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Article ; Online: QTL mapping of rat blood pressure loci on RNO1 within a homologous region linked to human hypertension on HSA15.

Blair Mell / Xi Cheng / Bina Joe

PLoS ONE, Vol 14, Iss 8, p e

2019 Volume 0221658

Abstract: Fine-mapping of regions linked to the inheritance of hypertension is accomplished by genetic dissection of blood pressure quantitative trait loci (BP QTLs) in rats. The goal of the current study was to further fine-map two genomic regions on rat ... ...

Abstract	Fine-mapping of regions linked to the inheritance of hypertension is accomplished by genetic dissection of blood pressure quantitative trait loci (BP QTLs) in rats. The goal of the current study was to further fine-map two genomic regions on rat chromosome 1 with opposing blood pressure effects (BP QTL1b1 and BP QTL1b1a), the homologous region of which on human chromosome 15 harbors BP QTLs. Two new substrains were constructed and studied from the previously reported BP QTL1b1, one having significantly lower systolic BP by 17 mmHg than that of the salt-sensitive (S) rat (P = 0.007). The new limits of BP QTL1b1 were between 134.09 Mb and 135.40 Mb with a 43% improvement from the previous 2.31 Mb to the current 1.31 Mb interval containing 4 protein-coding genes (Rgma, Chd2, Fam174b, and St8sia2), 2 predicted miRNAs, and 4 lncRNAs. One new substrain was constructed and studied from the previously reported BPQTL1b1a having a significantly higher systolic BP by 22 mmHg (P = 0.006) than that of the S rat. The new limits of BPQTL1b1a were between 133.53 Mb and 134.52 Mb with a 32% improvement from the previous1.45 Mb to the current 990.21 Kb interval containing 1 protein-coding gene, Mctp2, and a lncRNA. The congenic segments of these two BP QTLs overlapped between 134.09 Mb and 134.52 Mb. No exonic variants were detected in any of the genes. These findings reiterate complexity of genetic regulation of BP within QTL regions, where elements beyond protein-coding sequences could be factors in controlling BP.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of Upstream Transcriptional Regulators of Ischemic Cardiomyopathy Using Cardiac RNA-Seq Meta-Analysis

Ahmad Alimadadi / Sachin Aryal / Ishan Manandhar / Bina Joe / Xi Cheng

International Journal of Molecular Sciences, Vol 21, Iss 3472, p

2020 Volume 3472

Abstract: Ischemic cardiomyopathy (ICM), characterized by pre-existing myocardial infarction or severe coronary artery disease, is the major cause of heart failure (HF). Identification of novel transcriptional regulators in ischemic HF can provide important ... ...

Abstract	Ischemic cardiomyopathy (ICM), characterized by pre-existing myocardial infarction or severe coronary artery disease, is the major cause of heart failure (HF). Identification of novel transcriptional regulators in ischemic HF can provide important biomarkers for developing new diagnostic and therapeutic strategies. In this study, we used four RNA-seq datasets from four different studies, including 41 ICM and 42 non-failing control (NF) samples of human left ventricle tissues, to perform the first RNA-seq meta-analysis in the field of clinical ICM, in order to identify important transcriptional regulators and their targeted genes involved in ICM. Our meta-analysis identified 911 differentially expressed genes (DEGs) with 582 downregulated and 329 upregulated. Interestingly, 54 new DEGs were detected only by meta-analysis but not in individual datasets. Upstream regulator analysis through Ingenuity Pathway Analysis (IPA) identified three key transcriptional regulators. TBX5 was identified as the only inhibited regulator ( z -score = −2.89). F2R and SFRP4 were identified as the activated regulators ( z -scores = 2.56 and 2.00, respectively). Multiple downstream genes regulated by TBX5 , F2R , and SFRP4 were involved in ICM-related diseases such as HF and arrhythmia. Overall, our study is the first to perform an RNA-seq meta-analysis for clinical ICM and provides robust candidate genes, including three key transcriptional regulators, for future diagnostic and therapeutic applications in ischemic heart failure.
Keywords	ischemic cardiomyopathy ; heart failure ; transcriptional regulators ; meta-analysis ; RNA-seq ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Combating hypertension beyond genome-wide association studies

