Fold Decrease (fold + decrease)

Distribution by Scientific Domains


Selected Abstracts


Substrate and inhibitor specificity of Mycobacterium avium dihydrofolate reductase

FEBS JOURNAL, Issue 13 2007
Ronnie A. Böck
Dihydrofolate reductase (EC 1.5.1.3) is a key enzyme in the folate biosynthetic pathway. Information regarding key residues in the dihydrofolate-binding site of Mycobacterium avium dihydrofolate reductase is lacking. On the basis of previous information, Asp31 and Leu32 were selected as residues that are potentially important in interactions with dihydrofolate and antifolates (e.g. trimethoprim), respectively. Asp31 and Leu32 were modified by site-directed mutagenesis, giving the mutants D31A, D31E, D31Q, D31N and D31L, and L32A, L32F and L32D. Mutated proteins were expressed in Escherichia coli BL21(DE3)pLysS and purified using His-Bind resin; functionality was assessed in comparison with the recombinant wild type by a standard enzyme assay, and growth complementation and kinetic parameters were evaluated. All Asp31 substitutions affected enzyme function; D31E, D31Q and D31N reduced activity by 80,90%, and D31A and D31L by >,90%. All D31 mutants had modified kinetics, ranging from three-fold (D31N) to 283-fold (D31L) increases in Km for dihydrofolate, and 12-fold (D31N) to 223 077-fold (D31L) decreases in kcat/Km. Of the Leu32 substitutions, only L32D caused reduced enzyme activity (67%) and kinetic differences from the wild type (seven-fold increase in Km; 21-fold decrease in kcat/Km). Only minor variations in the Km for NADPH were observed for all substitutions. Whereas the L32F mutant retained similar trimethoprim affinity as the wild type, the L32A mutation resulted in a 12-fold decrease in affinity and the L32D mutation resulted in a seven-fold increase in affinity for trimethoprim. These findings support the hypotheses that Asp31 plays a functional role in binding of the substrate and Leu32 plays a functional role in binding of trimethoprim. [source]


Water Stability and Luminescence of Lanthanide Complexes of Tripodal Ligands Derived from 1,4,7-Triazacyclononane: Pyridinecarboxamide versus Pyridinecarboxylate Donors

HELVETICA CHIMICA ACTA, Issue 11 2009
Grégory Nocton
Abstract A series of europium(III) and terbium(III) complexes of three 1,4,7-triazacyclononane-based pyridine containing ligands were synthesized. The three ligands differ from each other in the substitution of the pyridine pendant arm, namely they have a carboxylic acid, an ethylamide, or an ethyl ester substituent, i.e., these ligands are 6,6,,6,-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[pyridine-2-carboxylic acid] (H3tpatcn), -tris[pyridine-2-carboxamide] (tpatcnam), and -tris[pyridine-2-carboxylic acid] triethyl ester (tpatcnes) respectively. The quantum yields of both the europium(III) and terbium(III) emission, upon ligand excitation, were highly dependent upon ligand substitution, with a ca. 50-fold decrease for the carboxamide derivative in comparison to the picolinic acid (=pyridine-2-carboxylic acid) based ligand. Detailed analysis of the radiative rate constants and the energy of the triplet states for the three ligand systems revealed a less efficient energy transfer for the carboxamide-based systems. The stability of the three ligand systems in H2O was investigated. Although hydrolysis of the ethyl ester occurred in H2O for the [Ln(tpatcnes)](OTf)3 complexes, the tripositive [Ln(tpatcnam)](OTf)3 complexes and the neutral [Ln(tpatcn)] complexes showed high stability in H2O which makes them suitable for application in biological media. The [Tb(tpatcn)] complex formed easily in H2O and was thermodynamically stable at physiological pH (pTb 14.9), whereas the [Ln(tpatcnam)](OTf)3 complexes showed a very high kinetic stability in H2O, and once prepared in organic solvents, remained undissociated in H2O. [source]


CD8+ T-cell interaction with HCV replicon cells: Evidence for both cytokine- and cell-mediated antiviral activity

