASA Technical Reports Server (NTRS)

Farassat, F.

1999-01-01

Consideration is given to the thickness noise term of the Ffowcs Williams-Hawkings equation when the time derivative is taken explicitly. An interpretation is presented of the integral I = function phi(x)delta-prime(f) dx, where it is initially assumed that the absolute value of Del-f is not equal to 1 on the surface f = 0.

PoMaMo--a comprehensive database for potato genome data.

PubMed

Meyer, Svenja; Nagel, Axel; Gebhardt, Christiane

2005-01-01

A database for potato genome data (PoMaMo, Potato Maps and More) was established. The database contains molecular maps of all twelve potato chromosomes with about 1000 mapped elements, sequence data, putative gene functions, results from BLAST analysis, SNP and InDel information from different diploid and tetraploid potato genotypes, publication references, links to other public databases like GenBank (http://www.ncbi.nlm.nih.gov/) or SGN (Solanaceae Genomics Network, http://www.sgn.cornell.edu/), etc. Flexible search and data visualization interfaces enable easy access to the data via internet (https://gabi.rzpd.de/PoMaMo.html). The Java servlet tool YAMB (Yet Another Map Browser) was designed to interactively display chromosomal maps. Maps can be zoomed in and out, and detailed information about mapped elements can be obtained by clicking on an element of interest. The GreenCards interface allows a text-based data search by marker-, sequence- or genotype name, by sequence accession number, gene function, BLAST Hit or publication reference. The PoMaMo database is a comprehensive database for different potato genome data, and to date the only database containing SNP and InDel data from diploid and tetraploid potato genotypes.

PoMaMo—a comprehensive database for potato genome data

PubMed Central

Meyer, Svenja; Nagel, Axel; Gebhardt, Christiane

2005-01-01

A database for potato genome data (PoMaMo, Potato Maps and More) was established. The database contains molecular maps of all twelve potato chromosomes with about 1000 mapped elements, sequence data, putative gene functions, results from BLAST analysis, SNP and InDel information from different diploid and tetraploid potato genotypes, publication references, links to other public databases like GenBank (http://www.ncbi.nlm.nih.gov/) or SGN (Solanaceae Genomics Network, http://www.sgn.cornell.edu/), etc. Flexible search and data visualization interfaces enable easy access to the data via internet (https://gabi.rzpd.de/PoMaMo.html). The Java servlet tool YAMB (Yet Another Map Browser) was designed to interactively display chromosomal maps. Maps can be zoomed in and out, and detailed information about mapped elements can be obtained by clicking on an element of interest. The GreenCards interface allows a text-based data search by marker-, sequence- or genotype name, by sequence accession number, gene function, BLAST Hit or publication reference. The PoMaMo database is a comprehensive database for different potato genome data, and to date the only database containing SNP and InDel data from diploid and tetraploid potato genotypes. PMID:15608284

Inherited biallelic CSF3R mutations in severe congenital neutropenia.

PubMed

Triot, Alexa; Järvinen, Päivi M; Arostegui, Juan I; Murugan, Dhaarini; Kohistani, Naschla; Dapena Díaz, José Luis; Racek, Tomas; Puchałka, Jacek; Gertz, E Michael; Schäffer, Alejandro A; Kotlarz, Daniel; Pfeifer, Dietmar; Díaz de Heredia Rubio, Cristina; Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Sánchez de Toledo Codina, José; Yagüe, Jordi; Touw, Ivo P; Unal, Ekrem; Klein, Christoph

2014-06-12

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. © 2014 by The American Society of Hematology.

Inherited biallelic CSF3R mutations in severe congenital neutropenia

PubMed Central

Triot, Alexa; Järvinen, Päivi M.; Arostegui, Juan I.; Murugan, Dhaarini; Kohistani, Naschla; Dapena Díaz, José Luis; Racek, Tomas; Puchałka, Jacek; Gertz, E. Michael; Schäffer, Alejandro A.; Kotlarz, Daniel; Pfeifer, Dietmar; Díaz de Heredia Rubio, Cristina; Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Sánchez de Toledo Codina, José; Yagüe, Jordi; Touw, Ivo P.; Unal, Ekrem

2014-01-01

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. PMID:24753537

Understanding Reflectance Anisotropy: Surface-structure signatures and bulk-related features

NASA Astrophysics Data System (ADS)

Gero Schmidt, W.

2000-03-01

Reflectance anisotropy spectroscopy (RAS) is becoming an increasingly important tool for in situ control of semiconductor processing with real-time feedback. The understanding and interpretation of the measured spectra, however, has been hampered by relatively slow theoretical progress. Using a massively parallel real-space multigrid technique [1] and ab initio pseudopotentials we calculated the optical spectra of a variety of III-V(001) growth structures and stepped Si(111):H surfaces. Our results agree well with experiment, notably with respect to the stoichiometric changes induced by different surface preparations. We identify two distinct sources for the optical anisotropy: (i) highly structure-dependent features are caused by transitions involving electronic surface states, and (ii) derivative-like oscillations or peaks at the bulk critical point energies arise from transitions between surface-modified bulk wave functions. The latter are nearly independent from the actual surface structure. The agreement between the calculated and measured spectra is further improved by applying quasi-particle corrections obtained from numerically efficient, simplified GW calculations [2]. The combination of converged first-principles calculations with an approximate treatment of many-particle effects allows the reliable identification of ``surface-structure fingerprints'' in the optical spectra, paving the way for the exploitation of their rich technological potential. [1ex] [1] EL Briggs, DJ Sullivan, J Bernholc, Phys. Rev. B 54, 14362 (1996). [2] F Bechstedt, R Del Sole, G Cappellini, L Reining, Solid State Commun. 84, 765 (1992).

Metformin effects on ovarian ultrasound appearance and steroidogenic function in normal-weight normoinsulinemic women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial.

PubMed

Romualdi, Daniela; Giuliani, Maddalena; Cristello, Francesca; Fulghesu, Anna Maria; Selvaggi, Luigi; Lanzone, Antonio; Guido, Maurizio

2010-05-01

To investigate metformin effects on the endocrine-metabolic parameters and ovarian morphology in normoinsulinemic women with polycystic ovary syndrome (PCOS). Randomized double-blind study. Operative Division of Endocrinological Gynecology, Università Cattolica del Sacro Cuore. Twenty-eight normal-weight normoinsulinemic PCOS women. Patients were randomized to receive metformin 500 mg twice a day (group A, 15 subjects) or placebo (group B, 13 subjects) for 6 months. Ultrasonographic pelvic exams, hormonal and lipid features, and oral glucose tolerance test were performed at baseline and after 3 and 6 months of treatment. Hormonal and glycoinsulinemic assessment, ovarian ultrasound appearance. Glycoinsulinemic assessment remained unvaried in both groups. About 70% of patients in group A experienced a restoration of menstrual cyclicity. Metformin significantly decreased testosterone levels at 3 and 6 months) and 17-hydroxyprogesterone levels at 6 months, and improved hirsutism score at 6 months. No clinical or hormonal modifications occurred in group B. Metformin, but not placebo, reduced ovarian volume and stromal/total area ratio at 3 and 6 months. Metformin seems to improve the menstrual pattern and ultrasonographic ovarian features in normoinsulinemic PCOS women. These effects seem to be, at least in part, independent of the insulin-lowering properties of the drug. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Associations between ankle-brachial index and cognitive function: results from the Lifestyle Interventions and Independence for Elders trial

USDA-ARS?s Scientific Manuscript database

OBJECTIVE: The objective of this study was to evaluate cross-sectional and longitudinal associations between ankle-brachial index (ABI) and indicators of cognitive function. DESIGN: Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial). SETTING: Eight US academic ce...

Investigation of Cool and Hot Executive Function in ODD/CD Independently of ADHD

ERIC Educational Resources Information Center

Hobson, Christopher W.; Scott, Stephen; Rubia, Katya

2011-01-01

Background: Children with oppositional defiant disorder/conduct disorder (ODD/CD) have shown deficits in "cool" abstract-cognitive, and "hot" reward-related executive function (EF) tasks. However, it is currently unclear to what extent ODD/CD is associated with neuropsychological deficits, independently of attention deficit hyperactivity disorder…

Proyecto para la medición sistemática de seeing en CASLEO

NASA Astrophysics Data System (ADS)

Fernández Lajus, E.; Forte, J. C.

La calidad del seeing astronómico es ciertamente uno de los parámetros mas importantes que caracterizan el sitio de un observatorio. Por tanto se desea determinar si el alto valor de seeing observado con el telescopio de 2.15 m se debe a efectos internos y/o del entorno a la cupula o si se debe simplemente al seeing propio del lugar. El actual mecanismo de refrigeración del espejo primario del 2.15, parece haber mejorado notablemente la calidad del seeing. Sin embargo se hace necesario saber hasta que punto el valor del seeing puede ser mejorado. La primera etapa del proyecto consistió en la puesta a punto del telescopio emplazado para este propósito y la adquisición de las primeras medidas tentativas de seeing.

Olfaction Is Related to Motor Function in Older Adults.

PubMed

Tian, Qu; Resnick, Susan M; Studenski, Stephanie A

2017-08-01

Among older adults, both olfaction and motor function predict future cognitive decline and dementia, suggesting potential shared causal pathways. However, it is not known whether olfactory and motor function are independently related in late life. We assessed cross-sectional associations of olfaction with motor and cognitive function, using concurrent data on olfactory function, mobility, balance, fine motor function, manual dexterity, and cognition in 163 Baltimore Longitudinal Study of Aging participants aged 60 and older without common neurological diseases (n = 114 with available cognitive data). Using multiple linear regression, we adjusted for age, sex, race, smoking history, height, and weight for mobility and balance, and education for cognition. We used multiple linear regression to test whether olfaction-motor associations were independent of cognition and depressive symptoms. Olfactory scores were significantly associated with mobility (usual gait speed, rapid gait speed, 400-m walk time, and Health ABC Physical Performance Battery score), balance, fine motor function, and manual dexterity (all p < .05). In those with available cognitive data, additional adjustment for depressive symptoms, verbal memory, or visuoperceptual speed demonstrated especially strong independent relationships with challenging motor tasks such as 400-m walk and nondominant hand manual dexterity (p < .005). This study demonstrates for the first time that, in older adults, olfactory function is associated with mobility, balance, fine motor function, and manual dexterity, and independent of cognitive function, with challenging upper and lower extremity motor function tasks. Longitudinal studies are needed to determine if olfactory performance predicts future mobility and functional decline. Published by Oxford University Press on behalf of The Gerontological Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Associations Between Ankle-Brachial Index and Cognitive Function: Results From the Lifestyle Interventions and Independence for Elders Trial.

PubMed

Espeland, Mark A; Newman, Anne B; Sink, Kaycee; Gill, Thomas M; King, Abby C; Miller, Michael E; Guralnik, Jack; Katula, Jeff; Church, Timothy; Manini, Todd; Reid, Kieran F; McDermott, Mary M

2015-08-01

The objective of this study was to evaluate cross-sectional and longitudinal associations between ankle-brachial index (ABI) and indicators of cognitive function. Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial). Eight US academic centers. A total of 1601 adults ages 70-89 years, sedentary, without dementia, and with functional limitations. Baseline ABI and interviewer- and computer-administered cognitive function assessments were obtained. These assessments were used to compare a physical activity intervention with a health education control. Cognitive function was reassessed 24 months later (interviewer-administered) and 18 or 30 months later (computer-administered) and central adjudication was used to classify individuals as having mild cognitive impairment, probable dementia, or neither. Lower ABI had a modest independent association with poorer cognitive functioning at baseline (partial r = 0.09; P < .001). Although lower baseline ABI was not associated with overall changes in cognitive function test scores, it was associated with higher odds for 2-year progression to a composite of either mild cognitive impairment or probable dementia (odds ratio 2.60 per unit lower ABI; 95% confidence interval 1.06-6.37). Across 2 years, changes in ABI were not associated with changes in cognitive function. In an older cohort sedentary individuals with dementia and with functional limitations, lower baseline ABI was independently correlated with cognitive function and associated with greater 2-year risk for progression to mild cognitive impairment or probable dementia. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Predictors of functional level and quality of life at 6 months after a first-ever stroke: the KOSCO study.

PubMed

Chang, Won Hyuk; Sohn, Min Kyun; Lee, Jongmin; Kim, Deog Young; Lee, Sam-Gyu; Shin, Yong-Il; Oh, Gyung-Jae; Lee, Yang-Soo; Joo, Min Cheol; Han, Eun Young; Kang, Chung; Kim, Yun-Hee

2016-06-01

Predicting functional outcome and quality of life (QOL) is critical to the treatment of patients with stroke. The purpose of this study was to analyze the factors influencing functional status and QOL of stroke patients 6 months after a first-ever stroke. This study was an interim analysis of the Korean Stroke Cohort for Functioning and Rehabilitation Study, designed to include 10 years of follow-up for first-ever stroke patients. This study analyzed data from 2857 patients who completed face-to-face assessments with the functional independence measurement (FIM) and Euro Quality of Life-5D (EQ-5D) at 6 months after stroke onset. A multivariate regression analysis was used to analyze factors that potentially influenced FIM and EQ-5D results at 6 months after stroke. Of the patients in this study, 80.1 % suffered from ischemic stroke and 19.9 % experienced hemorrhagic stroke. The independent predictors of functional independency measured by FIM at 6 months after stroke were age, initial stroke severity, duration of hospitalization, and functional level at discharge in terms of motor, ambulation, and language. For QOL measured by EQ-5D at 6 months after stroke, age, duration of hospitalization, and motor function at discharge were significant predictors. In conclusion, proper treatment to achieve maximal functional gain at discharge may be an important factor in improving functional independency and QOL in chronic stage stroke survivors. These results provide useful information for establishing comprehensive and systematic care for stroke patients.

Exploring the relation between positive emotions and the functional status of older adults living independently: a systematic review.

PubMed

Cabrita, Miriam; Lamers, Sanne M A; Trompetter, Hester R; Tabak, Monique; Vollenbroek-Hutten, Miriam M R

2017-11-01

Literature suggests that positive emotions positively influence physiological parameters but their relation to functioning in the daily life of older adults living independently remains unclear. The present work aims to investigate the relation between positive emotions and functional status in daily life of older people living independently. A systematic literature review was conducted using the PubMed, PsycINFO and Scopus electronic databases. Included works were peer-reviewed empirical studies that analysed the relation between positive emotions and ability to perform activities of daily living with older adults living independently. After removal of duplicates, 10 out of 963 papers met the inclusion criteria. Cross-sectional studies (n = 6) provided limited evidence about a relation between positive emotions and functioning in daily life. However, longitudinal studies (n = 4) provide significant evidence for an interaction between the two factors, suggesting that time influences this interaction. The variety on the design and samples of the studies included in this review does not allow a cohesive conclusion of the results. Nevertheless, limited evidence suggests that higher frequency in the experience of positive emotions might be associated with lower functional limitations. The issue of causality in emotions-functioning remains unclear from the review. Further observational studies are highly recommended, supported by innovative technologies.

A Lightweight TwiddleNet Portal

DTIC Science & Technology

2008-03-01

MAC PHY Media Independent Handover Function (Network)ES CS IS 802 Interface Client Station 802 Networks 3GPP 3 GPP 2 Network MIH Network...Entity ( . e g ). MIH Server Controller Media Independent Handover Function (Client) Information Service over L2 Transport Remote MIH Events over L2...Co-located with MIH MGMTMGMT E v e n t s E S C S IS E v e n t s E v e n t s E v e n t s Media Independent Handover User Media

Intertextual Sexual Politics: Illness and Desire in Enrique Gomez Carrillo's "Del amor", "del dolor y del vicio" and Aurora Caceres's "La rosa muerta"

ERIC Educational Resources Information Center

LaGreca, Nancy

2012-01-01

This study explores the intertextuality between Aurora Caceres's "La rosa muerta" (1914) and the novel "Del amor, del dolor y del vicio" (1898) by her ex-husband, Enrique Gomez Carrillo. Caceres strategically mentions Gomez Carrillo's novel in "La rosa muerta" to invite a reading of her work in dialogue with his. Both narratives follow the sexual…

Pre-fracture nutritional status is predictive of functional status at discharge during the acute phase with hip fracture patients: A multicenter prospective cohort study.

PubMed

Inoue, Tatsuro; Misu, Syogo; Tanaka, Toshiaki; Sakamoto, Hiroki; Iwata, Kentaro; Chuman, Yuki; Ono, Rei

2017-10-01

Malnutrition is common in patients with hip fractures, and elderly patients with hip fractures lose functional independence and often fail to recover previous functional status. The aim of this study was to determine whether pre-fracture nutritional status predicts functional status of patients with hip fracture at discharge from acute hospitals. In the present multicenter prospective cohort study, pre-fracture nutritional status was assessed using the Mini Nutritional Assessment Short-Form (MNA-SF). At discharge from acute hospitals, functional status was evaluated using a functional independent measurement instrument (FIM). Subsequently, multiple regression analyses were performed using FIM as the dependent variable and MNA-SF as the independent variable. Among the 204 patients analyzed in the present study, the mean length of hospital stay was 26.2 ± 12.6 days, and according to MNA-SF assessments, 51 (25.0%) patients were malnourished, 98 (48.0%) were at risk of malnutrition, and 55 (27.0%) were well-nourished before fracture. At discharge, FIM scores were higher in patients who were well-nourished than in those who were malnourished or were at risk of malnutrition (p < 0.01). After adjustment for confounding factors, multiple regression analyses showed that MNA-SF was a significant independent predictor for FIM at discharge (well-nourished vs. malnourished, β = -0.86, p < 0.01). Pre-fracture nutritional status was a significant independent predictor for functional status at discharge during the acute phase, warranting early assessment of nutritional status and early intervention for successful postoperative rehabilitation. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Variation in species diversity and functional traits of sponge communities near human populations in Bocas del Toro, Panama

PubMed Central

Matterson, Kenan O.; Freeman, Christopher J.; Archer, Stephanie K.; Thacker, Robert W.

2015-01-01

Recent studies have renewed interest in sponge ecology by emphasizing the functional importance of sponges in a broad array of ecosystem services. Many critically important habitats occupied by sponges face chronic stressors that might lead to alterations in their diversity, relatedness, and functional attributes. We addressed whether proximity to human activity might be a significant factor in structuring sponge community composition, as well as potential functional roles, by monitoring sponge diversity and abundance at two structurally similar sites that vary in distance to areas of high coastal development in Bocas Del Toro, Panama. We surveyed sponge communities at each site using belt transects and differences between two sites were compared using the following variables: (1) sponge species richness, Shannon diversity, and inverse Simpson’s diversity; (2) phylogenetic diversity; (3) taxonomic and phylogenetic beta diversity; (4) trait diversity and dissimilarity; and (5) phylogenetic and trait patterns in community structure. We observed significantly higher sponge diversity at Punta Caracol, the site most distant from human development (∼5 km). Although phylogenetic diversity was lower at Saigon Bay, the site adjacent to a large village including many houses, businesses, and an airport, the sites did not exhibit significantly different patterns of phylogenetic relatedness in species composition. However, each site had a distinct taxonomic and phylogenetic composition (beta diversity). In addition, the sponge community at Saigon included a higher relative abundance of sponges with high microbial abundance and high chlorophyll a concentration, whereas the community at Punta Caracol had a more even distribution of these traits, yielding a significant difference in functional trait diversity between sites. These results suggest that lower diversity and potentially altered community function might be associated with proximity to human populations. This study highlights the importance of evaluating functional traits and phylogenetic diversity in addition to common diversity metrics when assessing potential environmental impacts on benthic communities. PMID:26587347

FPGA-based real time controller for high order correction in EDIFISE

NASA Astrophysics Data System (ADS)

Rodríguez-Ramos, L. F.; Chulani, H.; Martín, Y.; Dorta, T.; Alonso, A.; Fuensalida, J. J.

2012-07-01

EDIFISE is a technology demonstrator instrument developed at the Institute of Astrophysics of the Canary Islands (IAC), intended to explore the feasibility of combining Adaptive Optics with attenuated optical fibers in order to obtain high spatial resolution spectra at the surroundings of a star, as an alternative to coronagraphy. A simplified version with only tip tilt correction has been tested at the OGS telescope in Observatorio del Teide (Canary islands, Spain) and a complete version is intended to be tested at the OGS and at the WHT telescope in Observatorio del Roque de los Muchachos, (Canary Islands, Spain). This paper describes the FPGA-based real time control of the High Order unit, responsible of the computation of the actuation values of a 97-actuactor deformable mirror (11x11) with the information provided by a configurable wavefront sensor of up to 16x16 subpupils at 500 Hz (128x128 pixels). The reconfigurable logic hardware will allow both zonal and modal control approaches, will full access to select which mode loops should be closed and with a number of utilities for influence matrix and open loop response measurements. The system has been designed in a modular way to allow for easy upgrade to faster frame rates (1500 Hz) and bigger wavefront sensors (240x240 pixels), accepting also several interfaces from the WFS and towards the mirror driver. The FPGA-based (Field Programmable Gate Array) real time controller provides bias and flat-fielding corrections, subpupil slopes to modal matrix computation for up to 97 modes, independent servo loop controllers for each mode with user control for independent loop opening or closing, mode to actuator matrix computation and non-common path aberration correction capability. It also provides full housekeeping control via UPD/IP for matrix reloading and full system data logging.

Changes in trophic flow structure of Independence Bay (Peru) over an ENSO cycle

NASA Astrophysics Data System (ADS)

Taylor, Marc H.; Wolff, Matthias; Mendo, Jaime; Yamashiro, Carmen

2008-10-01

During the strong warm El Niño (EN) that occurred in 1997/98, Independence Bay (14°S, Peru) showed a ca. 10 °C increase in surface temperatures, higher oxygen concentrations, and clearer water due to decreased phytoplankton concentrations. Under these quasi-tropical conditions, many benthic species suffered (e.g. macroalgae, portunid crabs, and polychaetes) while others benefited (e.g. scallop, sea stars, and sea urchins). The most obvious change was the strong recruitment success and subsequent proliferation of the scallop Argopecten purpuratus, whose biomass increased fiftyfold. To understand these changes, steady-state models of the bay ecosystem trophic structure were constructed and compared for a normal upwelling year (1996) and during an EN (1998), and longer-term dynamics (1996-2003) were explored based on time series of catch and biomass using Ecopath with Ecosim (EwE) software. Model inputs were based on surveys and landings data collected by the Instituto del Mar del Perú (IMARPE). Results indicate that while ecosystem size (total throughput) is reduced by 18% during EN, mainly as a result of decreased total primary production, benthic biomass remains largely unchanged despite considerable shifts in the dominant benthic taxa (e.g. scallops replace polychaetes as secondary consumers). Under normal upwelling conditions, predation by snails and crabs utilize the production of their prey almost completely, resulting in more efficient energy flow to higher trophic levels than occurs during EN. However during EN, the proliferation of the scallop A. purpuratus combined with decreased phytoplankton increased the proportion of directly utilized primary production, while exports and flows to detritus are reduced. The simulations suggest that the main cause for the scallop outburst and for the reduction in crab and macroalgae biomass was a direct temperature effect, whereas other changes are partially explained by trophic interactions. The simulations suggest that bottom-up effects largely control the system.

C-reactive protein and anti-Chlamydia pneumoniae antibodies as risk factors of cardiovascular death in incident patients on peritoneal dialysis.

PubMed

Paniagua, Ramón; Frías, Yolanda; de Ventura, Maria Jesús; Rodríguez, Ernesto; Hurtado, María Elena; Alcántara, Guadalupe; Vázquez, Roberto; Ortiz, Ruth; Salcedo, Mario; Rios, Maria Elena; Kaji, Julio; Amato, Dante

2003-01-01

Recently it has been pointed out that inflammation and infections caused by germs such as Chlamydia pneumoniae are independent cardiovascular risk factors for the general population, but information about these relationships in dialysis patients is scarce. This work was done to analyze the association of C-reactive protein (CRP) and IgG anti-Chlamydia pneumoniae antibodies (anti-Chlp-IgG) as independent cardiovascular risk factors in incident patients on continuous ambulatory peritoneal dialysis (CAPD). Single-cohort, prospective observational study. Three CAPD centers from the Instituto Mexicano del Seguro Social, and one from the Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico. A cohort of 75 adult incident patients on CAPD, without clinical signs of congestive heart failure, coronary heart disease, or peripheral arterial insufficiency. No restrictions for age, gender, or cause of renal failure were applied. Mortality. Demographic variables, body composition by electrical bioimpedance, serum glucose, urea, creatinine, lipids, homocysteine, nutritional markers (albumin, prealbumin, and transferrin), CRP, and anti-Chlp-IgG were measured and registered at the time of the first admission. When a patient died, the cause of death was determined by review of the clinical chart. Mean follow-up time was 10.25 patient-months. There were 14 cardiovascular deaths. CRP was positive (> 10 mg/L) in 64% of the patients, and anti-Chlp-IgG in 64%; 29% of the patients were positive for both markers. The relative risk for cardiovascular mortality was 6.23 for patients positive for either CRP or anti-Chlp-IgG, and increased to 9.52 when both markers were positive. Multivariate analysis revealed that CRP and anti-Chlp-IgG were stronger cardiovascular death predictors than age, diabetes, and nutritional status. These data suggest that inflammation and the presence of Chlamydia pneumoniae infections are important predictors of cardiovascular death in patients on CAPD.

Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway.

PubMed

Maekawa, Tomoki; Hosur, Kavita; Abe, Toshiharu; Kantarci, Alpdogan; Ziogas, Athanasios; Wang, Baomei; Van Dyke, Thomas E; Chavakis, Triantafyllos; Hajishengallis, George

2015-09-16

Del-1 is an endothelial cell-secreted anti-inflammatory protein. In humans and mice, Del-1 expression is inversely related to that of IL-17, which inhibits Del-1 through hitherto unidentified mechanism(s). Here we show that IL-17 downregulates human endothelial cell expression of Del-1 by targeting a critical transcription factor, C/EBPβ. Specifically, IL-17 causes GSK-3β-dependent phosphorylation of C/EBPβ, which is associated with diminished C/EBPβ binding to the Del-1 promoter and suppressed Del-1 expression. This inhibitory action of IL-17 can be reversed at the GSK-3β level by PI3K/Akt signalling induced by D-resolvins. The biological relevance of this regulatory network is confirmed in a mouse model of inflammatory periodontitis. Intriguingly, resolvin-D1 (RvD1) confers protection against IL-17-driven periodontal bone loss in a Del-1-dependent manner, indicating an RvD1-Del-1 axis against IL-17-induced pathological inflammation. The dissection of signalling pathways regulating Del-1 expression provides potential targets to treat inflammatory diseases associated with diminished Del-1 expression, such as periodontitis and multiple sclerosis.

Functional Independence, Diagnostic Groups, Hospital Stay, and Modality of Payment in Three Croatian Seaside Inpatient Rehabilitation Centers

PubMed Central

Mrčela, Nada Tomasović; Massari, Dražen; Vlak, Tonko

2010-01-01

Aim To determine patients’ functional independence, diagnostic groups, duration of hospital stay, and modality of payment of rehabilitation in major special hospitals for rheumatology and medical rehabilitation on the Croatian seaside. Methods In a cross-sectional study conducted from October 2006 until January 2009, we surveyed 400 patients treated at 3 special hospitals for medical rehabilitation. Their functional independence was assessed by modified Barthel index and they self-evaluated their health using the first item from the 36-Item Short-Form Health Survey questionnaire. Results On admission, almost half of the patients (46%) were fully functionally independent, 33% were slightly dependent, while 21% were moderately or severely dependent. At the end of the hospitalization, significant predictors for the increase in Barthel index were longer hospital stay (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.22), diagnosis of post-procedural musculoskeletal disorders (OR, 4.84; 95% CI, 1.90-10.57), diagnosis of conditions following acute ischemic heart disease (OR, 9.71; 95% CI, 3.40-27.75), and lower Barthel index at admission (OR, 0.96; 95% CI, 0.94-0.97). Of the 97 patients with dorsopathy, 73 (75%) were fully functionally independent and 57 (59%) paid for the treatment either themselves or contributed substantially to the total cost. Conclusion Assessment of patients’ functional status is important for the organization of inpatient rehabilitation. Patients with dorsopathy could be targeted as a population for medical tourism in rehabilitation medicine in order to maximize the use of rehabilitation hospitals. PMID:21162166

Physiotherapy treatment approaches for the recovery of postural control and lower limb function following stroke: a systematic review.

PubMed

Pollock, Alex; Baer, Gillian; Langhorne, Peter; Pomeroy, Valerie

2007-05-01

To determine whether there is a difference in global dependency and functional independence in patients with stroke associated with different approaches to physiotherapy treatment. We searched the Cochrane Stroke Group Trials Register (last searched May 2005), Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 2, 2005), MEDLINE (1966 to May 2005), EMBASE (1980 to May 2005) and CINAHL (1982 to May 2005). We contacted experts and researchers with an interest in stroke rehabilitation. Inclusion criteria were: (a) randomized or quasi-randomized controlled trials; (b) adults with a clinical diagnosis of stroke; (c) physiotherapy treatment approaches aimed at promoting postural control and lower limb function; (d) measures of disability, motor impairment or participation. Two independent reviewers categorized identified trials according to the inclusion/exclusion criteria, documented the methodological quality and extracted the data. Twenty trials (1087 patients) were included in the review. Comparisons included: neurophysiological approach versus other approach; motor learning approach versus other approach; mixed approach versus other approach for the outcomes of global dependency and functional independence. A mixed approach was significantly more effective than no treatment control at improving functional independence (standardized mean difference (SMD) 0.94, 95% confidence interval (CI) 0.08 to 1.80). There were no significant differences found for any other comparisons. Physiotherapy intervention, using a 'mix' of components from different 'approaches' is more effective than no treatment control in attaining functional independence following stroke. There is insufficient evidence to conclude that any one physiotherapy 'approach' is more effective in promoting recovery of disability than any other approach.

The Independent School Experience: Aspects of the Normative Environments of Single-Sex and Coed Secondary Schools.

ERIC Educational Resources Information Center

Trickett, Edison J.; And Others

1982-01-01

The normative environments of single-sex independent schools were found to be more academic, with greater task and competition orientation, than coeducational independent schools. Representative independent schools were compared to each other and to public schools with a discussion of learning involvement, function, purpose, and student and…

Hyperspectral functional imaging of the human brain

NASA Astrophysics Data System (ADS)

Toronov, Vladislav; Schelkanova, Irina

2013-03-01

We performed the independent component analysis of the hyperspectral functional near-infrared data acquired on humans during exercise and rest. We found that the hyperspectral functional data acquired on the human brain requires only two physiologically meaningful components to cover more than 50% o the temporal variance in hundreds of wavelengths. The analysis of the spectra of independent components showed that these components could be interpreted as results of changes in the cerebral blood volume and blood flow. Also, we found significant contributions of water and cytochrome c oxydase into changes associated with the independent components. Another remarkable effect of ICA was its good performance in terms of the filtering of the data noise.

Physical independence and mortality at the extreme limit of life span: supercentenarians study in Japan.

PubMed

Arai, Yasumichi; Inagaki, Hiroki; Takayama, Michiyo; Abe, Yukiko; Saito, Yasuhiko; Takebayashi, Toru; Gondo, Yasuyuki; Hirose, Nobuyoshi

2014-04-01

Prevention of disability is a major challenge in aging populations; however, the extent to which physical independence can be maintained toward the limit of human life span remains to be determined. We examined the health and functional status of 642 centenarians: 207 younger centenarians (age: 100-104 years), 351 semi-supercentenarians (age: 105-109 years), and 84 supercentenarians (age: >110 years). All-cause mortality was followed by means of an annual telephone or mailed survey. Age-specific disability patterns revealed that the older the age group, the higher the proportion of those manifesting independence in activities of daily living at any given age of entry. Multiple logistic regression analysis identified male gender and better cognitive function as consistent determinants of physical independence across all age categories. In a longitudinal analysis, better physical function was significantly associated with survival advantage until the age of 110. However, mortality beyond that age was predicted neither by functional status nor biomedical measurements, indicating alternative trajectories of mortality at the highest ages. These findings suggest that maintaining physical independence is a key feature of survival into extreme old age. Future studies illuminating genetic and environmental underpinnings of supercentenarians' phenotypes will provide invaluable opportunities not only to improve preventive strategies but also to test the central hypotheses of human aging.

Correction of Hirschsprung-Associated Mutations in Human Induced Pluripotent Stem Cells Via Clustered Regularly Interspaced Short Palindromic Repeats/Cas9, Restores Neural Crest Cell Function.

PubMed

Lai, Frank Pui-Ling; Lau, Sin-Ting; Wong, John Kwong-Leong; Gui, Hongsheng; Wang, Reeson Xu; Zhou, Tingwen; Lai, Wing Hon; Tse, Hung-Fat; Tam, Paul Kwong-Hang; Garcia-Barcelo, Maria-Mercedes; Ngan, Elly Sau-Wai

2017-07-01

Hirschsprung disease is caused by failure of enteric neural crest cells (ENCCs) to fully colonize the bowel, leading to bowel obstruction and megacolon. Heterozygous mutations in the coding region of the RET gene cause a severe form of Hirschsprung disease (total colonic aganglionosis). However, 80% of HSCR patients have short-segment Hirschsprung disease (S-HSCR), which has not been associated with genetic factors. We sought to identify mutations associated with S-HSCR, and used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system to determine how mutations affect ENCC function. We created induced pluripotent stem cell (iPSC) lines from 1 patient with total colonic aganglionosis (with the G731del mutation in RET) and from 2 patients with S-HSCR (without a RET mutation), as well as RET +/- and RET -/- iPSCs. IMR90-iPSC cells were used as the control cell line. Migration and differentiation capacities of iPSC-derived ENCCs were analyzed in differentiation and migration assays. We searched for mutation(s) associated with S-HSCR by combining genetic and transcriptome data from patient blood- and iPSC-derived ENCCs, respectively. Mutations in the iPSCs were corrected using the CRISPR/Cas9 system. ENCCs derived from all iPSC lines, but not control iPSCs, had defects in migration and neuronal lineage differentiation. RET mutations were associated with differentiation and migration defects of ENCCs in vitro. Genetic and transcriptome analyses associated a mutation in the vinculin gene (VCL M209L) with S-HSCR. CRISPR/Cas9 correction of the RET G731del and VCL M209L mutations in iPSCs restored the differentiation and migration capacities of ENCCs. We identified mutations in VCL associated with S-HSCR. Correction of this mutation in iPSC using CRISPR/Cas9 editing, as well as the RET G731del mutation that causes Hirschsprung disease with total colonic aganglionosis, restored ENCC function. Our study demonstrates how human iPSCs can be used to identify disease-associated mutations and determine how they affect cell functions and contribute to pathogenesis. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

DEL phenotype.