Sachin Aryal / Ishan Manandhar / Xue Mei / Beng S. Yeoh / Ramakumar Tummala / Piu Saha / Islam Osman / Jasenka Zubcevic / David J. Durgan / Matam Vijay-Kumar / Bina Joe

Cambridge Prisms: Precision Medicine, Vol

Microbiome and artificial intelligence as opportunities for precision medicine

2023 Volume 1

Abstract: The single largest contributor to human mortality is cardiovascular disease, the top risk factor for which is hypertension (HTN). The last two decades have placed much emphasis on the identification of genetic factors contributing to HTN. As a result, ... ...

Abstract	The single largest contributor to human mortality is cardiovascular disease, the top risk factor for which is hypertension (HTN). The last two decades have placed much emphasis on the identification of genetic factors contributing to HTN. As a result, over 1,500 genetic alleles have been associated with human HTN. Mapping studies using genetic models of HTN have yielded hundreds of blood pressure (BP) loci but their individual effects on BP are minor, which limits opportunities to target them in the clinic. The value of collecting genome-wide association data is evident in ongoing research, which is beginning to utilize these data at individual-level genetic disparities combined with artificial intelligence (AI) strategies to develop a polygenic risk score (PRS) for the prediction of HTN. However, PRS alone may or may not be sufficient to account for the incidence and progression of HTN because genetics is responsible for <30% of the risk factors influencing the etiology of HTN pathogenesis. Therefore, integrating data from other nongenetic factors influencing BP regulation will be important to enhance the power of PRS. One such factor is the composition of gut microbiota, which constitute a more recently discovered important contributor to HTN. Studies to-date have clearly demonstrated that the transition from normal BP homeostasis to a state of elevated BP is linked to compositional changes in gut microbiota and its interaction with the host. Here, we first document evidence from studies on gut dysbiosis in animal models and patients with HTN followed by a discussion on the prospects of using microbiota data to develop a metagenomic risk score (MRS) for HTN to be combined with PRS and a clinical risk score (CRS). Finally, we propose that integrating AI to learn from the combined PRS, MRS and CRS may further enhance predictive power for the susceptibility and progression of HTN.
Keywords	Machine learning ; high blood pressure ; gut microbiota ; genome-based risk scores ; personalized medicine ; Internal medicine ; RC31-1245 ; Therapeutics. Pharmacology ; RM1-950
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Cambridge University Press
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genetic predisposition for increased red blood cell distribution width is an early risk factor for cardiovascular and renal comorbidities

Xi Cheng / Blair Mell / Ahmad Alimadadi / Sarah Galla / Cameron G. McCarthy / Saroj Chakraborty / Venkatesha Basrur / Bina Joe

Disease Models & Mechanisms, Vol 13, Iss

2020 Volume 5

Abstract: Red blood cell distribution width (RDW) is a measurement of the variation in size and volume of red blood cells (RBCs). Increased RDW, indicating a high heterogeneity of RBCs, is prominently associated with a variety of illnesses, especially ... ...

