Today, the term “molecular biology” has a rather prosaic sound. After all, there is little in contemporary biology that isn't molecular. It's hard to remember that 50 years ago, molecular biology was distinctly countercultural. Whereas biochemistry proudly traced its roots to the sober field of chemistry, molecular biology stood for pure bravado and opportunism. Its immodest goal was to understand the program of life from gene to phenotype. Has it fulfilled its promise? The operon theory of Jacob and Monod stands as one of its signal achievements, but a modern view of how the circuit actually works illustrates its limitations as well as its accomplishments.
Amended on 4 November 2017
I wish to express my opinion. Analysis of human DNA has only led to the false and notorious result that "black is inferior to white".
I have done the generalized transduction of membrane protein RodA (RodA gene is co-tranduced with Lip gene at 15 min) for about 45 years ago, but the mechanism of generalized transduction has not yet been clear to me (Please see file; P1kc RodA E.coli). Virus such as HIV-1 can integrate into human DNA at where? I am now considering that membrane protein region is rich in codens for hydrophobic amino acids such as AT and/or TT, and P1kc has specially integrated into those DNA regions, where is rich in the hydrophobic membrane proteins. Phage lambda integrates specific fixed position of chromosomal DNA of E. coli at membrane protein region (between Gal gene and Bio gene at 17 min). The integration mechanism of bacteriophage and HIV-1 seems to be not fully clarified yet for me (please see file; HIV integration). With respect to this consideration, recently Polish Biochemists have published an interesting report; i.e.,
Rajewska M, Wegrzyn K, Konieczny I. (2012) AT-rich region and repeated sequences - the essential elements of replication origins of bacterial replicons. FEMS Microbiol Rev. 36, 408-34. doi: 10.1111/j.1574-6976.2011.00300.x. Epub 2011 Aug 25.
Now, glycobiology seems to be more important to giving the fruitful results (please see file; JMBT Alopecia). This fruitful result has been obtainable using quantitative and reliable HPLC-photometric method. Further, we have recently found that sulphated poly-fucose (fucoidan) can rescue the patients of liver cancer (please see files; HepG2 fucoidan and Rat DEN Np-Fuco).
Then, I have previously declared that the fucoidan effect is not linked to gene expression (cell division, apoptosis, autophagy etc.). Now, I am very doubtful about the notorious Molecular Genetics, since I have surely found that enzyme kinetics is mainly under the control of glycochain of eucaryotic enzymes (please see file; JMBT alopecia) and multimerization of enzymes (please see file; The Fascio effect).
Further added on 9 November 2017
Since virus is important than host genetics, I studied about the start of viral infection.
HIV and HCV seems to be infected during early fetal period in humans. Surely, drug abuse is dangerous to increase the risk to cancer (HCC is caused by HIV-1 and HCV; please see file again "HepG2 Fucoidan). However, since Fucoidan has been shown to be wonderful drug to HIV-1 and HCV, father and mother wishing to give birth should take Fucoidan as a preventing drug for babies.
Start of Infection of viruses:
Fetal period (Hc cells); Echovirus 9,DENV, HIV-2, HCV.
Serum study
4mo; Human parainfluenza virus 2/HPIV-2, Enterobacteria phage T4, HPV-39, Feline infectious peritonitis virus/a mutant of FCoV.
7mo; HIV-1, Autographa Californica nucleopolyhedrovirus/AcNPV (Baculovirus), Koala retrovirus/KoRV 8mo; HHV-5, HCoV 229E, 11mo20day; Avian infectious bronchitis virus/IBV/ACoV, HHV-6, HPV-30, Mimivirus.
12mo; HAdV-6. 1y4mo; Choristoneura fumiferana MNPV/CfMNPV, Influenza A virus/FluA, Enterobacteria phage P22.
1y11mo; HAV, O'nyong-nyong virus/ONNV, AKV Murine leukemia virus, HCoV OC43, Tacaribe virus/TCRV, Vaccinia virus Copenhagen/VACV. 3y4mo; HHV-4, SIV.
4y1mo; HCV (infected by the operation of liver-transplantation)
Adult
15y (HepG2); Rous sarcoma virus/RSV, GB virus C/GBV-HGV/GBV-C, Human poliovirus/PV, HHV-3, Newcastle disease virus/NDV, HAdV-2, Mumps virus/MuV, Nodamura virus/NoV, Variola virus/VARV, Human respiratory syncytial virus/HRSV, Avian infectious bursal disease virus/IBDV, HHV-1, BoHV-1, Influenza C virus/FluC, HHV-7, Orgyia pseudotsugata NPV/OpMNPV.
22y; Enterobacteria phage T5, Enterobacteria phage P1.
32y; Yellow fever virus/YFV, Sudan ebolavirus/EBOV, Canine coronavirus/CCoV.
33y; Zaire ebolavirus/EBOV (infected from the patient above), HPV-15, Measles virus/MeV.
52y; Human parainfluenza virus 5/HPIV-5, Bluetongue virus/BTV.