PubMed

Kwon, Dong H; Sandler, S G; Flegel, Willy A

2017-09-01

DEL red blood cells (RBCs) type as D- by routine serologic methods and are transfused routinely, without being identified as expressing a very weak D antigen, to D- recipients. DEL RBCs are detected only by adsorption and elution of anti-D or by molecular methods. Most DEL phenotypes have been reported in population studies conducted in East Asia, although DEL phenotypes have been detected also among Caucasian individuals. Approximately 98 percent of DEL phenotypes in East Asians are associated with the RHD*DEL1 or RHD*01EL.01 allele. The prevalence of DEL phenotypes has been reported among D- Han Chinese (30%), Japanese (28%), and Korean (17%) populations. The prevalence of DEL phenotypes is significantly lower among D- Caucasian populations (0.1%). Among the 3-5 percent of African individuals who are D-, there are no reports of the DEL phenotype. Case reports from East Asia indicate that transfusion of DEL RBCs to D- recipients has been associated with D alloimmunization. East Asian immigrants constitute 2.1 percent of the 318.9 million persons residing in the United States, and an estimated 2.8 percent are blood donors. Using these statistics, we estimate that 68-683 units of DEL RBCs from donors of East Asian ancestry are transfused as D- annually in the United States. Given the reports from East Asia of D alloimmunization attributed to transfusion of DEL RBCs, one would expect an occasional report of D alloimmunization in the United States following transfusion of DEL RBCs to a D- recipient. If such cases do occur, the most likely reason that they are not detected is the absence of active post-transfusion monitoring for formation of anti-D.

Functional Connectivity Parcellation of the Human Thalamus by Independent Component Analysis.

PubMed

Zhang, Sheng; Li, Chiang-Shan R

2017-11-01

As a key structure to relay and integrate information, the thalamus supports multiple cognitive and affective functions through the connectivity between its subnuclei and cortical and subcortical regions. Although extant studies have largely described thalamic regional functions in anatomical terms, evidence accumulates to suggest a more complex picture of subareal activities and connectivities of the thalamus. In this study, we aimed to parcellate the thalamus and examine whole-brain connectivity of its functional clusters. With resting state functional magnetic resonance imaging data from 96 adults, we used independent component analysis (ICA) to parcellate the thalamus into 10 components. On the basis of the independence assumption, ICA helps to identify how subclusters overlap spatially. Whole brain functional connectivity of each subdivision was computed for independent component's time course (ICtc), which is a unique time series to represent an IC. For comparison, we computed seed-region-based functional connectivity using the averaged time course across all voxels within a thalamic subdivision. The results showed that, at p < 10 -6 , corrected, 49% of voxels on average overlapped among subdivisions. Compared with seed-region analysis, ICtc analysis revealed patterns of connectivity that were more distinguished between thalamic clusters. ICtc analysis demonstrated thalamic connectivity to the primary motor cortex, which has eluded the analysis as well as previous studies based on averaged time series, and clarified thalamic connectivity to the hippocampus, caudate nucleus, and precuneus. The new findings elucidate functional organization of the thalamus and suggest that ICA clustering in combination with ICtc rather than seed-region analysis better distinguishes whole-brain connectivities among functional clusters of a brain region.

Validation of elk resource selection models with spatially independent data

Treesearch

Priscilla K. Coe; Bruce K. Johnson; Michael J. Wisdom; John G. Cook; Marty Vavra; Ryan M. Nielson

2011-01-01

Knowledge of how landscape features affect wildlife resource use is essential for informed management. Resource selection functions often are used to make and validate predictions about landscape use; however, resource selection functions are rarely validated with data from landscapes independent of those from which the models were built. This problem has severely...

Functional Skills of Individuals with Fragile X Syndrome: A Lifespan Cross-Sectional Analysis

ERIC Educational Resources Information Center

Bailey, Donald B., Jr.; Raspa, Melissa; Holiday, David; Bishop, Ellen; Olmsted, Murrey

2009-01-01

Parents of 1,105 male and 283 female children with fragile X syndrome described functional skill attainment in eating, dressing, toileting, bathing/hygiene, communication, articulation, and reading. The majority of adult children had mastered many skills independently. Most adults were verbal, used the toilet, dressed, ate independently, bathed,…

Does Parental Autonomy Support Relate to Adolescent Autonomy? An In-Depth Examination of a Seemingly Simple Question

ERIC Educational Resources Information Center

Fousiani, Kyriaki; Van Petegem, Stijn; Soenens, Bart; Vansteenkiste, Maarten; Chen, Beiwen

2014-01-01

In contemporary research on autonomy development, autonomy has been defined as independence (vs. dependence) or as self-endorsed (vs. controlled) functioning. Analogously, perceived parental autonomy support involves either perceived parental promotion of independence (PI) or perceived parental promotion of volitional functioning (PVF). The…

Lower leg muscle density is independently associated with fall status in community-dwelling older adults.

PubMed

Frank-Wilson, A W; Farthing, J P; Chilibeck, P D; Arnold, C M; Davison, K S; Olszynski, W P; Kontulainen, S A

2016-07-01

Muscle density is a risk factor for fractures in older adults; however, its association with falls is not well described. After adjusting for biologically relevant confounding factors, a unit decrease in muscle density was associated with a 17 % increase in odds of reporting a fall, independent of functional mobility. Falls are the leading cause of injury, disability, and fractures in older adults. Low muscle density (i.e., caused by muscle adiposity) and functional mobility have been identified as risk factors for incident disability and fractures in older adults; however, it is not known if these are also independently associated with falls. The purpose of this study was to explore the associations of muscle density and functional mobility with fall status. Cross-sectional observational study of 183 men and women aged 60-98 years. Descriptive data, including a 12-month fall recall, Timed Up and Go (TUG) test performance, lower leg muscle area, and density. Odds ratio (OR) of being a faller were calculated, adjusted for age, sex, body mass index, general health status, diabetes, and comorbidities. Every mg/cm(3) increase in muscle density (mean 70.2, SD 2.6 mg/cm(3)) independently reduced the odds of being a faller by 19 % (OR 0.81 [95 % CI 0.67 to 0.97]), and every 1 s longer TUG test time (mean 9.8, SD 2.6 s) independently increased the odds by 17 % (OR 1.17 [95 % CI 1.01 to 1.37]). When both muscle density and TUG test time were included in the same model, only age (OR 0.93 [95 % CI 0.87 to 0.99]) and muscle density (OR 0.83 [95 % CI 0.69 to 0.99]) were independently associated with fall status. Muscle density was associated with fall status, independent of functional mobility. Muscle density may compliment functional mobility tests as a biometric outcome for assessing fall risk in well-functioning older adults.

Design and Development of a Technology Platform for DNA-Encoded Library Production and Affinity Selection.

PubMed

Castañón, Jesús; Román, José Pablo; Jessop, Theodore C; de Blas, Jesús; Haro, Rubén

2018-06-01

DNA-encoded libraries (DELs) have emerged as an efficient and cost-effective drug discovery tool for the exploration and screening of very large chemical space using small-molecule collections of unprecedented size. Herein, we report an integrated automation and informatics system designed to enhance the quality, efficiency, and throughput of the production and affinity selection of these libraries. The platform is governed by software developed according to a database-centric architecture to ensure data consistency, integrity, and availability. Through its versatile protocol management functionalities, this application captures the wide diversity of experimental processes involved with DEL technology, keeps track of working protocols in the database, and uses them to command robotic liquid handlers for the synthesis of libraries. This approach provides full traceability of building-blocks and DNA tags in each split-and-pool cycle. Affinity selection experiments and high-throughput sequencing reads are also captured in the database, and the results are automatically deconvoluted and visualized in customizable representations. Researchers can compare results of different experiments and use machine learning methods to discover patterns in data. As of this writing, the platform has been validated through the generation and affinity selection of various libraries, and it has become the cornerstone of the DEL production effort at Lilly.

Deletion of the late cornified envelope (LCE) 3B and 3C genes as a susceptibility factor for psoriasis

PubMed Central

de Cid, Rafael; Riveira-Munoz, Eva; Zeeuwen, Patrick L.J.M.; Robarge, Jason; Liao, Wilson; Dannhauser, Emma N.; Giardina, Emiliano; Stuart, Philip E.; Nair, Rajan; Helms, Cynthia; Escaramís, Georgia; Ballana, Ester; Martín-Ezquerra, Gemma; den Heijer, Martin; Kamsteeg, Marijke; Joosten, Irma; Eichler, Evan E.; Lázaro, Conxi; Pujol, Ramón M.; Armengol, Lluís; Abecasis, Gonçalo; Elder, James T.; Novelli, Giuseppe; Armour, John A.L.; Kwok, Pui; Bowcock, Anne; Schalkwijk, Joost; Estivill, Xavier

2011-01-01

Psoriasis is a common inflammatory skin disease with a prevalence of 2% to 3% in Caucasians1. In a genome-wide search for copy number variants (CNV) using a sample pooling approach we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster2. The absence of LCE3B and LCE3C (LCE3C-LCE3B-del) is significantly associated (p=1.38E-08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the USA, and in a family-based study (p=5.4E-04). LCE3C-LCE3B-del is tagged by rs4112788 (r2=0.93), which is also strongly associated with psoriasis (p<6.6E-09). LCE3C-LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples, and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function plays a role in psoriasis susceptibility. PMID:19169253

Cerebral visual impairment and intellectual disability caused by PGAP1 variants.

PubMed

Bosch, Daniëlle G M; Boonstra, F Nienke; Kinoshita, Taroh; Jhangiani, Shalini; de Ligt, Joep; Cremers, Frans P M; Lupski, James R; Murakami, Yoshiko; de Vries, Bert B A

2015-12-01

Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI.

Influenza A Virus M2 Ion Channel Activity Is Essential for Efficient Replication in Tissue Culture

PubMed Central

Takeda, Makoto; Pekosz, Andrew; Shuck, Kevin; Pinto, Lawrence H.; Lamb, Robert A.

2002-01-01

The amantadine-sensitive ion channel activity of influenza A virus M2 protein was discovered through understanding the two steps in the virus life cycle that are inhibited by the antiviral drug amantadine: virus uncoating in endosomes and M2 protein-mediated equilibration of the intralumenal pH of the trans Golgi network. Recently it was reported that influenza virus can undergo multiple cycles of replication without M2 ion channel activity (T. Watanabe, S. Watanabe, H. Ito, H. Kida, and Y. Kawaoka, J. Virol. 75:5656–5662, 2001). An M2 protein containing a deletion in the transmembrane (TM) domain (M2-del29–31) has no detectable ion channel activity, yet a mutant virus was obtained containing this deletion. Watanabe and colleagues reported that the M2-del29–31 virus replicated as efficiently as wild-type (wt) virus. We have investigated the effect of amantadine on the growth of four influenza viruses: A/WSN/33; N31S-M2WSN, a mutant in which an asparagine residue at position 31 in the M2 TM domain was replaced with a serine residue; MUd/WSN, which possesses seven RNA segments from WSN plus the RNA segment 7 derived from A/Udorn/72; and A/Udorn/72. N31S-M2WSN was amantadine sensitive, whereas A/WSN/33 was amantadine resistant, indicating that the M2 residue N31 is the sole determinant of resistance of A/WSN/33 to amantadine. The growth of influenza viruses inhibited by amantadine was compared to the growth of an M2-del29–31 virus. We found that the M2-del29–31 virus was debilitated in growth to an extent similar to that of influenza virus grown in the presence of amantadine. Furthermore, in a test of biological fitness, it was found that wt virus almost completely outgrew M2-del29–31 virus in 4 days after cocultivation of a 100:1 ratio of M2-del29–31 virus to wt virus, respectively. We conclude that the M2 ion channel protein, which is conserved in all known strains of influenza virus, evolved its function because it contributes to the efficient replication of the virus in a single cycle. PMID:11773413

Vigilando la Calidad del Agua de los Grandes Rios de la Nacion: El Programa NASQAN del Rio Grande (Rio Bravo del Norte)

USGS Publications Warehouse

Lurry, Dee L.; Reutter, David C.; Wells, Frank C.; Rivera, M.C.; Munoz, A.

1998-01-01

La Oficina del Estudio Geologico de los Estados Unidos (U.S. Geological Survey, 0 USGS) ha monitoreado la calidad del agua de la cuenca del Rio Grande (Rio Bravo del Norte) desde 1995 como parte de la rediseiiada Red Nacional para Contabilizar la Calidad del Agua de los Rios (National Stream Quality Accounting Network, o NASOAN) (Hooper and others, 1997). EI programa NASOAN fue diseiiado para caracterizar las concentraciones y el transporte de sedimento y constituyentes quimicos seleccionados, encontrados en los grandes rios de los Estados Unidos - incluyendo el Misisipi, el Colorado y el Columbia, ademas del Rio Grande. En estas cuatro cuencas, el USGS opera actualmente (1998) una red de 40 puntos de muestreo pertenecientes a NASOAN, con un enfasis en cuantificar el flujo en masa (la cantidad de material que pasa por la estacion, expresado en toneladas por dial para cada constituyente. Aplicacando un enfoque consistente, basado en la cuantificacion de flujos en la cuenca del Rio Grande, el programa NASOAN esta generando la informacion necesaria para identificar fuentes regionales de diversos contaminantes, incluyendo sustancias qui micas agricolas y trazas elementos en la cuenca. EI efecto de las grandes reservas en el Rio Grande se puede observar segun los flujos de constituyentes discurren a 10 largo del rio. EI analisis de los flujos de constituyentes a escala de la cuenca proveera los medios para evaluar la influencia de la actividad humana sobre las condiciones de calidad del agua del Rio Grande.

Laboratory of the Neuropsychology and Cognitive Neurosciences Research Center of Universidad Católica del Maule, Chile.

PubMed

Lucero, Boris; Saracini, Chiara; Muñoz-Quezada, María Teresa; Mendez-Bustos, Pablo; Mora, Marco

2018-06-14

The Laboratory of the Neuropsychology and Cognitive Neurosciences Research Center (CINPSI Neurocog), located in the "Technological Park" building of the Catholic University of Maule (Universidad Católica del Maule, UCM) campus in Talca, Chile, has been established as "Psychology Lab" recently in July, 2016. Our lines of work include basic and applied research. Among the basic research, we study executive functions, decision-making, and spatial cognition. In the applied field, we have studied neuropsychological and neurobehavioral effects of pesticides exposure, among other interests. One of our aims is to develop collaboration both national and internationally. It is important to mention that to date there are only few psychology laboratories and research centers in Chile involved with the fields of neuropsychology and neurosciences. Thus, this scientific effort could be a groundbreaking initiative to develop specific knowledge in this area locally and interculturally through its international collaborations.

Illuminating water and life: Emilio Del Giudice.

PubMed

Ho, Mae-Wan

2015-01-01

The quantum electrodynamics theory of water put forward by Del Giudice and colleagues provides a useful foundation for a new science of water for life. The interaction of light with liquid water generates quantum coherent domains in which the water molecules oscillate between the ground state and an excited state close to the ionizing potential of water. This produces a plasma of almost free electrons favoring redox reactions, the basis of energy metabolism in living organisms. Coherent domains stabilized by surfaces, such as membranes and macromolecules, provide the excited interfacial water that enables photosynthesis to take place, on which most of life on Earth depends. Excited water is the source of superconducting protons for rapid intercommunication within the body. Coherent domains can also trap electromagnetic frequencies from the environment to orchestrate and activate specific biochemical reactions through resonance, a mechanism for the most precise regulation of gene function.

Novel ancestral Dysferlin splicing mutation which migrated from the Iberian peninsula to South America.

PubMed

Vernengo, Luis; Oliveira, Jorge; Krahn, Martin; Vieira, Emilia; Santos, Rosário; Carrasco, Luisa; Negrão, Luís; Panuncio, Ana; Leturcq, France; Labelle, Veronique; Bronze-da-Rocha, Elsa; Mesa, Rosario; Pizzarossa, Carlos; Lévy, Nicolas; Rodriguez, Maria-Mirta

2011-05-01

Primary dysferlinopathies are a group of recessive heterogeneous muscular dystrophies. The most common clinical presentations are Miyoshi myopathy and LGMD2B. Additional presentations range from isolated hyperCKemia to severe functional disability. Symptomatology begins in the posterior muscle compartment of the calf and its clinical course progresses slowly in Miyoshi myopathy whereas LGMD2B involves predominantly the proximal muscles of the lower limbs. The age of onset ranges from 13 to 60years in Caucasians. We present five patients that carry a novel mutation in the exon12/intron12 boundary: c.1180_1180+7delAGTGCGTG (r.1054_1284del). We provide evidence of a founder effect due to a common ancestral origin of this mutation, detected in heterozygosity in four patients and in homozygosity in one patient. Copyright © 2011 Elsevier B.V. All rights reserved.

Venetoclax for Treating Chronic Lymphocytic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Mistry, Hema; Nduka, Chidozie; Connock, Martin; Colquitt, Jill; Mantopoulos, Theodoros; Loveman, Emma; Walewska, Renata; Mason, James

2018-04-01

Venetoclax is licensed to treat relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL). As part of the Single Technology Appraisal (STA) ID944, the National Institute for Health and Care Excellence (NICE) invited AbbVie, the manufacturer, to submit evidence on the use of venetoclax, within its licensed indication. The Evidence Review Group (ERG), Warwick Evidence, was asked to provide an independent and critical review of the submitted evidence. Evidence came from three single-arm trials in CLL patients with or without 17p deletion [del(17p])/TP53 chromosomal abnormalities. The anticipated licensed indication specified that venetoclax-eligible del(17p)/TP53 patients should have not responded to, or be deemed unsuitable for, B-cell receptor inhibitor (BCRi) therapy, and that non-del(17p)/TP53 patients should have not responded to both chemoimmunotherapy and BCRi therapy. The three trials were heterogeneous in terms of both del(17p)/TP53 status and previous exposure to BCRi therapy. The M13-982 study investigated 158 R/R CLL patients with the 17p deletion, but only a small number had received previous BCRi therapy; the M12-175 study investigated 67 patients with CLL or small lymphocytic lymphoma, some with the 17p deletion, but very few previously treated with BCRi therapy; and the M14-032 study included 105 patients previously treated with BCRi therapy (either idelalisib or ibrutinib), some of whom had unknown mutation status. The ERG concluded that the study populations did not directly conform to those specified in the licensed indication or in the NICE scope. Outcomes reported included overall response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS); adverse events were reported for the pooled population of all three studies, as well as separately for each study. The median PFS was 41.4 and 27.2 months among patients in the M12-175 and M13-982 trials, respectively, whereas the median PFS was not reached in the M14-032 trial. Some results were designated academic in confidence and cannot be reported here. The submission provided a de novo partitioned survival cost-effectiveness model with three health states: pre-progression, post-progression and dead. Transition probabilities between health states were estimated using Weibull models for PFS and OS. The ERG judged the model structure to be appropriate. Venetoclax was compared with best supportive care (BSC) in patients with or without del(17p)/TP53 mutation status, and with palliative care (PC). To populate the del(17p)/TP53 venetoclax arm, the submission pooled del(17p)/TP53 patients from all three studies and fitted Weibull models for PFS and OS. PFS and OS models for non-del(17p)/TP53 venetoclax patients were obtained by applying hazard ratios (HRs) to the del(17p)/TP53 OS and PFS models, derived using Cox's regression analysis comparing del(17p)/TP53 and non-del(17p)/TP53 patients pooled from the M14-032 and M12-175 studies. The ERG expressed reservations about the company's pooling procedure, but acknowledged its expedience given the small evidence base. For the BSC comparator arm, the submission used the rituximab + placebo arm from a randomised controlled trial comparing idelalisib + rituximab versus placebo + rituximab ('study 116'). Weibull regression data for OS and PFS were taken from the idelalisib STA (ID764) submitted by Gilead to NICE. The ERG considered the use of the study 116 rituximab arm to be inconsistent with the licensed indication for venetoclax because these patients had neither not responded to nor were inappropriate for BCRi therapy, being eligible to be randomised to idelalisib. Another difficulty was the requirement for a technical correction in survival analysis because of considerable switching from rituximab to idelalisib. The ERG considered that post-progression survival of patients from the idelalisib arm of study 116 provided a more appropriate representation of BSC since these patients had not responded to BCRi therapy, consistent with venetoclax's licensed indication. For PC, the company submission used data from the UK CLL Forum. The company's base-case analysis indicated that venetoclax was clinically effective, but the resulting incremental cost-effectiveness ratios (ICERs) for del(17p)/TP53 (£39,940/quality-adjusted life-year [QALY] gained) and non-del(17p)/TP53 (£47,370/QALY gained) patients were well above the NICE threshold of £20,000-30,000/QALY. The ERG identified two errors in the implementation of the company's parametric models-one related to the implementation of HRs, and the other to the derivation of the Weibull shape parameters obtained from the Gilead idelalisib submission. The ERG made plausible adjustments to the company's base-case and corrected errors, resulting in a reduced estimate of the cost effectiveness of venetoclax in non-del(17p)/TP53 and del(17p)/TP53 indications; in the ERG's preferred base case, using post-progression survival of patients in the idelalisib arm of study 116 as the BSC comparator, deterministic ICERs were higher than the company's base-case for both indications: £57,476/QALY gained for del(17p)/TP53 and £77,779/QALY gained for non-del(17p)/TP53. The NICE Appraisal Committee's preliminary recommendation was that venetoclax used within its licensed indication should not be recommended for use in the National Health Service (NHS). In response to the preliminary recommendation, the company submitted new analyses; however, at a subsequent appraisal committee meeting, the original recommendation was upheld and the committee concluded there were large uncertainties around the clinical effectiveness of venetoclax and BSC, and that under the committee's preferred assumptions, the ICERs were higher than those generally considered cost effective, even when end-of-life criteria were taken into account. The company submitted further evidence, and the final guidance recommended venetoclax for use with the Cancer Drugs Fund for the two populations in this technology appraisal.

Application of abstract harmonic analysis to the high-speed recognition of images

NASA Technical Reports Server (NTRS)

Usikov, D. A.

1979-01-01

Methods are constructed for rapidly computing correlation functions using the theory of abstract harmonic analysis. The theory developed includes as a particular case the familiar Fourier transform method for a correlation function which makes it possible to find images which are independent of their translation in the plane. Two examples of the application of the general theory described are the search for images, independent of their rotation and scale, and the search for images which are independent of their translations and rotations in the plane.

Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia.

PubMed

Fervaha, G; Foussias, G; Agid, O; Remington, G

2014-10-01

Functional impairment is characteristic of most individuals with schizophrenia; however, the key variables that undermine community functioning are not well understood. This study evaluated the association between selected clinical variables and one-year longitudinal functional outcomes in patients with schizophrenia. The sample included 754 patients with schizophrenia who completed both baseline and one-year follow-up visits in the CATIE study. Patients were evaluated with a comprehensive battery of assessments capturing symptom severity and cognitive performance among other variables. The primary outcome variable was functional status one-year postbaseline measured using the Heinrichs-Carpenter Quality of Life Scale. Factor analysis of negative symptom items revealed two factors reflecting diminished expression and amotivation. Multivariate regression modeling revealed several significant independent predictors of longitudinal functioning scores. The strongest predictors were baseline amotivation and neurocognition. Both amotivation and neurocognition also had independent predictive value for each of the domains of functioning assessed (e.g., vocational). Both motivational and neurocognitive deficits independently contribute to longitudinal functional outcomes assessed 1 year later among patients with schizophrenia. Both of these domains of psychopathology impede functional recovery; hence, it follows that treatments ameliorating each of these symptoms should promote community functioning among individuals with schizophrenia. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Carotid artery wall shear stress is independently correlated with renal function in the elderly.

PubMed

Guo, Yuqi; Wei, Fang; Wang, Juan; Zhao, Yingxin; Sun, Shangwen; Zhang, Hua; Liu, Zhendong

2018-01-12

Hemodynamic has increasingly been regarded as an important factor of renal function. However, the relationship between carotid artery wall shear stress (WSS) and renal function is not clarified. To investigate the relationship between carotid WSS and renal function, we recruited 761 older subjects aged 60 years and over from community-dwelling in the Shandong area, China. Carotid WSS, endothelial function, and estimated glomerular filtration rate (eGFR) were assessed in all subjects. Subjects were grouped by the interquartile of the carotid artery mean WSS. We found that the eGFRs derived from serum creatinine and/or cystatin C using three CKD-EPI equations were significantly higher and albumin/creatinine ratio was lower in the higher interquartile groups than in the lower interquartile groups ( P <0.05). The mean WSS was independently correlated with eGFRs even after adjustment for confounders. Similar findings were found between carotid artery peak WSS and eGFRs and albumin/creatinine ratio. In addition, we found that endothelial function was strongly related to carotid WSS and renal function after adjustment for confounders. In conclusion, there is an independent correlation of carotid WSS with renal function in the elderly. The local rheologic forces may play an important role in renal function changing. The correlation may be mediated by regulation of endothelial function.

Rehabilitation outcomes in children with cerebral palsy during a 2 year period

PubMed Central

İçağasıoğlu, Afitap; Mesci, Erkan; Yumusakhuylu, Yasemin; Turgut, Selin Turan; Murat, Sadiye

2015-01-01

[Purpose] To observe motor and functional progress of children with cerebral palsy during 2 years. [Subjects and Methods] Pediatric cerebral palsy patients aged 3–15 years (n = 35/69) with 24-month follow-up at our outpatient cerebral palsy clinic were evaluated retrospectively. The distribution of cerebral palsy types was as follows: diplegia (n = 19), hemiplegia (n = 4), and quadriplegia (n = 12). Participants were divided into 3 groups according to their Gross Motor Functional Classification System scores (i.e., mild, moderate, and severe). All participants were evaluated initially and at the final assessment 2 years later. During this time, patients were treated 3 times/week. Changes in motor and functional abilities were assessed based on Gross Motor Function Measure-88 and Wee Functional Independence Measure. [Results] Significant improvements were observed in Gross Motor Function Measure-88 and Wee Functional Independence Measure results in all 35 patients at the end of 2 years. The Gross Motor Function Measure-88 scores correlated with Wee Functional Independence Measure Scores. Marked increases in motor and functional capabilities in mild and moderate cerebral palsy patients were observed in the subgroup assessments, but not in those with severe cerebral palsy. [Conclusion] Rehabilitation may greatly help mild and moderate cerebral palsy patients achieve their full potential. PMID:26644677

The novel c.247_249delTTC (p.F83del) GJB2 mutation in a family with prelingual sensorineural deafness.

PubMed

Petersen, Michael B; Grigoriadou, Maria; Koutroumpe, Maria; Kokotas, Haris

2012-07-01

Non-syndromic hearing loss is one of the most common hereditary determined diseases in human, and the disease is a genetically heterogeneous disorder. Mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of non-syndromic recessive hearing impairment in many countries and are largely dependent on ethnic groups. Due to the high frequency of the c.35delG GJB2 mutation in the Greek population, we have previously suggested that Greek patients with sensorineural, non-syndromic deafness should be tested for the c.35delG mutation and the coding region of the GJB2 gene should be sequenced in c.35delG heterozygotes. Here we present on the clinical and molecular genetic evaluation of a family suffering from prelingual, sensorineural, non-syndromic deafness. A novel c.247_249delTTC (p.F83del) GJB2 mutation was detected in compound heterozygosity with the c.35delG GJB2 mutation in the proband and was later confirmed in the father, while the mother was homozygous for the c.35delG GJB2 mutation. We conclude that compound heterozygosity of the novel c.247_249delTTC (p.F83del) and the c.35delG mutations in the GJB2 gene was the cause of deafness in the proband and his father. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Pre-injury psychosocial and demographic predictors of long-term functional outcomes post-TBI.

PubMed

Seagly, Katharine S; O'Neil, Rochelle L; Hanks, Robin A

2018-01-01

To determine whether pre-injury psychosocial and demographic factors differentially influence long-term functional outcomes post-TBI. Urban rehabilitation hospital. 149 individuals, ages 16-75, who sustained a mild complicated, moderate or severe TBI, were enrolled in a TBI Model System (TBIMS), and had functional outcome data five-15 years post-injury. Archival data were analysed with SPSS-18 using multiple regression to determine amount of variance accounted for in five functional domains. Predictors included age at injury, pre-injury education, Glasgow Coma Scale (GCS), pre-injury incarceration and psychiatric history. Craig Handicap Assessment and Reporting Technique (CHART), including Cognitive Independence, Physical Independence, Mobility, Occupation and Social Integration domains. Models were significant for Cognitive and Physical Independence, Mobility, and Occupation. Incarceration and psychiatric history accounted for the most variance in Cognitive and Physical Independence, over and above GCS and age at injury. Psychiatric history was also the strongest predictor of Occupation. Mobility was the only domain in which GCS accounted for the most variance. Pre-injury psychosocial and demographic factors may be more important than injury severity for predicting some long-term functional outcomes post-TBI. It would likely be beneficial to assess these factors in the inpatient setting, with input from a multidisciplinary team, as an early understanding of prognostic indicators can help guide treatment for optimal functional outcomes.

Cumulative incidence of functional decline after minor injuries in previously independent older Canadian individuals in the emergency department.

PubMed

Sirois, Marie-Josée; Émond, Marcel; Ouellet, Marie-Christine; Perry, Jeffrey; Daoust, Raoul; Morin, Jacques; Dionne, Clermont; Camden, Stéphanie; Moore, Lynne; Allain-Boulé, Nadine

2013-10-01

To estimate the cumulative incidence of functional decline in independent older adults 3 and 6 months after a minor injury treated in the emergency department (ED) and to identify predictors of this functional decline. Prospective cohort study. Three Canadian teaching EDs. Individuals aged 65 and older who were independent in basic activities of daily living before their injury and were evaluated in the ED for minor injuries (N = 335). Functional decline was defined as a loss of 2 or more out of 28 points on the self-reported Older Americans Resources Services scale. Sociodemographic, mobility, and clinical risk factors for functional decline in non-ED studies were measured at the ED visit and 3 and 6 months after the injury. Generalized linear mixed models were used to explore differences in functional decline between groups determined according to the different factors. The cumulative incidence of decline was 14.9% (95% confidence interval (CI) = 7.6-29.1%) at 3 months and 17.3% (95% CI = 9.7-30.9%) at 6 months. Predictors of functional decline were occasional use of a walking aid (relative risk (RR)=2.4, 95% CI = 1.4-4.2), needing help in instrumental activities of daily living (IADLs) before the injury (RR = 3.1, 95% CI=1.7-5.5), taking five or more daily medications (RR = 1.8, 95% CI = 1.0-3.2), and the emergency physicians' assessment of functional decline (RR = 2.8, 95% CI = 1.5-5.3). Minor injuries in independent older adults treated in EDs are associated with a 15% cumulative incidence of functional decline 3 months after the injury that persisted 6 months later. Simple-to-measure factors such as occasional use of a walking aid, daily medication, need for help with IADLs, and physician assessment of decline may help identify independent older adults at risk of functional decline during their consultation. These results confirm the need to improve risk assessment and management of this population in EDs. © 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.

Modelo semi-empírico de protuberancia solar a partir del diagnóstico de densidades

NASA Astrophysics Data System (ADS)

Cirigliano, D.; Vial, J. C.; Rovira, M.

A partir de la observación del espectro del quintuplete de C III alrededor de 1175 Å, se ha realizado el diagnóstico de la densidad y presión electrónica, basado en el cálculo del cociente de las intensidades observadas. Una vez establecida la densidad electrónica, y con el cálculo de las velocidades Doppler, hemos investigado el flujo de masa en la protuberancia en función de la temperatura. Estableciendo como hipótesis la conservación del número de partículas que ingresan y salen del cuerpo de la protuberancia, se investiga la variación del área de un tubo de flujo semi-empírico en función de la temperatura. A partir de dicho diagnóstico, se examina el comportamiento del radio del tubo magnético en función de la temperatura, los que dan cuenta de la abertura de las líneas de campo magnético que confinan el plasma y de la divergencia del campo magnético en diferentes alturas de la atmósfera solar.

Del(20q) in patients with chronic lymphocytic leukemia: a therapy-related abnormality involving lymphoid or myeloid cells.