Abstract	Red blood cell distribution width (RDW) is a measurement of the variation in size and volume of red blood cells (RBCs). Increased RDW, indicating a high heterogeneity of RBCs, is prominently associated with a variety of illnesses, especially cardiovascular diseases. However, the significance of this association to the onset and progression of cardiovascular and renal diseases is unknown. We hypothesized that a genetic predisposition for increased RDW is an early risk factor for cardiovascular and renal comorbidities. Since there is no known animal model of increased RDW, we examined a CRISPR/Cas9 gene-edited rat model (RfflTD) that presented with features of hematologic abnormalities as well as severe cardiac and renal comorbidities. A mass spectrometry-based quantitative proteomic analysis indicated anemia of these rats, which presented with significant downregulation of hemoglobin and haptoglobin. Decreased hemoglobin and increased RDW were further observed in RfflTD through complete blood count. Next, a systematic temporal assessment detected an early increased RDW in RfflTD, which was prior to the development of other comorbidities. The primary mutation of RfflTD is a 50 bp deletion in a non-coding region, and our study has serendipitously identified this locus as a novel quantitative trait locus (QTL) for RDW. To our knowledge, our study is the first to experimentally pinpoint a QTL for RDW and provides a novel genetic rat model mimicking the clinical association of increased RDW with poor cardio-renal outcome.
Keywords	red blood cell distribution width ; cardiovascular ; renal ; hematologic ; genetics ; proteomics ; Medicine ; R ; Pathology ; RB1-214
Subject code	616
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cryptorchidism and infertility in rats with targeted disruption of the Adamts16 locus.

Shakila Abdul-Majeed / Blair Mell / Surya M Nauli / Bina Joe

PLoS ONE, Vol 9, Iss 7, p e

2014 Volume 100967

Abstract: A Disintegrin And Metalloproteinase with ThromboSpondin motifs16 (ADAMTS-16) is a member of a family of metalloproteinases. Using a novel zinc-finger nuclease based gene-edited rat model harboring a targeted mutation of the Adamts16 locus, we previously ... ...

Abstract	A Disintegrin And Metalloproteinase with ThromboSpondin motifs16 (ADAMTS-16) is a member of a family of metalloproteinases. Using a novel zinc-finger nuclease based gene-edited rat model harboring a targeted mutation of the Adamts16 locus, we previously reported this gene to be linked to blood pressure regulation. Here we document our observation with this model that Adamts16 is essential for normal development of the testis. Absence of Adamts16 in the homozygous Adamts16mutant males resulted in cryptorchidism and male sterility. Heterozygous Adamts16mutant males were normal, indicating that this is a recessive trait. Testes of homozygous Adamts16mutant males were significantly smaller with significant histological changes associated with the lack of sperm production. Temporal histological assessments of the testis demonstrated that the seminiferous tubules did not support active spermatogenesis, but progressively lost germ cells, accumulated vacuoles and did not have any sperm. These observations, taken together with our previous report of renal abnormalities observed with the same Adamts16mutant rats, suggest an important mechanistic link between Adamts16 and the functioning of the male genitourinary system.
Keywords	Medicine ; R ; Science ; Q
Subject code	590
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pleiotropic Effect of a High Resolution Mapped Blood Pressure QTL on Tumorigenesis.

Xi Cheng / Harshal Waghulde / Blair Mell / Kathryn Smedlund / Guillermo Vazquez / Bina Joe

PLoS ONE, Vol 11, Iss 4, p e

2016 Volume 0153519

Abstract: This study is focused on a translationally significant, genome-wide-association-study (GWAS) locus for cardiovascular disease (QT-interval) on human chromosome 17. We have previously validated and high resolution mapped the homologous genomic segment of ... ...

Abstract	This study is focused on a translationally significant, genome-wide-association-study (GWAS) locus for cardiovascular disease (QT-interval) on human chromosome 17. We have previously validated and high resolution mapped the homologous genomic segment of this human locus to <42.5 kb on rat chromosome 10. This <42.5 kb segment in rats regulates both QT-interval and blood pressure and contains a single protein-coding gene, rififylin (Rffl). The expression of Rffl in the hearts and kidneys is differential between Dahl S and S.LEW congenic rats, which are the strains used for mapping this locus. Our previous study points to altered rate of endocytic recycling as the underlying mechanism, through which Rffl operates to control both QT-interval and blood pressure. Interestingly, Rffl also contributes to tumorigenesis by repressing caspases and tumor suppressor genes. Moreover, the expression of Methyl-CpG Binding Domain Protein 2 (Mbd2) in the hearts and kidneys is also higher in the S.LEW congenic strain than the background (control) Dahl S strain. Mbd2 can repress methylated tumor suppressor genes. These data suggest that the S.LEW congenic strain could be more susceptible to tumorigenesis. To test this hypothesis, the S and S.LEW strains were compared for susceptibility to azoxymethane-induced colon tumors. The number of colon tumors was significantly higher in the S.LEW congenic strain compared with the S rat. Transcriptomic analysis confirmed that the chemical carcinogenesis pathway was significantly up-regulated in the congenic strain. These studies provide evidence for a GWAS-validated genomic segment on rat chromosome 10 as being important for the regulation of cardiovascular function and tumorigenesis.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pleiotropic Effect of a High Resolution Mapped Blood Pressure QTL on Tumorigenesis.

