Background:Visual salience computed using algorithmic procedures have been shown to predict eye-movements in a number of contexts.However,despite calls to incorporate computationally-defined visual salience metrics as...Background:Visual salience computed using algorithmic procedures have been shown to predict eye-movements in a number of contexts.However,despite calls to incorporate computationally-defined visual salience metrics as a means of assessing the effectiveness of advertisements,few studies have incorporated these techniques in a marketing context.The present study sought to determine the impact of visual salience and knowledge of a brand on eye-movement patterns and buying preferences.Methods:Participants(N=38)were presented with 54 pairs of products presented on the left and right sides of a blank white screen.For each pair,one product was a known North American product,such as Fresca®,and one was an unknown British product of the same category,such as Irn Bru®.Participants were asked to select which product they would prefer to buy while their eye movements were recorded.Salience was computed using Itti&Koch’s[2001]computational model of bottom-up salience.Products were defined as highly salient if the majority of the first five predicted fixations were in the region of the product.Results:Results showed that participants were much more likely to prefer to buy known products,and tentative evidence suggests that participants had longer total dwell times when looking at unknown products.Salience appears to have had little or no effect on preference for a product,nor did it predict total dwell time or time to first fixation.There also appears to be no interaction between knowledge of a product and visual salience on any of the measures analyzed.Conclusions:The results indicate that product salience may not be a useful predictor of attention under the constraints of the present experiment.Future studies could use a different operational definition of visual salience which might be more predictive of visual attention.Furthermore,a more fine-grained analysis of product familiarity based on survey data may reveal patterns obscured by the definitional constraints of the present study.展开更多
Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously boun...Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq.The AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT transcription.The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related phenotypes.Methods We used in silico,in vitro,in vivo,and retrospective models to test this hypothesis.Results In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT mRNA.Unexpectedly,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression model.Genotype-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>T.However,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with HTN.Conclusions We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White participants.Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G.Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.展开更多
Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcr...Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcription,translation,DNA damage repair etc.,and it is upregulated during times of environmental stress.YBX1 is localized in both the cytoplasm and the nucleus.There,its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression.Additionally,YBX1 expression is upregulated in a variety of cancers,pointing towards its role as a potential oncogene.Under certain circumstances,YBX1 also promotes the expression of multidrug resistance 1(MDR1)gene,which is involved in the development of drug resistance.Thus,it is critical to understand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development.A number of recent studies have highlighted the mechanisms of YBX1 regulation.Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function.Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently,S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth.This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1.This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation,which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.展开更多
Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resourc...Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval.Protein arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer therapy.Previously,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in cancers.In this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in vitro.Furthermore,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug treatment.Using in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity.Finally,Clo and Can treatment have exhibited marked reduction in tumor growth in vivo.Overall,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies.Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.展开更多
文摘Background:Visual salience computed using algorithmic procedures have been shown to predict eye-movements in a number of contexts.However,despite calls to incorporate computationally-defined visual salience metrics as a means of assessing the effectiveness of advertisements,few studies have incorporated these techniques in a marketing context.The present study sought to determine the impact of visual salience and knowledge of a brand on eye-movement patterns and buying preferences.Methods:Participants(N=38)were presented with 54 pairs of products presented on the left and right sides of a blank white screen.For each pair,one product was a known North American product,such as Fresca®,and one was an unknown British product of the same category,such as Irn Bru®.Participants were asked to select which product they would prefer to buy while their eye movements were recorded.Salience was computed using Itti&Koch’s[2001]computational model of bottom-up salience.Products were defined as highly salient if the majority of the first five predicted fixations were in the region of the product.Results:Results showed that participants were much more likely to prefer to buy known products,and tentative evidence suggests that participants had longer total dwell times when looking at unknown products.Salience appears to have had little or no effect on preference for a product,nor did it predict total dwell time or time to first fixation.There also appears to be no interaction between knowledge of a product and visual salience on any of the measures analyzed.Conclusions:The results indicate that product salience may not be a useful predictor of attention under the constraints of the present experiment.Future studies could use a different operational definition of visual salience which might be more predictive of visual attention.Furthermore,a more fine-grained analysis of product familiarity based on survey data may reveal patterns obscured by the definitional constraints of the present study.