PubMed

Yin, C Cameron; Tang, Guilin; Lu, Gary; Feng, Xiaoli; Keating, Michael J; Medeiros, L Jeffrey; Abruzzo, Lynne V

2015-08-01

Deletion 20q (Del(20q)), a common cytogenetic abnormality in myeloid neoplasms, is rare in chronic lymphocytic leukemia. We report 64 patients with chronic lymphocytic leukemia and del(20q), as the sole abnormality in 40, a stemline abnormality in 21, and a secondary abnormality in 3 cases. Fluorescence in situ hybridization (FISH) analysis revealed an additional high-risk abnormality, del(11q) or del(17p), in 25/64 (39%) cases. In most cases, the leukemic cells showed atypical cytologic features, unmutated IGHV (immunoglobulin heavy-chain variable region) genes, and ZAP70 positivity. The del(20q) was detected only after chemotherapy in all 27 cases with initial karyotypes available. With a median follow-up of 90 months, 30 patients (47%) died, most as a direct consequence of chronic lymphocytic leukemia. Eight patients developed a therapy-related myeloid neoplasm, seven with a complex karyotype. Combined morphologic and FISH analysis for del(20q) performed in 12 cases without morphologic evidence of a myeloid neoplasm localized the del(20q) to the chronic lymphocytic leukemia cells in 5 (42%) cases, and to myeloid/erythroid cells in 7 (58)% cases. The del(20q) was detected in myeloid cells in all 4 cases of myelodysplastic syndrome. In aggregate, these data indicate that chronic lymphocytic leukemia with del(20q) acquired after therapy is heterogeneous. In cases with morphologic evidence of dysplasia, the del(20q) likely resides in the myeloid lineage. However, in cases without morphologic evidence of dysplasia, the del(20q) may represent clonal evolution and disease progression. Combining morphologic analysis with FISH for del(20q) or performing FISH on immunomagnetically selected sub-populations to localize the cell population with this abnormality may help guide patient management.

Del(20q) in patients with chronic lymphocytic leukemia: A therapy-related abnormality involving lymphoid or myeloid cells

PubMed Central

Yin, C. Cameron; Tang, Guilin; Lu, Gary; Feng, Xiaoli; Keating, Michael J.; Medeiros, L. Jeffrey; Abruzzo, Lynne V.

2015-01-01

Del(20q), a common cytogenetic abnormality in myeloid neoplasms, is rare in chronic lymphocytic leukemia. We report 64 patients with chronic lymphocytic leukemia and del(20q), as the sole abnormality in 40, a stemline abnormality in 21, and a secondary abnormality in 3 cases. FISH analysis revealed an additional high-risk abnormality, del(11q) or del(17p), in 27/64 (42%) cases. In most cases, the leukemic cells showed atypical cytologic features, unmutated IGHV genes and ZAP70 positivity. The del(20q) was detected only after chemotherapy in all 27 cases with initial karyotypes available. With a median follow-up of 90 months, 30 patients (47%) died, most as a direct consequence of chronic lymphocytic leukemia. Eight patients developed a therapy-related myeloid neoplasm, seven with a complex karyotype. Combined morphologic and FISH analysis for del(20q) performed in 12 cases without morphologic evidence of a myeloid neoplasm localized the del(20q) to the chronic lymphocytic leukemia cells in 5 (42%) cases, and to myeloid/erythroid cells in 7 (58)% cases. The del(20q) was detected in myeloid cells in all 4 cases of myelodysplastic syndrome. In aggregate, these data indicate that chronic lymphocytic leukemia with del(20q) acquired after therapy is heterogeneous. In cases with morphologic evidence of dysplasia, the del(20q) likely resides in the myeloid lineage. However, in cases without morphologic evidence of dysplasia, the del(20q) may represent clonal evolution and disease progression. Combining morphologic analysis with FISH for del(20q) or performing FISH on immunomagnetically-selected subpopulations to localize the cell population with this abnormality may help guide patient management. PMID:25953391

Conceptualizing Parental Autonomy Support: Adolescent Perceptions of Promotion of Independence versus Promotion of Volitional Functioning

ERIC Educational Resources Information Center

Soenens, Bart; Vansteenkiste, Maarten; Lens, Willy; Luyckx, Koen; Goossens, Luc; Beyers, Wim; Ryan, Richard M.

2007-01-01

In current research on parenting, 2 ways of conceptualizing perceived parental autonomy support can be distinguished. Parental autonomy support can be defined in terms of promotion of independence (PI) or in terms of promotion of volitional functioning (PVF). This study aimed to establish the empirical distinctiveness of both conceptualizations…

The Emergence of Untrained Mands and Tacts in Children with Autism

ERIC Educational Resources Information Center

Finn, Heather E.; Miguel, Caio F.; Ahearn, William H.

2012-01-01

Despite Skinner's (1957) assertion that verbal operants are initially functionally independent, recent studies have suggested that in some cases the acquisition of one verbal operant (e.g., mand) gives rise to the other (e.g., tact) without explicit training. The present study aimed to evaluate the functional independence of mands and tacts during…

The Revised Direct Assessment of Functional Status for Independent Older Adults

ERIC Educational Resources Information Center

McDougall, Graham J.; Becker, Heather; Vaughan, Phillip W.; Acee, Taylor W.; Delville, Carol L.

2010-01-01

Purpose: The original version of the Direct Assessment of Functional Status (DAFS), a measure of instrumental activities of daily living (IADLs), was found to have a ceiling effect in older adults living independently in the community. This suggested that the tasks measured, although relevant, do not require full use of this population's…

[Active aging from the perspective of aged individuals who are functionally independent].

PubMed

Ferreira, Olivia Galvão Lucena; Maciel, Silvana Carneiro; Silva, Antonia Oliveira; dos Santos, Walberto Silva; Moreira, Maria Adelaide Silva P

2010-12-01

The objective of this study was to identify the social representations of the elderly regarding active aging. Semi-structured interviews were performed with 100 functionally independent aged individuals from João Pessoa, Paraiba, Brazil. The data was organized and analyzed using Alceste software. Results showed that the aged individuals' statements about active aging are permeated with positive contents. However, when aging is not associated with the word active, it is still represented as losses and disabilities. Despite the existence of losses during the process, active aging should be encouraged among the elderly, as it means living a quality, plentiful life. Maintaining the elderly functionally independent is the first step to achieving active aging and thus improving their quality of life.

Targeted next-generation sequencing analysis identifies novel mutations in families with severe familial exudative vitreoretinopathy.

PubMed

Huang, Xiao-Yan; Zhuang, Hong; Wu, Ji-Hong; Li, Jian-Kang; Hu, Fang-Yuan; Zheng, Yu; Tellier, Laurent Christian Asker M; Zhang, Sheng-Hai; Gao, Feng-Juan; Zhang, Jian-Guo; Xu, Ge-Zhi

2017-01-01

Familial exudative vitreoretinopathy (FEVR) is a genetically and clinically heterogeneous disease, characterized by failure of vascular development of the peripheral retina. The symptoms of FEVR vary widely among patients in the same family, and even between the two eyes of a given patient. This study was designed to identify the genetic defect in a patient cohort of ten Chinese families with a definitive diagnosis of FEVR. To identify the causative gene, next-generation sequencing (NGS)-based target capture sequencing was performed. Segregation analysis of the candidate variant was performed in additional family members by using Sanger sequencing and quantitative real-time PCR (QPCR). Of the cohort of ten FEVR families, six pathogenic variants were identified, including four novel and two known heterozygous mutations. Of the variants identified, four were missense variants, and two were novel heterozygous deletion mutations [ LRP5 , c.4053 DelC (p.Ile1351IlefsX88); TSPAN12 , EX8Del]. The two novel heterozygous deletion mutations were not observed in the control subjects and could give rise to a relatively severe FEVR phenotype, which could be explained by the protein function prediction. We identified two novel heterozygous deletion mutations [ LRP5 , c.4053 DelC (p.Ile1351IlefsX88); TSPAN12 , EX8Del] using targeted NGS as a causative mutation for FEVR. These genetic deletion variations exhibit a severe form of FEVR, with tractional retinal detachments compared with other known point mutations. The data further enrich the mutation spectrum of FEVR and enhance our understanding of genotype-phenotype correlations to provide useful information for disease diagnosis, prognosis, and effective genetic counseling.

Targeted next-generation sequencing analysis identifies novel mutations in families with severe familial exudative vitreoretinopathy

PubMed Central

Huang, Xiao-Yan; Zhuang, Hong; Wu, Ji-Hong; Li, Jian-Kang; Hu, Fang-Yuan; Zheng, Yu; Tellier, Laurent Christian Asker M.; Zhang, Sheng-Hai; Gao, Feng-Juan; Zhang, Jian-Guo

2017-01-01

Purpose Familial exudative vitreoretinopathy (FEVR) is a genetically and clinically heterogeneous disease, characterized by failure of vascular development of the peripheral retina. The symptoms of FEVR vary widely among patients in the same family, and even between the two eyes of a given patient. This study was designed to identify the genetic defect in a patient cohort of ten Chinese families with a definitive diagnosis of FEVR. Methods To identify the causative gene, next-generation sequencing (NGS)-based target capture sequencing was performed. Segregation analysis of the candidate variant was performed in additional family members by using Sanger sequencing and quantitative real-time PCR (QPCR). Results Of the cohort of ten FEVR families, six pathogenic variants were identified, including four novel and two known heterozygous mutations. Of the variants identified, four were missense variants, and two were novel heterozygous deletion mutations [LRP5, c.4053 DelC (p.Ile1351IlefsX88); TSPAN12, EX8Del]. The two novel heterozygous deletion mutations were not observed in the control subjects and could give rise to a relatively severe FEVR phenotype, which could be explained by the protein function prediction. Conclusions We identified two novel heterozygous deletion mutations [LRP5, c.4053 DelC (p.Ile1351IlefsX88); TSPAN12, EX8Del] using targeted NGS as a causative mutation for FEVR. These genetic deletion variations exhibit a severe form of FEVR, with tractional retinal detachments compared with other known point mutations. The data further enrich the mutation spectrum of FEVR and enhance our understanding of genotype–phenotype correlations to provide useful information for disease diagnosis, prognosis, and effective genetic counseling. PMID:28867931

A novel MC4R deletion coexisting with FTO and MC1R gene variants, causes severe early onset obesity.

PubMed

Neocleous, Vassos; Shammas, Christos; Phelan, Marie M; Fanis, Pavlos; Pantelidou, Maria; Skordis, Nicos; Mantzoros, Christos; Phylactou, Leonidas A; Toumba, Meropi

2016-07-01

Heterozygous mutations on the melanocortin-4-receptor gene (MC4R) are the most frequent cause of monogenic obesity. We describe a novel MC4R deletion in a girl with severe early onset obesity, tall stature, pale skin and red hair. Clinical and hormonal parameters were evaluated in a girl born full-term by non-consanguineous parents. Her body mass index (BMI) at presentation (3 years) was 30 kg/m 2 (z-score: +4.5SDS). By the age of 5.2 years, she exhibited extreme linear growth acceleration and developed hyperinsulinemia. Direct sequencing of the MC4R, MC1Rand for the knownFTOsingle nucleotide polymorphism (SNP) rs9939609was performed for the patient and her family. A novel heterozygous MC4R p.Met215del (c.643_645delATG) deletion was identified in the patient, her father and her brother, both of whom exhibited a milder phenotype. 3D structural dynamic simulation studies investigated the conformational changes induced by the p.Met215del. The patient and her mother were also found to be carriers of the obesity risk associated FTOrs9939609SNP. Finally, the identification of the known p.Arg160Trp MC1Rvariant in the patient accounts for the red hair and pale skin phenotypic features. The p.Met215del causes global conformational and functional changes as it is localized at the alpha-helical transmembrane regions and the membrane spanning regions of the beta-barrel. This novel mutation produces a severe overgrowth phenotype that is apparent as from infancy and is progressive in childhood. The additional negative effect of environmental and unhealthy lifestyle habits as well as a possible co-interaction of FTOrs9939609 SNP may worsen the phenotype.

Effects of a recreational ice skating program on the functional mobility of a child with cerebral palsy.

PubMed

Walsh, Sharon Fleming; Scharf, Michael G

2014-04-01

The purpose of this study was to describe the effects of an ice skating program on the ambulation, strength, posture and balance of a child with cerebral palsy (CP). The subject was a five-year-old female with a diagnosis of CP and a Gross Motor Classification System level of III. The subject was a slow and labored household ambulator on level surfaces with bilateral forearm crutches and bilateral ankle foot orthoses. She was unable to transfer to and from the floor to stand independently, stand unsupported or take steps independently. Until the initiation of this study she was receiving physical therapy services 2×/week. For the purpose of this study she participated in a 1 h/week local ice skating program for people with disabilities for a period of four months. The subject displayed clinically significant improvements in functional mobility including: improved standing posture; independent transfer to and from the floor to stand; maintenance of independent standing for 3 min; independent walking for 10 feet; increased ability to isolate extremity musculature; increased strength; improved Gross Motor Function Measure-88 scores and increased endurance. A subsequent testing session four months after the ice skating program had ended displayed declines but not to pre-intervention levels in muscle strength; ability to transfer to and from the floor to stand; functional mobility and standing balance. The results appear to suggest that the participation in an ice skating program clinically improved this child's functional mobility. Further research needs to be done with regard to physical recreational programs and the benefit they can have on the function of children with activity limitations.

Effects of cooperation between translating ribosome and RNA polymerase on termination efficiency of the Rho-independent terminator

PubMed Central

Li, Rui; Zhang, Qing; Li, Junbai; Shi, Hualin

2016-01-01

An experimental system was designed to measure in vivo termination efficiency (TE) of the Rho-independent terminator and position–function relations were quantified for the terminator tR2 in Escherichia coli. The terminator function was almost completely repressed when tR2 was located several base pairs downstream from the gene, and TE gradually increased to maximum values with the increasing distance between the gene and terminator. This TE–distance relation reflected a stochastic coupling of the ribosome and RNA polymerase (RNAP). Terminators located in the first 100 bp of the coding region can function efficiently. However, functional repression was observed when the terminator was located in the latter part of the coding region, and the degree of repression was determined by transcriptional and translational dynamics. These results may help to elucidate mechanisms of Rho-independent termination and reveal genomic locations of terminators and functions of the sequence that precedes terminators. These observations may have important applications in synthetic biology. PMID:26602687

A comparison of functional academic and daily living skills in males with fragile X syndrome with and without autism.

PubMed

Raspa, Melissa; Franco, Vitor; Bishop, Ellen; Wheeler, Anne C; Wylie, Amanda; Bailey, Donald B

2018-05-03

Adaptive behaviors, such as functional academic and daily living skills, are critical for independence in adults with intellectual and developmental disabilities. However, little is known about these skills in fragile X syndrome (FXS), the most common form of inherited intellectual disability. The purposes of this study were to describe the functional academic and daily living skills of males diagnosed with FXS across different age groups and compare skill attainment by autism status and other common co-occurring conditions. We used survey methods to assess parent-reported functional academic and daily living skills in 534 males with FXS. Functional academic skills included time and schedules, money, math, reading, and writing skills. Daily living skills included hygiene, cooking, laundry and housekeeping, transportation, and safety skills. Analyses examined functional academic and daily living skills in a cross-sectional sample of males between ages 5 and 67. Differences in skill attainment were found by child age, co-morbid autism status, total number of co-occurring conditions, and respondent education. Functional academic and daily living skills were predictive of community employment and independent living. These data provide important information on the mastery of both foundational and more complex adaptive skills in males with FXS. Both functional academic and daily living skills were predictive of measures of independence above and beyond other child and family characteristics. These findings point to the need to focus interventions to support the attainment of independence in males with FXS. Copyright © 2018 Elsevier Ltd. All rights reserved.

Increasing Naval Security Cooperation between the U.S., Chile and Peru

DTIC Science & Technology

2009-03-01

del Mar: La Marina de Guerra en la historia del Perú (Lima: Marina de Guerra del Perú, 1994), 184. 108 Ibid., 188. 109 Ibid., 191-193. 42 “the...La Marina de Guerra en la historia del Perú, 205. 111 Ibid. 112 Ibid., 210. 113 Ibid., 229. 114 Ibid., 230. 115 Ibid., 246. 43 contributed to...la Puente Brunke, Los Hombres del Mar: La Marina de Guerra en la historia del Perú, 252. 117 Ibid., 264. 118 Ibid., 302. 119 Ibid., 342. 44

Abnormal functional network connectivity among resting-state networks in children with frontal lobe epilepsy.

PubMed

Widjaja, E; Zamyadi, M; Raybaud, C; Snead, O C; Smith, M L

2013-12-01

Epilepsy is considered a disorder of neural networks. The aims of this study were to assess functional connectivity within resting-state networks and functional network connectivity across resting-state networks by use of resting-state fMRI in children with frontal lobe epilepsy and to relate changes in resting-state networks with neuropsychological function. Fifteen patients with frontal lobe epilepsy and normal MR imaging and 14 healthy control subjects were recruited. Spatial independent component analysis was used to identify the resting-state networks, including frontal, attention, default mode network, sensorimotor, visual, and auditory networks. The Z-maps of resting-state networks were compared between patients and control subjects. The relation between abnormal connectivity and neuropsychological function was assessed. Correlations from all pair-wise combinations of independent components were performed for each group and compared between groups. The frontal network was the only network that showed reduced connectivity in patients relative to control subjects. The remaining 5 networks demonstrated both reduced and increased functional connectivity within resting-state networks in patients. There was a weak association between connectivity in frontal network and executive function (P = .029) and a significant association between sensorimotor network and fine motor function (P = .004). Control subjects had 79 pair-wise independent components that showed significant temporal coherence across all resting-state networks except for default mode network-auditory network. Patients had 66 pairs of independent components that showed significant temporal coherence across all resting-state networks. Group comparison showed reduced functional network connectivity between default mode network-attention, frontal-sensorimotor, and frontal-visual networks and increased functional network connectivity between frontal-attention, default mode network-sensorimotor, and frontal-visual networks in patients relative to control subjects. We found abnormal functional connectivity within and across resting-state networks in children with frontal lobe epilepsy. Impairment in functional connectivity was associated with impaired neuropsychological function.

Pulmonary function disparities exist and persist in Hispanic patients with cystic fibrosis: A longitudinal analysis.

PubMed

McGarry, Meghan E; Neuhaus, John M; Nielson, Dennis W; Burchard, Esteban; Ly, Ngoc P

2017-12-01

Hispanic patients with cystic fibrosis (CF) have decreased life expectancy compared to non-Hispanic white patients. Pulmonary function is a main predictor of life expectancy in CF. Ethnic differences in pulmonary function in CF have been understudied. The objective was to compare longitudinal pulmonary function between Hispanic and non-Hispanic white patients with CF. This cohort study of 15 018 6-25 years old patients in the CF Foundation Patient Registry from 2008 to 2013 compared FEV 1 percent predicted and longitudinal change in FEV 1 percent predicted in Hispanic to non-Hispanic white patients. We used linear mixed effects models with patient-specific slopes and intercepts, adjusting for 14 demographic and clinical variables. We did sub-analyses by CFTR class, F508del copies, and PERT use. Hispanic patients had lower FEV 1 percent predicted (79.9%) compared with non-Hispanic white patients (85.6%); (-5.8%, 95%CI -6.7% to -4.8%, P < 0.001), however, there was no difference in FEV 1 decline over time. Patients on PERT had a larger difference between Hispanic and non-Hispanic white patients in FEV 1 percent predicted than patients not on PERT (-6.0% vs -4.1%, P = 0.02). The ethnic difference in FEV 1 percent predicted was not statistically significant between CFTR classes (Class I-III: -6.1%, Class IV-V: -5.9%, Unclassified: -5.7%, P > 0.05) or between F508del copies (None: -7.6%, Heterozygotes: -5.6%, Homozygotes: -5.3%, P > 0.05). Disparities in pulmonary function exist in Hispanic patients with CF early in life and then persist without improving or worsening over time. It is valuable to investigate the factors contributing to pulmonary function in Hispanic patients with CF. © 2017 Wiley Periodicals, Inc.

Del-1 Expression as a Potential Biomarker in Triple-Negative Early Breast Cancer.

PubMed

Lee, Soo Jung; Lee, Jeeyeon; Kim, Wan Wook; Jung, Jin Hyang; Park, Ho Yong; Park, Ji-Young; Chae, Yee Soo

2018-01-01

A differential diagnostic role for plasma Del-1 was proposed for early breast cancer (EBC) in our previous study. We examined tumoral Del-1 expression and analyzed its prognostic impact among patients with EBC. Del-1 mRNA expression was assessed in breast epithelial and cancer cells. Meanwhile, the tumoral expression of Del-1 was determined based on tissue microarrays and immunohistochemistry results from 440 patients. While a high Del-1 mRNA expression was found in all the breast cancer cell lines, the expression was significantly higher in MDA-MB-231. Tumoral expression of Del-1 was also significantly associated with a negative expression of estrogen receptor or progesterone receptor, and low expression of Ki-67, particularly in the case of triple-negative breast cancer (TNBC) (p < 0.036). Furthermore, a correlation was found between Del-1 expression and an aggressive histological grade, nuclear mitosis, and polymorphism, suggesting a possible role in tumor progression. In the survival analysis, a worse distant disease-free survival trend was noted for the group overexpressing Del-1. While all the investigated breast cancer cell lines exhibited Del-1 expression, the expression rate and intensity were specifically prominent in TNBC. In addition, based on its relationship to an unfavorable histology and worse survival trend, Del-1 could act as a molecular target in TNBC patients. © 2018 S. Karger AG, Basel.

Characteristics and outcome of myelodysplastic syndromes (MDS) with isolated 20q deletion: a report on 62 cases.

PubMed

Braun, Thorsten; de Botton, Stéphane; Taksin, Anne-Laure; Park, Sophie; Beyne-Rauzy, Odile; Coiteux, Valérie; Sapena, Rosa; Lazareth, Anne; Leroux, Geneviève; Guenda, Khaled; Cassinat, Bruno; Fontenay, Michaela; Vey, Norbert; Guerci, Agnès; Dreyfus, François; Bordessoule, Dominique; Stamatoullas, Aspasia; Castaigne, Sylvie; Terré, Christine; Eclache, Virginie; Fenaux, Pierre; Adès, Lionel

2011-07-01

Isolated 20q deletion is common in MDS and considered of good prognosis, but no large series have been reported. We compared characteristics of 62 MDS patients with isolated del 20q, 36 patients with del 20q and other cytogenetic abnormalities, and 1335 MDS patients without del20q. Significant differences between MDS with isolated del 20q and patients without del 20q were lower platelet count (mean 144 vs. 196 G/l, p=0.005), lower marrow blast count (mean 3.9% vs. 5.6%, p=0.0008), and higher reticulocyte count (mean 72.5 vs. 51.7 G/l, p=0.04). Ten (16%) patients with isolated del 20q had Hb>12 g/dl and platelets <100 G/l, compared to 7.3% of patients without del 20q (p=0.025). Review of marrow slides of those 10 patients showed that could be readily identified as MDS prior to cytogenetics. Fourteen percent of patients with isolated del 20q progressed to AML compared to 11% with one and 24% with several additional abnormalities. Median survival was 54 months in patients with isolated del 20q, not reached and 12 months for del 20q with one and several additional abnormalities, respectively (p=0.035) confirming the favorable prognosis of del 20q without complex abnormalities. Copyright © 2011 Elsevier Ltd. All rights reserved.

Development and validation of criterion-referenced clinically relevant fitness standards for maintaining physical independence in later years.

PubMed

Rikli, Roberta E; Jones, C Jessie

2013-04-01

To develop and validate criterion-referenced fitness standards for older adults that predict the level of capacity needed for maintaining physical independence into later life. The proposed standards were developed for use with a previously validated test battery for older adults-the Senior Fitness Test (Rikli, R. E., & Jones, C. J. (2001). Development and validation of a functional fitness test for community--residing older adults. Journal of Aging and Physical Activity, 6, 127-159; Rikli, R. E., & Jones, C. J. (1999a). Senior fitness test manual. Champaign, IL: Human Kinetics.). A criterion measure to assess physical independence was identified. Next, scores from a subset of 2,140 "moderate-functioning" older adults from a larger cross-sectional database, together with findings from longitudinal research on physical capacity and aging, were used as the basis for proposing fitness standards (performance cut points) associated with having the ability to function independently. Validity and reliability analyses were conducted to test the standards for their accuracy and consistency as predictors of physical independence. Performance standards are presented for men and women ages 60-94 indicating the level of fitness associated with remaining physically independent until late in life. Reliability and validity indicators for the standards ranged between .79 and .97. The proposed standards provide easy-to-use, previously unavailable methods for evaluating physical capacity in older adults relative to that associated with physical independence. Most importantly, the standards can be used in planning interventions that target specific areas of weakness, thus reducing risk for premature loss of mobility and independence.

The dependency paradox in close relationships: accepting dependence promotes independence.

PubMed

Feeney, Brooke C

2007-02-01

Using multiple methods, this investigation tested the hypothesis that a close relationship partner's acceptance of dependence when needed (e.g., sensitive responsiveness to distress cues) is associated with less dependence, more autonomous functioning, and more self-sufficiency (as opposed to more dependence) on the part of the supported individual. In two studies, measures of acceptance of dependency needs and independent functioning were obtained through couple member reports, by observing couple members' behaviors during laboratory interactions, by observing responses to experimentally manipulated partner assistance provided during an individual laboratory task, and by following couples over a period of 6 months to examine independent goal striving as a function of prior assessments of dependency acceptance. Results provided converging evidence in support of the proposed hypothesis. Implications of the importance of close relationships for optimal individual functioning are discussed. ((c) 2007 APA, all rights reserved).

Produccion Gaseosa del Cometa Halley: Erupciones Y Fotodisociacion del Radical OH

NASA Astrophysics Data System (ADS)

Silva, A. M.; Mirabel, I. F.

1990-11-01

RESUMEN:En este trabajo informamos la detecci6n de 20 erupciones en la li'nea de =18cm (1667MHz) del radical OH en el Cometa Halley.Las observaciones incluyen todos los monitoreos existentes y se extienden desde 120 dias antes del perihelio hasta 90 dias despues.Se detectan bruscos crecimientos en el flujo medido,hasta un factor 1O,seguidos por decaimientos lentos asociados con la fotodisociaci6n del OH. Se obtuvieron valores para el tiempo de vida fotoquimico del OH y del H2O basandose en el modelo desarrollado previamente por Silva(1988). Esos tiempos de vida estan de acuerdo con predicciones teoricas y con las observaciones en el Ultravioleta, y los resultados, los que son fuertemente dependientes de la velocidad heliocentrica del Coineta (variando hasta un factor 6), han sido calculados para varios rangos de velocidad entre +28 y -28 km/seg. Key wo'L :

Accounting for Independent Schools.

ERIC Educational Resources Information Center

Sonenstein, Burton

The diversity of independent schools in size, function, and mode of operation has resulted in a considerable variety of accounting principles and practices. This lack of uniformity has tended to make understanding, evaluation, and comparison of independent schools' financial statements a difficult and sometimes impossible task. This manual has…

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Seung-Hwan; Kim, Dong-Young; Jing, Feifeng

Developmental endothelial locus-1 (Del-1) is an endogenous anti-inflammatory molecule that is highly expressed in the lung and the brain and limits leukocyte migration to these tissues. We previously reported that the expression of Del-1 is positively regulated by p53 in lung endothelial cells. Although several reports have implicated the altered expression of Del-1 gene in cancer patients, little is known about its role in tumor cells. We here investigated the effect of Del-1 on the features of human lung carcinoma cells. Del-1 mRNA was found to be significantly decreased in the human lung adenocarcinoma cell lines A549 (containing wild typemore » of p53), H1299 (null for p53) and EKVX (mutant p53), compared to in human normal lung epithelial BEAS-2B cells and MRC-5 fibroblasts. The decrease of Del-1 expression was dependent on the p53 activity in the cell lines, but not on the expression of p53. Neither treatment with recombinant human Del-1 protein nor the introduction of adenovirus expressing Del-1 altered the expression of the apoptosis regulators BAX, PUMA and Bcl-2. Unexpectedly, the adenovirus-mediated overexpression of Del-1 gene into the lung carcinoma cell lines promoted proliferation and invasion of the lung carcinoma cells, as revealed by BrdU incorporation and transwell invasion assays, respectively. In addition, overexpression of the Del-1 gene enhanced features of epithelial–mesenchymal transition (EMT), such as increasing vimentin while decreasing E-cadherin in A549 cells, and increases in the level of Slug, an EMT-associated transcription regulator. Our findings demonstrated for the first time that there are deleterious effects of high levels of Del-1 in lung carcinoma cells, and suggest that Del-1 may be used as a diagnostic or prognostic marker for cancer progression, and as a novel therapeutic target for lung carcinoma. - Highlights: • Developmental Endothelial Locus-1 (Del-1) expression is downregulated in human lung cancer cells. • Overexpression of the Del-1 gene potentiates proliferation and invasion of lung carcinoma cells. • Del-1 may be used as a diagnostic or prognostic marker for lung cancer progression.« less

Structure-Function Analysis of Rny1 in tRNA Cleavage and Growth Inhibition

PubMed Central

Luhtala, Natalie; Parker, Roy

2012-01-01

T2 ribonucleases are conserved nucleases that affect a variety of processes in eukaryotic cells including the regulation of self-incompatibility by S-RNases in plants, modulation of host immune cell responses by viral and schistosome T2 enzymes, and neurological development and tumor progression in humans. These roles for RNaseT2’s can be due to catalytic or catalytic-independent functions of the molecule. Despite this broad importance, the features of RNaseT2 proteins that modulate catalytic and catalytic-independent functions are poorly understood. Herein, we analyze the features of Rny1 in Saccharomyces cerevisiae to determine the requirements for cleaving tRNA in vivo and for inhibiting cellular growth in a catalytic-independent manner. We demonstrate that catalytic-independent inhibition of growth is a combinatorial property of the protein and is affected by a fungal-specific C-terminal extension, the conserved catalytic core, and the presence of a signal peptide. Catalytic functions of Rny1 are independent of the C-terminal extension, are affected by many mutations in the catalytic core, and also require a signal peptide. Biochemical flotation assays reveal that in rny1Δ cells, some tRNA molecules associate with membranes suggesting that cleavage of tRNAs by Rny1 can involve either tRNA association with, or uptake into, membrane compartments. PMID:22829915

Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer

PubMed Central

Narizhneva, Natalia V.; Tararova, Natalia D.; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G.; Purmal, Andrei A.; Gudkov, Andrei V.; Gurova, Katerina V.

2010-01-01

In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization. PMID:19946220

Geology and geochemistry of Pelagatos, Cerro del Agua, and Dos Cerros monogenetic volcanoes in the Sierra Chichinautzin Volcanic Field, south of México City

NASA Astrophysics Data System (ADS)

Agustín-Flores, Javier; Siebe, Claus; Guilbaud, Marie-Noëlle

2011-04-01

This study focuses on the geology and geochemistry of three closely-spaced monogenetic volcanoes that are located in the NE sector of the Sierra Chichinautzin Volcanic Field near México City. Pelagatos (3020 m.a.s.l.) is a small scoria cone (0.0017 km 3) with lava flows (0.036 km 3) that covered an area of 4.9 km 2. Cerro del Agua scoria cone (3480 m.a.s.l., 0.028 km 3) produced several lava flows (0.24 km 3) covering an area of 17.6 km 2. Dos Cerros is a lava shield which covers an area of 80.3 km 2 and is crowned by two scoria cones: Tezpomayo (3080 m.a.s.l., 0.022 km 3) and La Ninfa (3000 m.a.s.l., 0.032 km 3). The eruptions of Cerro del Agua and Pelagatos occurred between 2500 and 14,000 yr BP. The Dos Cerros eruption took place close to 14,000 yr BP as constrained by radiocarbon dating. Rocks from these three volcanoes are olivine-hypersthene normative basaltic andesites and andesites with porphyritic, aphanitic, and glomeroporphyritic textures. Their mineral assemblages include olivine, clinopyroxene, and orthopyroxene phenocrysts (≤ 10 vol.%) embedded in a trachytic groundmass which consists mainly of plagioclase microlites and glass. Pelagatos rocks also present quartz xenocrysts. Due to their high Cr and Ni contents, and high Mg#s, Pelagatos rocks are considered to be derived from primitive magmas, hence the importance of this volcano for understanding petrogenetic processes in this region. Major and trace element abundances and petrography of products from these volcanoes indicate a certain degree of crystal fractionation during ascent to the surface. However, the magmas that formed the volcanoes evolved independently from each other and are not cogenetically related. REE, HFSE, LILE, and isotopic (Sr, Nd, and Pb) compositions point towards a heterogeneous mantle source that has been metasomatized by aqueous/melt phases from the subducted Cocos slab. There is no clear evidence of important crustal contributions in the compositions of Pelagatos and Cerro del Agua rocks. The Sr-isotopic composition of Dos Cerros, however, indicates a small degree of crustal contamination.

Assessing Glacier Hazards At Ghiacciaio Del Belvedere, Macugnaga, Italian Alps

NASA Astrophysics Data System (ADS)

Haeberli, W.; Chiarle, M.; Mortara, G.; Mazza, A.

The uppermost section of the Valle Anzasca behind and above the community of Macugnaga in the Italian Alps is one of the most spectacular high-mountain land- scapes in Europe, with gigantic rock walls and numerous steep hanging glaciers. Its main glacier, Ghiacciaio del Belvedere at the foot of the huge Monte Rosa east face, is a heavily debris-covered glacier flowing on a thick sediment bed. Problems with floods, avalanches and debris flows from this ice body have been known for extended time periods. Most recently, however, the evolution of this highly dynamic environ- ment has become more dramatic. An outburst of Lago delle Locce, an ice-dammed lake at the confluenec of the tributary Ghiacciaio delle Locce with Ghiacciaio del Belvedere, caused heavy damage in 1979 and necessitated site investigation and con- struction work to be done for flood protection. The intermittent glacier growth ten- dency in the 1970es induced strong bulging of the glacier surface and, in places, caused the glacier tongue to override historical morains and to destroy newly-grown forest stands. A surge-type flow acceleration started in the lower parts of the Monte- Rosa east face during summer 2000, leading to strong crevassing and deformation of Ghiacciaio del Belvedere and extreme bulging of its orographic right margin. High water pressure and accelerated movement lasted into winter 2001/2002: the ice now started overriding the LIA moraine near Rifugio Zamboni of the CAI. In addition but rather independently, a most active detachment zone for rock falls and debris flows developed for several years now in the east face of Monte Rosa, somewhat more to the south of the accelerated glacier movement and at an altitude where relatively warm permafrost must be expected. Besides the scientific interest in these phenomena, the growing hazard potential to the local infrastructure must be considered seriously. Es- pecially potentials for the destabilization of large rock and ice masses in the east face of Monte Rosa, for interruption of the access trail to the Rifugio Zamboni by overrid- ing and/or collapse of the lateral moraine, for impacts by ice invading various instal- lations (cable car, restaurant, ski runs, trails) near the moraine hill of Belvedere, and for sudden outbursts of pressurized subglacial water or the newly formed supraglacial lake must be envisaged.

Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

PubMed Central

Céspedes, Miguel Angel; Galindo, Maximo Ibo; Couso, Juan Pablo

2010-01-01

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function. PMID:21079739

Detecting coupled collective motions in protein by independent subspace analysis

NASA Astrophysics Data System (ADS)

Sakuraba, Shun; Joti, Yasumasa; Kitao, Akio

2010-11-01

Protein dynamics evolves in a high-dimensional space, comprising aharmonic, strongly correlated motional modes. Such correlation often plays an important role in analyzing protein function. In order to identify significantly correlated collective motions, here we employ independent subspace analysis based on the subspace joint approximate diagonalization of eigenmatrices algorithm for the analysis of molecular dynamics (MD) simulation trajectories. From the 100 ns MD simulation of T4 lysozyme, we extract several independent subspaces in each of which collective modes are significantly correlated, and identify the other modes as independent. This method successfully detects the modes along which long-tailed non-Gaussian probability distributions are obtained. Based on the time cross-correlation analysis, we identified a series of events among domain motions and more localized motions in the protein, indicating the connection between the functionally relevant phenomena which have been independently revealed by experiments.

Biologic consequences of Stat1-independent IFN signaling

PubMed Central

Gil, M. Pilar; Bohn, Erwin; O'Guin, Andrew K.; Ramana, Chilakamarti V.; Levine, Beth; Stark, George R.; Virgin, Herbert W.; Schreiber, Robert D.

2001-01-01

Although Stat1 is required for many IFN-dependent responses, recent work has shown that IFNγ functions independently of Stat1 to affect the growth of tumor cells or immortalized fibroblasts. We now demonstrate that both IFNγ and IFNα/β regulate proliferative responses in cells of the mononuclear phagocyte lineage derived from Stat1-null mice. Using both representational difference analysis and gene arrays, we show that IFNγ exerts its Stat1-independent actions on mononuclear phagocytes by regulating the expression of many genes. This result was confirmed by monitoring changes in expression and function of the corresponding gene products. Regulation of the expression of these genes requires the IFNγ receptor and Jak1. The physiologic relevance of IFN-dependent, Stat1-independent signaling was demonstrated by monitoring antiviral responses in Stat1-null mice. Thus, the IFN receptors engage alternative Stat1-independent signaling pathways that have important physiological consequences. PMID:11390995

Selective Attention, Working Memory, and Executive Function as Potential Independent Sources of Cognitive Dysfunction in Schizophrenia.

PubMed

Gold, James M; Robinson, Benjamin; Leonard, Carly J; Hahn, Britta; Chen, Shuo; McMahon, Robert P; Luck, Steven J

2017-11-11

People with schizophrenia demonstrate impairments in selective attention, working memory, and executive function. Given the overlap in these constructs, it is unclear if these represent distinct impairments or different manifestations of one higher-order impairment. To examine this question, we administered tasks from the basic cognitive neuroscience literature to measure visual selective attention, working memory capacity, and executive function in 126 people with schizophrenia and 122 healthy volunteers. Patients demonstrated deficits on all tasks with the exception of selective attention guided by strong bottom-up inputs. Although the measures of top-down control of selective attention, working memory, and executive function were all intercorrelated, several sources of evidence indicate that working memory and executive function are separate sources of variance. Specifically, both working memory and executive function independently contributed to the discrimination of group status and independently accounted for variance in overall general cognitive ability as assessed by the MATRICS battery. These two cognitive functions appear to be separable features of the cognitive impairments observed in schizophrenia. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Acerca del moho

EPA Pesticide Factsheets

El moho forma parte del medio ambiente natural. Afuera del hogar, el moho juega un papel en la naturaleza al desintegrar materias organicas tales como las hojas que se han caido o los arboles muertos. El moho puede crecer adentro del hogar cuando las espor

Misura de Massa e Larghezza degli Stati $$x_1$$ e $$x_2$$ del Charmonio Formati in Interazioni $$p - \\bar{p}$$

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pallavicini, Marco

1995-01-01

Oggetto di questa tesi è la misura di alcune caratteristiche fisiche ( massa, larghezza, e larghezza parziale in p - p) degli stati 3 Pi e 3 A del charmonio, - overo del sistema legato di un quark "charm" e del suo antiquark-, nell'ambito dell'esperimento E-760, installato nell'accumulatore di antiprotoni del Fermilab (U.S.A).

Cystatin C and Cardiac Measures in Children and Adolescents With CKD.

PubMed

Brady, Tammy M; Townsend, Kelly; Schneider, Michael F; Cox, Christopher; Kimball, Thomas; Madueme, Peace; Warady, Bradley; Furth, Susan; Mitsnefes, Mark

2017-02-01

Cardiovascular disease (CVD) is highly prevalent among children with chronic kidney disease (CKD). Cystatin C is an established marker of kidney function and an emerging biomarker for CVD events. We quantified the relationship between cystatin C level and cardiac structure and function over time among children with CKD and assessed whether cystatin C level and diastolic function retained an association after accounting for kidney function. Prospective cohort study. 678 children and adolescents with mild to moderate CKD enrolled in the CKD in Children (CKiD) Study with 1,228 echocardiographically obtained cardiac structure and function measurements. Serum cystatin C (mg/L) measured annually. Cardiac structure (left ventricular mass index [g/m 2.7 ]) and cardiac function (shortening fraction; E/A, E'/A', E/E' ratios) measured every other year. Demographics and anthropometrics, measured glomerular filtration rate (mGFR), heart rate, blood pressure, hemoglobin z score, serum albumin level, and calcium-phosphorus product. Independent of time, each 1-mg/L increase in cystatin C level was independently associated with a concurrent 7.7% (95% CI, 5.3%-10.0%) increase in left ventricular mass index, a -4.7% (95% CI, -7.0% to -2.4%) change in E/A ratio, a -6.6% (95% CI, -9.0% to -4.2%) change in E'/A' ratio, and a 2.5% (95% CI, 0.3%-4.7%) increase in E/E' ratio. mGFR was also independently associated with E'/A' ratio. When cystatin C level and mGFR were included in the same model, cystatin C level remained independently associated with E'/A' ratio, whereas mGFR was not. 24% of the cohort was missing data for outcomes of interest or measurements; study population includes only children and adolescents with mild to moderate CKD. In this study of children and adolescents with mild to moderate CKD, cystatin C level was independently associated with cardiac structure and diastolic function. Cystatin C level remained able to predict diastolic function decline via E'/A' ratio even after adjusting for mGFR, suggesting that cystatin C level may have an independent role in CVD risk stratification among children and adolescents with CKD. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Maximizing the Independence of Deaf-Blind Teenagers.

ERIC Educational Resources Information Center

Venn, J. J.; Wadler, F.

1990-01-01

The Independent Living Project for Deaf/Blind Youth emphasized the teaching of home management, personal management, social/emotional skills, work skills, and communication skills to increase low-functioning teenagers' autonomy. The project included an independent living apartment in which a video monitoring system was used for indirect…

Blind separation of positive sources by globally convergent gradient search.

PubMed

Oja, Erkki; Plumbley, Mark

2004-09-01

The instantaneous noise-free linear mixing model in independent component analysis is largely a solved problem under the usual assumption of independent nongaussian sources and full column rank mixing matrix. However, with some prior information on the sources, like positivity, new analysis and perhaps simplified solution methods may yet become possible. In this letter, we consider the task of independent component analysis when the independent sources are known to be nonnegative and well grounded, which means that they have a nonzero pdf in the region of zero. It can be shown that in this case, the solution method is basically very simple: an orthogonal rotation of the whitened observation vector into nonnegative outputs will give a positive permutation of the original sources. We propose a cost function whose minimum coincides with nonnegativity and derive the gradient algorithm under the whitening constraint, under which the separating matrix is orthogonal. We further prove that in the Stiefel manifold of orthogonal matrices, the cost function is a Lyapunov function for the matrix gradient flow, implying global convergence. Thus, this algorithm is guaranteed to find the nonnegative well-grounded independent sources. The analysis is complemented by a numerical simulation, which illustrates the algorithm.

Use of Video Modeling and Video Prompting Interventions for Teaching Daily Living Skills to Individuals with Autism Spectrum Disorders: A Review

ERIC Educational Resources Information Center

Gardner, Stephanie; Wolfe, Pamela

2013-01-01

Identifying methods to increase the independent functioning of individuals with autism spectrum disorders (ASD) is vital in enhancing their quality of life; teaching students with ASD daily living skills can foster independent functioning. This review examines interventions that implement video modeling and/or prompting to teach individuals with…

Upper limb motor function in young adults with spina bifida and hydrocephalus

PubMed Central

Salman, M. S.; Jewell, D.; Hetherington, R.; Spiegler, B. J.; MacGregor, D. L.; Drake, J. M.; Humphreys, R. P.; Gentili, F.

2011-01-01

Objective The objective of the study was to measure upper limb motor function in young adults with spina bifida meningomyelocele (SBM) and typically developing age peers. Method Participants were 26 young adults with SBM, with a Verbal or Performance IQ score of at least 70 on the Wechsler scales, and 27 age- and gender-matched controls. Four upper limb motor function tasks were performed under four different visual and cognitive challenge conditions. Motor independence was assessed by questionnaire. Results Fewer SBM than control participants obtained perfect posture and rebound scores. The SBM group performed less accurately and was more disrupted by cognitive challenge than controls on limb dysmetria tasks. The SBM group was slower than controls on the diadochokinesis task. Adaptive motor independence was related to one upper limb motor task, arm posture, and upper rather than lower spinal lesions were associated with less motor independence. Conclusions Young adults with SBM have significant limitations in upper limb function and are more disrupted by some challenges while performing upper limb motor tasks. Within the group of young adults with SBM, upper spinal lesions compromise motor independence more than lower spinal lesions. PMID:19672605

PDGFRα promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: A study from India.

PubMed

Guru, Sameer Ahmad; Mir, Rashid; Bhat, Musadiq; Najar, Imtiyaz; Zuberi, Mariyam; Sumi, Mamta; Masroor, Mirza; Gupta, Naresh; Saxena, Alpana

2017-10-01

Platelet-derived growth factor receptor has been implicated in many malignant and non-malignant diseases. Platelet-derived growth factor receptor-α is a tyrosine kinase and a side target for imatinib, a revolutionary drug for the treatment of chronic myeloid leukemia that has dramatically improved the survival of chronic myeloid leukemia patients. Given the importance of platelet-derived growth factor receptor in platelet development and its inhibition by imatinib, it was intriguing to analyze the role of platelet-derived growth factor receptor-α in relation to imatinib treatment in the development of imatinib-induced thrombocytopenia in chronic myeloid leukemia patients. We hypothesized that two known functional polymorphisms, +68GA insertion/deletion and -909C/A, in the promoter region of the platelet-derived growth factor receptor-α gene may affect the susceptibility of chronic myeloid leukemia patients receiving imatinib treatment to the development of thrombocytopenia. A case-control study was conducted among a cohort of chronic myeloid leukemia patients admitted to the Lok Nayak Hospital, New Delhi, India. A set of 100 patients of chronic myeloid leukemia in chronic phase and 100 age- and sex-matched healthy controls were studied. After initiation of imatinib treatment, the hematological response of chronic myeloid leukemia patients was monitored regularly for 2 years, in which the development of thrombocytopenia was the primary end point. Platelet-derived growth factor receptor-α promoter polymorphisms +68GA ins/del and -909C/A were studied by allele-specific polymerase chain reaction. Platelet-derived growth factor receptor-α messenger RNA expression was evaluated by quantitative real-time polymerase chain reaction. The messenger RNA expression results were expressed as 2 -Δct ± standard deviation. The distribution of +68GA ins/del promoter polymorphism genotypes differed significantly between the thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p < 0.0001). Moreover, +68GA del/del and ins/del genotypes in imatinib-treated chronic myeloid leukemia patients were associated with an increased risk of developing thrombocytopenia, with odds ratios 6.5 (95% confidence interval = 2.02-0.89, p = 0.001) and 6.0 (95% confidence interval = 2.26-15.91, p = 0.0002), respectively. Similarly, -909C/A promoter polymorphism genotype distribution also differed significantly between thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p = 0.02), and a significantly increased risk of imatinib-induced thrombocytopenia was associated with -909C/A polymorphism mutant homozygous (AA) genotypes the odds ratio being 7.7 (95% confidence interval 1.50 to 39.91, p = 0.009). However, no significant risk of imatinib-induced thrombocytopenia was found to be associated with heterozygous genotype (-909C/A) with odds ratio 1.9 (95% confidence interval = 0.86-4.56, p = 1.14). Platelet-derived growth factor receptor-α messenger RNA expression was significantly higher in chronic myeloid leukemia patients compared to controls (p = 0.008). Moreover, patients with imatinib-induced thrombocytopenia had a significantly lower platelet-derived growth factor receptor-α messenger RNA expression, compared to patients without thrombocytopenia (p = 0.01). A differential expression of platelet-derived growth factor receptor-α messenger RNA was observed with respect to different +68 GA ins/del and -909C/A polymorphism genotypes. The +68GA deletion allele and -909A allele were significantly associated with lower expression of platelet-derived growth factor receptor-α messenger RNA. The platelet-derived growth factor receptor-α +68GA del/del, +68GA ins/del, and -909AA genotypes are associated with an increased risk of developing thrombocytopenia in imatinib-treated chronic myeloid leukemia patients. A significantly lower platelet-derived growth factor receptor-α messenger RNA expression accompanies the +68GA deletion allele in an allele dose-dependent manner. Platelet-derived growth factor receptor-α -909AA genotype is also associated with lower expression of platelet-derived growth factor receptor-α. The downregulation of platelet-derived growth factor receptor-α expression may play a causative role in imatinib-induced thrombocytopenia, a common side effect, in the subset of chronic myeloid leukemia patients with platelet-derived growth factor receptor-α +68 GA ins/del, +68 GA del/del, and -909C/A genotypes.

Dissection of Insertion–Deletion Variants within Differentially Expressed Genes Involved in Wood Formation in Populus

PubMed Central

Gong, Chenrui; Du, Qingzhang; Xie, Jianbo; Quan, Mingyang; Chen, Beibei; Zhang, Deqiang

2018-01-01

Short insertions and deletions (InDels) are one of the major genetic variants and are distributed widely across the genome; however, few investigations of InDels have been conducted in long-lived perennial plants. Here, we employed a combination of RNA-seq and population resequencing to identify InDels within differentially expressed (DE) genes underlying wood formation in a natural population of Populus tomentosa (435 individuals) and utilized InDel-based association mapping to detect the causal variants under additive, dominance, and epistasis underlying growth and wood properties. In the present paper, 5,482 InDels detected from 629 DE genes showed uneven distributions throughout all 19 chromosomes, and 95.9% of these loci were diallelic InDels. Seventy-four InDels (positive false discovery rate q ≤ 0.10) from 68 genes exhibited significant additive/dominant effects on 10 growth and wood-properties, with an average of 14.7% phenotypic variance explained. Potential pleiotropy was observed in one-third of the InDels (representing 24 genes). Seven genes exhibited significantly differential expression among the genotypic classes of associated InDels, indicating possible important roles for these InDels. Epistasis analysis showed that overlapping interacting genes formed unique interconnected networks for each trait, supporting the putative biochemical links that control quantitative traits. Therefore, the identification and utilization of InDels in trees will be recognized as an effective marker system for molecular marker-assisted breeding applications, and further facilitate our understanding of quantitative genomics. PMID:29403506

Radio-Observaciones del OH EN la Coma del Cometa Halley Desde EL Hemisferio Sur

NASA Astrophysics Data System (ADS)

Silva, A. M.; Bajaja, E.; Morras, R.; Cersosimo, J. C.; Martin, M. C.; Arnal, E. M.; Poppel, W. G. L.; Colomb, F. R.; Mazzaro, J.; Olalde, J. C.; Boriakoff, V.; Mirabel, I. F.

1987-05-01

Se utilizó una antena de 30 metros del Instituto Argentino de Radioastronomía para observaciones diarias Cf ebrero a abril de 1986) de la transición en 1667 MHz ( λ = 18 cm) del OH en la coma del cometa Halley. De las observaciones realizadas se concluye: 1) El número promedio de moléculas de OH en la coma durante 37 días de observación fue de (8.9±3.5)x1034 moléculas, lo que implica una tasa de producción promedio de OH de 1.8x1029 moléculas seg-1 y consecuentemente una pérdida de masa promedio de 17±6 toneladas seg-1 . Este valor está de acuerdo con las mediciones realizadas por las sondas Vega y Giotto. 2) El monitoreo desde el lAR revela la existencia de variaciones bruscas en los flujos de absorción del OH. Estas variaciones son consistentes con los modelos que representan la producción gaseosa a partir de ejecciones y/o desprendimientos discretos de materia congelada del núcleo. 3) Las variaciones en la densidad de flujo son consistentes con las estimaciones de los tiem- pos de vida medios del H2O y del OH en presencia del campo de radiación solar. 4) Se encuentra una correlación entre la intensidad del flujo absorbido y anisotropías en Ia dinamica de la coma.

Decidability of formal theories and hyperincursivity theory

NASA Astrophysics Data System (ADS)

Grappone, Arturo G.

2000-05-01

This paper shows the limits of the Proof Standard Theory (briefly, PST) and gives some ideas of how to build a proof anticipatory theory (briefly, PAT) that has no such limits. Also, this paper considers that Gödel's proof of the undecidability of Principia Mathematica formal theory is not valid for axiomatic theories that use a PAT to build their proofs because the (hyper)incursive functions are self-representable.

La Communicacion en la educacion de Adultos y el Desarrollo Rural (Adult Literacy and Rural Development). Cuadernos del CREFAL 14.

ERIC Educational Resources Information Center

Vejarano, Gilberto M.; And Others

This booklet presents the ideas that came out of the Regional Meeting for Adult Literacy and Rural Development. The meeting took place in September 1981 at the Regional Center for Adult Education and Functional Literacy for Latin America (CREFAL) in Mexico. Basically, a discussion of adult literacy in the rural areas of Latin America is presented.…

Funcion del "Vulgo" en la Preception Dramatica de la Edad de Oro (The Function of the "Masses" in the Didactic Drama of the [Spanish] Golden Age).

ERIC Educational Resources Information Center

Porqueras Mayo, A.; Sanchez Escribano, F.

1967-01-01

A concept of the masses, or populace, conveyed a positive connotation in both Biblical and Renaissance literature. During Spain's Golden Age (seventeenth century) writers, especially didactic dramatists, tended to register negative and prejudiced attitudes toward the common folk and to regard them as "masa inculta" or uncultured masses. Primarily,…

Suggested Curriculum Guidelines for an Effective Bilingual Program, 1972-1973. Destrezas Comunicativas del Idioma Espanol. Spanish Language Skills. Third Grade, Level 3.

ERIC Educational Resources Information Center

Artesia Public Schools, NM.

This volume contains suggested curriculum guidelines for an effective bilingual program, with specific focus on Spanish language skills for the third grade level. The philosophy of the program views bilingual education as a vehicle and pedagogical tool to be used to better prepare all children to function in society. The point of departure for…

Suggested Curriculum Guidelines for an Effective Bilingual Program. 1972-1973. Destrezas Comunicativas del Idioma Espanol. Spanish Language Skills. Second Grade, Level 2.

ERIC Educational Resources Information Center

Artesia Public Schools, NM.

This volume contains suggested curriculum guidelines for an effective bilingual program, with specific focus on Spanish language skills for the second grade level. The philosophy of the program views bilingual education as a vehicle and pedagogical tool to be used to better prepare all children to function in society. The point of departure for…

Predictions for Proteins, RNAs and DNAs with the Gaussian Dielectric Function Using DelPhiPKa

PubMed Central

Wang, Lin; Li, Lin; Alexov, Emil

2015-01-01

We developed a Poisson-Boltzmann based approach to calculate the PKa values of protein ionizable residues (Glu, Asp, His, Lys and Arg), nucleotides of RNA and single stranded DNA. Two novel features were utilized: the dielectric properties of the macromolecules and water phase were modeled via the smooth Gaussian-based dielectric function in DelPhi and the corresponding electrostatic energies were calculated without defining the molecular surface. We tested the algorithm by calculating PKa values for more than 300 residues from 32 proteins from the PPD dataset and achieved an overall RMSD of 0.77. Particularly, the RMSD of 0.55 was achieved for surface residues, while the RMSD of 1.1 for buried residues. The approach was also found capable of capturing the large PKa shifts of various single point mutations in staphylococcal nuclease (SNase) from PKa -cooperative dataset, resulting in an overall RMSD of 1.6 for this set of pKa’s. Investigations showed that predictions for most of buried mutant residues of SNase could be improved by using higher dielectric constant values. Furthermore, an option to generate different hydrogen positions also improves PKa predictions for buried carboxyl residues. Finally, the PKa calculations on two RNAs demonstrated the capability of this approach for other types of biomolecules. PMID:26408449

Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells.

PubMed

Ruffin, Manon; Roussel, Lucie; Maillé, Émilie; Rousseau, Simon; Brochiero, Emmanuelle

2018-04-01

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.

An evaluation of Delaware's DelTrac program : building an integrated transportation management system

DOT National Transportation Integrated Search

2004-06-01

The DelTrac deployment experience included both successes and unmet challenges. Programmatically, the DelTrac approach to managing ITS has been successful at creating a great deal of integration and cooperation between organizations at DelDOT. Stakeh...

An Annotated Bibliography of Latin American Military Journals.

DTIC Science & Technology

1965-12-01

CABALLERIA Y UNIDADES BLINDADAS) REVISTA DE INFANTERIA REVISTA DE INGENIERIA MILITÄR (Organo de la Academia Politecnica Militär) REVISTA DEL...Appendix--continued ■84- PERU BOLETIN DEL MINISTERIO DE GUERRA Y MARINA (Continued as MEMORIAL DEL EJERCITO) INFANTERIA INGENIERIA REVISTA DEL

Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells

PubMed Central

Stanton, Bruce A.; Coutermarsh, Bonita; Barnaby, Roxanna; Hogan, Deborah

2015-01-01

Background P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF). Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770. Methods and Results F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del) were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del-CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid) significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR. Conclusion The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials. PMID:26018799

Pseudomonas aeruginosa Reduces VX-809 Stimulated F508del-CFTR Chloride Secretion by Airway Epithelial Cells.

PubMed

Stanton, Bruce A; Coutermarsh, Bonita; Barnaby, Roxanna; Hogan, Deborah

2015-01-01

P. aeruginosa is an opportunistic pathogen that chronically infects the lungs of 85% of adult patients with Cystic Fibrosis (CF). Previously, we demonstrated that P. aeruginosa reduced wt-CFTR Cl secretion by airway epithelial cells. Recently, a new investigational drug VX-809 has been shown to increase F508del-CFTR Cl secretion in human bronchial epithelial (HBE) cells, and, in combination with VX-770, to increase FEV1 (forced expiratory volume in 1 second) by an average of 3-5% in CF patients homozygous for the F508del-CFTR mutation. We propose that P. aeruginosa infection of CF lungs reduces VX-809 + VX-770- stimulated F508del-CFTR Cl secretion, and thereby reduces the clinical efficacy of VX-809 + VX-770. F508del-CFBE cells and primary cultures of CF-HBE cells (F508del/F508del) were exposed to VX-809 alone or a combination of VX-809 + VX-770 for 48 hours and the effect of P. aeruginosa on F508del-CFTR Cl secretion was measured in Ussing chambers. The effect of VX-809 on F508del-CFTR abundance was measured by cell surface biotinylation and western blot analysis. PAO1, PA14, PAK and 6 clinical isolates of P. aeruginosa (3 mucoid and 3 non-mucoid) significantly reduced drug stimulated F508del-CFTR Cl secretion, and plasma membrane F508del-CFTR. The observation that P. aeruginosa reduces VX-809 and VX-809 + VX-770 stimulated F508del CFTR Cl secretion may explain, in part, why VX-809 + VX-770 has modest efficacy in clinical trials.

Recovery after chronic stress within spatial reference and working memory domains: correspondence with hippocampal morphology.

PubMed

Hoffman, A N; Krigbaum, A; Ortiz, J B; Mika, A; Hutchinson, K M; Bimonte-Nelson, H A; Conrad, C D

2011-09-01

Chronic stress results in reversible spatial learning impairments in the Morris water maze that correspond with hippocampal CA3 dendritic retraction in male rats. Whether chronic stress impacts different types of memory domains, and whether these can similarly recover, is unknown. This study assessed the effects of chronic stress with and without a post-stress delay to evaluate learning and memory deficits within two memory domains, reference and working memory, in the radial arm water maze (RAWM). Three groups of 5-month-old male Sprague-Dawley rats were either not stressed [control (CON)], or restrained (6 h/day for 21 days) and then tested on the RAWM either on the next day [stress immediate (STR-IMM)] or following a 21-day delay [stress delay (STR-DEL)]. Although the groups learned the RAWM task similarly, groups differed in their 24-h retention trial assessment. Specifically, the STR-IMM group made more errors within both the spatial reference and working memory domains, and these deficits corresponded with a reduction in apical branch points and length of hippocampal CA3 dendrites. In contrast, the STR-DEL group showed significantly fewer errors in both the reference and working memory domains than the STR-IMM group. Moreover, the STR-DEL group showed better RAWM performance in the reference memory domain than did the CON group, and this corresponded with restored CA3 dendritic complexity, revealing long-term enhancing actions of chronic stress. These results indicate that chronic stress-induced spatial working and reference memory impairments, and CA3 dendritic retraction, are reversible, with chronic stress having lasting effects that can benefit spatial reference memory, but with these lasting beneficial effects being independent of CA3 dendritic complexity. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male.

PubMed

Cramer, Thomas J; Anderson, Kristin; Navaz, Karanjia; Brown, Justin M; Mosnier, Laurent O; von Drygalski, Annette

2016-03-01

In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement. Genotyping showed the rare heterozygous FVII 9729del4 mutation. Bleed evacuation was complicated by epidural abscess requiring craniectomy, bone graft procedures, and prolonged administration of recombinant human (rh) activated FVII (FVIIa). The patient recovered without neurological deficits, and remains on prophylactic low dose treatment with rhFVIIa in relation to risky athletic activities. For clinicians, it is important to recognize that effects of rhFVIIa within these pathways are independent of its contribution to blood clot formation and cannot be assessed by clotting assays. Reduced FVII levels should therefore not be dismissed, as even a mild reduction may result in spontaneous bleeding. Treatment of mild FVII deficiency requires a careful case-by-case approach, based on the clinical scenario. Copyright © 2015 Elsevier Inc. All rights reserved.

Efectos combinados de la ampliación de la atención primaria de salud y de las transferencias condicionadas de dinero en efectivo sobre la mortalidad infantil en Brasil, 1998–2010*

PubMed Central

Guanais, Frederico C.

2015-01-01

Objetivos. Examiné los efectos combinados del acceso a la atención primaria mediante el Programa de Salud Familiar (PSF) y las transferencias condicionadas de dinero en efectivo del Programa Bolsa Familia (PBF) sobre la mortalidad infantil posneonatal (MIPN) en Brasil. Métodos. Empleé un análisis ecológico longitudinal usando datos en panel de 4 583 municipios brasileños de 1998 al 2010, con 54 253 observaciones en total. Estimé modelos de regresión de efectos fijos por mínimos cuadrados ordinarios, con la tasa de MIPN como la variable dependiente y el PSF, el PBF y sus interacciones como las principales variables independientes de interés. Resultados. La asociación de una mayor cobertura del PSF con una menor tasa de MIPN se volvió más fuerte conforme aumentaba la cobertura del PBF. En los promedios de todas las demás variables, cuando la cobertura de PBF era 25%, la MIPN predicha fue 5,24 (intervalo de confianza [IC] de 95% = 4,95, 5,53) para una cobertura del PSF de 0%, y de 3,54 (IC de 95% = 2,77, 4,31) para una cobertura del PSF de 100%. Cuando la cobertura del PBF era de 60%, la MIPN predicha fue 4,65 (IC de 95% = 4,36, 4,94) para una cobertura del PSF de 0%, y de 1,38 (IC de 95% = 0,88, 1,89) para una cobertura del PSF de 100%. Conclusiones. El efecto del PSF depende de la ampliación del PBF. Para las poblaciones empobrecidas y subatendidas, la combinación de intervenciones tanto del lado de la oferta como del lado de la demanda podría ser necesaria para mejorar los resultados en salud.

State of the Diversity Practice in Independent Schools

ERIC Educational Resources Information Center

Torres, Amada

2015-01-01

During the spring of 2014, the National Association of Independent Schools (NAIS) commissioned Insightlink Communications, a market research firm, to conduct the second survey on the state of the diversity practice in independent schools. The goals of the study included defining the roles played by diversity practitioners, their functions, and…

Analisis del contenido curricular de los Documentos Normativos del Programa de Ciencias en el area de biologia para la escuela superior del sistema de educacion publica de Puerto Rico: 1993-2012

NASA Astrophysics Data System (ADS)

Davila Montanez, Melissa

Esta investigacion de naturaleza cualitativa se ocupo de realizar un analisis de contenido documental de los Documentos Normativos del Programa de Ciencias en el area de biologia de la escuela superior del sistema de educacion publica de Puerto Rico del periodo 1993-2012. Los documentos analizados fueron: Guia Curricular, 1995; Marco Curricular, 2003; Estandares de Excelencia, 1996, 2000 y Estandares de Contenido y Expectativas de Grado, 2007. Se indago si hubo cambios en significados en los Componentes Estructurales: Naturaleza de la ciencia, Paradigmas para la ensenanza de la ciencia, Funcion del curriculo formal, Mision de la ensenanza de la ciencia; Contenidos, destrezas y competencias, Estrategias de ensenanza y Evaluacion/Assessment del aprendizaje. El analisis sugiere que no hubo cambios sustanciales en los significados de los Componentes Estructurales. Los documentos estudiados muestran mayormente caracteristicas similares, aunque los documentos mas recientes eran mas descriptivos, explicativos y especificos.

N-terminal pro–brain natriuretic peptide and abnormal brain aging

PubMed Central

Sabayan, Behnam; van Buchem, Mark A.; de Craen, Anton J.M.; Sigurdsson, Sigurdur; Zhang, Qian; Harris, Tamara B.; Gudnason, Vilmundur; Arai, Andrew E.

2015-01-01

Objective: To investigate the independent association of serum N-terminal fragment of the prohormone natriuretic peptide (NT-proBNP) with structural and functional features of abnormal brain aging in older individuals. Methods: In this cross-sectional study based on the Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study, we included 4,029 older community-dwelling individuals (born 1907 to 1935) with a measured serum level of NT-proBNP. Outcomes included parenchymal brain volumes estimated from brain MRI, cognitive function measured by tests of memory, processing speed, and executive functioning, and presence of depressive symptoms measured using the Geriatric Depression Scale. In a substudy, cardiac output of 857 participants was assessed using cardiac MRI. Results: In multivariate analyses, adjusted for sociodemographic and cardiovascular factors, higher levels of NT-proBNP were independently associated with lower total (p < 0.001), gray matter (p < 0.001), and white matter (p = 0.001) brain volumes. Likewise, in multivariate analyses, higher levels of NT-proBNP were associated with worse scores in memory (p = 0.005), processing speed (p = 0.001), executive functioning (p < 0.001), and more depressive symptoms (p = 0.002). In the substudy, the associations of higher NT-proBNP with lower brain parenchymal volumes, impaired executive function and processing speed, and higher depressive symptoms were independent of the level of cardiac output. Conclusions: Higher serum levels of NT-proBNP, independent of cardiovascular risk factors and a measure of cardiac function, are linked with alterations in brain structure and function. Roles of natriuretic peptides in the process of brain aging need to be further elucidated. PMID:26231259

Influence of androgen receptor CAG polymorphism on sexual function recovery after testosterone therapy in late-onset hypogonadism.

PubMed

Tirabassi, Giacomo; Corona, Giovanni; Biagioli, Andrea; Buldreghini, Eddi; delli Muti, Nicola; Maggi, Mario; Balercia, Giancarlo

2015-02-01

Androgen receptor (AR) CAG polymorphism has been found to influence sexual function. However, no study has evaluated its potential to condition sexual function recovery after testosterone replacement therapy (TRT) in a large cohort of hypogonadic subjects. To evaluate the role of this polymorphism in sexual function improvement after TRT in late-onset hypogonadism (LOH). Seventy-three men affected by LOH were retrospectively considered. Evaluations were performed before TRT started (time 0) and before the sixth undecanoate testosterone injection. International Index of Erectile Function (IIEF) questionnaire (erectile function [EF], orgasmic function [OF], sexual desire [SD], intercourse satisfaction [IS], overall satisfaction [OS], and total IIEF-15 score); total and free testosterone and estradiol; AR gene CAG repeat number. TRT induced a significant increase in total and free testosterone and estradiol. All IIEF domains significantly improved after TRT. AR CAG repeats negatively and significantly correlated with all the variations (Δ-) of sexual function domains, except for Δ-OS. Conversely, Δ-total testosterone was found to be positively and significantly correlated with sexual function domain variations, except for Δ-IS and Δ-OS. Δ-estradiol did not correlate significantly with any of the variations of sexual function domains. After inclusion in generalized linear models, the number of AR gene CAG triplets was found to be independently and negatively associated with Δ-EF, Δ-SD, Δ-IS, and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated with Δ-EF, Δ-OF, Δ-SD, and Δ-Total IIEF-15 score. However, after including time 0 total testosterone in the model, AR gene CAG triplets remained independently and negatively associated only with Δ-EF and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated only with Δ-EF. Longer length of AR gene CAG repeat tract seems to lower TRT-induced improvement of sexual function in LOH. © 2014 International Society for Sexual Medicine.