Moreover, amended on 25 November 2017
Since virus rules gene expression (due thanks to Dr. Joel Subach, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA), I have further studied about the abnormal expression of Mucin, which is usually expressed in the Epithelial cells. Mucin genes in cultured liver cells seem to be up-regulated by HHV (except HHV-5 and HHV-6) and down-regulated by HIV and HCV.
Fetal liver hepatocyte Hc has not expressed Mucin. HHV is not present, but suppressor viruses HIV-2 and HCV are present at 5.1 μg/mg cell protein.
Hepatoma HepG2 has no Mucin. Inducer HHV is present at 5.9 μg/mg cell protein, but suppressors of HIV (HIV-1, HIV-2, and RSV) + HCV + HGV (38.8 μg/mg cell protein) completely suppress the expression of Mucin.
Healed HepG2 (by fucoidan for three days) has Mucin-16/Ovarian cancer related tumor marker CA125 (expressed in corneal and conjunctival epithelia) at 67.4 μg/mg cell protein, which suggests that fucoidan treatment for three days is not sufficient to reduce HHV although complete suppression of retrovirus and +ssRNA has been achieved. Inducer HHV (except HHV-5 and HHV-6) is present at 24.4 μg/mg cell protein, but suppressors of HIV-1 and HCV are very small amount at 2.7 μg/mg cell protein. Interestingly, effect of oral fucoidan therapy on HHV-1 in mice has been demonstrated to need for three weeks. "Hayashi K, Nakano T, Hashimoto M, Kanekiyo K, Hayashi T. (2008) Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection. Int. Immunopharmacol., 8, 109-116. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. [email protected] Fucoidan, a sulfated polysaccharide isolated from an edible brown alga Undaria pinnatifida, was previously shown to be a potent inhibitor of the in vitro replication of herpes simplex virus type 1 (HSV-1 or HHV-1). HSV-1 is a member of herpes viruses that cause infections ranging from trivial mucosal ulcers to life-threatening disorders in immunocompromised hosts. In the in vivo conditions, the replication of HSV-1 is controlled under the immunoresponse coordinated by both the innate and adaptive immune systems. In the present study, the effects of the fucoidan were examined on in vivo viral replication and the host's immune defense system. Oral administration of the fucoidan protected mice from infection with HSV-1 as judged from the survival rate and lesion scores. Phagocytic activity of macrophages and B cell blastogenesis in vitro were significantly stimulated by the fucoidan, while no significant change in the release of NO(2)(-) by macrophages was observed. In in vivo studies, oral administration of the fucoidan produced the augmentation of NK activity in HSV-1-infected mice immunosuppressed by 5-fluorouracil treatment. CTL activity in HSV-1-infected mice was also enhanced by oral administration of the fucoidan. The production of neutralizing antibodies in the mice inoculated with HSV-1 was significantly promoted during the oral administration of the fucoidan for 3 weeks. These results suggested that oral intake of the fucoidan might take the protective effects through direct inhibition of viral replication and stimulation of both innate and adaptive immune defense functions." Therefore, we have used the oral administration of the Mozuku (fucoidan) for 3 weeks in the SD rat (please see file; Rat DEN Np-Fuco).
HCC tissue (named No.6) only has Mucin-2/Intestinal mucin-2 (expressed in colon, small intestine, colonic tumors, bronchus, cervix and gall bladder) among 5 liver tissues at 10.6 μg/mg tissue protein. Inducer virus HHV (except HHV-5 and HHV-6) is present at 25.2 μg/mg tissue protein, and suppressor viruses of SIV and HCV and CSFV are present only at 17.2 μg/mg tissue protein. Therefore, inducing power of HHV is superior to suppressor viruses.
Further added on 10 November 2017
Further, abnormal expression of intestinal enzyme in liver is studied. Two liver tissues out of 5 liver tissues have expressed intestinal enzymes.
Liver tissue of pseudo-liver cancer expressed Sucrase-isomaltase, intestinal/Isomaltase at 21.2 μg/mg tissue protein and Maltase-glucosylamylase, intestinal at 21.6 μg/mg tissue protein. Variola virus/VARV at 13.3 μg/mg tissue protein and Vaccinia virus/VACV at 0.91 μg/mg tissue protein (total 14.2 μg/mg tissue protein) seem to induce Sucrase and Maltase. Influenza A virus/FluA (3.1 μg/mg tissue protein), Influenza C virus/FluC (0.52 μg/mg tissue protein), and Dengue virus type-4/DENV-4 (5.2 μg/mg tissue protein) at total 8.8 μg/mg tissue protein seem to inhibit the induction, but power of induction seems to be stronger.
LC tissue with leprosy has expressed Lactase-glycosylceramidase at 19.9 μg/mg tissue protein and Sucrase-isomaltase, intestinal at 6.8 μg/mg tissue protein. VARV and VACV (inducer virus) is present in this tissue at 20.0 μg/mg tissue protein. Inhibiting viruses of FluA and FluB are present at 8.3 μg/mg tissue protein, but inducing power is stronger.
