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De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies

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Science  04 Dec 2015:
Vol. 350, Issue 6265, pp. 1262-1266
DOI: 10.1126/science.aac9396

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  • All roads lead to Rome: various forms of insoluble salts and heart disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Shanshan An, student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Kaiqiao Yang, student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Liang Cui, student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    The insoluble and rigid calcium oxalate was proposed as one of the major causes of heart disease (1), since ethanol and acetic acid, both similar in structure to oxalate, are beneficial to heart disease and extend lifespans.(2-4) Numerous forms of insoluble and rigid salts are involved in renal calculi, urethral stones and gallstones (5-7), and some of them have been reported to be associated with cardiovascular diseases.(8) For instance, urate deposits are typical of gout and renal stones, which are often accompanied by arteriosclerosis and coronary heart disease.(9-10) Cholesterol is a hydrophobic molecule with a hydroxyl group, which possesses secondary chemical bonding to cations including calcium. The formation of cholesterol crystals in gall bladder is linked to gallstones (11), and the intake of excess cholesterol accounts in part for increased risk for heart disease.(12) Calcium carbonate is rigid and insoluble in neutral pH, and sugar-sweetened carbonated beverage consumption was associated with higher prevalence of coronary heart disease.(13)
    In summary, many types of insoluble and rigid salts may be involved in the etiology of cardiovascular diseases, and are concerns for heart disease sufferers. These salts can work alone or in combination to do harm on human health. Preventive measures can be adopted to minimize the negative effects of insoluble salts for the wellbeing of heart disease patients.(14-16)

    Shanshan An, Kaiqiao Yang, Liang Cui, Qiuyun...

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    Competing Interests: None declared.
  • RE: Maximizing the health benefits of coffee intake for the prevention of heart disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Xiaoxuan Wu, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Wei Yang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Coffee intake reduces the risk of cardiovascular diseases.(1-2) Yet, there were mixed reports on the increased cancer risks posed by overconsumption of coffee.(3) Caffeine traps protons via hydrogen bonds, perhaps accounting at least in part for the observed phenomena via the mutagenic potential of locally formed HCl.(2) The consumption of lactic acid-containing yogurt can be adopted to maximize the benefits of coffee and reduce the risks of tumorigenesis, since weak organic acid counteracts strong acids.(4) Yogurt were previously reported to lower cancer risks.(5) Plant-based diet is also rich in weak organic acids. The evaporation and absorption of acetic acid from an open-cap vinegar bottle is favorable with the intake of coffee.(6-7) The drinking of 1-2 bags of green tea with water refills can also reduce potential cancer risks associated with the overconsumption of coffee.(8)

    Xiaoxuan Wu, Wei Yang, Qiuyun Liu*
    State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Lab of Microbial Metabolic Engineering and Synthetic Biology, School of Life Sciences, Sun Yat-sen University, China.
    *Corresponding author: lsslqy@mail.sysu.edu.cn (Q. Liu)

    References
    1. Andersen LF, et al. Consumption of coffee is associated with reduced risk of death attributed to inflammatory and cardiovascular diseases in the Iowa Women's Healt...

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    Competing Interests: None declared.
  • The underlying mechanism for the increased cardiomyopathy risk with D389V in MYBPC3Δ25bp carriers
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Xingqiang Lai, Postdoctoral, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518033, China
      • Xiao Bao, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Shuli Wang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    In their recent study, Viswanathan et al. reported that MYBPC3Δ25bp carriers with D389V are associated with the increased risk attributed to MYBPC3Δ25bp.(1) However, the underlying mechanism is undetermined. The two γ-methyl groups in valine enable hyperconjugation and electron delocalization, which reinforce the van der Waals interaction between the side group and carbonyl group. This extends the C=O bond length which augments the secondary chemical bonding of carbonyl oxygen atom to cations, particularly divalent cations.(2) This feature of valine residues enhances the formation of insoluble and rigid salts such as calcium oxalate, which was postulated as one of the major causes of heart disease.(3-4) Being structurally similar to oxalate, ethanol and acetic acid extend lifespans4, perhaps via the inhibition of oxalate generation. The long bond length of C=O in glycine also augments the formation of insoluble salts.3 In support of the aforementioned theory, the valine content is 8.8% and glycine content is 7.5% in cMyBP-C protein encoded by MYBPC3 gene. The replacement by valine residue worsens the condition with insoluble salts. This subset of patients can include fish in their diet, as the proteins of aquatic creatures are rich in hydrogen bond donors and acceptors which attract protons and enhance the formation of weak acids that help dissolve insoluble salts and relieve symptoms.(4)