HEPATOLOGY, Issue 6 2003
Chen Liu
The interaction between the host immune response and infected hepatocytes plays a central role in the pathogenesis of hepatitis C virus (HCV). The lack of a suitable animal or in vitro model has hindered our understanding of the host T-cell/HCV interaction. Our aim was to develop an in vitro model to study the mechanisms of HCV-specific T-cell-mediated antiviral and cytolytic function. The HCV replicon was HLA typed and lymphocytes were obtained from an HLA class I-matched subject. CD8+ T cells were expanded with 2 HCV-specific/HLA-restricted peptides for NS3. Lymphocyte preparations were cocultured with HCV replicon (FCA1) and control (Huh7) cells labeled with 51Cr. After a 48-hour incubation, the cells were harvested for RNA extraction. Standard blocking assays were performed in the presence of anti-interferon gamma (IFN-,), anti-tumor necrosis factor , (TNF-,), and anti-FasL. Cytolytic activity was measured by 51Cr release. HCV replicon cells express homozygous HLA-A11 alleles and present HCV nonstructural proteins. HCV-specific expansion of CD8+ cells led to a 10-fold decrease in HCV replication by Northern blot analysis and 21% specific lysis of FCA1 cells (compared with 2% of control Huh7 cells). Twenty percent of this antiviral activity was independent of T-cell binding, suggesting cytokine-mediated antiviral activity. The CD8+ antiviral effect was markedly reduced by blocking either IFN-, or FasL but was unaffected by blocking TNF-,. In conclusion, HCV-specific CD8+ cells inhibit viral RNA replication by cytokine-mediated and direct cytolytic effects. This T-cell/HCV subgenomic replicon system represents a model for the investigation of CD8 cell interaction with HCV-infected hepatocytes. [source]


Effects of modification of membrane lipid composition on Bacillus subtilis sporulation and spore properties

JOURNAL OF APPLIED MICROBIOLOGY, Issue 6 2009
K.K. Griffiths
Abstract Aims:, To determine effects of inner membrane lipid composition on Bacillus subtilis sporulation and spore properties. Methods and Results:, The absence of genes encoding lipid biosynthetic enzymes had no effect on B. subtilis sporulation, although the expected lipids were absent from spores' inner membrane. The rate of spore germination with nutrients was decreased c. 50% with mutants that lacked the major cardiolipin (CL) synthase and another enzyme for synthesis of a major phospholipid. Spores lacking the minor CL synthase or an enzyme essential for glycolipid synthesis exhibited 50,150% increases in rates of dodecylamine germination, while spores lacking enzymes for phosphatidylethanolamine (PE), phosphatidylserine (PS) and lysylphosphatidylglycerol (l-PG) synthesis exhibited a 30,50% decrease. Spore sensitivity to H2O2 and tert-butylhydroperoxide was increased 30,60% in the absence of the major CL synthase, but these spores' sensitivity to NaOCl or OxoneÔ was unaffected. Spores of lipid synthesis mutants were less resistant to wet heat, with spores lacking enzymes for PE, PS or l-PG synthesis exhibiting a two to threefold decrease and spores of other strains exhibiting a four to 10-fold decrease. The decrease in spore wet heat resistance correlated with an increase in core water content. Conclusions:, Changing the lipid composition of the B. subtilis inner membrane did not affect sporulation, although modest effects on spore germination and wet heat and oxidizing agent sensitivity were observed, especially when multiple lipids were absent. The increases in rates of dodecylamine germination were likely due to increased ability of this compound to interact with the spore's inner membrane in the absence of some CL and glycolipids. The effects on spore wet heat sensitivity are likely indirect, because they were correlated with changes in core water content. Significance and Impact of the Study:, The results of this study provide insight into roles of inner membrane lipids in spore properties. [source]