Cognitive deficits are associated with poorer simulated driving in older adults with heart failure

PubMed Central

2013-01-01

Background Cognitive impairment is prevalent in older adults with heart failure (HF) and associated with reduced functional independence. HF patients appear at risk for reduced driving ability, as past work in other medical samples has shown cognitive dysfunction to be an important contributor to driving performance. The current study examined whether cognitive dysfunction was independently associated with reduced driving simulation performance in a sample of HF patients. Methods 18 persons with HF (67.72; SD = 8.56 year) completed echocardiogram and a brief neuropsychological test battery assessing global cognitive function, attention/executive function, memory and motor function. All participants then completed the Kent Multidimensional Assessment Driving Simulation (K-MADS), a driving simulator scenario with good psychometric properties. Results The sample exhibited an average Mini Mental State Examination (MMSE) score of 27.83 (SD = 2.09). Independent sample t-tests showed that HF patients performed worse than healthy adults on the driving simulation scenario. Finally, partial correlations showed worse attention/executive and motor function were independently associated with poorer driving simulation performance across several indices reflective of driving ability (i.e., centerline crossings, number of collisions, % of time over the speed limit, among others). Conclusion The current findings showed that reduced cognitive function was associated with poor simulated driving performance in older adults with HF. If replicated using behind-the-wheel testing, HF patients may be at elevated risk for unsafe driving and routine driving evaluations in this population may be warranted. PMID:24499466

Increasing the Endoplasmic Reticulum Pool of the F508del Allele of the Cystic Fibrosis Transmembrane Conductance Regulator Leads to Greater Folding Correction by Small Molecule Therapeutics.

PubMed

Chung, W Joon; Goeckeler-Fried, Jennifer L; Havasi, Viktoria; Chiang, Annette; Rowe, Steven M; Plyler, Zackery E; Hong, Jeong S; Mazur, Marina; Piazza, Gary A; Keeton, Adam B; White, E Lucile; Rasmussen, Lynn; Weissman, Allan M; Denny, R Aldrin; Brodsky, Jeffrey L; Sorscher, Eric J

2016-01-01

Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present. In human primary airway cells, the paucity of Band B F508del is even more pronounced, although F508del and WT mRNA concentrations are comparable. Therefore, to augment levels of "repairable" F508del CFTR and identify small molecules that then correct this pool, we developed compound library screening protocols based on automated protein detection. First, cell-based imaging measurements were used to semi-quantitatively estimate distribution of F508del CFTR by high content analysis of two-dimensional images. We evaluated ~2,000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository in a pilot screen and identified agents that increase the F508del protein pool. Second, we analyzed ~10,000 compounds representing diverse chemical scaffolds for effects on total CFTR expression using a multi-plate fluorescence protocol and describe compounds that promote F508del maturation. Together, our findings demonstrate proof of principle that agents identified in this fashion can augment the level of endoplasmic reticulum (ER) resident "Band B" F508del CFTR suitable for pharmacologic correction. As further evidence in support of this strategy, PYR-41-a compound that inhibits the E1 ubiquitin activating enzyme-was shown to synergistically enhance F508del rescue by C18, a small molecule corrector. Our combined results indicate that increasing the levels of ER-localized CFTR available for repair provides a novel route to correct F508del CFTR.

Self-Care Self-Efficacy Correlates with Independence in Basic Activities of Daily Living in Individuals with Chronic Stroke.

PubMed

Frost, Yael; Weingarden, Harold; Zeilig, Gabi; Nota, Ayala; Rand, Debbie

2015-07-01

(1) To characterize the self-care self-efficacy (SCSE) of community dwelling individuals with chronic stroke and (2) to determine the contribution of SCSE to the independence in basic and instrumental activities of daily living (BADL and IADL) and the participation of individuals with chronic stroke. SCSE is the confidence in one's own ability to perform self-care activities. This cross-sectional study included fifty community-dwelling individuals mean (SD) age 59.8 (9.3) years, mean (SD) 3.1 (1.7) years post-stroke who were able to walk at least 10 meters. SCSE was assessed using the Stroke Self-Efficacy Questionnaire (SSEQ), BADL was assessed by the Functional Independence Measure (FIM) (interview), the IADL questionnaire assessed IADL and the Physical Activity Scale for Individuals with Physical Disabilities (PASIPD) assessed participation. Correlation and regression analyses were performed after controlling for grip strength, executive functions and gait speed, factors known to influence independence in daily living. The mean SCSE level was moderate-high (70%). Significant moderate correlations were found between SCSE to independence in BADL (r = .596, P < .001), IADL (r = .567, P < .001) and participation (r = .340, P < .005). SCSE of our cohort explained 7.4% of the variance of the individual's independence in BADL after controlling for executive functions and gait speed, but did not contribute to their independence in IADL and participation. Higher SCSE of individuals with chronic stroke contributes to more independence in BADL. Additional questionnaires regarding self efficacy for IADL should be developed and investigated. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

An experiment of formation of charmoni states in annihilation P-Pbarra. Un esperimento di formazione di stati del charmonio in annichilazione P-Pbarra (in Italian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pallavicini, Marco

1995-01-01

Oggetto di questa tesi e la misura di alcune caratteristiche fisiche (massa, larghezza, e larghezza parziale in p -more » $$\\bar{p}$$) degli stati 3P 1 e 3P 2 del charmonio, -ovvero del sistema legato di un quark "charm" e del suo antiquark-, nell'amito dell'esperimento E-760, installato nell'accumulatore di antiprotoni del Fermilab.« less

Multifractal analysis of managed and independent float exchange rates

NASA Astrophysics Data System (ADS)

Stošić, Darko; Stošić, Dusan; Stošić, Tatijana; Stanley, H. Eugene

2015-06-01

We investigate multifractal properties of daily price changes in currency rates using the multifractal detrended fluctuation analysis (MF-DFA). We analyze managed and independent floating currency rates in eight countries, and determine the changes in multifractal spectrum when transitioning between the two regimes. We find that after the transition from managed to independent float regime the changes in multifractal spectrum (position of maximum and width) indicate an increase in market efficiency. The observed changes are more pronounced for developed countries that have a well established trading market. After shuffling the series, we find that the multifractality is due to both probability density function and long term correlations for managed float regime, while for independent float regime multifractality is in most cases caused by broad probability density function.

Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening

NASA Astrophysics Data System (ADS)

Kalid, Ori; Mense, Martin; Fischman, Sharon; Shitrit, Alina; Bihler, Hermann; Ben-Zeev, Efrat; Schutz, Nili; Pedemonte, Nicoletta; Thomas, Philip J.; Bridges, Robert J.; Wetmore, Diana R.; Marantz, Yael; Senderowitz, Hanoch

2010-12-01

Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.

The Risk for Fall and Functional Dependence in Polish Adults 60–87 Years Old.

PubMed

Domaradzki, Jaroslaw; Koziel, Slawomir; Ignasiak, Zofia; Sławińska, Teresa; Skrzek, Anna; Kołodziej, Małgorzata

2017-03-01

The constantly rising percentage of the elderly (60+), who are particularly at risk of the dangerous consequence of falls, results not only in the loss of independence in daily life, but also in a serious threat to health and life. Therefore, many authors emphasize the necessity of conducting prophylaxis and prevention among senior citizens. The most important aspect of fall prophylaxis is care about the optimum level of agility. Exercise should focus on increasing muscular strength, balance and dexterity. The aim of the present study is to determine the relationship between functional fitness and the risk for falls of older people in the light of maintaining physical independence. The research group consisted of 522 persons: 142 males and 380 females aged 60-84 years from Wroclaw (a city in the south-west of Poland). All subjects provided written consent, and were measured and tested in 2009 through 2015, excluding the winter months. Body height and weight were measured. Body mass index was calculated. The Senior Fitness Test was used to assess functional capacity and efficiency. The results of the Senior Fitness Test were used to estimate Maintaining Physical Independence in Older Adults. The differences in the means of the results of all the tests between the age and sex-specific groups were assessed by means of a two-way analysis of variance, where sex and age were factors and results of appropriate test dependent variables. Logistic regression was used to estimate the risk for fall, based on the incidence of fall in the last year, for each test comparing the individuals met referenced criteria to maintain functionally dependence and independent, controlled for age and BMI. The risk for falls was more than twice greater in the case of the studied females, whose muscular strength of the upper part of the body was lower. The females in whose cases no fewer than two tests failed to ascertain functional independence, had a greater risk for falls. In the case of the males, no statistically-significant connections between functional independence and the risk for falls was found.

Kurt Gödels Brünner Verwandte

NASA Astrophysics Data System (ADS)

Müller, Dora

2007-11-01

The author of this memoir Dora Müller (born 1920) belongs - as well as Kurt Gödel-to the German minority playing an important role in the past life of Brno. The marriage of his son included her among the Gödels collaterals. She was chemist, but also pianist, historician, participant of antinacist movement and iniciator of Czech-German understanding after war. Following her personal experiences, remembrances of Gödels relatives and documental materials, she evokes the atmosphere of broader family milieu of Kurt Gödel.

Resolving the Orientation of Cylinders and Cuboids from Projected Area Measurements

DTIC Science & Technology

2016-05-01

fabs ( e1 ) + Ay * fabs ( e2...Az * fabs ( e3 ) - A_xy; 90 g = Ax * fabs ( e4 ) + Ay * fabs ( e5 ) + Az * fabs ( e6 ) - A_xz; 91 h = Ax * fabs ( e7 ) + Ay * fabs ( e8 ) + Az * fabs ( e9...b23 * h; 128 del_r = b31 * f + b32 * g + b33 * h; 129 130 p -= del_p; 131 y -= del_y; 132 r -= del_r; 133 134 if ( fabs ( del_p ) < TOL && fabs (

Effects of cooperation between translating ribosome and RNA polymerase on termination efficiency of the Rho-independent terminator.

PubMed

Li, Rui; Zhang, Qing; Li, Junbai; Shi, Hualin

2016-04-07

An experimental system was designed to measure in vivo termination efficiency (TE) of the Rho-independent terminator and position-function relations were quantified for the terminator tR2 in Escherichia coli The terminator function was almost completely repressed when tR2 was located several base pairs downstream from the gene, and TE gradually increased to maximum values with the increasing distance between the gene and terminator. This TE-distance relation reflected a stochastic coupling of the ribosome and RNA polymerase (RNAP). Terminators located in the first 100 bp of the coding region can function efficiently. However, functional repression was observed when the terminator was located in the latter part of the coding region, and the degree of repression was determined by transcriptional and translational dynamics. These results may help to elucidate mechanisms of Rho-independent termination and reveal genomic locations of terminators and functions of the sequence that precedes terminators. These observations may have important applications in synthetic biology. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

[Effectiveness of a cognitive-motorphysiotherapeutical therapy intervention in institutionalized older adults with mild cognitive impairment and mild dementia].

PubMed

Menezes, Alessandra Vieira; Aguiar, Alessandra da Silva de; Alves, Elysama Fernandes; Quadros, Layse Biz de; Bezerra, Poliana Penasso

2016-11-01

The aim of this study was to investigate the effectiveness of four months of cognitive-motor physiotherapy intervention, with a single weekly visit, on cognitive function, mobility and functional independence of institutionalized elderly individuals with mild cognitive impairment and mild dementia. In a controlled clinical trial, 15 subjects were allocated to experimental and control groups. Regarding the assessment of the subjects the following instruments were applied: Mini-Mental State Examination, Clinical Dementia Rating Scale, Verbal Fluency Test and Frontal Assessment Battery for analyzing cognitive functions; Berg Balance Scale and Timed Up and Go Test to verify mobility, and; Barthel Scale and Pfeffer Index for measurement of functional independence. The statistical procedures involved the application of Student's t-test with a 5% significance threshold. With respect to the results, the experimental group performed better only in mobility-related tests at the end of the intervention (p < 0.05). The proposed intervention showed efficacy on mobility, but not on cognition and functional independence. The short period of time and low weekly basis may be related to the results obtained.

Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep

PubMed Central

Suárez-Vega, Aroa; Gutiérrez-Gil, Beatriz; Benavides, Julio; Perez, Valentín; Tosser-Klopp, Gwenola; Klopp, Christophe; Keennel, Stephen J.; Arranz, Juan José

2015-01-01

In this study, we demonstrate the use of a genome-wide association mapping together with RNA-seq in a reduced number of samples, as an efficient approach to detect the causal mutation for a Mendelian disease. Junctional epidermolysis bullosa is a recessive genodermatosis that manifests with neonatal mechanical fragility of the skin, blistering confined to the lamina lucida of the basement membrane and severe alteration of the hemidesmosomal junctions. In Spanish Churra sheep, junctional epidermolysis bullosa (JEB) has been detected in two commercial flocks. The JEB locus was mapped to Ovis aries chromosome 11 by GWAS and subsequently fine-mapped to an 868-kb homozygous segment using the identical-by-descent method. The ITGB4, which is located within this region, was identified as the best positional and functional candidate gene. The RNA-seq variant analysis enabled us to discover a 4-bp deletion within exon 33 of the ITGB4 gene (c.4412_4415del). The c.4412_4415del mutation causes a frameshift resulting in a premature stop codon at position 1472 of the integrin β4 protein. A functional analysis of this deletion revealed decreased levels of mRNA in JEB skin samples and the absence of integrin β4 labeling in immunohistochemical assays. Genotyping of c.4412_4415del showed perfect concordance with the recessive mode of the disease phenotype. Selection against this causal mutation will now be used to solve the problem of JEB in flocks of Churra sheep. Furthermore, the identification of the ITGB4 mutation means that affected sheep can be used as a large mammal animal model for the human form of epidermolysis bullosa with aplasia cutis. Our approach evidences that RNA-seq offers cost-effective alternative to identify variants in the species in which high resolution exome-sequencing is not straightforward. PMID:25955497

Biallelic Variants in TTLL5, Encoding a Tubulin Glutamylase, Cause Retinal Dystrophy

PubMed Central

Sergouniotis, Panagiotis I.; Chakarova, Christina; Murphy, Cian; Becker, Mirjana; Lenassi, Eva; Arno, Gavin; Lek, Monkol; MacArthur, Daniel G.; Bhattacharya, Shomi S.; Moore, Anthony T.; Holder, Graham E.; Robson, Anthony G.; Wolfrum, Uwe; Webster, Andrew R.; Plagnol, Vincent

2014-01-01

In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with “cone-first” retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs∗2];[Glu529Valfs∗2], and c.[401delT(;)3354G>A], p.[Leu134Argfs∗45(;)Trp1118∗]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543∗) in TTLL5. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TTLL5 mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TTLL5 has been previously reported to be essential for the correct function of sperm flagella in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families. PMID:24791901

A naturally occurring InDel variation in BraA.FLC.b (BrFLC2) associated with flowering time variation in Brassica rapa.

PubMed

Wu, Jian; Wei, Keyun; Cheng, Feng; Li, Shikai; Wang, Qian; Zhao, Jianjun; Bonnema, Guusje; Wang, Xiaowu

2012-08-28

Flowering time is an important trait in Brassica rapa crops. FLOWERING LOCUS C (FLC) is a MADS-box transcription factor that acts as a potent repressor of flowering. Expression of FLC is silenced when plants are exposed to low temperature, which activates flowering. There are four copies of FLC in B. rapa. Analyses of different segregating populations have suggested that BraA.FLC.a (BrFLC1) and BraA.FLC.b (BrFLC2) play major roles in controlling flowering time in B. rapa. We analyzed the BrFLC2 sequence in nine B. rapa accessions, and identified a 57-bp insertion/deletion (InDel) across exon 4 and intron 4 resulting in a non-functional allele. In total, three types of transcripts were identified for this mutated BrFLC2 allele. The InDel was used to develop a PCR-based marker, which was used to screen a collection of 159 B. rapa accessions. The deletion genotype was present only in oil-type B. rapa, including ssp. oleifera and ssp. tricolaris, and not in other subspecies. The deletion genotype was significantly correlated with variation in flowering time. In contrast, the reported splicing site variation in BrFLC1, which also leads to a non-functional locus, was detected but not correlated with variation in flowering time in oil-type B. rapa, although it was correlated with variation in flowering time in vegetable-type B. rapa. Our results suggest that the naturally occurring deletion mutation across exon 4 and intron 4 in BrFLC2 gene contributes greatly to variation in flowering time in oil-type B. rapa. The observed different relationship between BrFLC1 or BrFLC2 and flowering time variation indicates that the control of flowering time has evolved separately between oil-type and vegetable-type B. rapa groups.

Combining GWAS and RNA-Seq Approaches for Detection of the Causal Mutation for Hereditary Junctional Epidermolysis Bullosa in Sheep.

PubMed

Suárez-Vega, Aroa; Gutiérrez-Gil, Beatriz; Benavides, Julio; Perez, Valentín; Tosser-Klopp, Gwenola; Klopp, Christophe; Keennel, Stephen J; Arranz, Juan José

2015-01-01

In this study, we demonstrate the use of a genome-wide association mapping together with RNA-seq in a reduced number of samples, as an efficient approach to detect the causal mutation for a Mendelian disease. Junctional epidermolysis bullosa is a recessive genodermatosis that manifests with neonatal mechanical fragility of the skin, blistering confined to the lamina lucida of the basement membrane and severe alteration of the hemidesmosomal junctions. In Spanish Churra sheep, junctional epidermolysis bullosa (JEB) has been detected in two commercial flocks. The JEB locus was mapped to Ovis aries chromosome 11 by GWAS and subsequently fine-mapped to an 868-kb homozygous segment using the identical-by-descent method. The ITGB4, which is located within this region, was identified as the best positional and functional candidate gene. The RNA-seq variant analysis enabled us to discover a 4-bp deletion within exon 33 of the ITGB4 gene (c.4412_4415del). The c.4412_4415del mutation causes a frameshift resulting in a premature stop codon at position 1472 of the integrin β4 protein. A functional analysis of this deletion revealed decreased levels of mRNA in JEB skin samples and the absence of integrin β4 labeling in immunohistochemical assays. Genotyping of c.4412_4415del showed perfect concordance with the recessive mode of the disease phenotype. Selection against this causal mutation will now be used to solve the problem of JEB in flocks of Churra sheep. Furthermore, the identification of the ITGB4 mutation means that affected sheep can be used as a large mammal animal model for the human form of epidermolysis bullosa with aplasia cutis. Our approach evidences that RNA-seq offers cost-effective alternative to identify variants in the species in which high resolution exome-sequencing is not straightforward.

fMRI-vs-MEG evaluation of post-stroke interhemispheric asymmetries in primary sensorimotor hand areas.

PubMed

Altamura, Claudia; Torquati, Kahtya; Zappasodi, Filippo; Ferretti, Antonio; Pizzella, Vittorio; Tibuzzi, Francesco; Vernieri, Fabrizio; Pasqualetti, Patrizio; Landi, Doriana; Del Gratta, Cosimo; Romani, Gian-Luca; Maria Rossini, Paolo; Tecchio, Franca

2007-04-01

Growing evidence emphasizes a positive role of brain ipsilesional (IL) reorganization in stroke patients with partial recovery. Ten patients affected by a monohemispheric stroke in the middle cerebral artery territory underwent functional magnetic resonance (fMRI) and magnetoencephalography (MEG) evaluation of the primary sensory (S1) activation via the same paradigm (median nerve galvanic stimulation). Four patients did not present S1 fMRI activation [Rossini, P.M., Altamura, C., Ferretti, A., Vernieri, F., Zappasodi, F., Caulo, M., Pizzella, V., Del Gratta, C., Romani, G.L., Tecchio, F., 2004. Does cerebrovascular disease affect the coupling between neuronal activity and local haemodynamics? Brain 127, 99-110], although inclusion criteria required bilateral identifiable MEG responses. Mean Euclidean distance between fMRI and MEG S1 activation Talairach coordinates was 10.1+/-2.9 mm, with a 3D intra-class correlation (ICC) coefficient of 0.986. Interhemispheric asymmetries, evaluated by an MEG procedure independent of Talairach transformation, were outside or at the boundaries of reference ranges in 6 patients. In 3 of them, the IL activation presented medial or lateral shift with respect to the omega-shaped post-rolandic area while in the other 3, IL areas were outside the peri-rolandic region. In conclusion, despite dissociated intensity, the MEG and fMRI activations displayed good spatial consistency in stroke patients, thus confirming excessive interhemispheric asymmetries as a suitable indicator of unusual recruitments in the ipsilesional hemisphere, within or outside the peri-rolandic region.

Health-related quality of life in adult dermatitis patients stratified by filaggrin genotype.

PubMed

Heede, Nina G; Thyssen, Jacob P; Thuesen, Betina H; Linneberg, Allan; Szecsi, Pal B; Stender, Steen; Johansen, Jeanne D

2017-03-01

Information concerning health-related quality of life (HRQoL) and comorbidities of adult dermatitis patients stratified by loss-of-function mutations in the filaggrin gene (FLG) is limited. To investigate HRQoL, skin symptoms and comorbidities in adult FLG mutation carriers. This cross-sectional study included patients diagnosed with atopic dermatitis and/or hand eczema (n = 520). Patients completed questionnaires about dermatitis, skin symptoms, HRQoL, and comorbidities, including actinic keratosis, and atopic and mental disorders. FLG mutations (R501X, 2282del4, and R2447X) were identified in 16.9% of patients, and were significantly associated not only with atopic dermatitis, but also independently with skin fissures on the fingers and heels, and self-reported actinic keratosis. Although FLG mutations were significantly associated with reduced HRQoL, as measured by use of the Dermatology Life Quality Index (DLQI), no association with self-reported anxiety or depression was identified. Notably, the highest median DLQI score, reflecting greater impairment, was reported by patients with both FLG mutations and atopic dermatitis. Overall, 19.7% of patients with both atopic dermatitis and FLG mutations reported a 'large or extremely large' impact on their lives; this represents twice the prevalence seen in patients with atopic dermatitis and wild-type FLG (9.6%). Patients with both atopic dermatitis and common FLG mutations are more frequently affected by reduced HRQoL. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Renal function had an independent relationship with coronary artery calcification in Chinese elderly men.

PubMed

Fu, Shihui; Zhang, Zhao; Luo, Leiming; Ye, Ping

2017-04-07

Although previous studies have analyzed the relationship between renal function and coronary artery calcification (CAC) in pre-dialysis and dialysis patients, limited studies have discussed the relationship between renal function and CAC in Chinese elderly men without obvious damage of renal function. The present study was designed to explore the relationship between renal function and CAC in Chinese elderly men without obvious damage of renal function. This cross-sectional study was carried out in 105 male participants older than 60 years with glomerular filtration rate (GFR) ≥ 45 ml/min/1.73 m 2 . CAC was detected by high-definition computerized tomography (HDCT), which is a highly sensitive technique for detecting the CAC and provides the most accurate CAC scores up to date. Age was 72 ± 8.4 years on average and ranged from 60 to 89 years. Simple correlation analysis indicated that all kinds of CAC scores including the Agatston, volume and mass scores inversely correlated with GFR values (p < 0.05 for all). In multivariate linear regression analysis, GFR values were independently associated with all these CAC scores (p < 0.05 for all). Renal function had an independent relationship with CAC detected by HDCT in Chinese elderly men, demonstrating that the relationship between renal function and CAC started at the early stage of renal function decline.

Identification of a conserved branched RNA structure that functions as a factor-independent terminator.

PubMed

Johnson, Christopher M; Chen, Yuqing; Lee, Heejin; Ke, Ailong; Weaver, Keith E; Dunny, Gary M

2014-03-04

Anti-Q is a small RNA encoded on pCF10, an antibiotic resistance plasmid of Enterococcus faecalis, which negatively regulates conjugation of the plasmid. In this study we sought to understand how Anti-Q is generated relative to larger transcripts of the same operon. We found that Anti-Q folds into a branched structure that functions as a factor-independent terminator. In vitro and in vivo, termination is dependent on the integrity of this structure as well as the presence of a 3' polyuridine tract, but is not dependent on other downstream sequences. In vitro, terminated transcripts are released from RNA polymerase after synthesis. In vivo, a mutant with reduced termination efficiency demonstrated loss of tight control of conjugation function. A search of bacterial genomes revealed the presence of sequences that encode Anti-Q-like RNA structures. In vitro and in vivo experiments demonstrated that one of these functions as a terminator. This work reveals a previously unappreciated flexibility in the structure of factor-independent terminators and identifies a mechanism for generation of functional small RNAs; it should also inform annotation of bacterial sequence features, such as terminators, functional sRNAs, and operons.

Identification of a conserved branched RNA structure that functions as a factor-independent terminator

PubMed Central

Johnson, Christopher M.; Chen, Yuqing; Lee, Heejin; Ke, Ailong; Weaver, Keith E.; Dunny, Gary M.

2014-01-01

Anti-Q is a small RNA encoded on pCF10, an antibiotic resistance plasmid of Enterococcus faecalis, which negatively regulates conjugation of the plasmid. In this study we sought to understand how Anti-Q is generated relative to larger transcripts of the same operon. We found that Anti-Q folds into a branched structure that functions as a factor-independent terminator. In vitro and in vivo, termination is dependent on the integrity of this structure as well as the presence of a 3′ polyuridine tract, but is not dependent on other downstream sequences. In vitro, terminated transcripts are released from RNA polymerase after synthesis. In vivo, a mutant with reduced termination efficiency demonstrated loss of tight control of conjugation function. A search of bacterial genomes revealed the presence of sequences that encode Anti-Q–like RNA structures. In vitro and in vivo experiments demonstrated that one of these functions as a terminator. This work reveals a previously unappreciated flexibility in the structure of factor-independent terminators and identifies a mechanism for generation of functional small RNAs; it should also inform annotation of bacterial sequence features, such as terminators, functional sRNAs, and operons. PMID:24550474

The influence of COPD on health-related quality of life independent of the influence of comorbidity.

PubMed

van Manen, Jeannette G; Bindels, Patrick J E; Dekker, Friedo W; Bottema, Bernardus J A M; van der Zee, Jaring S; Ijzermans, C Joris; Schadé, Egbert

2003-12-01

The goal of this study was to determine the influence of chronic obstructive pulmonary disease (COPD) on health-related quality of life (HRQL) independent of comorbidity. Patients with COPD in general practice, >/=40 years, were selected. To recruit controls, a random sample of persons without COPD and >/=40 years, was taken. HRQL was assessed with the SF-36 and comorbidity was determined by questionnaire. The influence of COPD on HRQL independent of comorbidity (represented by adjusted regression coefficients) was significant for physical functioning (-27.6), role functioning due to physical problems (-21.6), vitality (-14.4), and general health (-25.7), and was minor and not significant for social functioning (-5.6), mental health (-1.3), role functioning due to emotional problems (-2.7), and bodily pain (-2.5). Comorbidity contributed significantly to the HRQL of all domains (-7.6 to -27.1). COPD patients can be impaired in all domains of HRQL. However, impairments in physical functioning, vitality, and general health are related to COPD and to some extent to comorbidity, while impairments in social and emotional functioning do not seem to be related to COPD, but only to comorbidity.

Gait speed in older people: an easy test for detecting cognitive impairment, functional independence, and health state.

PubMed

Garcia-Pinillos, Felipe; Cozar-Barba, Manuela; Munoz-Jimenez, Marcos; Soto-Hermoso, Victor; Latorre-Roman, Pedro

2016-05-01

With ageing, physical and cognitive functions become impaired. Analyzing and determining the association between both functions can facilitate the prevention and diagnosis of associated problems. Some previous works have proposed batteries of physical performance tests to determine both physical and cognitive functions. However, only a few studies have used the gait speed (GS) test as a tool to evaluate parameters representative of health in the elderly such as functionality, mobility, independence, autonomy, and comorbidity. Therefore, the aim of this study was to determine the association between physical and cognitive functions in older people (over 65 years old) and to detect the most appropriate physical test to assess cognitive impairment, functional independence, comorbidity, and perceived health in this population. One hundred six older adults (38 men, 68 women) participated voluntarily in this cross-sectional study. To assess the physical function handgrip strength, GS, 30-s chair stand tests, and body composition analysis were performed. To evaluate cognitive function, the Mini-Mental State Examination, Barthel index, and Charlson index were employed. No significant differences (P ≥ 0.05) between sexes were found. Multiple regression analysis of the Mini-Mental State Examination and physical fitness variables, adjusted for age and sex, indicates that GS is a predictor of Mini-Mental State Examination score (R(2) = 0.138). The results showed that GS is an important predictor of functional capacity (physical and cognitive function) in adults over 65 years old. © 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.

Association of serum albumin levels with kidney function decline and incident chronic kidney disease in elders.

PubMed

Lang, Joshua; Katz, Ronit; Ix, Joachim H; Gutierrez, Orlando M; Peralta, Carmen A; Parikh, Chirag R; Satterfield, Suzanne; Petrovic, Snezana; Devarajan, Prasad; Bennett, Michael; Fried, Linda F; Cummings, Steven R; Sarnak, Mark J; Shlipak, Michael G

2018-06-01

Previous studies in HIV-infected individuals have demonstrated serum albumin to be strongly associated with kidney function decline, independent of urine albumin and inflammatory markers. Lower serum albumin concentrations may be an under-appreciated risk factor for kidney function decline in elders. We performed a cohort analysis in the Health Aging and Body Composition Study, a cohort of well-functioning, bi-racial, community-dwelling elders between the age of 70 and 79 years. We examined the associations of serum albumin concentration with longitudinal kidney function decline by estimated glomerular filtration rate (eGFR). Outcomes included linear eGFR decline, rapid kidney function decline defined as >30% decrease in eGFR, defined as a final eGFR <60 mL/min/1.73 m2 in those with an eGFR >60 mL/min/1.73 m2 at baseline. Cystatin C-based eGFR was calculated at baseline, Year 3 and Year 10. Mean age was 74 years, and mean eGFR was 73 mL/min/1.73 m2 at baseline. The mean rate of eGFR change was 1.81 mL/min/1.73 m2 per year. After multivariate adjustment, lower serum albumin concentrations were strongly and independently associated with kidney function decline (-0.11 mL/min/1.73 m2 per year for each standard deviation decrease serum albumin; -0.01 to - 0.20) with no attenuation after adjustment for urine albumin and inflammatory markers (-0.12, -0.03 to - 0.22). When divided into quartiles, serum albumin levels ≤3.80 g/dL were associated with increased odds of rapid kidney function decline (odds ratio 1.59; 1.12-2.26) and increased risk of incident chronic kidney disease (incident rate ratio 1.29; 1.03-1.62) relative to levels >4.21g/dL. Urine albumin to creatinine ratio (ACR) was also significantly and independently associated with kidney function decline (-0.08 mL/min/1.73 m2 per year for urine ACR >30 mg/g; -0.82 to - 0.13). Lower serum albumin levels are strongly and independently associated with kidney function decline in elders, independent of clinical risk factors, urine albumin and measured inflammatory markers.

Increasing Independence in Children with Autism Spectrum Disorders Using Video Self Modeling

ERIC Educational Resources Information Center

Bucalos, Julie Iberer

2013-01-01

Independent task completion was examined using a multiple probe across participants research design for three students with autism spectrum disorders (ASD) functioning in an inclusive classroom. Results were positive and suggest that video self-modeling (VSM) is a viable solution to decrease prompt dependence and increase independence and task…

Optimization of Aimpoints for Coordinate Seeking Weapons

DTIC Science & Technology

2015-09-01

aiming) and independent ( ballistic ) errors are taken into account, before utilizing each of the three damage functions representing the weapon. A Monte...characteristics such as the radius of the circle containing the weapon aimpoint, impact angle, dependent (aiming) and independent ( ballistic ) errors are taken...Dependent (Aiming) Error .................................8 2. Single Weapon Independent ( Ballistic ) Error .............................9 3

F-35 Force Development Evaluation and Weapons School Beddown Environmental Impact Statement

DTIC Science & Technology

2011-05-01

deficiencias encontradas después del despliegue del sistema; ♦ explora medios no materiales (por ejemplo, tácticas) para satisfacer requisitos...del adecuado desempeño del avión en combate al proporcionar entrenamiento, información sobre las capacidades operativas y nuevos requisitos. Además

Age-independent anti-Müllerian hormone (AMH) standard deviation scores to estimate ovarian function.

PubMed

Helden, Josef van; Weiskirchen, Ralf

2017-06-01

To determine single year age-specific anti-Müllerian hormone (AMH) standard deviation scores (SDS) for women associated to normal ovarian function and different ovarian disorders resulting in sub- or infertility. Determination of particular year median and mean AMH values with standard deviations (SD), calculation of age-independent cut off SDS for the discrimination between normal ovarian function and ovarian disorders. Single-year-specific median, mean, and SD values have been evaluated for the Beckman Access AMH immunoassay. While the decrease of both median and mean AMH values is strongly correlated with increasing age, calculated SDS values have been shown to be age independent with the differentiation between normal ovarian function measured as occurred ovulation with sufficient luteal activity compared with hyperandrogenemic cycle disorders or anovulation associated with high AMH values and reduced ovarian activity or insufficiency associated with low AMH, respectively. These results will be helpful for the treatment of patients and the ventilation of the different reproductive options. Copyright © 2017 Elsevier B.V. All rights reserved.

[Development and reliability evaluation of an instrument to measure health-related quality of life in independent elderly].