    Xingqiang Lai, 1 Xiao Bao, 2 Shuli Wang, 2 Qiuyun Liu2,*
    1The Eighth Aff...

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    Competing Interests: None declared.
  • The use of geothermal hot water for the prevention of heart disease and dementia
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Sirui Yan, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Xingqiang Lai, Postdoctoral, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518033, China
      • Cui Yang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Hot springs are usually located to the west of higher altitude regions.(1) Traditionally geothermal hot water or sauna are adopted to protect human health, showing benefits to diseases ranging from cardiovascular disorders, dementia and Alzheimer’s disease, etc.(2-4) The hyperthermia in these treatments reduces the activities of the Krebs cycle enzymes, thus minimizing the generation of oxalate via the shunt of the cycle. The insoluble and rigid calcium oxalate was proposed as a major cause of heart disease.(5) However, there is a negative side of these regimens. High temperature causes DNA damage such as DNA breaks and nicks, which may account for the increased cancer risks in the individuals frequently receiving such treatments.(6) To maximize the benefits while minimizing the negative effects of these regimens, plant-based diet can be adopted since it is rich in weak organic acids which antagonize HCl and reduce cancer incidences.(7-10) Yogurt is favorable as it contains lactic acid.(11) Dilute acetic acid can be smeared on the skin to minimize cancer risks.(12-13) Physical exercises generate lactic acid, and divert protons for energy production and reduce proton stresses in internal organs.(14) Heart disease sufferers should monitor their conditions closely as hyperthermia may occasionally generate undesirable effects. A modest temperature and short duration may be better suited to these patients, who should get out of the tub slowly to avoid insufficient blood supply...

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    Competing Interests: None declared.
  • Prevention of heart disease and cancer triggered by uric acid buildup
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Fan Feng, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Wenwen Yu, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Wenze Chen, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Weiwei Zhang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Uric acid or uric acid stones are associated with increased risks for heart disease and cancer.(1-2) The keto form of uric acid possesses potent hydrogen bonding to protons, potentially contributing to higher incidences of urinary cancer and some other cancers than that in the general population.(3-5) The stable keto form, namely the lactam form of the uric acid, can crystalize in the heart and cause cardiac disorder, in a way similar to heart disease caused by the insoluble and rigid calcium oxalate.(6) Uric acid and calcium oxalate both are the components of renal stones.(1-2) To prevent the onset and disease advance of uric acid buildup or stones, plant-based diet is favorable as it is rich in weak organic acids capable of solubilizing insoluble crystals.(6) Additionally, weak acids counteract strong acids since HCl is mutagenic and potentially carcinogenic.(3-5) However, fruits and vegetables high in oxalate or calcium are to be avoided as calcium oxalate accumulation may compound the condition with uric acid stones. Orange juice is beneficial since it is rich in citric acid and other weak acids. Moderate physical exercises divert protons for energy production and the generated lactic acid is advantageous to both heart disease and cancer.(7) Drinking adequate amount of water is helpful for reduction of stone sizes and excretion of uric acid.(8) Preventive measures combined with western medicine can yield positive outcomes on heart disorder and cancer in the sufferers o...