Xi Cheng / Harshal Waghulde / Blair Mell / Kathryn Smedlund / Guillermo Vazquez / Bina Joe

PLoS ONE, Vol 11, Iss 4, p e

2016 Volume 0153519

Abstract	This study is focused on a translationally significant, genome-wide-association-study (GWAS) locus for cardiovascular disease (QT-interval) on human chromosome 17. We have previously validated and high resolution mapped the homologous genomic segment of this human locus to <42.5 kb on rat chromosome 10. This <42.5 kb segment in rats regulates both QT-interval and blood pressure and contains a single protein-coding gene, rififylin (Rffl). The expression of Rffl in the hearts and kidneys is differential between Dahl S and S.LEW congenic rats, which are the strains used for mapping this locus. Our previous study points to altered rate of endocytic recycling as the underlying mechanism, through which Rffl operates to control both QT-interval and blood pressure. Interestingly, Rffl also contributes to tumorigenesis by repressing caspases and tumor suppressor genes. Moreover, the expression of Methyl-CpG Binding Domain Protein 2 (Mbd2) in the hearts and kidneys is also higher in the S.LEW congenic strain than the background (control) Dahl S strain. Mbd2 can repress methylated tumor suppressor genes. These data suggest that the S.LEW congenic strain could be more susceptible to tumorigenesis. To test this hypothesis, the S and S.LEW strains were compared for susceptibility to azoxymethane-induced colon tumors. The number of colon tumors was significantly higher in the S.LEW congenic strain compared with the S rat. Transcriptomic analysis confirmed that the chemical carcinogenesis pathway was significantly up-regulated in the congenic strain. These studies provide evidence for a GWAS-validated genomic segment on rat chromosome 10 as being important for the regulation of cardiovascular function and tumorigenesis.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator

Cameron G. McCarthy / Saroj Chakraborty / Gagandeep Singh / Beng San Yeoh / Zachary J. Schreckenberger / Avinash Singh / Blair Mell / Nicole R. Bearss / Tao Yang / Xi Cheng / Matam Vijay-Kumar / Camilla F. Wenceslau / Bina Joe

JCI Insight, Vol 6, Iss

2021 Volume 20

Abstract: Autophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the ... ...

Abstract	Autophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced autophagy leads to the accumulation of cellular debris, resulting in inflammation and oxidative stress, which are then reversed by reconstitution or upregulation of autophagic activity. Evolutionarily, autophagy also functions to mobilize endogenous nutrients in response to starvation. Therefore, we hypothesized that the biosynthesis of the most physiologically abundant ketone body, β-hydroxybutyrate (βHB), would be autophagy dependent and exert vasodilatory effects via its canonical receptor, Gpr109a. To the best of our knowledge, we have revealed for the first time that the biosynthesis of βHB can be impaired by preventing autophagy. Subsequently, βHB caused potent vasodilation via potassium channels but not Gpr109a. Finally, we observed that chronic consumption of a high-salt diet negatively regulates both βHB biosynthesis and hepatic autophagy and that reconstitution of βHB bioavailability prevents high-salt diet–induced endothelial dysfunction. In summary, this work offers an alternative mechanism to the antiinflammatory and antioxidative stress hypothesis of autophagy-dependent vasculoprotection. Furthermore, it reveals a direct mechanism by which ketogenic interventions (e.g., intermittent fasting) improve vascular health.
Keywords	Vascular biology ; Medicine ; R
Subject code	572
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Bioinformatic analysis reveals new determinants of antigenic 14-3-3 proteins and a novel antifungal strategy.