PubMed

Lima, Maria José Barbosa de; Portela, Margareth Crisóstomo

2010-08-01

This study presents an instrument, the health-related quality of life (HRQOL) profile for independent elderly, to measure the health-related quality of life of the functionally independent elderly assisted in the outpatient setting, based on the adaptation of four validated scales: Short-Form Health Survey (SF-36), Duke-UNC Health Profile (DUHP), Sickness Impact Profile (SIP), and Nottingham Health Profile (NHP). The study also evaluates the instrument's reliability based on its use by two different observers with a 15-day interval. The instrument includes five dimensions (health perception, symptoms, physical function, psychological function, and social function) and 45 items. Reliability evaluation of the QUASI instrument was based on interviews with 142 elderly outpatients in the city of Rio de Janeiro, Brazil. Prevalence-adjusted kappa statistic was used to assess all 45 items. Correlation was also calculated between overall scores and scores on individual dimensions. In the reliability evaluation, 39 of the 45 items showed prevalence-adjusted kappa greater than 0.60.

First Principle Predictions of Isotopic Shifts in H2O

NASA Technical Reports Server (NTRS)

Schwenke, David W.; Kwak, Dochan (Technical Monitor)

2002-01-01

We compute isotope independent first and second order corrections to the Born-Oppenheimer approximation for water and use them to predict isotopic shifts. For the diagonal correction, we use icMRCI wavefunctions and derivatives with respect to mass dependent, internal coordinates to generate the mass independent correction functions. For the non-adiabatic correction, we use scaled SCF/CIS wave functions and a generalization of the Handy method to obtain mass independent correction functions. We find that including the non-adiabatic correction gives significantly improved results compared to just including the diagonal correction when the Born-Oppenheimer potential energy surface is optimized for H2O-16. The agreement with experimental results for deuterium and tritium containing isotopes is nearly as good as our best empirical correction, however, the present correction is expected to be more reliable for higher, uncharacterized levels.

Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing

PubMed Central

Gibson, Jane; Wang, Jun; Walewska, Renata; Parker, Helen; Parker, Anton; Davis, Zadie; Gardiner, Anne; McIver-Brown, Neil; Kalpadakis, Christina; Xochelli, Aliki; Anagnostopoulos, Achilles; Fazi, Claudia; de Castro, David Gonzalez; Dearden, Claire; Pratt, Guy; Rosenquist, Richard; Ashton-Key, Margaret; Forconi, Francesco; Collins, Andrew; Ghia, Paolo; Matutes, Estella; Pangalis, Gerassimos; Stamatopoulos, Kostas; Oscier, David; Strefford, Jonathan C

2015-01-01

Purpose Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted re-sequencing and explored potential clinical implications in a multinational cohort of 175 SMZL patients. Results We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%) and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time-to-first-treatment (0.12 vs. 1.11 yrs; P=0.01). In multivariate analysis mutations in NOTCH2 (HR 2.12, 95%CI 1.02-4.4, P=0.044) and 100% germline IGHV gene identity (HR 2.19, 95%CI 1.05-4.55, P=0.036) were independent markers of short time-to-first-treatment, while TP53 mutations were an independent marker of short overall survival (HR 2.36, 95% CI 1.08-5.2, P=0.03). Conclusion We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively. PMID:25779943

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

PubMed Central

McGraw, K L; Zhang, L M; Rollison, D E; Basiorka, A A; Fulp, W; Rawal, B; Jerez, A; Billingsley, D L; Lin, H-Y; Kurtin, S E; Yoder, S; Zhang, Y; Guinta, K; Mallo, M; Solé, F; Calasanz, M J; Cervera, J; Such, E; González, T; Nevill, T J; Haferlach, T; Smith, A E; Kulasekararaj, A; Mufti, G; Karsan, A; Maciejewski, J P; Sokol, L; Epling-Burnette, P K; Wei, S; List, A F

2015-01-01

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis. PMID:25768405

PubMed

Martínez Carrión, José Miguel; Cámara, Antonio D; Pérez-Castroviejo, Pedro María

2016-12-12

Objetivo: analizar la geografía del estado nutricional en España y su evolución entre mediados del siglo xixy comienzos del siglo xx, etapa previa a la transición nutricional con alta prevalencia de malnutrición.Métodos: se utilizan datos antropométricos agregados (promedios provinciales de estatura) del reclutamiento militar en 1858 y 1913, así como promedios provinciales de estatura y peso procedentes de una revisión realizada entre 119.571 soldados en 1903-1906. Con estos datos se elaboran cartografía y estadísticos descriptivos.Resultados: los parámetros antropométricos de los españoles se situaban entre los valores de complexión más bajos de Europa antes de la transición nutricional. Entre 1858 y 1913, la altura media creció solo 1,43 cm. En ese periodo hubo cambios significativos en la geografía antropométrica marcados por la configuración de una polaridad nutricional a las puertas de la I Guerra Mundial: las provincias del centro y del sur de país exhiben mayor incidencia de la malnutrición crónica que las provincias del arco Noreste, que disfrutan de ventaja relativa en términos nutricionales.Conclusión:las desigualdades territoriales que configuraron una geografía polarizada del estado nutricional en España pueden asociarse en parte a los cambios ambientales del periodo, caracterizados por el inicio de la modernización y la industrialización y, asimismo, por la privación derivada de las crisis agrarias, las enfermedades y el relativo atraso tecnológico. Se destaca la relevancia de la historia antropométrica para el estudio de los niveles de vida en poblaciones del pasado y del proceso de transición nutricional.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.

PubMed

Dusatkova, Petra; Pfäffle, Roland; Brown, Milton R; Akulevich, Natallia; Arnhold, Ivo J P; Kalina, Maria A; Kot, Karolina; Krzisnik, Ciril; Lemos, Manuel C; Malikova, Jana; Navardauskaite, Ruta; Obermannova, Barbora; Pribilincova, Zuzana; Sallai, Agnes; Stipancic, Gordana; Verkauskiene, Rasa; Cinek, Ondrej; Blum, Werner F; Parks, John S; Austerlitz, Frederic; Lebl, Jan

2016-03-01

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations

PubMed Central

Dusatkova, Petra; Pfäffle, Roland; Brown, Milton R; Akulevich, Natallia; Arnhold, Ivo JP; Kalina, Maria A; Kot, Karolina; Krzisnik, Ciril; Lemos, Manuel C; Malikova, Jana; Navardauskaite, Ruta; Obermannova, Barbora; Pribilincova, Zuzana; Sallai, Agnes; Stipancic, Gordana; Verkauskiene, Rasa; Cinek, Ondrej; Blum, Werner F; Parks, John S; Austerlitz, Frederic; Lebl, Jan

2016-01-01

Two variants (c.[301_302delAG][301_302delAG] and c.[150delA][150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG][301_302delAG] or c.[150delA][150delA] or c.[301_302delAG][ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations – a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants – c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1–116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1–29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2–17.0) and 16.4 (14.4–20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4–52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants. PMID:26059845

La utilizacion de los mapas conceptuales en la ensenanza de biologia y su efecto sobre el dominio del proceso de fotosintesis en los estudiantes universitarios

NASA Astrophysics Data System (ADS)

Gonzalez Rivera, Maria M.

Se investigo el efecto de los mapas conceptuales sobre el dominio del proceso de fotosintesis en estudiantes universitarios. La investigacion utilizo dos estrategias: mapas conceptuales individuales y mapas conceptuales colaborativos, con el fin de investigar si existen diferencias significativas en el dominio del proceso de fotosintesis. El analisis de los datos incluyo aspectos cualitativos y cuantitativos. Se desprende del estudio que el 80% de los estudiantes describen la utilizacion de los mapas conceptuales como una experiencia beneficiosa. El 70% de los estudiantes expreso que los mapas conceptuales son utiles en el aprendizaje del proceso de fotosintesis y el 61% indico que facilitan la comprension de los conceptos. Los hallazgos mas importantes del analisis cuantitativo indican que los estudiantes que utilizaron los mapas conceptuales mejoraron significativamente su desempeno en la posprueba global. Se utilizo la prueba Mann-Whitney para investigar si existian diferencias significativas en la posprueba y preprueba global, el valor de W = 1945.0, para un valor p de 0.00, lo cual establece diferencias significativas. Para determinar si existian diferencias significativas entre la posprueba y preprueba del grupo individual, se realizo la prueba nuevamente. El valor de W correspondio a 490.5, que es significativo, con un valor p de 0.00. Se concluye que existen diferencias significativas entre la ejecucion de la posprueba y preprueba del grupo individual. Los datos proveen suficiente evidencia para sostener que los estudiantes que utilizaron la estrategia de mapas conceptuales individuales mejoraron el dominio del proceso de fotosintesis significativamente. Se realizo nuevamente la prueba para los resultados de posprueba y preprueba del grupo colaborativo. El valor de W correspondio a 446 con un valor p de 0.00. Se concluyo que existen diferencias significativas entre la ejecucion de la posprueba y preprueba del grupo colaborativo. Finalmente, se efectuo una prueba Mann-Whitney comparando la posprueba de ambos grupos. El valor de W fue de a 777, para un valor p de 0.2782. Aunque las puntuaciones de las pospruebas del grupo colaborativo fueron mayores que las puntuaciones de la posprueba del grupo individual, la diferencia no fue estadisticamente significativa.

Development of a grid-independent approximate Riemannsolver. Ph.D. Thesis - Michigan Univ.

NASA Technical Reports Server (NTRS)

Rumsey, Christopher Lockwood

1991-01-01

A grid-independent approximate Riemann solver for use with the Euler and Navier-Stokes equations was introduced and explored. The two-dimensional Euler and Navier-Stokes equations are described in Cartesian and generalized coordinates, as well as the traveling wave form of the Euler equations. The spatial and temporal discretization are described for both explicit and implicit time-marching schemes. The grid-aligned flux function of Roe is outlined, while the 5-wave grid-independent flux function is derived. The stability and monotonicity analysis of the 5-wave model are presented. Two-dimensional results are provided and extended to three dimensions. The corresponding results are presented.

Association of methylenetetrahydrofolate reductase (MTHFR 677C>T) and thymidylate synthase (TSER and TS 1494del6) polymorphisms with premature ovarian failure in Korean women.

PubMed

Rah, HyungChul; Jeon, Young Joo; Choi, Youngsok; Shim, Sung Han; Yoon, Tae Ki; Choi, Dong Hee; Cha, Sun Hee; Kim, Nam Keun

2012-11-01

The aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C>T) and thymidylate synthase (TS) gene variants (TS enhancer region [TSER] and TS 1494del6) confer a risk for premature ovarian failure (POF). We genotyped 136 POF patients and 236 controls among Korean women for the three single nucleotide polymorphism sites using polymerase chain reaction restriction fragment length polymorphism analysis. Differences in the MTHFR 677C>T, TSER, and TS 1494del6 genotype frequencies between POF patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as a measure of the strength of the association between genotypes and POF. The MTHFR 677CT and CT + TT variant genotypes were more frequent in POF patients than in controls (OR, 2.249; 95% CI, 1.317-3.843; and OR, 2.132; 95% CI, 1.268-3.585, respectively). The combined genotype frequencies of MTHFR 677CT + TT/TSER 3R3R and 677CT + TT/TS 1494del6 del6/del6 were higher in patients than in controls (OR, 2.300; 95% CI, 1.219-4.337; and OR, 3.314; 95% CI, 1.623-6.767, respectively). The T-3R-del6 and T-2R-del6 (MTHFR 677C>T/TSER/TS 1494del6) haplotypes were more frequent in patients (OR, 1.450; 95% CI, 1.050-2.002; and OR, 2.911; 95% CI, 1.191-7.117, respectively), whereas the C-2R-del6 haplotype was less frequent in patients (OR, 0.372; 95% CI, 0.152-0.912). The T-del6 (MTHFR 677/TS 1494del6) haplotype frequency was higher among patients (OR, 1.653; 95% CI, 1.206-2.266), whereas the C-del6 haplotype frequency was lower among patients (OR, 0.700; 95% CI, 0.516-0.950). We did not find an association between TSER or TS 1494del6 polymorphisms and POF. Our data suggest that the MTHFR 677T allele may increase the risk for POF, which could lead to the development of novel genetic markers for predicting the risk of POF in patients.

[A study of factors related to activities of daily living (ADL) of the elderly receiving in-home service longitudinal study using functional independence measures].

PubMed

Suzuki, Ikuko; Yanagi, Hisako; Tomura, Shigeo

2007-02-01

We conducted a longitudinal study using Functional Independence Measures to clarify factor related to independence of activities of daily living of elderly receiving in-home service under the long-term care insurance system Fifty-four elderly users of the in-home service of Ibaraki Prefecture assented to participate in this study and were analyzed. A researcher conducted survey at the baseline and after follow-up by visiting the elderly at each home. The evaluation standards used here were the Japanese version of Functional Independence Measure (FIM), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS-15). The FIM score (mean+/-SD) was decreased 83.6+/-36.4 to 81.7+/-37.4 during the 112+/-22.2 day follow up period. Thirty-nine elderly demonstrated improvement or no change in FIM and 15 had declining scores. To clarify independent factors related to FIM change, we conducted a step-wise multifactor logistic regression analysis, and the results suggested importance for "in-home service availability" and "home care period less than one year". Our study suggested that it is important for maintenance or improvement of ADL in home care elderly to provide sufficient home .care services from the beginning under the long-term care insurance system.

Erosion of functional independence early in the evolution of a microbial mutualism

PubMed Central

Hillesland, Kristina L.; Lim, Sujung; Flowers, Jason J.; Turkarslan, Serdar; Pinel, Nicolas; Zane, Grant M.; Elliott, Nicholas; Qin, Yujia; Wu, Liyou; Baliga, Nitin S.; Zhou, Jizhong; Wall, Judy D.; Stahl, David A.

2014-01-01

Many species have evolved to function as specialized mutualists, often to the detriment of their ability to survive independently. However, there are few, if any, well-controlled observations of the evolutionary processes underlying the genesis of new mutualisms. Here, we show that within the first 1,000 generations of initiating independent syntrophic interactions between a sulfate reducer (Desulfovibrio vulgaris) and a hydrogenotrophic methanogen (Methanococcus maripaludis), D. vulgaris frequently lost the capacity to grow by sulfate respiration, thus losing the primary physiological attribute of the genus. The loss of sulfate respiration was a consequence of mutations in one or more of three key genes in the pathway for sulfate respiration, required for sulfate activation (sat) and sulfate reduction to sulfite (apsA or apsB). Because loss-of-function mutations arose rapidly and independently in replicated experiments, and because these mutations were correlated with enhanced growth rate and productivity, gene loss could be attributed to natural selection, even though these mutations should significantly restrict the independence of the evolved D. vulgaris. Together, these data present an empirical demonstration that specialization for a mutualistic interaction can evolve by natural selection shortly after its origin. They also demonstrate that a sulfate-reducing bacterium can readily evolve to become a specialized syntroph, a situation that may have often occurred in nature. PMID:25267659

A Unimodal Model for Double Observer Distance Sampling Surveys.

PubMed

Becker, Earl F; Christ, Aaron M

2015-01-01

Distance sampling is a widely used method to estimate animal population size. Most distance sampling models utilize a monotonically decreasing detection function such as a half-normal. Recent advances in distance sampling modeling allow for the incorporation of covariates into the distance model, and the elimination of the assumption of perfect detection at some fixed distance (usually the transect line) with the use of double-observer models. The assumption of full observer independence in the double-observer model is problematic, but can be addressed by using the point independence assumption which assumes there is one distance, the apex of the detection function, where the 2 observers are assumed independent. Aerially collected distance sampling data can have a unimodal shape and have been successfully modeled with a gamma detection function. Covariates in gamma detection models cause the apex of detection to shift depending upon covariate levels, making this model incompatible with the point independence assumption when using double-observer data. This paper reports a unimodal detection model based on a two-piece normal distribution that allows covariates, has only one apex, and is consistent with the point independence assumption when double-observer data are utilized. An aerial line-transect survey of black bears in Alaska illustrate how this method can be applied.

Normative functional fitness standards and trends of Portuguese older adults: cross-cultural comparisons.

PubMed

Marques, Elisa A; Baptista, Fátima; Santos, Rute; Vale, Susana; Santos, Diana A; Silva, Analiza M; Mota, Jorge; Sardinha, Luís B

2014-01-01

This cross-sectional study was designed to develop normative functional fitness standards for the Portuguese older adults, to analyze age and gender patterns of decline, to compare the fitness level of Portuguese older adults with that of older adults in other countries, and to evaluate the fitness level of Portuguese older adults relative to recently published criterion fitness standards associated with maintaining physical independence. A sample of 4,712 independent-living older adults, age 65-103 yr, was evaluated using the Senior Fitness Test battery. Age-group normative fitness scores are reported for the 10th, 25th, 50th, 75th, and 90th percentiles. Results indicate that both women and men experience age-related losses in all components of functional fitness, with their rate of decline being greater than that observed in other populations, a trend which may cause Portuguese older adults to be at greater risk for loss of independence in later years. These newly established normative standards make it possible to assess individual fitness level and provide a basis for implementing population-wide health strategies to counteract early loss of independence.

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

PubMed Central

Myrick, Leila K.; Deng, Pan-Yue; Hashimoto, Hideharu; Oh, Young Mi; Cho, Yongcheol; Poidevin, Mickael J.; Suhl, Joshua A.; Visootsak, Jeannie; Cavalli, Valeria; Jin, Peng; Cheng, Xiaodong; Warren, Stephen T.; Klyachko, Vitaly A.

2015-01-01

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP’s canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP’s interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes. PMID:25561520

Structural and functional correlates of hypnotic depth and suggestibility.

PubMed

McGeown, William Jonathan; Mazzoni, Giuliana; Vannucci, Manila; Venneri, Annalena

2015-02-28

This study explores whether self-reported depth of hypnosis and hypnotic suggestibility are associated with individual differences in neuroanatomy and/or levels of functional connectivity. Twenty-nine people varying in suggestibility were recruited and underwent structural, and after a hypnotic induction, functional magnetic resonance imaging at rest. We used voxel-based morphometry to assess the correlation of grey matter (GM) and white matter (WM) against the independent variables: depth of hypnosis, level of relaxation and hypnotic suggestibility. Functional networks identified with independent components analysis were regressed with the independent variables. Hypnotic depth ratings were positively correlated with GM volume in the frontal cortex and the anterior cingulate cortex (ACC). Hypnotic suggestibility was positively correlated with GM volume in the left temporal-occipital cortex. Relaxation ratings did not correlate significantly with GM volume and none of the independent variables correlated with regional WM volume measures. Self-reported deeper levels of hypnosis were associated with less connectivity within the anterior default mode network. Taken together, the results suggest that the greater GM volume in the medial frontal cortex and ACC, and lower connectivity in the DMN during hypnosis facilitate experiences of greater hypnotic depth. The patterns of results suggest that hypnotic depth and hypnotic suggestibility should not be considered synonyms. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

N-terminal pro-brain natriuretic peptide and abnormal brain aging: The AGES-Reykjavik Study.

PubMed

Sabayan, Behnam; van Buchem, Mark A; de Craen, Anton J M; Sigurdsson, Sigurdur; Zhang, Qian; Harris, Tamara B; Gudnason, Vilmundur; Arai, Andrew E; Launer, Lenore J

2015-09-01

To investigate the independent association of serum N-terminal fragment of the prohormone natriuretic peptide (NT-proBNP) with structural and functional features of abnormal brain aging in older individuals. In this cross-sectional study based on the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we included 4,029 older community-dwelling individuals (born 1907 to 1935) with a measured serum level of NT-proBNP. Outcomes included parenchymal brain volumes estimated from brain MRI, cognitive function measured by tests of memory, processing speed, and executive functioning, and presence of depressive symptoms measured using the Geriatric Depression Scale. In a substudy, cardiac output of 857 participants was assessed using cardiac MRI. In multivariate analyses, adjusted for sociodemographic and cardiovascular factors, higher levels of NT-proBNP were independently associated with lower total (p < 0.001), gray matter (p < 0.001), and white matter (p = 0.001) brain volumes. Likewise, in multivariate analyses, higher levels of NT-proBNP were associated with worse scores in memory (p = 0.005), processing speed (p = 0.001), executive functioning (p < 0.001), and more depressive symptoms (p = 0.002). In the substudy, the associations of higher NT-proBNP with lower brain parenchymal volumes, impaired executive function and processing speed, and higher depressive symptoms were independent of the level of cardiac output. Higher serum levels of NT-proBNP, independent of cardiovascular risk factors and a measure of cardiac function, are linked with alterations in brain structure and function. Roles of natriuretic peptides in the process of brain aging need to be further elucidated. © 2015 American Academy of Neurology.

Functional Gain After Inpatient Stroke Rehabilitation: Correlates and Impact on Long-Term Survival.

PubMed

Scrutinio, Domenico; Monitillo, Vincenzo; Guida, Pietro; Nardulli, Roberto; Multari, Vincenzo; Monitillo, Francesco; Calabrese, Gianluigi; Fiore, Pietro

2015-10-01

Prediction of functional outcome after stroke rehabilitation (SR) is a growing field of interest. The association between SR and survival still remains elusive. We sought to investigate the factors associated with functional outcome after SR and whether the magnitude of functional improvement achieved with rehabilitation is associated with long-term mortality risk. The study population consisted of 722 patients admitted for SR within 90 days of stroke onset, with an admission functional independence measure (FIM) score of <80 points. We used univariable and multivariable linear regression analyses to assess the association between baseline variables and FIM gain and univariable and multivariable Cox analyses to assess the association of FIM gain with long-term mortality. Age (P<0.001), marital status (P=0.003), time from stroke onset to rehabilitation admission (P<0.001), National Institutes of Health Stroke Scale score at rehabilitation admission (P<0.001), and aphasia (P=0.021) were independently associated with FIM gain. The R2 of the model was 0.275. During a median follow-up of 6.17 years, 36.9% of the patients died. At multivariable Cox analysis, age (P<0.0001), coronary heart disease (P=0.018), atrial fibrillation (P=0.042), total cholesterol (P=0.015), and total FIM gain (P<0.0001) were independently associated with mortality. The adjusted hazard ratio for death significantly decreased across tertiles of increasing FIM gain. Several factors are independently associated with functional gain after SR. Our findings strongly suggest that the magnitude of functional improvement is a powerful predictor of long-term mortality in patients admitted for SR. © 2015 American Heart Association, Inc.

18 CFR 358.5 - Independent functioning rule.

Code of Federal Regulations, 2010 CFR

2010-04-01

... its marketing function employees. (b) Separation of functions. (1) A transmission provider is prohibited from permitting its marketing function employees to: (i) Conduct transmission functions; or (ii... differs in any way from the access available to other transmission customers. (2) A transmission provider...

Recent advances on the encoding and selection methods of DNA-encoded chemical library.

PubMed

Shi, Bingbing; Zhou, Yu; Huang, Yiran; Zhang, Jianfu; Li, Xiaoyu

2017-02-01

DNA-encoded chemical library (DEL) has emerged as a powerful and versatile tool for ligand discovery in chemical biology research and in drug discovery. Encoding and selection methods are two of the most important technological aspects of DEL that can dictate the performance and utilities of DELs. In this digest, we have summarized recent advances on the encoding and selection strategies of DEL and also discussed the latest developments on DNA-encoded dynamic library, a new frontier in DEL research. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Impact of Multiple Concussions on Emotional Distress, Post-Concussive Symptoms, and Neurocognitive Functioning in Active Duty United States Marines Independent of Combat Exposure or Emotional Distress

PubMed Central

Lathan, Corinna E.; Bleiberg, Joseph; Tsao, Jack W.

2014-01-01

Abstract Controversy exists as to whether the lingering effects of concussion on emotional, physical, and cognitive symptoms is because of the effects of brain trauma or purely to emotional factors such as post-traumatic stress disorder or depression. This study examines the independent effects of concussion on persistent symptoms. The Defense Automated Neurobehavioral Assessment, a clinical decision support tool, was used to assess neurobehavioral functioning in 646 United States Marines, all of whom were fit for duty. Marines were assessed for concussion history, post-concussive symptoms, emotional distress, neurocognitive functioning, and deployment history. Results showed that a recent concussion or ever having experienced a concussion was associated with an increase in emotional distress, but not with persistent post-concussive symptoms (PPCS) or neurocognitive functioning. Having had multiple lifetime concussions, however, was associated with greater emotional distress, PPCS, and reduced neurocognitive functioning that needs attention and rapid discrimination, but not for memory-based tasks. These results are independent of deployment history, combat exposure, and symptoms of post-traumatic stress disorder and depression. Results supported earlier findings that a previous concussion is not generally associated with post-concussive symptoms independent of covariates. In contrast with other studies that failed to find a unique contribution for concussion to PPCS, however, evidence of recent and multiple concussion was seen across a range of emotional distress, post-concussive symptoms, and neurocognitive functioning in this study population. Results are discussed in terms of implications for assessing concussion on return from combat. PMID:25003552

Functional Capacity in Adults With Cerebral Palsy: Lower Limb Muscle Strength Matters.

PubMed

Gillett, Jarred G; Lichtwark, Glen A; Boyd, Roslyn N; Barber, Lee A

2018-05-01

To investigate the relation between lower limb muscle strength, passive muscle properties, and functional capacity outcomes in adults with cerebral palsy (CP). Cross-sectional study. Tertiary institution biomechanics laboratory. Adults with spastic-type CP (N=33; mean age, 25y; range, 15-51y; mean body mass, 70.15±21.35kg) who were either Gross Motor Function Classification System (GMFCS) level I (n=20) or level II (n=13). Not applicable. Six-minute walk test (6MWT) distance (m), lateral step-up (LSU) test performance (total repetitions), timed up-stairs (TUS) performance (s), maximum voluntary isometric strength of plantar flexors (PF) and dorsiflexors (DF) (Nm.kg -1 ), and passive ankle joint and muscle stiffness. Maximum isometric PF strength independently explained 61% of variance in 6MWT performance, 57% of variance in LSU test performance, and 50% of variance in TUS test performance. GMFCS level was significantly and independently related to all 3 functional capacity outcomes, and age was retained as a significant independent predictor of LSU and TUS test performance. Passive medial gastrocnemius muscle fascicle stiffness and ankle joint stiffness were not significantly related to functional capacity measures in any of the multiple regression models. Low isometric PF strength was the most important independent variable related to distance walked on the 6MWT, fewer repetitions on the LSU test, and slower TUS test performance. These findings suggest lower isometric muscle strength contributes to the decline in functional capacity in adults with CP. Copyright © 2018 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Association of Leukoaraiosis With Convalescent Rehabilitation Outcome in Patients With Ischemic Stroke.

PubMed

Senda, Joe; Ito, Keiichi; Kotake, Tomomitsu; Kanamori, Masahiko; Kishimoto, Hideo; Kadono, Izumi; Suzuki, Yoshiro; Katsuno, Masahisa; Nishida, Yoshihiro; Ishiguro, Naoki; Sobue, Gen

2016-01-01

We investigated the factors influencing inpatient convalescent rehabilitation outcomes in patients with ischemic stroke, particularly severity of leukoaraiosis on magnetic resonance imaging. Participants included 520 patients with ischemic stroke (317 men and 203 women; mean age, 72.8±8.4 years) who were transferred from acute care hospitals for inpatient convalescent rehabilitation. Ischemic stroke subtypes included lacunar infarction (n=41), atherothrombosis (n=223), artery-to-artery embolism (n=67), cardiogenic embolism (n=97), undetermined embolism (n=76), and uncategorized ischemic stroke (n=16). Leukoaraiosis was graded according to periventricular hyperintensity (PVH) and deep white matter hyperintensity on magnetic resonance imaging. Functional Independence Measure scores were assessed on admission and at discharge. Multiple regression analysis revealed that rehabilitation outcomes, measured as total Functional Independence Measure scores, were significantly associated with leukoaraiosis estimated by PVH grade. This association was observed after adjustment for factors such as severity, age, and poststroke history. In all patients, PVH grades were associated with Functional Independence Measure motor scores (P<0.001), whereas in patients with artery-to-artery embolism or cardiogenic embolism and deep white matter hyperintensity grades were associated with Functional Independence Measure cognitive scores (P<0.05). Our study revealed that the degree of leukoaraiosis was associated with inpatient convalescent rehabilitation outcome in patients with ischemic stroke. Furthermore, the PVH grade was associated with motor function outcome, whereas the deep white matter hyperintensity grade correlated with cognitive function outcome, likely because the progression patterns and anatomic backgrounds of PVH and deep white matter hyperintensity differ according to ischemic stroke subtype. © 2015 American Heart Association, Inc.

Cognitive and physical functions related to the level of supervision and dependence in the toileting of stroke patients.

PubMed

Sato, Atsushi; Okuda, Yutaka; Fujita, Takaaki; Kimura, Norihiko; Hoshina, Noriyuki; Kato, Sayaka; Tanaka, Shigenari

2016-01-01

This study aimed to clarify which cognitive and physical factors are associated with the need for toileting assistance in stroke patients and to calculate cut-off values for discriminating between independent supervision and dependent toileting ability. This cross-sectional study included 163 first-stroke patients in nine convalescent rehabilitation wards. Based on their FIM Ⓡ instrument score for toileting, the patients were divided into an independent-supervision group and a dependent group. Multiple logistic regression analysis and receiver operating characteristic analysis were performed to identify factors related to toileting performance. The Minimental State Examination (MMSE); the Stroke Impairment Assessment Set (SIAS) score for the affected lower limb, speech, and visuospatial functions; and the Functional Assessment for Control of Trunk (FACT) were analyzed as independent variables. The multiple logistic regression analysis showed that the FIM Ⓡ instrument score for toileting was associated with the SIAS score for the affected lower limb function, MMSE, and FACT. On receiver operating characteristic analysis, the SIAS score for the affected lower limb function cut-off value was 8/7 points, the MMSE cut-off value was 25/24 points, and the FACT cut-off value was 14/13 points. Affected lower limb function, cognitive function, and trunk function were related with the need for toileting assistance. These cut-off values may be useful for judging whether toileting assistance is needed in stroke patients.

Study on changes in cognitive function of elderly individuals certified for long-term care insurance.

PubMed

Horiguchi, Minako; Kokubu, Keiko; Mori, Toru

2017-01-01

Objectives　To elucidate the changes in cognitive function in elderly individuals as observed in the results of a long-term care certification survey.Methods　The data were obtained from the long-term care insurance of 121 subjects who applied for benefit renewal between 2010 and 2011, in a city in Japan. The subjects were grouped into one of three groups (improved, maintained, or worsened) according to the change in status of overall cognitive function. Analyses were completed with this grouping as the main dependent variable and with sex, age, degree of independence at the initial insurance application in 2006, and levels of seven categories of cognitive function as independent variables.Results　There was a statistically significant association between age and deterioration of various cognitive functions. Sex had no significant effect on the rate of deterioration. The initial degree of independence was positively associated with the cognitive function change. Multivariate analysis (logistic regression analysis) incorporating age, sex, and initial degree of dependence as independent variables revealed that sex does not significantly influence the prognosis of cognitive function. Changes in the score of each of the seven cognitive functions were analyzed with ANOVA, with categories of functions and individuals as sources of variance. Both function category and individuals were significantly associated with deterioration. Among the seven categories of functions, "understanding daily activities" had the greatest deterioration, while "calling him/herself by his/her own name" had the least.Conclusion　Cognitive function, as observed in the long-term care certification survey, is more likely to deteriorate in elderly individuals and in those who were at higher levels of dependency index at the time of initial certification, and this effect is observed equally in men and women. Our results suggest that, in providing long-term care for elderly people, it may be useful to call the clients by their names and ask them to name themselves, as well as to try to improve their understanding regarding the daily activities by articulating the components of each activity.