WATER QUALITY IMPACTS AND INDICATORS OF METABOLIC ACTIVITY OF THE ZEBRA MUSSEL INVASION OF THE SENECA RIVER,

JOURNAL OF THE AMERICAN WATER RESOURCES ASSOCIATION, Issue 3 2004
Steven W. Effler
ABSTRACT: The conspicuous shifts in summertime values of common measures of water qualify that have persisted for 10 years (1993 to 2002) in the Seneca River, New York, as a result of the zebra mussel invasion are documented. Resolution of patterns in time and space is supported by water quality monitoring that extends back to the late 1970s. Patterns are evaluated to describe the stability of impacts and quantify metabolic activity of the invader. The water quality impacts that have persisted unabated for 10 years since the invasion are the most severe documented for a river in North America. Changes in summer median conditions since the invasion include: (1) a 16-fold decrease in chlorophyll concentration (Chi), (2) a 2.5-fold increase in Secchi disc transparency, (3) a 17-fold increase in soluble reactive phosphorus concentration, (4) a 3.7-fold increase in total ammonia concentration, (5) a greater than 25 percent decrease in dissolved oxygen (DO) concentration, and (6) a decrease in pH of 0.55 units. The strength of these signatures has been driven by anthropogenic influences that include upstream nutrient loading and morphometric modifications of the river, and the functioning of Cross Lake, through which the river flows. This hypereutrophic lake sustains dense zebra mussel populations and related water quality impacts in the river downstream of the lake outflow by acting as a source of veligers and suitable food for this bivalve. Evidence is presented that levels of metabolic activity of the zebra mussel in this river have been resource limited, manifested through increased consumption of Chl and DO with increased delivery of these constituents in the lake's outflow. [source]


FIELD EXPERIMENTS SHOW THAT ACOUSTIC PINGERS REDUCE MARINE MAMMAL BYCATCH IN THE CALIFORNIA DRIFT GILL NET FISHERY

MARINE MAMMAL SCIENCE, Issue 2 2003
Jay Barlow
Abstract A controlled experiment was carried out in 1996,1997 to determine whether acoustic deterrent devices (pingers) reduce marine mammal bycatch in the California drift gill net fishery for swordfish and sharks. Using Fisher's exact test, bycatch rates with pingers were significantly less for all cetacean species combined (P < 0.001) and for all pinniped species combined (P= 0.003). For species tested separately with this test, bycatch reduction was statistically significant for short-beaked common dolphins (P= 0.001) and California sea lions (P= 0.02). Bycatch reduction is not statistically significant for the other species tested separately, but sample sizes and statistical power were low, and bycatch rates were lower in pingered nets for six of the eight other cetacean and pinniped species. A log-linear model relating the mean rate of entanglement to the number of pingers deployed was fit to the data for three groups: short-beaked common dolphins, other cetaceans, and pinnipeds. For a net with 40 pingers, the models predict approximately a 12-fold decrease in entanglement for short-beaked common dolphins, a 4-fold decrease for other cetaceans, and a 3-fold decrease for pinnipeds. No other variables were found that could explain this effect. The pinger experiment ended when regulations were enacted to make pingers mandatory in this fishery. [source]


Casein-specific immunoglobulins in cow's milk allergic patient subgroups reveal a shift to IgA dominance in tolerant patients

PEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 1 2007
Gaynour B. G. Sletten
Differences in casein-specific immunoglobulin (Ig) G-subclass and IgA serum levels between reactive and tolerant patients may hint at the immunopathogenesis during tolerance development in cow's milk allergy (CMA). , -, ,- and , -casein-specific IgG1, IgG4, IgE and IgA serum levels were compared in clinically reactive and tolerized IgE-mediated (n = 15) and non-IgE-mediated (n = 14) CMA with delayed gastrointestinal symptoms, using enzyme-linked immunosorbent assay (ELISA) and immunoblot techniques. The median anti-casein IgE levels in clinically reactive IgE-mediated CMA patients (n = 9) were 140- to 180-fold higher than in tolerized patients (n = 6) and 160- to 200-fold higher than in controls (n = 10). Median , -, ,- and , -casein-specific IgG1 and IgG4 levels were nine- to 60-fold higher in reactive patients and five- to 60-fold in tolerized patients. Clinical tolerance in IgE-mediated CMA was thus associated with decreased casein-specific IgE, IgG4 and IgG1, whereas serum IgA anti- , -, , - and , -casein remained practically unaltered. Tolerized cow's milk protein (CMP)-sensitive atopic dermatitis had, in particular, decreased , -casein-specific IgG1 levels, compared with clinically reactive patients. The ELISA levels to immunoblot correlation profile for the , -, , - and , -casein-specific IgE suggested that the IgE-mediated CMA patients predominantly reacted to tertiary , - and , -casein epitopes whereas the IgE in non-IgE-mediated patients reacted to linearized , -, , - and , -casein epitopes. Clinical tolerance in non-IgE-mediated CMA patients (n = 9) was associated with a four- to 10-fold decrease in casein-specific IgE levels, accompanied by a five- to eightfold decrease in IgG1 and five- to 60-fold decrease in IgG4 levels, whereas casein-specific IgA levels remained unaltered. Thus, tolerance in both patient groups was characterized by a generalized decreased humoral immune response to caseins, which induced a functional shift to IgA dominance. [source]