Furthermore amended on 25 November 2017
Furthermore, Brain and Skeletal muscle specific protein HIVEP2/Transcription factor HIVEP2 expression has been studied. It seems that Retroviruses + HAdV up-regulate and HCV+DENV down-regulate this Transcription factor HIVEP2. HAdV can also up-regulate KAP expression as below. Therefore, virus can regulate several numbers of genes.
Fetal hepatocyte Hc cells has no HIVEP2/Transcription factor HIVEP2. Inducer virus of HIV-2 is present at 2.9 μg/mg cell protein. Repressor virus of HCV + Dengue virus 92/DENV-92 is present at 8.7 μg/mg cell protein. Thus, repressor is present 5.8 μg/mg cell protein higher amount.
Hepatoma HepG2 (cultured without fucoidan for 3 days) has HIVEP2/Transcription factor HIVEP2 at 5.4 μg/mg cell protein. Inducer virus of Retroviruses+HAdV is present at 16.5 μg/mg cell protein, and repressor virus HCV is present at 7.8 μg/mg cell protein. Thus, inducer virus is present 8.7 μg/mg cell protein higher amount.
Healed HepG2 (cultured with fucoidan for 3 days) has no HIVEP2. Inducer virus of HIV-1 + HAdV is present at 2.1 μg/mg cell protein, and repressor virus HCV is present at 1.9 μg/mg cell protein. Thus, inducer virus and repressor virus is present at the similar amount.
LC tissue (named No.6) has HIVEP2 at 13.8 μg/mg tissue protein. Inducer virus of Retroviruses +HAdV is present at 30.5 μg/mg tissue protein, and repressor viruses of HCV and Dengue virus/DENV-4 are present at 8.2 μg/mg tissue protein. Thus, inducer virus is present at 22.3 μg/mg tissue protein higher amount.
HCC tissue (named No.6) has HIVEP2 at 9.5 μg/mg tissue protein. Inducer virus of Retroviruses + HAdV is present at 20.9 μg/mg tissue protein, and repressor viruses of HCV (0.61) and Dengue virus/DENV-4 (19.8) are present at 20.4 μg/mg tissue protein. Thus, repression power of DENV seems to be weak.
Liver tissue of pseudo-liver cancer has HIVEP2 at 16.3 μg/mg tissue protein. Inducer virus of Retroviruses + HAdV is present at 15.1 μg/mg tissue protein, and repressor viruses of HCV and Dengue virus/DENV-4 are present at 9.6 μg/mg tissue protein. Thus, inducer virus is present at 5.5 μg/mg tissue protein higher amount.
LC tissue with leprosy has no HIVEP2. Inducer virus of Retroviruses + HAdV is present at 2.0 μg/mg tissue protein, and repressor virus of HCV is present at 21.9 μg/mg tissue protein. Thus, repressor virus is present at 19.9 μg/mg tissue protein higher amount.
HCC tissue with PBC has no HIVEP2. Inducer virus of Retroviruses + HAdV is present at 33.9 μg/mg tissue protein, and repressor virus of HCV is present at 35.4 μg/mg tissue protein. Thus, repressor virus is present at 1.5 μg/mg tissue protein higher amount. Repression power of HCV seems to be strong.
With respect to (3) Biological ageing. I have previously reported as to human life span as 174 y using second-order approximation (please see the file; J Chrom B rat BIN LIP Km).
However, this estimation has been strongly criticized by a Physicist Dr. Kenji Nishi, Ph.D. (studied at MIT, Boston, MA, USA) that the use of second-order approximation is not suitable to estimate. Then, I have re-estimated by using linear regression line method and found that the destined length of the human life seems to be c.a. 750 y. Now, I am considering that senility or ageing is essentially not present with respect to the protein metabolism, and only infectious diseases may be occurred in the old persons due to inadequate taking of nutrition.
Therefore, importance of nutrition has recently published (please see file; Feed by Measure).
Amended on 12 November 2017
Plants have no life span, or they can live forever. The main difference between animal and plant is that Animal has Biotinidase, but Plant has no Biotinidase at all. Therefore, the life span and biotinidase activity may be strongly linked.
Activations of purified human biotinidase at 128 and 150% have been observed at 50 nM mercuric ions and at 5 μM cupric ions, respectively (please see file; Thiol-type BIN). Therefore, the ancient Chinese-Emperor of Shi Huangdi (Qin dynasty; BC 3 C), who believes the “Taoism” and finds “the elixir of immortality by mercury”, may have possessed a good intuition. Although gold ion has not yet been tested on the thiol-BIN/LIP activity, an English philosopher of Roger Bacon (1214-1292) has already recommended the oral intake of gold as “the elixir of immortality” in his book of “Liber Sex Scientiarum”. The addition of Fe+++ at 250 nM in the cell-culture medium is interestingly also effective to fast growth (our unpublished observation), and the additions of Hg and Au ions to the culture medium should then also be re-studied (please see file again; Feed by Measure).
On the other hand, we have also found that serum biotinyl-peptides derived from four-kinds of carboxylase (please see file; 4-kinds of carboxylase) seem to be the inhibitor of human serum biotinidase (please see file; BIN peptide inhibitor). Then, the presence of various proteases in human serum is important to maintain the biotinidase activity.
Protease content in healthy human serum has been determined.