Jenna E McGowan / Jacqueline Kratch / Saurabh Chattopadhyay / Bina Joe / Heather R Conti / Ritu Chakravarti

PLoS ONE, Vol 12, Iss 12, p e

2017 Volume 0189503

Abstract: The ubiquitously expressed 14-3-3 family of proteins is evolutionarily conserved from yeast to mammals. Their involvement in humoral and cellular immune responses is emerging through studies in drosophila and humans. In humans, a select group of 14-3-3 ... ...

Abstract	The ubiquitously expressed 14-3-3 family of proteins is evolutionarily conserved from yeast to mammals. Their involvement in humoral and cellular immune responses is emerging through studies in drosophila and humans. In humans, a select group of 14-3-3 isoforms are antigenic; however the determinants of their antigenicity are not known. Here, we show that although mammalian 14-3-3 proteins are mostly conserved, subtle differences between their isoforms may give rise to their antigenicity. We observed syntenic relations among all the isoforms of 14-3-3 for mammals, but not with that of birds or amphibians. However, the parasitic 14-3-3 isoforms, which have known antigenic properties, show unique sequence, structure and evolution compared to the human 14-3-3. Moreover we report, for the first time the existence of a bacterial 14-3-3 protein. Contrary to the parasitic isoforms, both bacterial and yeast 14-3-3 exhibited significant homology with mammalian 14-3-3 in protein sequence as well as structure. Furthermore, a human 14-3-3 inhibitor caused significant killing of Candida albicans, which could be due to the inhibition of the structurally similar yeast homologue of 14-3-3, BMH, which is essential for its life cycle. Overall, our bioinformatic analysis combined with the demonstration of a novel antifungal role of a peptide inhibitor of human 14-3-3 indicates that the sequences and structural similarities between the mammalian, bacterial and fungal proteins are likely determinants of the antigenic nature of these proteins. Further, we propose that molecular mimicry triggered by microbial infections with either yeast or bacteria may contribute to the antigenic role of human 14-3-3.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mass-spectrometric identification of T-kininogen I/thiostatin as an acute-phase inflammatory protein suppressed by curcumin and capsaicin.

Bina Joe / Anitha Nagaraju / Lalitha R Gowda / Venkatesha Basrur / Belur R Lokesh

PLoS ONE, Vol 9, Iss 10, p e

2014 Volume 107565

Abstract: Curcumin and capsaicin are dietary xenobiotics with well-documented anti-inflammatory properties. Previously, the beneficial effect of these spice principles in lowering chronic inflammation was demonstrated using a rat experimental model for arthritis. ... ...

Abstract	Curcumin and capsaicin are dietary xenobiotics with well-documented anti-inflammatory properties. Previously, the beneficial effect of these spice principles in lowering chronic inflammation was demonstrated using a rat experimental model for arthritis. The extent of lowering of arthritic index by the spice principles was associated with a significant shift in macrophage function favoring the reduction of pro-inflammatory molecules such as reactive oxygen species and production and release of anti-inflammatory metabolites of arachidonic acid. Beyond the cellular effects on macrophage function, oral administration of curcumin and capsaicin caused alterations in serum protein profiles of rats injected with adjuvant to develop arthritis. Specifically, a 72 kDa acidic glycoprotein, GpA72, which was elevated in pre-arthritic rats, was significantly lowered by feeding either curcumin or capsaicin to the rats. Employing the tandem mass spectrometric approach for direct sequencing of peptides, here we report the identification of GpA72 as T-kininogen I also known as Thiostatin. Since T-kininogen I is an early acute-phase protein, we additionally tested the efficiency of curcumin and capsaicin to mediate the inflammatory response in an acute phase model. The results demonstrate that curcumin and capsaicin lower the acute-phase inflammatory response, the molecular mechanism for which is, in part, mediated by pathways associated with the lowering of T-kininogen I.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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