Re-examining the role of Lys67 in class C ,-lactamase catalysis

PROTEIN SCIENCE, Issue 3 2009
Yu Chen
Abstract Lys67 is essential for the hydrolysis reaction mediated by class C ,-lactamases. Its exact catalytic role lies at the center of several different proposed reaction mechanisms, particularly for the deacylation step, and has been intensely debated. Whereas a conjugate base hypothesis postulates that a neutral Lys67 and Tyr150 act together to deprotonate the deacylating water, previous experiments on the K67R mutants of class C ,-lactamases suggested that the role of Lys67 in deacylation is mainly electrostatic, with only a 2- to 3-fold decrease in the rate of the mutant vs the wild type enzyme. Using the Class C ,-lactamase AmpC, we have reinvestigated the activity of this K67R mutant enzyme, using biochemical and structural studies. Both the rates of acylation and deacylation were affected in the AmpC K67R mutant, with a 61-fold decrease in kcat, the deacylation rate. We have determined the structure of the K67R mutant by X-ray crystallography both in apo and transition state-analog complexed forms, and observed only minimal conformational changes in the catalytic residues relative to the wild type. These results suggest that the arginine side chain is unable to play the same catalytic role as Lys67 in either the acylation or deacylation reactions catalyzed by AmpC. Therefore, the activity of this mutant can not be used to discredit the conjugate base hypothesis as previously concluded, although the reaction catalyzed by the K67R mutant itself likely proceeds by an alternative mechanism. Indeed, a manifold of mechanisms may contribute to hydrolysis in class C ,-lactamases, depending on the enzyme (wt or mutant) and the substrate, explaining why different mutants and substrates seem to support different pathways. For the WT enzyme itself, the conjugate base mechanism may be well favored. [source]


Characterization of Herpes Simplex Virus type 1 thymidine kinase mutants engineered for improved ganciclovir or acyclovir activity

PROTEIN SCIENCE, Issue 9 2002
Mark S. Kokoris
Abstract Herpes Simplex Virus type 1 (HSV-1) thymidine kinase (TK) is currently the most widely used suicide agent for gene therapy of cancer. Tumor cells that express HSV-1 thymidine kinase are rendered sensitive to prodrugs due to preferential phosphorylation by this enzyme. Although ganciclovir (GCV) is the prodrug of choice for use with TK, this approach is limited in part by the toxicity of this prodrug. From a random mutagenesis library, seven thymidine kinase variants containing multiple amino acid substitutions were identified on the basis of activity towards ganciclovir and acyclovir based on negative selection in Escherichia coli. Using a novel affinity chromatography column, three mutant enzymes and the wild-type TK were purified to homogeneity and their kinetic parameters for thymidine, ganciclovir, and acyclovir determined. With ganciclovir as the substrate, one mutant (mutant SR39) demonstrated a 14-fold decrease in Km compared to the wild-type enzyme. The most dramatic change is displayed by mutant SR26, with a 124-fold decrease in Km with acyclovir as the substrate. Such new "prodrug kinases" could provide benefit to ablative gene therapy by now making it feasible to use the relatively nontoxic acyclovir at nanomolar concentrations or ganciclovir at lower, less immunosuppressive doses. [source]


The C-terminal domain of biotin protein ligase from E. coli is required for catalytic activity