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    Competing Interests: None declared.
  • Coix seed diet for prevention of rheumatic heart disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Fan Feng, student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Li Xu, Researcher, The fifth Affiliated Hospital of Guangzhou Medical University, Guanzhou, China
      • Jingli Peng, student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Leucine supplement was proposed to be beneficial to rheumatic heart disease sufferers.(1) The lack of gamma methyl group in leucine allows poor van der Waals interaction between the side group and the carbonyl group. Semen coicis (coix seed) was frequently used in Chinese herbal medicine to promote diuresis and alleviate edema.(2) It was reported that coix seeds harbor high leucine content (3), perhaps accounting for its favorable effect on rheumatic diseases. The weak hydrogen bonding on the carbonyl oxygen of leucine (1,4) also explains the low energy output of the coix seed diet.(2-3) The weak secondary chemical bonding to other cations on the carbonyl oxygen of leucine1 leads to lower level of insoluble and rigid calcium oxalate, reducing risks of cardiovascular diseases.(2-3,5-6) Since leucine is abundant and inherently hydrophobic, the coix seed diet needs to be boiled or cooked for relatively long periods. The absorption of leucine from a food source such as coix seeds could be more advantageous than leucine supplement as the amino acid is more uniformly distributed in the foodstuff, allowing slow and steady natural assimilation with less side effects. Adverse reactions should be monitored with the intake of the diet, and the patients must consult physicians when individuals experience unpleasant feelings.

    Fan Feng,1 Li Xu,2 Jingli Peng,1 Qiuyun Liu 1*
    1State Key Laboratory of Biocontrol, Biomedical Center, School of Life Sciences, Sun Yat-sen Universi...

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    Competing Interests: None declared.
  • Basic amino acid polymorphisms in the risk factors of heart disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Jingli Peng, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Yan Cao, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Zhenlang Chen, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Valine or/and glycine are sometimes over 5% in some risk factors of heart disease.(1) Due to their long C=O bond lengths, the carbonyl oxygen atoms of the two amino acids may boast strong cation affinities (2), particularly affinities to divalent cations. A positively charged basic amino acid polymorphism present in these proteins possesses anion affinities, and it accelerates the buildup of the anion pools and the formation of calcium oxalate. The insoluble and rigid calcium oxalate was proposed as a major causative factor of heart disease.(1-2) Consequently the basic amino acid polymorphism triggers cardiovascular disorders. As lysine is essential, arginine is semi-essential and histidine is essential to infants, a carbohydrate/vitamin diet lasting for two or a few days can alleviate disease symptoms by reducing both basic amino acids and valine.(1,3) Mediterranean diet can also be adopted to reduce the amount of calcium oxalate in the body and is favorable to heart disease sufferers.(4) Patients should monitor their condition closely during dietary restrictions, and adjustments need to be made when unpleasant feeling appears.

    Jingli Peng, Yan Cao, Zhenlang Chen, Qiuyun Liu*
    School of Life Sciences, Sun Yat-sen University, China.
    *Corresponding author: lsslqy@mail.sysu.edu.cn (Q. Liu)

    References
    1. Gan T, Fu M, Wu J, et al. How to design carbohydrate diet regimens for heart disease patients. E...

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    Competing Interests: None declared.
  • Trans fat and heart disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Shanshan An, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Man Tang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Jiaming Zhang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Trans fat, or trans fatty acids, trans-unsaturated fatty acids, are unsaturated fat that are widely produced in food industry.(1) Trans fat is associated with increased risk of cardiovascular disease.(2) Unsaturated fatty acids predominantly have cis configurations in living organisms.(3) Incomplete hydrogenation of the unsaturated fatty acids in food industry turns some of the cis double bonds into trans double bonds (4), posing risks to consumers worldwide.
    In contrast to cis unsaturated fat, trans fatty acids are energetically more favorable than cis fatty acids, and are solid at room temperatures.(5) The insoluble and rigid calcium salt of trans fatty acids confers heart disease risks, in a way similar to the insoluble and solid calcium oxalate.(6) Similar in structure to oxalate, ethanol and acetic acid relieve cardiovascular diseases and extend lifespans, perhaps by the inhibition of oxalate production.(7-8) Calcium oxalate is a primary component of kidney stones.(9)
    To lower the risks of cardiovascular diseases, the intake of trans fat-rich food should be limited. As aquatic creatures, fish are rich in hydrogen bond donors and acceptors, which attract protons and form acids helping dissolve the insoluble and rigid salts.(10) Acetic acid- and lactic acid-rich food inhibits the generation of oxalate, and also dissolves insoluble salts.(11) A beneficial microbiota produces weak organic acids, and is advantageous to heart disease sufferers.11 Moderate physic...