Sera of 8mo (TP; 58.4 mg/mL) and 12mo (common cold; TP; 77.4 mg/mL) female babies have no proteases.
33y (male, TP; 92.4 mg/mL) has 6.8 μg/mg serum protein (0.628 mg/mL) of proteases. His serum contains Aminoacylproline aminopeptidase/Xaa-Pro aminopeptidase 1 at 3.3 μg/mg serum protein and Calpain-11 at 3.5 μg/mg serum protein.
52y (female, TP; 79.2 mg/mL) has 9.0 μg/mg serum protein (0.713 mg/mL) of proteases. Her serum contains ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial at 3.0, Cytosolic carboxypeptidase 2 at 3.9, and Lactotransferrin/Lactoferrin at 2.1 μg/mg serum protein, respectively.
Further, old healthy persons excrete mambrane proteins from organs into the blood more amounts than young healthy persons.
Serum of 8mo girl has 0.93 mg/mL of membrane proteins.
Serum of 12 mo girl has 3.3 mg/mL of membrane proteins, but this increase may be due to common cold.
Serum of 33 y (male) has 8.4 mg/mL membrane proteins.
Serum of 52 y (female) has 4.8 mg/mL membrane proteins.
Thus, the velocity of membrane-protein metabolism seems to be higher in old persons than young persons.
Therefore, I recommend to take sufficient amount of “Meat” in the old persons as compared to young persons.
Further amended on 4 December 2017
I have studied about the gene expression of Apolipoprotein B-100, which is a differentiation marker for the adult liver. It seems that Apo B-100 is induced by HHV, MeV, MuV, and HPV, and is repressed by Flavi-virus. Putative inducer Enterovirus 71 (EV71) is not present in my database.
Fetal normal hepatocyte Hc has inducer virus (HHV, MeV, MuV, and HPV) at 9.0 μg/mg of cell protein. It has repressor virus (HCV and DENV) at 8.7 μg/mg of cell protein. Power of inducer and repressor virus is balanced, and normal fetal liver cells do not express Apo B-100.
Hepatoma HepG2 (derived from 15y Caucasoid male) has expressed no Apo B-100. Inducer (HHV, MeV, MuV, and HPV) is present at 6.2 μg/mg of cell protein, and is repressor (Flavi-virus; HCV and HGV) is present at 23.2 μg/mg of cell protein. Then, repressor power is stronger at 17.0 μg/mg of cell protein, and hepatoma can not express Apo B-100.
On the other hand, healed HepG2 (treated with fucoidan for 3 days) has epressed Apo B-100 at 29.7 μg/mg of cell protein. Inducer (HHV, MuV, and HPV) is present at 34.2 μg/mg of cell protein, and is repressor (Flavi-virus; HCV) is present at 1.9 μg/mg of cell protein. Then, inducer power is stronger at 32.3 μg/mg of cell protein, and healed hepatoma can express Apo B-100.
Liver tissues;
Normal liver tissue (pseudo liver cancer) has Apolipoprotein B-100/Apo B-100 at 65.7 μg/mg of tissue protein. Inducer (HHV, MuV, MeV, and HPV) is present at 96.8 μg/mg of tissue protein, and repressor (Flavi-virus; HCV, DENV, and JEV) is present at 37.6 μg/mg of tissue protein. Then, inducer power is stronger at 59.2 μg/mg of tissue protein, and Normal liver tissue (pseudo liver cancer) has expressed Apo B-100, which seems to be normal adult.
LC tissue (with leprosy) has expressed Apolipoprotein B-100/Apo B-100 at 10.0 μg/mg of tissue protein. Inducer (HHV and HPV) is present at 23.1 μg/mg of tissue protein, and repressor (Flavi-virus; HCV) is present at 21.9 μg/mg of tissue protein. Then, inducer power is stronger at 1.2 μg/mg of tissue protein, and LC tissue (with leprosy) has expressed Apo B-100, which seems to be normal adult.
HCC tissue (with PBC) has expressed no Apolipoprotein B-100. This tissue has inducer (HHV and HPV) at 21.2 μg/mg of tissue protein, and repressor (Flavi-virus; HCV and CSFV) is present at 79.0 μg/mg of tissue protein. Then, repressor power is stronger at 57.8 μg/mg of tissue protein, and HCC tissue (with PBC) has expressed no Apo B-100, which seems to be abnormal gene expression.
LC tissue (named No.6) has expressed no Apolipoprotein B-100. This tissue has inducer (HHV and HPV) at 40.4 μg/mg of tissue protein, and repressor (Flavi-virus; HCV, Louping ill virus, CFAV, and DENV) is present at 63.5 μg/mg of tissue protein. Then, repressor power is stronger at 23.1 μg/mg of tissue protein, and LC tissue (named No.6) has expressed no Apo B-100, which seems to be abnormal gene expression.
HCC tissue (named No.6) has Apolipoprotein B-100/Apo B-100 at 93.3 μg/mg of tissue protein. Inducer (HHV, MeV, and HPV) is present at 52.9 μg/mg of tissue protein, and repressor (Flavi-virus; HCV, DENV, and CSFV) is present at 21.2 μg/mg of tissue protein. Then, inducer power is stronger at 31.7 μg/mg of tissue protein, and HCC tissue (named No.6) has highly expressed Apo B-100.