Additional Saturday rehabilitation improves functional independence and quality of life and reduces length of stay: a randomized controlled trial

PubMed Central

2013-01-01

Background Many inpatients receive little or no rehabilitation on weekends. Our aim was to determine what effect providing additional Saturday rehabilitation during inpatient rehabilitation had on functional independence, quality of life and length of stay compared to 5 days per week of rehabilitation. Methods This was a multicenter, single-blind (assessors) randomized controlled trial with concealed allocation and 12-month follow-up conducted in two publically funded metropolitan inpatient rehabilitation facilities in Melbourne, Australia. Patients were eligible if they were adults (aged ≥18 years) admitted for rehabilitation for any orthopedic, neurological or other disabling conditions excluding those admitted for slow stream rehabilitation/geriatric evaluation and management. Participants were randomly allocated to usual care Monday to Friday rehabilitation (control) or to Monday to Saturday rehabilitation (intervention). The additional Saturday rehabilitation comprised physiotherapy and occupational therapy. The primary outcomes were functional independence (functional independence measure (FIM); measured on an 18 to 126 point scale), health-related quality of life (EQ-5D utility index; measured on a 0 to 1 scale, and EQ-5D visual analog scale; measured on a 0 to 100 scale), and patient length of stay. Outcome measures were assessed on admission, discharge (primary endpoint), and at 6 and 12 months post discharge. Results We randomly assigned 996 adults (mean (SD) age 74 (13) years) to Monday to Saturday rehabilitation (n = 496) or usual care Monday to Friday rehabilitation (n = 500). Relative to admission scores, intervention group participants had higher functional independence (mean difference (MD) 2.3, 95% confidence interval (CI) 0.5 to 4.1, P = 0.01) and health-related quality of life (MD 0.04, 95% CI 0.01 to 0.07, P = 0.009) on discharge and may have had a shorter length of stay by 2 days (95% CI 0 to 4, P = 0.1) when compared to control group participants. Intervention group participants were 17% more likely to have achieved a clinically significant change in functional independence of 22 FIM points or more (risk ratio (RR) 1.17, 95% CI 1.03 to 1.34) and 18% more likely to have achieved a clinically significant change in health-related quality of life (RR 1.18, 95% CI 1.04 to 1.34) on discharge compared to the control group. There was some maintenance of effect for functional independence and health-related quality of life at 6-month follow-up but not at 12-month follow-up. There was no difference in the number of adverse events between the groups (incidence rate ratio = 0.81, 95% CI 0.61 to 1.08). Conclusions Providing an additional day of rehabilitation improved functional independence and health-related quality of life at discharge and may have reduced length of stay for patients receiving inpatient rehabilitation. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12609000973213 Please see related commentary: http://www.biomedcentral.com/10.1186/1741-7015-11-199. PMID:24228854

Using the iPod to Teach Freedom and Independence

ERIC Educational Resources Information Center

Schmitz, Mike

2010-01-01

Technology is making it easier for people with disabilities to function independently in their homes, workplaces, schools, and communities. Things that were once thought impossible are now possible with the aid of new tools available to assist in the transition toward independent living. None have had as big an impact as the iPod Touch. When most…

CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

PubMed Central

Huijts, Petra EA; Hollestelle, Antoinette; Balliu, Brunilda; Houwing-Duistermaat, Jeanine J; Meijers, Caro M; Blom, Jannet C; Ozturk, Bahar; Krol-Warmerdam, Elly MM; Wijnen, Juul; Berns, Els MJJ; Martens, John WM; Seynaeve, Caroline; Kiemeney, Lambertus A; van der Heijden, Henricus F; Tollenaar, Rob AEM; Devilee, Peter; van Asperen, Christi J

2014-01-01

The 1100delC mutation in the CHEK2 gene has a carrier frequency of up to 1.5% in individuals from North-West Europe. Women heterozygous for 1100delC have an increased breast cancer risk (odds ratio 2.7). To explore the prevalence and clinical consequences of 1100delC homozygosity in the Netherlands, we genotyped a sporadic breast cancer hospital-based cohort, a group of non-BRCA1/2 breast cancer families, and breast tumors from a tumor tissue bank. Three 1100delC homozygous patients were found in the cohort of 1434 sporadic breast cancer patients, suggesting an increased breast cancer risk for 1100delC homozygotes (odds ratio 3.4, 95% confidence interval 0.4–32.6, P=0.3). Another 1100delC homozygote was found in 592 individuals from 108 non-BRCA1/2 breast cancer families, and two more were found after testing 1706 breast tumors and confirming homozygosity on their wild-type DNA. Follow-up data was available for five homozygous patients, and remarkably, three of them had developed contralateral breast cancer. A possible relationship between 1100delC and lung cancer risk was investigated in 457 unrelated lung cancer patients but could not be confirmed. Due to the small number of 1100delC homozygotes identified, the breast cancer risk estimate associated with this genotype had limited accuracy but is probably higher than the risk in heterozygous females. Screening for CHEK2 1100delC could be beneficial in countries with a relatively high allele frequency. PMID:23652375

The -2549 insertion/deletion polymorphism in the promoter region of VEGF is associated with the risk of recurrent spontaneous abortion.

PubMed

Hashemi, Mohammad; Danesh, Hiva; Bizhani, Fatemeh; Mokhtari, Mojgan; Bahari, Gholamreza; Tabasi, Farhad; Taheri, Mohsen

2018-03-01

Recurrent spontaneous abortion (RSA) is a common health problem affecting women of reproductive age. Altered expression of vascular endothelial growth factor ( VEGF ) has been associated with spontaneous abortion. The present case-control study aimed to evaluate the impact of the 18-bp insertion/deletion (ins/del) polymorphism (rs35569394) in the promoter region of the VEGF gene on idiopathic RSA. Genomic DNA from 93 patients with RSA and 93 healthy fertile women of southeastern Iran was isolated using the salting-out method. Genotyping of the rs35569394 variant was performed by a polymerase chain reaction (PCR) method. The findings indicated that the VEGF 18-bp ins/del variant significantly increased the risk of RSA under codominant (ins/ins vs. del/del; OR=2.85, 95% CI=1.31-6.22, P=0.019), dominant (del/ins+ins/ins vs. del/del; OR=2.19, 95% CI=1.20-4.01, P=0.015) and allelic (ins vs. del; OR=1.90, 95% CI=1.25-2.88, P=0.003) inheritance models. In summary, the findings propose a significant association between the VEGF 18-bp ins/del polymorphism and risk of RSA in a sample of the southeast Iranian population. Further studies on larger sample sizes and different ethnicities are required to validate the present findings.

Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes.

PubMed

Nagel, Jord H A; Peeters, Justine K; Smid, Marcel; Sieuwerts, Anieta M; Wasielewski, Marijke; de Weerd, Vanja; Trapman-Jansen, Anita M A C; van den Ouweland, Ans; Brüggenwirth, Hennie; van I Jcken, Wilfred F J; Klijn, Jan G M; van der Spek, Peter J; Foekens, John A; Martens, John W M; Schutte, Mieke; Meijers-Heijboer, Hanne

2012-04-01

CHEK2 1100delC is a moderate-risk cancer susceptibility allele that confers a high breast cancer risk in a polygenic setting. Gene expression profiling of CHEK2 1100delC breast cancers may reveal clues to the nature of the polygenic CHEK2 model and its genes involved. Here, we report global gene expression profiles of a cohort of 155 familial breast cancers, including 26 CHEK2 1100delC mutant tumors. In line with previous work, all CHEK2 1100delC mutant tumors clustered among the hormone receptor-positive breast cancers. In the hormone receptor-positive subset, a 40-gene CHEK2 signature was subsequently defined that significantly associated with CHEK2 1100delC breast cancers. The identification of a CHEK2 gene signature implies an unexpected biological homogeneity among the CHEK2 1100delC breast cancers. In addition, all 26 CHEK2 1100delC tumors classified as luminal intrinsic subtype breast cancers, with 8 luminal A and 18 luminal B tumors. This biological make-up of CHEK2 1100delC breast cancers suggests that a relatively limited number of additional susceptibility alleles are involved in the polygenic CHEK2 model. Identification of these as-yet-unknown susceptibility alleles should be aided by clues from the 40-gene CHEK2 signature.

Unidades del paisaje de Puerto Rico: la influencia del clima, el substrato y la topografia

Treesearch

William Gould; Michael E. Jimenez; Gary Potts; Maya Quinones; Sebastian Martinuzzi

2008-01-01

El mapa de unidades del paisaje de Puerto Rico representa variaciones climaticas, topograficas y del substrato mediante la integracion de seis zonas climaticas (Ewel y Whitmore, 1973), seis substratos (Bawiec, 2001; USGS, 2005), cinco posiciones topograficas, o topoformas (Martinuzzi et al. 2007), y cuerpos de agua (USGS 2005). Los substratos representan el conjunto...

Extracorporeal membrane oxygenation in children with heart disease and del22q11 syndrome: a review of the Extracorporeal Life Support Organization Registry.

PubMed

Prodhan, P; Gossett, J M; Rycus, P T; Gupta, P

2015-11-01

The study objective was to evaluate outcomes among children with del22q11 (DiGeorge) syndrome supported on ECMO for heart disease. The ELSO registry database was queried to include all children <18 years undergoing heart surgery for either common atrio-ventricular canal, tetralogy of Fallot, truncus arteriosus or transposition of the great vessels and interrupted aortic arch and requiring ECMO, from 1998-2011. The outcomes evaluated included mortality, ECMO duration and length of hospital stay in patients with del22q11 syndrome and with no del22q11 syndrome. Eighty-eight ECMO runs occurred in children with del22q11 syndrome while 2694 ECMO runs occurred in children without del22q11 syndrome. For patients with heart defects receiving ECMO, del22q11 syndrome did not confer a significant mortality risk or an increased risk of infectious complications before or while on ECMO support. Neither the duration of ECMO nor mechanical ventilation prior to ECMO deployment were prolonged in patients with del22q11 syndrome compared to the controls. © The Author(s) 2015.

Connectivity Predicts Deep Brain Stimulation Outcome in Parkinson Disease

PubMed Central

Horn, Andreas; Reich, Martin; Vorwerk, Johannes; Li, Ningfei; Wenzel, Gregor; Fang, Qianqian; Schmitz-Hübsch, Tanja; Nickl, Robert; Kupsch, Andreas; Volkmann, Jens; Kühn, Andrea A.; Fox, Michael D.

2018-01-01

Objective The benefit of deep brain stimulation (DBS) for Parkinson disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remain unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort. Methods A training dataset of 51 PD patients with STN DBS was combined with publicly available human connectome data (diffusion tractography and resting state functional connectivity) to identify connections reliably associated with clinical improvement (motor score of the Unified Parkinson Disease Rating Scale [UPDRS]). This connectivity profile was then used to predict outcome in an independent cohort of 44 patients from a different center. Results In the training dataset, connectivity between the DBS electrode and a distributed network of brain regions correlated with clinical response including structural connectivity to supplementary motor area and functional anticorrelation to primary motor cortex (p<0.001). This same connectivity profile predicted response in an independent patient cohort (p<0.01). Structural and functional connectivity were independent predictors of clinical improvement (p<0.001) and estimated response in individual patients with an average error of 15% UPDRS improvement. Results were similar using connectome data from normal subjects or a connectome age, sex, and disease matched to our DBS patients. Interpretation Effective STN DBS for PD is associated with a specific connectivity profile that can predict clinical outcome across independent cohorts. This prediction does not require specialized imaging in PD patients themselves. PMID:28586141

Bose-Einstein condensation and independent production of pions

NASA Astrophysics Data System (ADS)

Bialas, A.; Zalewski, K.

1998-09-01

The influence of the HBT effect on the momentum spectra of independently produced pions is studied using the method developed earlier for discussion of multiplicity distributions. It is shown that in this case all the spectra and multiparticle correlation functions are expressible in terms of one function of two momenta. It is also shown that at the critical point all pions are attracted into one quantum state and thus form a Bose-Einstein condensate.

The Balthazar Scales of Adaptive Behavior. Measures of Program Development for the Severely and Profoundly Mentally Retarded. Section 1. Skills of Functional Independence. Part Three: Program Scoring Form.

ERIC Educational Resources Information Center

Balthazar, Earl E.

The scoring form for functional independence skills for the mentally retarded includes a section for recording subjects' demographic characteristics as well as tests used, date administered, and raw score. Other sections provide for a brief description of the program being used, an item scoring sheet for the Eating Scales (dependent feeding,…

Effect of a Combined Tai Chi, Resistance Training and Dietary Intervention on Cognitive Function in Obese Older Women.

PubMed

Xu, F; Delmonico, M J; Lofgren, I E; Uy, K M; Maris, S A; Quintanilla, D; Taetzsch, A G; Letendre, J; Mahler, L

2017-01-01

Cognitive decline in older adults is a major public health problem and can compromise independence and quality of life. Exercise and diet have been studied independently and have shown to be beneficial for cognitive function, however, a combined Tai Chi, resistance training, and diet intervention and its influence on cognitive function has not been undertaken. The current study used a 12-week non-randomized research design with experiment and control groups to examine the effect of a combined Tai Chi, resistance training, and diet intervention on cognitive function in 25 older obese women. Results revealed improvements in domain specific cognitive function in our sample. Baseline cognitive function was correlated with changes in dietary quality. These findings suggest that Tai Chi and resistance training combined with diet intervention might be beneficial for community-based programs aiming to improve cognitive function.

A probabilistic framework to infer brain functional connectivity from anatomical connections.

PubMed

Deligianni, Fani; Varoquaux, Gael; Thirion, Bertrand; Robinson, Emma; Sharp, David J; Edwards, A David; Rueckert, Daniel

2011-01-01

We present a novel probabilistic framework to learn across several subjects a mapping from brain anatomical connectivity to functional connectivity, i.e. the covariance structure of brain activity. This prediction problem must be formulated as a structured-output learning task, as the predicted parameters are strongly correlated. We introduce a model selection framework based on cross-validation with a parametrization-independent loss function suitable to the manifold of covariance matrices. Our model is based on constraining the conditional independence structure of functional activity by the anatomical connectivity. Subsequently, we learn a linear predictor of a stationary multivariate autoregressive model. This natural parameterization of functional connectivity also enforces the positive-definiteness of the predicted covariance and thus matches the structure of the output space. Our results show that functional connectivity can be explained by anatomical connectivity on a rigorous statistical basis, and that a proper model of functional connectivity is essential to assess this link.

[The risk factors for worsening renal function in patients with chronic heart failure].

PubMed

Yang, Xiao-hong; Sun, Zhi-jun; Zheng, Li-qiang; Jia, Yuan-chun; Dong, Ling-ling

2011-07-01

To investigate the risk factors of worsening renal function (WRF) in patients with chronic heart failure (CHF) and WRF influence on prognosis. A case-control study were undertaken to analyze independent risk factor statistically related to incidence of WRF, and to assess the influence of WRF on prognosis. The independent predictors of WRF were creatinine level at admission (OR 2.248, 95%CI 1.088 - 4.647, P = 0.029) and NYHA class on admission (OR 2.485, 95%CI 1.385 - 4.459, P = 0.002). The mortality of patient with WRF was obviously higher than that of control group during hospitalization (OR 3.824, 95%CI 2.452 - 5.637, P < 0.015). WRF is a common complication among patients hospitalized for CHF, and is obviously associated with mortality during hospitalization. Higher creatinine level and weak heart function are independent risk factors for incidence of WRF of patients with CHF.

Neural networks: further insights into error function, generalized weights and others

PubMed Central

2016-01-01

The article is a continuum of a previous one providing further insights into the structure of neural network (NN). Key concepts of NN including activation function, error function, learning rate and generalized weights are introduced. NN topology can be visualized with generic plot() function by passing a “nn” class object. Generalized weights assist interpretation of NN model with respect to the independent effect of individual input variables. A large variance of generalized weights for a covariate indicates non-linearity of its independent effect. If generalized weights of a covariate are approximately zero, the covariate is considered to have no effect on outcome. Finally, prediction of new observations can be performed using compute() function. Make sure that the feature variables passed to the compute() function are in the same order to that in the training NN. PMID:27668220

A Factor Analysis of Functional Independence and Functional Assessment Measure Scores Among Focal and Diffuse Brain Injury Patients: The Importance of Bifactor Models.

PubMed

Gunn, Sarah; Burgess, Gerald H; Maltby, John

2018-04-30

To explore the factor structure of the UK Functional Independence Measure and Functional Assessment Measure (FIM+FAM) among focal and diffuse acquired brain injury patients. Criterion standard. A National Health Service acute acquired brain injury inpatient rehabilitation hospital. Referred sample of N=447 adults admitted for inpatient treatment following an acquired brain injury significant enough to justify intensive inpatient neurorehabilitation INTERVENTION: Not applicable. Functional Independence Measure and Functional Assessment Measure. Exploratory factor analysis suggested a 2-factor structure to FIM+FAM scores, among both focal-proximate and diffuse-proximate acquired brain injury aetiologies. Confirmatory factor analysis suggested a 3-factor bifactor structure presented the best fit of the FIM+FAM score data across both aetiologies. However, across both analyses, a convergence was found towards a general factor, demonstrated by high correlations between factors in the exploratory factor analysis, and by a general factor explaining the majority of the variance in scores on confirmatory factor analysis. Our findings suggested that although factors describing specific functional domains can be derived from FIM+FAM item scores, there is a convergence towards a single factor describing overall functioning. This single factor informs the specific group factors (eg, motor, psychosocial, and communication function) after brain injury. Further research into the comparative value of the general and group factors as evaluative/prognostic measures is indicated. Copyright © 2018 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Percepcion de los profesores universitarios acerca del concepto cultura cientifica y de sus implicaciones en el nuevo bachillerato del Recinto de Rio Piedras de la Universidad de Puerto Rico

NASA Astrophysics Data System (ADS)

Ramos Pastrana, Nilsa

El Senado Academico del Recinto de Rio Piedras de la Universidad de Puerto Rico aprobo en el ano academico 2005-2006 la Certificacion 46, que contiene los lineamientos de un nuevo bachillerato. Este nuevo bachillerato introdujo cambios significativos en el curriculo tradicional. Entre ellos se encuentra la reduccion del componente de educacion general y el de Ciencias Biologicas en particular. La reduccion de creditos en el componente de Ciencias Biologicas ha obligado a reevaluar el concepto de cultura cientifica que desarrollan esos cursos. El proposito del estudio consistio en auscultar las percepciones de los profesores de las Facultades de Administracion de Empresas, Humanidades, Ciencias Sociales, Ciencias Naturales, Educacion y Estudios Generales del Recinto de Rio Piedras de la Universidad de Puerto Rico en torno al concepto de cultura cientifica, los contenidos disciplinares del curso de Ciencias Biologicas y la reduccion de creditos en el nuevo bachillerato. Las preguntas que guiaron la investigacion fueron: ¿cuales son las percepciones que tienen los profesores de las Facultades de Administracion de Empresas, Ciencias Sociales, Estudios Generales, Ciencias Naturales, Humanidades y Educacion, en torno al concepto de cultura cientifica y los contenidos disciplinares del curso de Ciencias Biologicas? ¿cuales son las percepciones que tienen los profesores de Ciencias Biologicas en torno al concepto cultura cientifica y los contenidos disciplinares del curso de Ciencias Biologicas? ¿existen diferencias significativas por facultad, genero, experiencia, rango y nombramiento en las percepciones que tienen los profesores del Recinto de Rio Piedras de la Universidad de Puerto Rico sobre los elementos que caracterizan la cultura cientifica y los contenidos biologicos que deben tener los egresados del Recinto? ¿que implicaciones curriculares tienen estos testimonios en el desarrollo del concepto de cultura cientifica en el nuevo bachillerato? Para realizar la investigacion se utilizo una metodologia cuantitativa y la herramienta para lograrlo fue una encuesta. La encuesta se analizo estadisticamente mediante analisis de frecuencias y por cientos, prueba ANOVA, prueba t, pruebas Post Hoc de Tukey y de Levene. Tambien se realizo nuevamente una prueba de confiabilidad mediante el alfa de Cronbach. Los resultados reflejaron que los profesores de las Facultades de Administracion de Empresas, Ciencias Sociales, Ciencias Naturales, Educacion, Humanidades, Estudios Generales y el Departamento de Ciencias Biologicas tienen una percepcion muy positiva del concepto de cultura cientifica, los contenidos curriculares de Ciencias Biologicas y del nuevo bachillerato.

[Overload felt by the figure of the main caregiver in a cohort of patients with multiple pathologies].

PubMed

Moreno-Gaviño, Lourdes; Bernabeu-Wittel, Máximo; Alvarez-Tello, Margarita; Rincón Gómez, Manuel; Bohórquez Colombo, Pilar; Cassani Garza, Manuel; Ollero Baturone, Manuel; García-Morillo, Salvador

2008-04-01

To determine the profile of the main caregiver (MC) and the factors associated with her/his care burden, in a multi-centre cohort of patients with multiple pathologies (PMP). Multi-centre cross-sectional study. Four health districts in the Virgen del Rocío University Hospitals Health Area, Seville, Spain. The PMP cohort was created by checking all the patients who satisfied the health department criteria for PMP (2002): patients suffering from chronic diseases in 2 or more of the 7 clinical categories defined. The profile of PMP caregiver was determined for all patients. The caregiver strain index (CSI) was determined by the index of care stress (ICS). Predictive factors were analysed by the Student t, ANOVA, and Pearson's tests. Multivariate analysis was performed by a forward stepwise linear regression model. The interview was attended by 461 (69%) out of 662 eligible PMP. Of these, 293 (63.6%) had an MC whose mean age was 62 (15) years; 80% of them were women. First-degree relatives made up 88% of caregivers, with spouses 49.7% of them (n=146). In 41.5%, the CSI was >7 points (mean CSI was 5.35 [3.5]). This was higher in those caring for PMP with neurological illnesses (7 [3.2 vs 4.5 [3.3]; P=.0001). The CSI was compared directly with the medical vulnerability of the PMP (R=0.37; P=.001), cognitive deterioration on the Pfeiffer scale (PS) (R=0.4; P=.0001), and inversely with functional status on Barthel's scale (BS) (R=-0.67; P=.0001). Patient's age (P=.03), his/her medical vulnerability (P=.016) and functional (P< .0001) and cognitive (P=.019) deterioration were independently associated with the CSI. The profile of the MC of the PMP cohort corresponded mainly to first-degree female relatives around sixty years old. The burden of care was high in more than a third of them. Predictive factors were age, medical vulnerability, and the functional and cognitive deterioration of the PMP.

Interstitial 13q14 deletions detected in the karyotype and translocations with concomitant deletion at 13q14 in chronic lymphocytic leukemia: different genetic mechanisms but equivalent poorer clinical outcome.

PubMed

Puiggros, Anna; Venturas, Marta; Salido, Marta; Blanco, Gonzalo; Fernandez-Rodriguez, Concepción; Collado, Rosa; Valiente, Alberto; Ruiz-Xivillé, Neus; Carrió, Ana; Ortuño, Francisco José; Luño, Elisa; Calasanz, María José; Ardanaz, María Teresa; Piñán, María Ángeles; Talavera, Elisabet; González, María Teresa; Ortega, Margarita; Marugán, Isabel; Ferrer, Ana; Gimeno, Eva; Bellosillo, Beatriz; Delgado, Julio; Hernández, José Ángel; Hernández-Rivas, Jesús María; Espinet, Blanca

2014-09-01

Deletion of 13q14 as the sole abnormality is a good prognostic marker in chronic lymphocytic leukemia (CLL). Nonetheless, the prognostic value of reciprocal 13q14 translocations [t(13q)] with related 13q losses has not been fully elucidated. We described clinical and biological characteristics of 25 CLL patients with t(13q), and compared with 62 patients carrying interstitial del(13q) by conventional G-banding cytogenetics (CGC) [i-del(13q)] and 295 patients with del(13q) only detected by fluorescence in situ hybridization (FISH) [F-del(13q)]. Besides from the CLL FISH panel (D13S319, CEP12, ATM, TP53), we studied RB1 deletions in all t(13q) cases and a representative group of i-del(13q) and F-del(13q). We analyzed NOTCH1, SF3B1, and MYD88 mutations in t(13q) cases by Sanger sequencing. In all, 25 distinct t(13q) were described. All these cases showed D13S319 deletion while 32% also lost RB1. The median percentage of 13q-deleted nuclei did not differ from i-del(13q) patients (73% vs. 64%), but both were significantly higher than F-del(13q) (52%, P < 0.001). Moreover, t(13q) patients showed an increased incidence of biallelic del(13q) (52% vs. 11.3% and 14.9%, P < 0.001) and higher rates of concomitant 17p deletion (37.5% vs. 8.6% and 7.2%, P < 0.001). RB1 involvement was significantly higher in the i-del(13q) group (79%, P < 0.001). Two t(13q) patients (11.8%) carried NOTCH1 mutations. Time to first treatment in t(13q) and i-del(13q) was shorter than F-del(13q) (67, 44, and 137 months, P = 0.029), and preserved significance in the multivariate analysis. In conclusion, t(13q) and del(13q) patients detected by CGC constitute a subgroup within the 13q-deleted CLL patients associated with a worse clinical outcome. © 2014 Wiley Periodicals, Inc.

Patient and Family Member Factors Influencing Outcomes of Poststroke Inpatient Rehabilitation.

PubMed

Fang, Yunhua; Tao, Qian; Zhou, Xiaoxuan; Chen, Shanjia; Huang, Jia; Jiang, Yingping; Wu, Yi; Chen, Lidian; Tao, Jing; Chan, Chetwyn C

2017-02-01

To investigate how family members' attitudes toward functional regain, and patients' knowledge and intention of independence influence poststroke rehabilitation. Cross-sectional study. Three rehabilitation inpatient settings. Younger (n=79) and older (n=84) poststroke patients, along with their family members (spouses, n=104; children, n=59). Not applicable. Custom-designed questionnaires were used to tap into the patients' knowledge about rehabilitation (Patient's Rehabilitation Questionnaire-Knowledge About Rehabilitation) and intention of independence (Patient's Rehabilitation Questionnaire-Intention of Independence), and family members' attitudes toward patients in performing basic activities of daily living (BADL) (Family Member Attitudes Questionnaire-BADL) and instrumental activities of daily living (Family Member Attitudes Questionnaire-instrumental activities of daily living). The rehabilitation outcomes included gains in motor, cognitive, and emotional functions, and self-care independence, measured with common clinical instruments. The Family Member Attitudes Questionnaire-BADL predicted cognitive outcome and the Patient's Rehabilitation Questionnaire-Intention of Independence predicted motor outcome for both groups. Differential age-related effects were revealed for the Patient's Rehabilitation Questionnaire-Intention of Independence in predicting emotional outcome only for the younger group, and self-care independence only for the older group. Patients' intention of independence positively affected motor recovery, while family members' positive attitudes promoted cognitive regain. The findings suggested plausible age-related differences in how patients' intentions affect emotion versus self-care independence outcomes. Future studies should explore strategies for promoting positive attitudes toward independence among patients and family members during poststroke rehabilitation. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Novel Somatic Mutation in LEMD3 Splice Site Results in Buschke-Ollendorff Syndrome with Polyostotic Melorheostosis and Osteopoikilosis.

PubMed

Gutierrez, Daniel; Cooper, Kevin D; Mitchell, Anna L; Cohn, Heather I

2015-01-01

Buschke-Ollendorff syndrome is a rare autosomal dominant disorder caused by loss of function in LEMD3, resulting in connective tissue nevi and varying bone dysplasia. Although typically benign, we describe a novel LEMD3 splice site mutation (IVS12 + 1delG) in a 13-year-old boy with Buschke-Ollendorff syndrome presenting with severe skeletal deformities, polyostotic melorheostosis, and osteopoikilosis. © 2015 Wiley Periodicals, Inc.

Valores, Creencias Y Objectivos: Base del programa de la Escuela Experimental P.K. Yonge. (Values, Beliefs and Objectives: The Basis of Experimental Schools P.K. Yonge's Program.)

ERIC Educational Resources Information Center

Florida Univ., Gainesville. Coll. of Education.

The values, beliefs, and objectives that form the core of the program at the Experimental School P.K. Yonge in the University of Florida are presented in this paper which is written in Spanish. This experimental school serves approximately 900 students from grades one through twelve. The function of the school is to conduct research to solve…

Systemic Functional Linguistics and Discourse Analysis as Alternatives When Dealing with Texts (La lingüística sistémica funcional y el análisis del discurso como alternativas para trabajar con textos)

ERIC Educational Resources Information Center

García Montes, Paula Andrea; Sagre Barboza, Ana María; Lacharme Olascoaga, Alba Isabel

2014-01-01

This article presents a case study research with aims to find out which activities, methodological and textual aspects used in a reading strategies course were causing a group of students difficulties when analyzing critically written information. We conducted the study at Universidad de Córdoba (Colombia) with seventh semester students from the…

Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients

PubMed Central

Ueda, Takahiro; Compe, Emmanuel; Catez, Philippe; Kraemer, Kenneth H.

2009-01-01

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a “causative” XPD point mutation R683W and different second mutant alleles, considered “null alleles.” However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. Although all the mutations inhibited the nucleotide excision repair (NER) by disturbing the XPD helicase function, each of them disrupted specific molecular steps during transcription: XPD/Q452X hindered the transactivation process, XPD/I455del disturbed RNA polymerase II phosphorylation, and XPD/199insPP inhibited kinase activity of the cdk7 subunit of TFIIH. The broad range and severity of clinical features in XP patients arise from a broad set of deficiencies in NER and transcription that result from the combination of mutations found on both XPD alleles. PMID:19934020

pKa predictions for proteins, RNAs, and DNAs with the Gaussian dielectric function using DelPhi pKa.

PubMed

Wang, Lin; Li, Lin; Alexov, Emil

2015-12-01

We developed a Poisson-Boltzmann based approach to calculate the pKa values of protein ionizable residues (Glu, Asp, His, Lys and Arg), nucleotides of RNA and single stranded DNA. Two novel features were utilized: the dielectric properties of the macromolecules and water phase were modeled via the smooth Gaussian-based dielectric function in DelPhi and the corresponding electrostatic energies were calculated without defining the molecular surface. We tested the algorithm by calculating pKa values for more than 300 residues from 32 proteins from the PPD dataset and achieved an overall RMSD of 0.77. Particularly, the RMSD of 0.55 was achieved for surface residues, while the RMSD of 1.1 for buried residues. The approach was also found capable of capturing the large pKa shifts of various single point mutations in staphylococcal nuclease (SNase) from pKa-cooperative dataset, resulting in an overall RMSD of 1.6 for this set of pKa's. Investigations showed that predictions for most of buried mutant residues of SNase could be improved by using higher dielectric constant values. Furthermore, an option to generate different hydrogen positions also improves pKa predictions for buried carboxyl residues. Finally, the pKa calculations on two RNAs demonstrated the capability of this approach for other types of biomolecules. © 2015 Wiley Periodicals, Inc.

Social responsiveness and competence in Prader-Willi syndrome: direct comparison to autism spectrum disorder.

PubMed

Dimitropoulos, Anastasia; Ho, Alan; Feldman, Benjamin

2013-01-01

Prader-Willi syndrome (PWS), a neurodevelopmental disorder primarily characterized by hyperphagia and food preoccupations, is caused by the absence of expression of the paternally active genes in the proximal arm of chromosome 15. Although maladaptive behavior and the cognitive profile in PWS have been well characterized, social functioning has only more recently been systematically examined. Findings to date indicate the social impairment exhibited may reflect specific difficulty interpreting and using social information effectively. In addition, evidence suggests that there is an increased risk of social deficits in people with the maternally-derived uniparental disomy (mUPD) subtype of PWS in comparison to those with 15q11-13 paternal deletion (DEL). Using the Social Responsiveness Scale (SRS) and the Social Competence Inventory, our goal was to compare social functioning in PWS to individuals with autism spectrum disorder (ASD). Participants with mUPD scored similarly to the ASD group across most SRS domains. All groups had difficulty with social competence, although the DEL group scored highest on prosocial behavior. Findings suggest further characterization of social behavior in PWS is necessary to aid in advancing the understanding of the contributions of genes in the 15q11-13 critical region to ASD susceptibility, particularly with respect to the overexpression of maternally expressed genes in this region, as well as aiding in awareness and development/implementation of interventions.

El Alcalde José Carlos Aponte Dalmau del Municipio de Carolina es nombrado a formar parte del Comité Asesor de Gobiernos Locales de la EPA a nivel de todos los Estados Unidos

EPA Pesticide Factsheets

Comunicado de prensa de la EPA: El Alcalde José Carlos Aponte Dalmau del Municipio de Carolina es nombrado a formar parte del Comité Asesor de Gobiernos Locales de la EPA a nivel de todos los Estados Unidos

Attitude and knowledge about foot health: a spanish view.

PubMed

López-López, Daniel; García-Mira, Ricardo; Palomo-López, Patricia; Sánchez-Gómez, Rubén; Ramos-Galván, José; Tovaruela-Carrión, Natalia; García-Sánchez, Matilde

2017-04-06

to explore attitudes towards patients' self-reported data about foot health-related beliefs from a behavioural and attitudinal perspective. a sample of 282 participants of a mean age of 39.46 ± 16.026 came to a health centre where self-reported demographic, clinical characteristics and beliefs relating to foot health data were registered, informants' completed all the stages of the research process. the results of the analysis revealed an 8-factor factorial structure based on (1) podiatric behaviours, (2) the intention to carry out protective behaviour, (3) attitudinal beliefs, (4) normative beliefs, (5) needs, (6) apathy, (7) self-care, and (8) the general perception of foot health. They all explained 62.78% of the variance, and were considered as independent variables in a regression analysis to determine which provided the best explanations for the importance attributed to foot health. the participants in the study revealed a positive attitude in relation to foot health care and responsible behaviour. explorar as atitudes em relação aos dados auto-relatados dos pacientes sobre crenças relacionadas à saúde do pé, desde uma perspectiva comportamental e atitudinal. uma amostra de 282 participantes com idade média de 39,46 ± 16,026 chegaram a um centro de saúde onde foram registradas características demográficas, clínicas e crenças auto-relatadas referentes a dados de saúde do pé, os quais completaram todas as fases do processo de pesquisa. os resultados da análise revelaram uma estrutura fatorial de 8 fatores baseada em (1) comportamentos podiátricos, (2) a intenção de realizar comportamentos protetores, (3) crenças atitudinais, (4) crenças normativas, (6) apatia, (7) autocuidado, e (8) a percepção geral da saúde do pé. Todos eles explicaram 62,78% da variância e foram considerados como variáveis ​​independentes em uma análise de regressão para determinar quais forneceram as melhores explicações para a importância atribuída à saúde do pé. os participantes do estudo revelaram uma atitude positiva em relação à saúde do pé e comportamento responsável. explorar las actitudes relacionadas con datos autoinformados sobre las creencias de la salud del pie desde una perspectiva actitudinal. una muestra de 282 participantes edad media 39.46 ± 16.026 acudieron a un centro de salud donde se registraron datos autoinformados de las características demográficas, características clínicas y creencias relacionadas con la salud del pie, completándose todas las etapas del proceso de investigación. los resultados del análisis revelaron una estructura factorial de 8 factores basado en (1) conductas podológicas, (2) la intención de llevar a cabo una conducta de protección, (3) las creencias actitudinales, (4) las creencias normativas, (5) las necesidades, (6) la apatía, (7) el autocuidado, y (8) la percepción general de salud podal. Todos ellos explicaron un 62,78% de la varianza, y fueron considerados como variables independientes en una ecuación de regresión para determinar cuáles de ellos explicaban mejor la importancia atribuida a la salud del pie. los participantes en el estudio revelaron una actitud positiva en relación al cuidado de la salud del pie y al comportamiento responsable.

Excess breast cancer risk in first degree relatives of CHEK2∗1100delC positive familial breast cancer cases.