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    Competing Interests: None declared.
  • Why plant-based diet reduces risks of heart disease
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Zhixue Wang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
      • Hongyu Zhong, student, Sheffield Medical School, University of Sheffield, , Sheffield ,S10 2RX, United Kingdom
      • Xi Luo, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Plant-based diet lowers the risks of heart disease (1). It was hypothesized that oxalate is one of the major culprits of the disease (2-3). Organic acids such as citric acid and L-malic acid are abundant in plants, and have been reported to be cardioprotective (4). Calcium citrate is more soluble than calcium oxalate (5-6). The intake of citric acid from plants might help dissolve insoluble salts of oxalate and reduce stresses, accounting for its cardioprotective functions. It has been previously reported that citric acid can help remove oxalate stones (7). Some other organic acids may share properties similar to citric acid, collectively contributing to the beneficial effects of the plant-based diet on the cardiovascular system in addition to polyunsaturated fatty acids, low levels of some essential amino acids and so on (8).

    Zhixue Wang, 1,3 Hongyu Zhong, 2,3 Xi Luo, 1,3 Qiuyun Liu1*
    1 Guangdong Provincial Key Laboratory of Improved Variety Reproduction in Aquatic Economic Animals, Biomedical Center, State Key Laboratory of Biocontrol, Lab of Microbial Metabolic Engineering and Synthetic Biology, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
    2 Department of Infection, Immunity & Cardiovascular Disease, Sheffield Medical School, University of Sheffield, Beech Hill Rd, Sheffield S10 2RX, United Kingdom
    3 Equal contributions.

    *Correspondence author.
    E-mail address:...

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    Competing Interests: None declared.
  • Furthering our understandings on coding SNPs: β-branched amino acids in diseases
    • Qiuyun Liu, Professor, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China
    • Other Contributors:
      • Yuchuan Wang, Postdoctoral, School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China
      • Xiaoyi Hu, Researcher, Department of Medicine, Division of Immunology, Columbia University Medical Center, New York 10032, USA
      • Jiaming Zhang, Student, School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China
      • Ye Gao, Student, Division of Biological Sciences, University of California, San Diego, USA.
      • Yan Huang, Student, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China

    Leucine, isoleucine and valine possess 0, 1 and 2 γ-methyl group(s) respectively. The replacements of the former by the latter in mitochondrial proteins have been associated with dilated cardiomyopathy, ischemic cardiomyopathy, cardiomegaly or hypertrophic cardiomyopathy etc. (1) What is the mechanism underlying the potentially growing osmotic pressure generated by the increasing number of γ-methyl groups?
    The single γ-methyl group in isoleucine causes electron delocalization and σ-σ hyperconjugation corroborated by bond length data (2), and van der Waals interactions between the side group and the carbonyl carbon in isoleucine may contribute to proton affinity of the carbonyl oxygen (3). The σ22 element of the 13C chemical shift anisotropy for the deprotonated carboxyl group in isoleucine indicated that the carbonyl oxygen is capable of strong hydrogen bonding (4). The σ22 element for the deprotonated carboxyl group in alanine indicates weak hydrogen bonding of carbonyl oxygen (4), which can be attributed to σ-σ hyperconjugation and van der Waals interactions with the carbonyl oxygen leading to modest C═O bond length. The van der Waals interactions with carbonyl oxygen have minor effects on the reduction of covalent bond length of carbon-oxygen (4) and consequently to some extent weaken the secondary chemical bonds on the oxygen atom of alanine.
    Valine residue possesses two γ-methyl groups, which exhibits hyperconjugation and robust van der Waals interactions...

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    Competing Interests: None declared.

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