This my result strongly suggests that Jacob's theory onto gene expression (such as Isopropyl β-D-1-thiogalactopyranoside (IPTG) as an inducer for the Lactose operon) is entirely false with respect to humans. The lactose operon may be ruled by mainly bacterial virus (bacteriophage) instead of IPTG in Escherichia coli.
Furthermore added on 17 November 2017
"....The controversy behind prions" is surely due to hydrophobic nature of prion protein. Prion proteins are hydrophobic membrane glycoproteins; i.e., hydrophobicity of Putative testis-specific prion protein/Prnt is 0.575 and that of Major prion protein/Prnp is 0.601, respectively. Hydrophobicity of Insulin receptor is 0.533 and pig brain lipoamidase is 0.532, respectively (please see file; Purify Brain Lipoamidase).
Quantitative analysis by PCR, Western blot, ELISA on membrane glycoproteins is not possible at all (see file; IEF for hydrophobic protein). Only our new proteomics PDMD (protein-direct-microsequencing-deciphering) method uniquely and quantitatively determines the hydrophobic membrane glycoproteins at this time (see file again; HepG2 fucoidan).
Bovine Major prion protein/Prnp has been detected from contamination of Bovine Lactoferrin (Sigma; L9507), but Bovine milk (n = 1) and Human breast milk (n = 1) of Japan has no prion protein (our unpublished observation).
Only one serum (32y, Japanese female, with Gait disorder) has Putative testis-specific prion protein/Protein M8/Prnt at 5.0 μg/mg of serum protein. This serum uniquely has Genome polyprotein (Yellow fever virus; YFV) at 6.1 μg/mg of serum protein, and this YFV seems to have induced the expression of Prnt.
Her serum has Large structural protein/RNA-directed RNA polymerase L/Protein L (EBOV; Sudan ebolavirus) at 4.4 μg/mg of serum protein, and one healthy serum (33y, male) has RNA-directed RNA polymerase L/L protein/Protein L (EBOV; Zaire ebolavirus) at 3.0 μg/mg of serum protein, respectively.
EBOV seems to induce different genes Phospholipid-transporting ATPase IB at 8.1 μg/mg of serum protein in her serum, and Probable phospholipid-transporting ATPase IIB at 5.5 μg/mg of serum protein in his serum, respectively. Then, fucoidan also may be effective to prion disease due to reducing YFV (enveloped Flavivirus) and EBOV (please see file; Feed by Measure).
Therefore, PDMD method is expected to clarify the prion problemn.
Further, amended on 27 November 2017
We have previously reported that serum of biotin-deficiency children with alopecia have a membrane protein of Human hair keratin-associated proteins (KAPs) (please see file; JMBT Alopecia).
We would like to explain why alopecia patient excretes KAP into his or her blood.
HCC tissue (named No.6) expresses Keratin type II/Cytokeratin 5/VK5 at 2.7 and Keratin type II cytoskeletal 7/Cytokeratin 7/VK7 at 0.68 μg/mg of tissue protein, respectively (total 3.4 μg/mg of tissue protein). This tissue also has HAdV proteins at 4.6 μg/mg of tissue protein. Therefore, Keratin-related gene seems to be induced by HAdV.
Serum of biotin-deficient girl with alopecia (3y, with GSD-1b) has KAP at 19.3 μg/mg of serum protein, and has protein of Bacillus phage SPP1 at 8.7 μg/mg of serum protein. Therefore, her KAP has been induced by Bacillus phage SPP1. Further, her serum has bacterial protein of Actinomycete (Streptomyces avermitilis) at 19.3 μg/mg of serum protein, and this bacterium seems to have performed the excretion of KAP from skin into blood.
Serum of biotin-deficient girl with alopecia (1y; with Conjunctivitis) has KAP at 11.5 μg/mg of serum protein, and has protein of HAdV at 7.7 μg/mg of serum protein. KAP seems to be up-regulated by HAdV. Further, her serum has bacterial protein of Actinomycete (Mycobacterium tuberculosis) at 7.9 μg/mg of serum protein, and this bacterium seems to have performed the excretion of KAP from skin into blood.
Serum of biotin-deficient boy with alopecia (4mo) has KAP at 9.9 μg/mg of serum protein, and has protein of Enterobacteria phage T4 at 2.4 μg/mg of serum protein. KAP seems to be up-regulated by Enterobacteria phage T4. Further, his serum has bacterial protein of Actinomycete (Mycobacterium vanbaalenii) at 9.9 μg/mg of serum protein, and this bacterium seems to have performed the excretion of KAP from skin into blood.
Bacteriophage or HAdV, and Actinomycete in serum of healed patients (getting the normal hair growth) have been disappeared.
Adult biotin-deficient patient (32y, female; with gait disorder and without alopecia) has no Bacteriophage or HAdV, and Actinomycete, and KAP may not be excreted in her blood.