PubMed

Adank, Muriel A; Verhoef, Senno; Oldenburg, Rogier A; Schmidt, Marjanka K; Hooning, Maartje J; Martens, John W M; Broeks, Annegien; Rookus, Matti; Waisfisz, Quinten; Witte, Birgit I; Jonker, Marianne A; Meijers-Heijboer, Hanne

2013-05-01

The CHEK2∗1100delC mutation confers a relative risk of two for breast cancer (BC) in the general population. This study aims to explore the excess cancer risk due to the CHEK2∗1100delC mutation within a familial non-BRCA1/2 breast cancer setting. Cancer incidences were compared between first degree relatives of 107 familial breast cancer patients positive for the CHEK2∗1100delC mutation (CHEK2 positive families) and first degree relatives of 314 familial breast cancer patients without the CHEK2∗1100delC mutation (CHEK2 negative families). All families were derived from the same pool of familial non-BRCA1/2 breast cancer families (n=2554). Medical information of 2188 first degree relatives of these families was analysed for cancer risk. CHEK2∗1100delC status of relatives was unknown. Increased breast cancer risk (hazard ratio (HR) 2.0 (95% confidence interval (CI): 1.4-2.7), p<0.001) was observed in sisters of CHEK2∗1100delC positive index cases compared to sisters of CHEK2∗1100delC negative index cases. HR was 1.6 (95% CI: 1.0-2.4) for mothers of CHEK2 positive versus negative index cases (p=0.041). For second primary breast cancers HR was increased in CHEK2∗1100delC positive index cases (HR 2.1, 95% CI: 1.3-3.3, p=0.003) and their sisters (HR 2.6, 95% CI: 1.1-6.1, p=0.025). There is an excess breast cancer risk in first degree relatives of CHEK2∗1100delC positive non-BRCA1/2 familial breast cancer patients compared to non-CHEK2∗1100delC familial breast cancer relatives. Genotyping for the CHEK2∗1100delC mutation in a familial breast cancer setting contributes to optimal clinical surveillance in countries in which this mutation is prevalent. Carriers and female relatives are eligible for stringent breast surveillance programs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pelvic trauma with displaced sacral fractures: functional outcome at one year.

PubMed

Tötterman, Anna; Glott, Thomas; Søberg, Helene Lundgaard; Madsen, Jan Erik; Røise, Olav

2007-06-01

A prospective single-cohort study of 31 patients surgically treated for pelvic injuries with displaced sacral fractures. To describe the medium term functional outcome in unstable sacral fractures. Displaced sacral fractures pose a special challenge in orthopedic surgery due to the high rate of associated injuries. Little information is available on the medium-term functional outcome of patients with injuries which include unstable sacral fractures. We examined 31 patients with displaced sacral fractures having 10 mm or more displacement, 1 year (mean, 1.4 years; range, 1.0-2.5 years) after injury. Data from a previous study were supplemented with functional outcome measures (work status, independence in ADL, and SF-36). An association between outcome and tested variables was sought. Fifteen months after injury, 65% of the patients had regained their independence in functions pertaining to daily activities; 33% had returned to work. All dimensions of perceived health were affected. Polytrauma and impairments relative to voiding and sexual function had a detrimental effect on outcome. Fracture characteristics were not predictive of poor outcome. Although the majority of patients achieved independent living, medium-term follow-up indicated significant residual disability. The complex nature of these fractures and the associated injuries should be considered in the rehabilitation of these patients.

Association between serum bicarbonate and pH with depression, cognition and sleep quality in hemodialysis patients.

PubMed

Afsar, Baris; Elsurer, Rengin

2015-07-01

Metabolic acidosis is a common feature in chronic renal failure patients, worsening progressively as renal function declines. There are conflicting data in hemodialysis (HD) patients with regard to acidosis, alkalosis and mortality. In HD patients, cognitive impairment, depression, sleep disorders and impaired quality of life are very common. Besides, these conditions are related with increased morbidity and mortality. However, no previous study investigated the relationship between pH, venous bicarbonate and anion gap with depression, sleep problems and cognitive function in HD patients. In this study we investigated these relationships. In total, 65 HD patients were included. The demographic parameters and laboratory parameters including bicarbonate, pH and anion gap was measured for all patients. Depressive symptoms, sleep quality and cognitive function, were measured by Beck depression inventory, The Pittsburgh Sleep Quality Index and by Mini Mental State Examination, respectively. We found that, sleep quality but not cognitive function or depression was independently related with venous pH and bicarbonate. Anion gap has no independent relationship with sleep quality, cognitive function and depression. In conclusion, metabolic acidosis and bicarbonate levels were independently related with sleep quality in HD patients. However, there was no association between metabolic acidosis and bicarbonate levels with cognitive function and depression.

Oral bacteria influenced by the functional status of the elderly people and the type and quality of facilities for the bedridden.

PubMed

Tada, A; Watanabe, T; Yokoe, H; Hanada, N; Tanzawa, H

2002-01-01

To analyse the relationship between oral bacteria and the health and functional status of the elderly. The bacteria species in the oral cavity of the elderly were examined. It was found that the bedridden subjects staying at two hospitals for long-term (HOBR) showed significantly lower detection rates of commensal bacteria species and significantly higher detection rates of Pseudomonas aeruginosa, of methicillin-resistant Staphylococcus aureus (MRSA) and of coagulase(-) Staph. aureus than those living independently (the independent). In addition, the detection rate of Haemophilus parainfluenzae in NUBR was discovered to be higher than that found in the independent. In HOBR, the detection rate of Ps. aeruginosa was significantly higher among in-patients who required continual care than those in need of partial care, while the detection rate of MRSA was significantly higher among in-patients with low serum albumin than those with normal serum albumin. Oral bacteria examination analysis proved that the risks of infection of some pathogenic bacteria species were correlated with functional status, physical function and nutritional state. Our study suggests that the oral bacteria, especially pathogenic bacteria were influenced by the functional status of the elderly and the type and quality of the facilities for the bedridden, physical function and nutritional state.

Effectiveness of Neuro-Developmental Treatment (Bobath Concept) on postural control and balance in Cerebral Palsied children.

PubMed

Tekin, Fatih; Kavlak, Erdogan; Cavlak, Ugur; Altug, Filiz

2018-01-01

The aim of this study was to show the effects of an 8-week Neurodevelopmental Treatment based posture and balance training on postural control and balance in diparetic and hemiparetic Cerebral Palsied children (CPC). Fifteen CPC (aged 5-15 yrs) were recruited from Denizli Yağmur Çocukları Rehabilitation Centre. Gross Motor Function Classification System, Gross Motor Function Measure, 1-Min Walking Test, Modified Timed Up and Go Test, Paediatric Balance Scale, Functional Independence Measure for Children and Seated Postural Control Measure were used for assessment before and after treatment. An 8-week NDT based posture and balance training was applied to the CPC in one session (60-min) 2 days in a week. After the treatment program, all participants showed statistically significant improvements in terms of gross motor function (p< 0.05). They also showed statistically significant improvements about balance abilities and independence in terms of daily living activities (p< 0.05). Seated Postural Control Measure scores increased after the treatment program (p< 0.05). The results of this study indicate that an 8-week Neurodevelopmental Treatment based posture and balance training is an effective approach in order to improve functional motor level and functional independency by improving postural control and balance in diparetic and hemiparetic CPC.

Physical functional outcome assessment of patients with major burns admitted to a UK Burn Intensive Care Unit.

PubMed

Smailes, Sarah T; Engelsman, Kayleen; Dziewulski, Peter

2013-02-01

Determining the discharge outcome of burn patients can be challenging and therefore a validated objective measure of functional independence would assist with this process. We developed the Functional Assessment for Burns (FAB) score to measure burn patients' functional independence. FAB scores were taken on discharge from ICU (FAB 1) and on discharge from inpatient burn care (FAB 2) in 56 patients meeting the American Burn Association criteria for major burn. We retrospectively analysed prospectively collected data to measure the progress of patients' physical functional outcomes and to evaluate the predictive validity of the FAB score for discharge outcome. Mean age was 38.6 years and median burn size 35%. Significant improvements were made in the physical functional outcomes between FAB 1 and FAB 2 scores (p<0.0001). 48 patients were discharged home, 8 of these with social care. 8 patients were transferred to another hospital for further inpatient rehabilitation. FAB 1 score (≤ 9) is strongly associated with discharge outcome (p<0.006) and as such can be used to facilitate early discharge planning. FAB 2 score (≤ 26) independently predicts discharge outcome (p<0.0001) and therefore is a valid outcome measure to determine discharge outcome of burn patients. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

El uso de la neuromodulación para el tratamiento del temblor

PubMed Central

Bendersky, Damián; Ajler, Pablo; Yampolsky, Claudio

2014-01-01

Introducción: El temblor puede ser un desorden incapacitante y el tratamiento de primera línea para estos pacientes es farmacológico. Sin embargo, este tratamiento puede llevar a una reducción satisfactoria del temblor en sólo el 50% de los pacientes con temblor esencial. La talamotomía era el tratamiento de elección para el temblor refractario al tratamiento médico hasta que comenzó a utilizarse la estimulación cerebral profunda (ECP) del núcleo ventral intermedio (Vim) del tálamo. En la actualidad, raramente se realiza la talamotomía. Métodos: Este artículo es una revisión no sistemática de las indicaciones, resultados, parámetros de programación y técnica quirúrgica de la ECP del Vim para el tratamiento del temblor. Resultados: Aunque los resultados clínicos son similares usando la talamotomía o la ECP del Vim, la primera causa más efectos adversos que la última. Además, la ECP puede ser usada bilateralmente, mientras que la talamotomía tiene un alto riesgo de causar disartria cuando se realiza de ambos lados. La ECP del Vim logró una adecuada mejoría del temblor en varias series de pacientes con temblor causado por temblor esencial, enfermedad de Parkinson o esclerosis múltiple. Además del Vim, hay otros blancos que están siendo usados por varios autores, tales como la zona incerta y las radiaciones prelemniscales. Conclusión: La ECP del Vim es un tratamiento útil para el temblor incapacitante refractario al tratamiento médico. Es esencial realizar una precisa selección de pacientes, así como utilizar una técnica quirúrgica correcta. Aún se desconoce el mejor blanco estereotáctico para el temblor, aunque el Vim es el más usado. PMID:25165613

A 10-Year Follow-Up Study of Social Ties and Functional Health among the Old: The AGES Project

PubMed Central

Murata, Chiyoe; Saito, Tami; Tsuji, Taishi; Saito, Masashige

2017-01-01

In Asian nations, family ties are considered important. However, it is not clear what happens among older people with no such ties. To investigate the association, we used longitudinal data from the Aichi Gerontological Evaluation Study (AGES) project. Functionally independent older people at baseline (N = 14,088) in 10 municipalities were followed from 2003 to 2013. Social ties were assessed by asking about their social support exchange with family, relatives, friends, or neighbors. Cox proportional hazard models were employed to investigate the association between social ties and the onset of functional disability adjusting for age, health status, and living arrangement. We found that social ties with co-residing family members, and those with friends or neighbors, independently protected functional health with hazard ratios of 0.81 and 0.85 among men. Among women, ties with friend or neighbors had a stronger effect on health compared to their male counterparts with a hazard ratio of 0.89. The fact that social ties with friends or neighbors are associated with a lower risk of functional decline, independent of family support, serves to underscore the importance of promoting social ties, especially among those lacking family ties. PMID:28671627

Mobility one week after a hip fracture - can it be predicted?

PubMed

Fitzgerald, Michelle; Blake, Catherine; Askin, David; Quinlan, John; Coughlan, Tara; Cunningham, Caitriona

2018-05-01

Better patient outcomes and more efficient healthcare could be achieved by predicting post hip fracture function at an early stage. This study aimed to identify independent predictors of mobility outcome one week post hip fracture surgery. All hip fracture inpatients (n=77) were included in this 6 month prospective observational cohort study. Predictor variables were obtained on the first postoperative day and included premorbid function using the New Mobility Score (NMS). Mobility outcome measures one week postoperatively included the Cumulated Ambulatory Score (CAS). Data were analysed with SPSS using binary multiple logistic regression analysis RESULTS: Patients who fell outdoors (OR 3.848; 95% CI, 1.053-14.061), had no delay to surgery (OR 5.472; 95% CI, 1.073-27.907) and had high pre-fracture function (OR3.366; 95% CI, 1.042-10.879) were predicted to achieve independent mobility (CAS = 6) one week postoperatively. Fall location, time to surgery and baseline function predict independent mobility one week after hip fracture, and can be used for early rehabilitation stratification. The NMS and CAS are recommended as standardised hip fracture clinical measures. Orthogeriatric and physiotherapy service initiatives may improve early functional outcome. Copyright © 2017. Published by Elsevier Ltd.

Inpatient rehabilitation outcomes for patients receiving left ventricular assist device.

PubMed

Alsara, Osama; Reeves, Ronald K; Pyfferoen, Mary D; Trenary, Tamra L; Engen, Deborah J; Vitse, Merri L; Kessler, Stacy M; Kushwaha, Sudhir S; Clavell, Alfredo L; Thomas, Randal J; Lopez-Jimenez, Francisco; Park, Soon J; Perez-Terzic, Carmen M

2014-10-01

The aim of this study was to evaluate outcomes of patients participating in inpatient rehabilitation program after left ventricular assist device (LVAD) implantation. Medical records of 94 patients who received LVADs between January 1, 2008, and June 30, 2010, at the Mayo Clinic in Rochester, MN, were retrospectively reviewed for demographic data, and inpatient rehabilitation functional outcomes were measured by the Functional Independence Measure scale. After successful implantation of LVAD, the patients were either discharged directly home from acute care (44%) or admitted to inpatient rehabilitation (56%). The patients admitted to inpatient rehabilitation were older than those discharged home. They were also more medically complex and more likely to have the LVAD placed as destination therapy. At discharge, significant improvement occurred in 17 of the 18 activities evaluated by the Functional Independence Measure scale. The mean total Functional Independence Measure scale score at admission was 77.1 compared with a score of 95.2 at discharge (P < 0.0001). Approximately half of the patients who received LVAD therapy were admitted in the inpatient rehabilitation. After the implantation of LVAD and inpatient rehabilitation, significant functional improvements were observed. Further studies addressing the role of inpatient rehabilitation for LVAD patients are warranted.

Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development.

PubMed

Zhao, Xiaofeng; Peng, Xu; Sun, Shaogang; Park, Ann Y J; Guan, Jun-Lin

2010-06-14

Focal adhesion kinase (FAK) is essential for vascular development as endothelial cell (EC)-specific knockout of FAK (conditional FAK knockout [CFKO] mice) leads to embryonic lethality. In this study, we report the differential kinase-independent and -dependent functions of FAK in vascular development by creating and analyzing an EC-specific FAK kinase-defective (KD) mutant knockin (conditional FAK knockin [CFKI]) mouse model. CFKI embryos showed apparently normal development through embryonic day (E) 13.5, whereas the majority of CFKO embryos died at the same stage. Expression of KD FAK reversed increased EC apoptosis observed with FAK deletion in embryos and in vitro through suppression of up-regulated p21. However, vessel dilation and defective angiogenesis of CFKO embryos were not rescued in CFKI embryos. ECs without FAK or expressing KD FAK showed increased permeability, abnormal distribution of vascular endothelial cadherin (VE-cadherin), and reduced VE-cadherin Y658 phosphorylation. Together, our data suggest that kinase-independent functions of FAK can support EC survival in vascular development through E13.5 but are insufficient for maintaining EC function to allow for completion of embryogenesis.

Max Brödel: his art, legacy, and contributions to neurosurgery through medical illustration.

PubMed

Patel, Smruti K; Couldwell, William T; Liu, James K

2011-07-01

Max Brödel is considered the father of modern medical illustration. This report reviews his contributions to neurosurgery as a medical illustrator. Max Brödel, a young artist from Leipzig, Germany, was hired at Johns Hopkins Hospital in 1894, where he illustrated an operative textbook of gynecology for Howard A. Kelly. Although Brödel did not have any formal medical training, he quickly acquired knowledge of anatomy, pathology, physiology, and surgery. Brödel's extraordinary illustrations were characterized by an aerial perspective that conveyed the surgeon's operative viewpoint and precise surgical anatomy. He masterfully incorporated tissue realism with cross-sectional anatomy to accentuate concepts while maintaining topographical accuracy. Brödel's reputation spread quickly and resulted in collaborations with prominent surgeons, such as Cushing, Halsted, and Dandy. Cushing, who also possessed artistic talent, became a pupil of Brödel and remained a very close friend. In 1911, Brödel was appointed the director of the Department of Art as Applied to Medicine at Johns Hopkins, the first academic department of its kind in the world. For the next several decades, he trained generations of renowned medical illustrators. Just as Osler, Halsted, and Cushing passed their skills and knowledge to future leaders of medicine and surgery, Brödel did the same for the field of medical illustration. The advancement of neurosurgical education has been greatly facilitated by Max Brödel's artistic contributions. His unique ability to synthesize art and medicine resulted in timeless illustrations that remain indispensable to surgeons. The art produced by his legacy of illustrators continues to flourish in neurosurgical literature today.

Doping test results dependent on genotype of uridine diphospho-glucuronosyl transferase 2B17, the major enzyme for testosterone glucuronidation.

PubMed

Schulze, Jenny Jakobsson; Lundmark, Jonas; Garle, Mats; Skilving, Ilona; Ekström, Lena; Rane, Anders

2008-07-01

Testosterone abuse is conventionally assessed by the urinary testosterone/epitestosterone (T/E) ratio, levels above 4.0 being considered suspicious. The large variation in testosterone glucuronide (TG) excretion and its strong association with a deletion polymorphism in the uridine diphospho-glucuronosyl transferase (UGT) 2B17 gene challenge the accuracy of the T/E ratio test. Our objective was to investigate whether genotype-based cutoff values will improve the sensitivity and specificity of the test. This was an open three-armed comparative study. A total of 55 healthy male volunteers with either two, one, or no allele [insertion/insertion, insertion/deletion, or deletion/deletion (del/del)] of the UGT2B17 gene was included in the study. A single im dose of 500 mg testosterone enanthate was administered. Urinary excretion of TG after dose and the T/E ratio during 15 d were calculated. The degree and rate of increase in the TG excretion rate were highly dependent on the UGT2B17 genotype with a 20-fold higher average maximum increase in the insertion/insertion group compared with the del/del group. Of the del/del subjects, 40% never reached the T/E ratio of 4.0 on any of the 15 d after the dose. When differentiated cutoff levels for the del/del (1.0) and the other genotypes (6.0) were applied, the sensitivity increased substantially for the del/del group, and false positives in the other genotypes were eliminated. Consideration of the genetic variation in disposition of androgens will improve the sensitivity and specificity of the testosterone doping test. This is of interest not only for combating androgen doping in sports, but also for detecting and preventing androgen abuse in society.

[Not Available].

PubMed

Cruz-Sáez, María Soledad; Pascual Jimeno, Aitziber; Wlodarczyk, Anna; Polo-López, Rocío; Echeburúa Odriozola, Enrique

2016-07-19

Introducción: los problemas relacionados con el peso constituyen un problema importante de salud pública debido a su alta prevalencia y a las adversas consecuencias que tienen para la salud.Objetivo: el objetivo principal de este estudio fue analizar si la depresión y la ansiedad tienen un papel mediador en la relación entre la insatisfacción corporal y las conductas de control del peso en chicas adolescentes con sobrepeso.Material y métodos: en el estudio participaron 140 mujeres de 16 a 20 años con sobrepeso. Las participantes tuvieron que cumplimentar la escala de insatisfacción corporal del EDI-2, las escalas de ansiedad y depresión del GHQ-28 y una adaptación de las escalas del EAT survey para evaluar las conductas de control del peso. Para los análisis estadísticos se utilizaron métodos de diferencias de medias, correlaciones y de mediación secuencial.Resultados: las adolescentes con sobrepeso y alta insatisfacción corporal presentaban más sintomatología ansiosa y depresiva, así como mayor cantidad de conductas de control del peso. Los resultados del análisis de mediación secuencial evidencian que el efecto de la insatisfacción corporal en las conductas de control del peso está parcialmente mediado por las variables depresión y ansiedad. Mientras que la sintomatología ansiosa presenta efectos directos e indirectos sobre las conductas de control de peso, la sintomatología depresiva solamente presenta un efecto indirecto.Conclusiones:los resultados del estudio destacan el rol mediador de la sintomatología depresiva y, especialmente, de la ansiedad en el desarrollo de conductas no saludables de control del peso.

Characterization of a new GmFAD3A allele in Brazilian CS303TNKCA soybean cultivar.

PubMed

Silva, Luiz Claudio Costa; Bueno, Rafael Delmond; da Matta, Loreta Buuda; Pereira, Pedro Henrique Scarpelli; Mayrink, Danyelle Barbosa; Piovesan, Newton Deniz; Sediyama, Carlos Sigueyuki; Fontes, Elizabeth Pacheco Batista; Cardinal, Andrea J; Dal-Bianco, Maximiller

2018-05-01

We molecularly characterized a new mutation in the GmFAD3A gene associated with low linolenic content in the Brazilian soybean cultivar CS303TNKCA and developed a molecular marker to select this mutation. Soybean is one of the most important crops cultivated worldwide. Soybean oil has 13% palmitic acid, 4% stearic acid, 20% oleic acid, 55% linoleic acid and 8% linolenic acid. Breeding programs are developing varieties with high oleic and low polyunsaturated fatty acids (linoleic and linolenic) to improve the oil oxidative stability and make the varieties more attractive for the soy industry. The main goal of this study was to characterize the low linoleic acid trait in CS303TNKCA cultivar. We sequenced CS303TNKCA GmFAD3A, GmFAD3B and GmFAD3C genes and identified an adenine point deletion in the GmFAD3A exon 5 (delA). This alteration creates a premature stop codon, leading to a truncated protein with just 207 residues that result in a non-functional enzyme. Analysis of enzymatic activity by heterologous expression in yeast support delA as the cause of low linolenic acid content in CS303TNKCA. Thus, we developed a TaqMan genotyping assay to associate delA with low linolenic acid content in segregating populations. Lines homozygous for delA had a linolenic acid content of 3.3 to 4.4%, and the variation at this locus accounted for 50.83 to 73.70% of the phenotypic variation. This molecular marker is a new tool to introgress the low linolenic acid trait into elite soybean cultivars and can be used to combine with high oleic trait markers to produce soybean with enhanced economic value. The advantage of using CS303TNKCA compared to other lines available in the literature is that this cultivar has good agronomic characteristics and is adapted to Brazilian conditions.

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes.

PubMed

Mullegama, Sureni V; Pugliesi, Loren; Burns, Brooke; Shah, Zalak; Tahir, Raiha; Gu, Yanghong; Nelson, David L; Elsea, Sarah H

2015-06-01

Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith-Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders.

Newborns' temperature submitted to radiant heat and to the Top Maternal device at birth.

PubMed

Albuquerque, Rosemeire Sartori de; Mariani, Corintio; Bersusa, Ana Aparecida Sanches; Dias, Vanessa Macedo; Silva, Maria Izabel Mota da

2016-08-08

to compare the axillar temperatures of newborns that are put immediately after birth in skin-to-skin contact under the Top Maternal device, as compared to those in a radiant heat crib. comparatives observational study of the case-control type about temperature of 60 babies born at the Obstetric Center and Normal Delivery Center of a public hospital of the municipality of Sao Paulo, being them: 29 receiving assistance in heated crib and 31 in skin-to skin contact, shielded by a cotton tissue placed on mother's thorax, called Top Maternal. the temperature of the babies of the skin-to-skin contact group presented higher values in a larger share of the time measures verified, as compared to those that were placed in radiant heat crib, independently from the place of birth. Differences between the two groups were not statistically significant. the study contributes to generate new knowledge, supporting the idea of keeping babies with their mothers immediately after birth protected with the Maternal Top, without harming their wellbeing, as it keeps the axillar temperature in recommendable levels. comparar a temperatura axilar dos recém-nascidos acomodados - imediatamente após o nascimento - em contato pele a pele, sob o Top Maternal, em berço de calor radiante. estudo comparativo observacional do tipo Caso-Controle sobre a temperatura de 60 bebês nascidos no Centro Obstétrico e Centro de Parto Normal de um hospital público do município de São Paulo, sendo: 29 assistidos em berço aquecido e 31 em contato pele a pele, protegidos por uma malha de algodão colocada sobre o tórax da mãe, denominada Top Maternal. a temperatura dos bebês do grupo de contato pele a pele teve maior valor na maioria dos tempos verificados comparada à dos que foram colocados em berço de calor radiante, independentemente do local de nascimento. A diferença entre os grupos não foi estatisticamente significante. o estudo contribui com a geração de um novo conhecimento que sustenta a manutenção dos bebês com suas mães imediatamente após o nascimento por meio do contato pele a pele protegidos pelo Top Maternal, sem prejuízos ao seu bem-estar, uma vez que a temperatura axilar se manteve em níveis recomendáveis. comparar la temperatura axilar de los recién nacidos (Rn) acomodados, inmediatamente después del nacimiento, en contacto piel con piel, bajo el Top Maternal, en cuna de calor radiante. estudio comparativo observacional del tipo Caso Control sobre la temperatura de 60 bebés nacidos en el Centro Obstétrico y Centro de Parto Normal de un hospital público del municipio de Sao Paulo, siendo: 29 asistidos en cuna calentada y 31 en contacto piel con piel, protegidos por un tejido de algodón colocado sobre el tórax de la madre, denominado Top Maternal. la temperatura de los bebés del grupo de contacto piel con piel fue más alta en la mayoría de los tiempos verificados, ello comparado con los que fueron colocados en cuna de calor radiante, independientemente del local de nacimiento. La diferencia entre los grupos no fue estadísticamente significativa. el estudio contribuye con la generación de un nuevo conocimiento que sustenta que se debe mantener a los bebés con sus madres inmediatamente después del nacimiento por medio del contacto piel con piel protegidos por el Top Maternal, sin perjuicios a su bienestar, una vez que la temperatura axilar se mantuvo en niveles recomendables.

[Influence of factors on independence of patients after stroke in early rehabilitation stage].

PubMed

Petruseviciene, Daiva; Krisciūnas, Aleksandras

2005-01-01

Brain stroke is the main cause of disability starting from age of 40 years. Due to this disability, a person loses his ability to work because of long-lasting disorders of biosocial functions. According to literature, occupational therapy for such patients, taking regard to their social, cultural and economic background, significantly increases their self-care and independence and helps to educate working skills. OBJECTIVE. To evaluate conditional disorders of patients with stroke under rehabilitation and to establish the influence of extent of brain damage, localization, age and gender on effectiveness of occupational therapy. Study included 47 men and 53 women diagnosed with brain ischemia or hemorrhage (ischemic or hemorrhagic stroke). Out of them, 30 were of working age (18-59 years old) and 70 of non-working age (more than 60 years old). The mean age was 63.4+/-1.2 years. In order to assess the functional status of patients, they were tested using the Functional Independence Measure (FIM). At the start of rehabilitation, the mean FIM score was 47.4+/-16.1 (48.9+/-15.6 for men and 46.3+/-16.6 for women, p>0.05). At the end of early rehabilitation, the mean FIM score reached up to 89.9+/-22.3 (94.7+/-18.9 for men and 85.7+/-24.3 for women, p<0.05). Evaluation of functional status showed that at the start of rehabilitation functional status was worse in women than men, nevertheless, women's functional status improved during rehabilitation, though the difference between men and women still remained. Occupational therapy was less effective for patients who suffered from hemiplegia than for patients with hemiparesis (p<0.01). Older patients (more than 60 years) had more expressed functional disorders, and worse functional recovery comparing with younger, working age patients (18-59 years old). Evaluation of occupational therapy effectiveness at the end of early rehabilitation showed that extent of brain damage influences independence of patients suffering from brain stroke (p<0.01).

Prognostic Value of Improved Kidney Function After Transcatheter Aortic Valve Implantation for Aortic Stenosis.

PubMed

Nijenhuis, Vincent Johan; Peper, Joyce; Vorselaars, Veronique M M; Swaans, Martin J; De Kroon, Thom; Van der Heyden, Jan A S; Rensing, Benno J W M; Heijmen, Robin; Bos, Willem-Jan W; Ten Berg, Jurrien M

2018-05-15

Transcatheter aortic valve implantation (TAVI) is associated with acute kidney injury (AKI), but can also improve the kidney function (IKF). We assessed the effects of kidney function changes in relation to baseline kidney function on 2-year clinical outcomes after TAVI. In total, 639 consecutive patients with aortic stenosis who underwent TAVI were stratified into 3 groups according to the ratio of serum creatinine post- to pre-TAVI: IKF (≤0.80; n = 95 [15%]), stable kidney function (0.80 to 1.5; n = 477 [75%]), and AKI (≥1.5; n = 67 [10%]). Different AKI risk scores were compared using receiving-operator characteristics. Median follow-up was 24 (8 to 44) months. At 3 months, the increase in estimated glomerular filtration rate in the IKF group remained, and the decreased estimated glomerular filtration rate in the AKI group recovered. Compared with a stable kidney function, AKI showed a higher 2-year mortality rate (adjusted hazard ratio [HR] 3.69, 95% confidence interval [CI] 2.43 to 5.62) and IKF a lower mortality rate (adjusted hazard ratio 0.53, 95% CI 0.30 to 0.93). AKI also predicted major and life-threatening bleeding (adjusted odds ratio 2.94, 95% CI 1.27 to 6.78). Independent predictors of AKI were chronic kidney disease and pulmonary hypertension. Independent predictors of IKF were female gender, a preserved kidney function, absence of atrial fibrillation, and hemoglobin level. Established AKI risk scores performed moderately and did not differentiate between AKI and IKF. In conclusion, AKI is transient and is independently associated with a higher mortality rate, whereas IKF is sustained and is associated with a lower mortality rate. These effects are independent of baseline kidney function. Further studies are warranted to investigate the role of IKF and generate a dedicated prediction model. Copyright © 2018 Elsevier Inc. All rights reserved.

Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein

PubMed Central

Beckman, Joshua A.; Liao, James K.; Hurley, Shauna; Garrett, Leslie A.; Chui, Daoshan; Mitra, Debi; Creager, Mark A.

2009-01-01

Cigarette smoking impairs endothelial function. Hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins) may favorably affect endothelial function via nonlipid mechanisms. We tested the hypothesis that statins would improve endothelial function independent of changes in lipids in cigarette smokers. Twenty normocholesterolemic cigarette smokers and 20 matched healthy control subjects were randomized to atorvastatin 40 mg daily or placebo for 4 weeks, washed out for 4 weeks, and then crossed-over to the other treatment. Baseline low-density lipoprotein (LDL) levels were similar in smokers and healthy subjects, 103±22 versus 95±27 mg/dL, respectively (P=NS) and were reduced similarly in smokers and control subjects by atorvastatin, to 55±30 and 58±20 mg/dL, respectively (P=NS). Vascular ultrasonography was used to determine brachial artery, flow-mediated, endothelium-dependent, and nitroglycerin-mediated, endothelium-independent vasodilation. To elucidate potential molecular mechanisms that may account for changes in endothelial function, skin biopsy specimens were assayed for eNOS mRNA, eNOS activity, and nitrotyrosine. Endothelium-dependent vasodilation was less in smokers than nonsmoking control subjects during placebo treatment, 8.0±0.6% versus 12.1±1.1%, (P=0.003). Atorvastatin increased endothelium-dependent vasodilation in smokers to 10.5±1.3% (P=0.017 versus placebo) but did not change endothelium-dependent vasodilation in control subjects (to 11.0±0.8%, P=NS). Endothelium-independent vasodilation did not differ between groups during placebo treatment and was not significantly affected by atorvastatin. Multivariate analysis did not demonstrate any association between baseline lipid levels or the change in lipid levels and endothelium-dependent vasodilation. Cutaneous nitrotyrosine levels and skin microvessel eNOS mRNA, but not ENOS activity, were increased in smokers compared with controls but unaffected by atorvastatin treatment. Atorvastatin restores endothelium-dependent vasodilation in normocholesterolemic cigarette smokers independent of changes in lipids. These results are consistent with a lipid-independent vascular benefit of statins but could not be explained by changes in eNOS message and tissue oxidative stress. These findings implicate a potential role for statin therapy to restore endothelial function and thereby investigate vascular disease in cigarette smokers. PMID:15178637

The impact of subjective cognitive fatigue and depression on cognitive function in patients with multiple sclerosis.

PubMed

Golan, Daniel; Doniger, Glen M; Wissemann, Karl; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Fafard, Lori; Lavi, Idit; Wilken, Jeffrey; Gudesblatt, Mark

2018-02-01

The association between subjective cognitive fatigue and objective cognitive dysfunction in patients with multiple sclerosis (PwMS) has been studied, with conflicting results. To explore the impact of fatigue on cognitive function, while controlling for the influence of depression, disability, comorbidities, and psychotropic medications. PwMS completed a computerized cognitive testing battery with age- and education-adjusted cognitive domain scores. Disability (Expanded Disability Status Scale (EDSS)), cognitive fatigue, and depression were concurrently evaluated. In all, 699 PwMS were included. Both cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: information processing speed, executive function, attention, motor function, and memory (-0.15 ⩽ r ⩽ -0.14 for cognitive fatigue; -0.24 ⩽ r ⩽ -0.19 for depression). Multivariate analysis revealed significant but small independent correlations only between depression and neuropsychological test results, while cognitive fatigue had no independent correlation with objective cognitive function except for a trend toward impaired motor function in highly fatigued PwMS. Depression and cognitive fatigue accounted for no more than 6% of the variance in objective cognitive domain scores. Cognitive fatigue is not independently related to objective cognitive impairment. Depression may influence cognitive function of PwMS primarily when it is severe. Cognitive impairment in PwMS should not be ascribed to fatigue or mild depression.