PROTEIN SCIENCE, Issue 12 2001
Anne Chapman-Smith
BCCP, biotin carboxyl carrier protein; IPTG, isopropyl-1-thio-,-D-galactopyranoside; PAGE, polyacrylamide gel electrophoresis; S.D., standard deviation Abstract Biotin protein ligase of Escherichia coli, the BirA protein, catalyses the covalent attachment of the biotin prosthetic group to a specific lysine of the biotin carboxyl carrier protein (BCCP) subunit of acetyl-CoA carboxylase. BirA also functions to repress the biotin biosynthetic operon and synthesizes its own corepressor, biotinyl-5,-AMP, the catalytic intermediate in the biotinylation reaction. We have previously identified two charge substitution mutants in BCCP, E119K, and E147K that are poorly biotinylated by BirA. Here we used site-directed mutagenesis to investigate residues in BirA that may interact with E119 or E147 in BCCP. None of the complementary charge substitution mutations at selected residues in BirA restored activity to wild-type levels when assayed with our BCCP mutant substrates. However, a BirA variant, in which K277 of the C-terminal domain was substituted with Glu, had significantly higher activity with E119K BCCP than did wild-type BirA. No function has been identified previously for the BirA C-terminal domain, which is distinct from the central domain thought to contain the ATP binding site and is known to contain the biotin binding site. Kinetic analysis of several purified mutant enzymes indicated that a single amino acid substitution within the C-terminal domain (R317E) and located some distance from the presumptive ATP binding site resulted in a 25-fold decrease in the affinity for ATP. Our data indicate that the C-terminal domain of BirA is essential for the catalytic activity of the enzyme and contributes to the interaction with ATP and the protein substrate, the BCCP biotin domain. [source]


Evidence for downregulation of calcium signaling proteins in advanced mouse adenocarcinoma

THE PROSTATE, Issue 2 2005
Viola C. Ruddat
Abstract BACKGROUND Prostate cancer (PCa) is the leading cancer related death in America. Gleason grading is currently the predominant method for prediction, with only few biomarkers available. More biomarkers, especially as they relate to cancer progression are desirable. METHODS The abundance of several important proteins in prostate tissue was compared between wild-type mouse dorsal prostate and well-differentiated transgenic adenocarcinoma mouse prostate (TRAMP) mouse dorsal prostates, and between wild-type mouse dorsal prostate and poorly-differentiated TRAMP mouse tumor tissue. 2DIGE method in conjunction with MALDI-ToF and Western blots was used to determine differential expression. RESULTS In TRAMP dorsal prostates with well-differentiated adenocarcinoma, there were few significant changes in the protein abundances compared to wild-type dorsal prostates, with the exception of increases in proliferating cell nuclear antigen (PCNA) and beta tubulin, two proteins implicated in cell proliferation, and a more than 2-fold increase in Hsp60, a protein involved in the suppression of apoptosis. In the poorly-differentiated tumors, the changes in protein abundance were substantial. While some of those changes could be related to the disappearance of stromal tissue or the appearance of epithelial tissue, other changes in protein abundance were more significant to the cancer development itself. Most notable was the overall decrease in calcium homeostasis proteins with a 10-fold decrease in calreticulin and Hsp70 and a 40-fold decrease in creatine kinase bb in the cancerous tissue. CONCLUSIONS Proteomics of TRAMP mice provide an excellent method to observe changes in protein abundance, revealing changes in pathways during cancer progression. © 2005 Wiley-Liss, Inc. [source]


Defective sperm decondensation: a cause for fertilization failure

ANDROLOGIA, Issue 1 2002
A. D. Esterhuizen
Summary. The study aimed to evaluate the role of chromatin packaging (CMA3 staining), sperm morphology during sperm-zona binding, sperm decondensation and the presence of polar bodies in oocytes that failed in vitro fertilization (IVF). The percentage CMA3 staining categorized the data into three groups, < 44%, n = 10; , 44,59%, n = 10; and ,60%, n = 29. Morphology groups were ,,4% (n = 11); > 4,14% (n = 19); and >14% (n = 19). One hundred and seventy-two oocytes that failed IVF were evaluated for sperm-zona binding, ooplasma penetration and sperm decondensation. Odds ratio analyses indicated that being in the ,60% CMA3 staining group resulted in a 15.6 fold increase in the risk of decondensation failure, relative to CMA3 staining of <44%. For morphology, there was a 2.17 fold decrease in the risk of fertilization failure in the morphology group with >4,14% normal cells, while it increased 2.45 fold for the morphology group with ,4% normal cells. Using CMA3 fluorescence to discriminate, 51% of the oocytes in the group with elevated CMA3 fluorescence had no sperm in the ooplasma compared to 32% and 16% penetration failure in the CMA3 staining groups ,44,59% and <44%, respectively. Sperm chromatin packaging quality and sperm morphology assessments are useful clinical indicators of human fertilization failure. Immunofluorescence techniques could be used to provide a clear diagnosis of failed fertilization. [source]