Therefore, although we have not met the adult alopecia patient, posssible Adult-Alopecia patient with biotin deficiency may have been co-infected by Bacteriophage or HAdV, and Actinomycete.
Then, the alopecia patients with biotin deficiency may also be healed by the fucoidan therapy instead of the dangerous biotin therapy. Fucoidan (the best of all medicines) can also reduce bacteria via improving the innate immunity. “Kitikiew S, Chen JC, Putra DF, Lin YC, Yeh ST and Liou CH: Fucoidan effectively provokes the innate immunity of white shrimp Litopenaeus varnamei and its resistance against experimental Vibrio alginolyticus infection. Fish Shelfish Immunol 34: 280-290, 2013.” (please see file; fucoidan bacteria)
Further, amended on 22 November 2017
Since virus rules gene expression, the origin of Insulin-Dependent Diabetes Mellitus (IDDM) has been studied. IDDM seems to be induced by Paramyxoviridae such as Mumps virus (MuV) and Measles virus (MeV).
Hepatoma HepG2 (without fucoidan) has Nucleoprotein/Nucleocapsid protein/Protein N (MuV) at 0.06, Hemagglutinin-neuraminidase (Newcastle disease virus; NDV) at 1.6, and Protein L (Human respiratory syncytial virus; HRSV) at 1.7 μg/mg cell protein, respectively (total 3.4 μg/mg cell protein). MuV+NDV+HRSV seem to induce Leptin receptor overlapping transcript-like 1 at 0.10 μg/mg cell protein and Bardet-Biedl syndrome 10 protein at 3.9 μg/mg cell protein (total 4.0 μg/mg cell protein). However, virus concentrations blow 2.5% may not induce IDDM.
Healed HepG2 (by fucoidan) has Protein L (MuV) at 2.2 μg/mg cell protein. MuV seems to induce Glucocorticoid receptor (GR) at 2.2 μg/mg cell protein. Fucoidan can reduce NDV and HRSV at 0.102 mg/mL within three days.
Healthy serum (33y, male) has RNA-directed RNA polymerase L/Protein L (MeV) at 20.4 μg/mg serum protein. MeV seems to induce Pyruvate kinase PKM/Cytosolic thyroid hormone-binding protein at 16.0 μg/mg serum protein and Synaptotagmin-14 at 4.7 μg/mg serum protein (total 20.7 μg/mg serum protein). However, virus concentrations blow 2.5% may not induce IDDM in this healthy person.
LC liver tissue (named No.6) has Fusion glycoprotein (Bovine respiratory syncytial virus; BRSV) at 5.2 μg/mg tissue protein. BRSV seems to induce Long-chain specific acyl-CoA dehydrogenase, mitochondrial/LCAD at 1.9, Glucose transporter type 1 erythrocyte/brain at 2.1, and Glycogen phosphorylase, liver form at 0.9 μg/mg tissue protein, respectively (total 4.9 μg/mg tissue protein).
HCC liver tissue (named No.6) has Nucleocapsid protein at 0.033 and RNA-directed RNA polymerase L/Protein L (MeV) at 18.4 μg/mg tissue protein, and Matrix protein (SeV) at 4.9 μg/mg tissue protein, respectively (total 23.3 μg/mg tissue protein). MeV and SeV seem to induce Insulinase/IDE at 13.3, Sodium/glucose cotransporter-like protein at 1.2, and Fructose-bisphosphate aldolase C/Brain-type aldolaseat 8.0 μg/mg tissue protein, respectively (total 22.5 μg/mg tissue protein). However, virus concentrations blow 2.5% may not induce IDDM in this No.6 patient.
LC tissue with leprosy has L protein (SeV) at 13.3 μg/mg tissue protein. SeV seems to induce Sucrase-isomaltase, intestinal at 6.8, Solute carrier family 2, facilitated glucose transporter member 1/Glucose transporter type 3, brain at 4.9, and Phosphoenolpyruvate carboxykinase/PEPCK-C/Phosphoenolpyruvate carboxykinase, cytosolic [GTP] at 3.7 μg/mg tissue protein, respectively (total 15.4 μg/mg tissue protein). However, virus concentrations blow 2.5% may not induce IDDM in this LC patient.
HCC tissue with PBC has Fusion glycoprotein (NDV) at 4.5 μg/mg tissue protein and Hemagglutinin-neuraminidase (NDV) at 3.0 μg/mg tissue protein (total 7.5 μg/mg tissue protein). NDV seems to induce Glycogen debranching enzyme at 1.2, Glycogen phosphorylase at 3.6, Insulin-like growth factor-binding protein 5/IGFBP-5/IBP-5 at 3.0, and Insulin-like growth factor binding-protein 3/IGFBP-3/IBP-3 at 0.7 μg/mg tissue protein, respectively (total 8.5 μg/mg tissue protein). However, virus concentrations blow 2.5% may not induce IDDM in this LC patient.