基金National Center for Research Resources,Grant/Award Number:RR020128NHGRI,National Institute of General Medical Sciences,Grant/Award Numbers:1R01GM120156-01A1,K23GM147805,R35GM131812,T32GM008425+3 种基金NHLBI,NINDS,NCI,Grant/Award Number:1R03CA223906-01NIDA,NIMH,Office of the Director of the National Institutes of Health,Indiana University School of Medicine,Grant/Award Number:NIH/NCRRRR020128NIH-NIGMS,Grant/Award Numbers:t32gm008425,r35gm131812,1r01gm120156-01a1,k23gm147805NIH-NCI,Grant/Award Number:1R03CA223906-01。
文摘Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq.The AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT transcription.The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related phenotypes.Methods We used in silico,in vitro,in vivo,and retrospective models to test this hypothesis.Results In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT mRNA.Unexpectedly,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression model.Genotype-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>T.However,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with HTN.Conclusions We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White participants.Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G.Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.
基金This research is supported by grants 4186265(American Cancer Society)and 23-862-07 and 036433730102(Indiana University)to TL.
文摘Y box binding protein-1(YBX1)belongs to a DNA-and RNA-binding family of transcription factors,containing the highly conserved cold shock domain(CSD).YBX1 is involved in a number of cellular functions including transcription,translation,DNA damage repair etc.,and it is upregulated during times of environmental stress.YBX1 is localized in both the cytoplasm and the nucleus.There,its nuclear translocation is observed in a number of cancers and is associated with poor prognosis and disease progression.Additionally,YBX1 expression is upregulated in a variety of cancers,pointing towards its role as a potential oncogene.Under certain circumstances,YBX1 also promotes the expression of multidrug resistance 1(MDR1)gene,which is involved in the development of drug resistance.Thus,it is critical to understand the mechanism of YBX1 regulation and its downstream effects on promoting cancer development.A number of recent studies have highlighted the mechanisms of YBX1 regulation.Mass spectrometric analyses have reported several post-translational modifications that possibly play an important role in modulating YBX1 function.Phosphorylation is the most widely occurring post-translational modification in YBX1.In vivo analyses of sites like S102 and more recently,S165 illustrate the relationship of post-translational regulation of YBX1 in promoting cell proliferation and tumor growth.This review provides a comprehensive and up-to-date account of post-translational modifications identified in YBX1.This knowledge is a key in allowing us to better understand the mechanism of YBX1 regulation,which will aid in development of novel therapeutic strategies to target YBX1 in many types of cancer in the future.
基金This work was supported by grants from Indiana Center for Technology and Science Innovation(CTSl),USA(No.2286230 to TL)and Indiana Drug Discovery Alliance(IDDA),USA(No.2286233 to TL),both are funded in part by National Institutes of Health,USA(No.UL1TR002529)National Institutes of Health,USA(No.1R01GM120156-01A1 to TL+5 种基金No.R03 CA223906-01 to TL)This work was also supported by National Institutes of Health,USA(No.P41-GM103426 and DP20D007237 to REA),National Science Foundation,USA(No.CHE060073N to REA)National Institutes of Health,USA(No.R01 CA069202 to ZYZ)MLF and MRK were supported by IUSCCC Cancer Center,USA(No.P30 CA082709),National Institutes of Health,USA(No.R01CA167291and R01CA254110).MRK was also supported by National Institutes of Health,USA(No.R01CA205166,R01CA231267,and R01HL140961)MLF was also supported by National Institutes of Health,USA(No.R01CA211098,U01HL143403,and NF180045)MLF and MRK were additionally supported by the Riley Children's Foundation,USA.
文摘Market drugs,suchas Foodand Drug Administration(FDA)or European Medicines Agency(EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics.This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval.Protein arginine methyltransferase 5(PRMT5)overexpression has been linked to promoting the tumor phenotype in several cancers,including pancreatic ductal adenocarcinoma(PDAC),colorectal cancer(CRC),and breast cancer(BC),making PRMT5 an important target for cancer therapy.Previously,we showed that PRMT5-mediated methylation of the nuclear factor(NF)-kB,partially contributes to its constitutive activation observed in cancers.In this study,we utilized an AlphaLiSA-based high-throughput screening method adapted in our lab,and identified one FDA-approved drug,Candesartan cilexetil(Can,used in hypertension treatment)and one EMA-approved drug,Cloperastine hydrochloride(Clo,used in cough treatment)that had significant PRMT5-inhibitory activity,and their anti-tumor properties were validated using cancer phenotypic assays in vitro.Furthermore,PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-kB methylation and its subsequent activation upon drug treatment.Using in silico prediction,we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity.Finally,Clo and Can treatment have exhibited marked reduction in tumor growth in vivo.Overall,we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies.Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.