Managing invasive carp (Cyprinus carpio L.) for habitat enhancement at Botany Wetlands, Australia

AQUATIC CONSERVATION: MARINE AND FRESHWATER ECOSYSTEMS, Issue 5 2005
L. Pinto
Abstract 1.In Australia, the carp Cyprinus carpio L. is regarded as a threat to the native fish and the aquatic environment. In recent years, Botany Wetlands, a significant coastal wetland in the Sydney region, has been invaded by the undesirable cyprinids, carp and goldfish (Carrasius auratus L.). 2.In 1996 a cyprinid removal programme commenced at Botany Wetlands with the objective of managing the invasive species, increasing fish diversity, reducing cyanobacterial blooms and hence enhancing the aquatic habitat. Using electrofishing and gill netting, 4073 carp and 261 goldfish, amounting to 10 117 kg of cyprinid biomass were removed between 1996 and 2004. The captured carp ranged from 60 to 835 mm. Males matured before females. Carp between 350 and 680 mm in length grew at the rate of 1.66±0.38 g day,1. 3.The success of the programme was monitored by assessing four indicators related to carp populations and two related to habitat. The former included the pattern of length,frequency distribution, mean weight per size class, condition factor (CF) and the catch per unit effort (CPUE), and the latter the Secchi disc transparency and cyanobacterial counts. After 8 yr of removal, the plots of carp length,frequency distribution flattened, CF decreased from 2.86 to 1.82 and CPUE decreased from 97 kg day,1 to 50 kg day,1. A 10-fold decrease occurred in cyanobacterial counts and the Secchi disc transparency increased by 20%. More than 20 000 fingerlings of native Australian bass Macquaria novemaculeata (S.) have been introduced to the wetlands, increasing the potential for juvenile carp predation and biodiversity. Copyright © 2005 John Wiley & Sons, Ltd. [source]


,2 adrenergic receptor 5, haplotypes influence promoter activity

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2002
Sharon E Johnatty
Transcriptional control of the human ,2 adrenergic receptor gene (ADRB2) predominantly resides within a 549 base pair region immediately 5, to the start of translation. Within this region, four naturally occurring polymorphisms, ,468 C,G, ,367 T,C, ,47 T,C, and ,20 T,C, have been identified. To determine the individual site and haplotype effects of these polymorphisms, we generated 16 luciferase-based mutant constructs which were transiently transfected into HEK293 cells, and measured ADRB2 promoter-driven luciferase activity. Two of the 16 mutant constructs, GCCT (,468G, ,367C, ,47C, ,20T) and CTCT, showed a highly significant 3 fold decrease in luciferase induction relative to the reference CTTT. These haplotype effects could not be accounted for by the separate and additive effects of each site. These findings indicate that promoter polymorphisms interact to significantly alter ,2 adrenergic receptor expression, and should be examined further for their association with disease-related phenotypes. British Journal of Pharmacology (2002) 137, 1213,1216. doi:10.1038/sj.bjp.0704935 [source]


Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK-3,) and Alzheimer's disease risk

ACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009
I. Mateo
Objective,,, Glycogen synthase kinase-3, (GSK-3,) and cyclin-dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK-3, genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. Methods,,, In a case,control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3,-UTR, rs735555) and GSK-3, (,50, rs334558) polymorphisms on susceptibility to AD. Results,,, Subjects carrying both the CDK5R1 (3,-UTR, rs735555) AA genotype and the GSK-3, (,50, rs334558) CC genotype had a 12.5-fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01,0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. Conclusion,,, These data support a role for tau phosphorylation regulating genes in risk for AD. [source]