Liver tissue of pseudo-liver cancer has RNA-directed RNA polymerase L/Protein L (MeV) at 52.7 μg/mg tissue protein. MeV seems to induce Maltase-glucosylamylase, intestinal at 21.6, Sucrase-isomaltase, intestinal/Isomaltase at 21.2, and Sodium-glucose cotransporter at 11.2 μg/mg tissue protein, respectively (total 54.0 μg/mg tissue protein). This liver tissue of pseudo-liver cancer also has Nucleocapsid protein (MuV) at 1.8 μg/mg tissue protein. MuV seems to induce Glycogen branching enzyme/1,4-alpha-glucan branching enzyme at 1.9 μg/mg tissue protein and Insulinoma-associated protein 1/Zinc finger protein IA-1 at 0.44 μg/mg tissue protein. This person may have had a complications of IDDM due to MeV (5.2%).
Then, Fucoidan (the best of all medicines in addition to the drug for the cancer of HCC) may also prevent IDDM, since Paramyxoviridae may also be decreased by fucoidan. Fucoidan may also prevent Diabetic nephropathy, since fucoidan may inhibit the excretion of the membrane-glycoprotein of kidney-type biotinidase from kidney cell-membrane into urine via normalization of biotin metabolism of IDDM patients (please see file; Dr. Terentyeva Urine BIN).
Further, added on 25 November 2017
It has been reported by Dr. Cheng J, et al. in a report “Cheng J, et al. (2009) Cytomegalovirus Infection Causes an Increase of Arterial Blood Pressure. PLoS Pathog5(5): e1000427. https://doi.org/10.1371/journal.ppat.1000427” that the Hypertension or High blood pressure is caused by HHV-5 (Human cytomegalovirus). Therefore, I have researched about this interesting link in my protein database. And, I have found that the infections by HHV-5, Human parainfluenza virus (hPIV), Simian virus 41 (SV41), and Sendai virus (SeV; mPIV-1) seem to be the origin of Hypertension.
Although children (below 4y) has infected by HHV-5 at low frequency of 11% (1/9), old people with liver diseases has HHV-5 at 100% (4/4).
Serum of 8mo girl (with gastritis) has Protein HXLF3 (HHV-5) at 25.4 μg/mg of serum protein protein (2.54 %), and her gastritis may be due to HHV-5. But, her serum at 12mo (4 mo later) does not have HHV-5. This may be by the latent infection of HHV-5. Her serum at 8mo has expressed blood-pressure-related proteins of Microtubule-associated protein 1A/MAP 1A at 14.5, Kinesin-like protein KIF 27 at 4.5, FK506-binding protein 15 at 3.3, and Nephrin/Renal glomerulus-specific cell adhesion receptor at 3.6 μg/mg of serum protein, respectively (total 25.9 μg/mg of serum protein). Then, her gastritis may be related to hypertension or congestive gastropathy.
Serum of 4mo boy (with biotin deficiency) has Protein L (hPIV-2) at 9.8 μg/mg of serum protein, and has expressed Doublecortin domain-containing protein 5 at 5.7 μg/mg of serum protein and Janus kinase and microtubule-interacting protein 1/GABA-B receptor-binding protein at 3.1 μg/mg of serum protein (total 8.8 μg/mg of serum protein).
Serum of healthy female (52y) has Large structural protein (hPIV-5; Simian virus 5; SV5) at 4.0 μg/mg of serum protein, and has expressed Tubulin delta chain at 9.8 μg/mg of serum protein.
Hepatome HepG2 (cultured without fucoidan for 3 days) has Protein UL50 (HHV-5) at 2.7 μg/mg of cell protein, and has expressed Kinesin-like protein KIF3B at 14.7 μg/mg of cell protein.
Healed HepG2 (cultured with fucoidan at 0.102 mg/mL for 3 days) has Ribonucleotide reductase (HHV-5) at 1.9 μg/mg of cell protein, and has expressed Microtubule-associated protein 2/MAP 2 at 3.3 μg/mg of cell protein and Tubulin-specific chaperone D/Tubulin-folding cofactor D at 5.7 μg/mg of cell protein. It seemed that 3 weeks may be necessary for reducing HHV-5 as indicated by Dr. Hayashi K et al. (Hayashi K, Nakano T, Hashimoto M, Kanekiyo K and Hayashi T: Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection. Int Immunopharmacol 8: 109-116, 2008).
Liver tissue with pseudo-liver cancer has Hypothetical protein HHLF3 (HHV-5) at 2.8 μg/mg of tissue protein and Major capsid protein (HHV-5) at 2.1 μg/mg of tissue protein (total 4.9 μg/mg of tissue protein), and this tissue has expressed Vasopressin V1a receptor/Antiuretic hormone receptor 1a at 1.7 μg/mg of tissue protein and Oxytocin receptor/OT-R at 6.1 μg/mg of tissue protein (total 7.8 μg/mg of tissue protein).
LC tissue with leprosy has ICP36 protein (HHV-5) at 2.6 μg/mg of tissue protein and L protein (Sendai virus; SeV) at 13.3 μg/mg of tissue protein (total 15.9 μg/mg of tissue protein). This tissue has expressed Adenomatous polyposis coli protein/APC protein/Deleted in polyposis 2.5 at 26.0 μg/mg of tissue protein.
HCC tissue with PBC has 64 KD Lower matrix phosphoprotein (HHV-5) at 7.8 μg/mg of tissue protein, and also has Adenomatous polyposis coli protein/APC protein at 6.4 μg/mg of tissue protein. LC tissue (named No.6) has Hypothetical protein UL17 (HHV-5) at 0.23, Hypothetical protein UL95 (HHV-5) at 7.1, and Probable DNA packaging protein (HHV-5) at 1.8 μg/mg of tissue protein, respectively (total 9.1 μg/mg of tissue protein). This tissue also has RNA-directed RNA polymerase L (Simian virus 41/SV41) at 20.1 μg/mg of tissue protein. Then, total virus protein becomes 29.2 μg/mg of tissue protein (2.9%). This tissue has expressed Adenomatous polyposis coli protein/APC protein at 21.2, Centromeric protein C/CENP-C at 2.5, and Centromeric protein E/CENP-E/Inesin-7 at 15.6 μg/mg of tissue protein, respectively (total tubulin-related proteins 3.9%).
HCC tissue (No.6) has Hypothetical protein HHRF1 (HHV-5) at 0.3, Hypothetical protein UL87 (HHV-5) at 5.7, Protein UL50 (HHV-5) at 0.22, and Protein UL94 (HHV-5) at 2.3 μg/mg of tissue protein, respectively (total HHV-5 protein 8.5 μg/mg of tissue protein). Further, this tissue has Matrix protein (Sendai virus; SeV) at 4.9 μg/mg of tissue protein. This tissue expresses MAP-2B/Microtubule-associated protein 2 at 10.6, Neurofilament triplet M protein/Neurofilament medium polypeptide/NF-M at 1.1, Endothelin-2/ET-2 at 0.18, and Erythrocyte adducin alpha subunit/Alpha-adducin at 0.41 μg/mg of tissue protein, respectively (total tubulin related proteins become 12.3 μg/mg of tissue protein). Therefore, this patient named No.6 has been high blood pressure except his HCC liver tissue.
Therefore, Fucoidan and/or edible Mozuku seems to be also the best drug for hypertension, since amount of HHV-5, hPIV, SV41, and SeV may be reduced within 3 weeks of feeding.
Further, added on 29 November 2017
Homeobox proteins are very important in the morphogenesis. The effect of virus on the gene expression of Homeobox proteins are studied.
HCC tissue (with PBC) has Homeobox protein MSX-1/Hox-7 (linked to cleft lip or harelip) at 1.1 μg/mg of tissue protein. This gene seems to be up-regulated by Genome polyprotein (HAV) at 24.0 μg/mg of tissue protein, and down-regulated by RNA-directed RNA polymerase subunit P3/RNA-directed RNA polymerase catalytic subunit (Influenza A virus/FluA) at 2.8, Hemagglutinin (FluA) at 1.9, and Nucleoprotein (Influenza B virus/FluB) at 2.1 μg/mg of tissue protein, respectively (total 6.8 μg/mg of tissue protein). Thus, induction power by HAV is stronger at 17.2 μg/mg of tissue protein.
LC tissue with leprosy has Homeobox protein OTX1 at 6.6 μg/mg of tissue protein and Homeobox/POU domain protein RDC-1/Brain-specific homeobox/POU domain protein 3A at 1.6 μg/mg of tissue protein (total 8.2 μg/mg of tissue protein). This tissue has inducing virus of Genome polyprotein (HAV) at 14.4 μg/mg of tissue protein, and repressing virus of RNA-directed RNA polymerase subunit P3 (FluA) at 2.4, Matrix (M1) protein (FluA) at 2.8, and Neuraminidase (FluB) at 3.1 μg/mg of tissue protein (total 8.3 μg/mg of tissue protein). Thus, induction power by HAV is stronger at 6.1 μg/mg of tissue protein.
Liver tissue with pseudo-liver cancer has Homeobox protein B7/Homeobox protein Hox-2C at 1.3, and Zinc finger E-box-binding homeobox 1/NIL-2-A zinc finger protein at 1.6 μg/mg of tissue protein (total 2.9 μg/mg of tissue protein). This tissue has inducing virus of RNA-directed RNA polymerase L (Vesicular stomatitis virus/VSIV) at 9.7 μg/mg of tissue protein, but has no HAV. This tissue has repressing virus of Hemagglutinin (FluA) at 3.1 μg/mg of tissue protein and Matrix (M) protein (FluC) at 0.52 μg/mg of tissue protein (total 3.6 μg/mg of tissue protein). Thus, induction power by VSIV is stronger at 6.1 μg/mg of tissue protein.
LC tissue (named No.6) has Homeobox protein HOX-B7/Homeobox protein Hox-2C at 0.6 μg/mg of tissue protein. This tissue has inducing virus of Genome polyprotein (Louping ill virus/LIV) at 6.4 μg/mg of tissue protein, and repressing virus of Neuraminidase (FluA) at 1.7 μg/mg of tissue protein. Induction power seems to be strong.
HCC tissue (No.6) has no Homeobox protein. This tissue has inducing virus of RNA-directed RNA polymerase L (Vesicular stomatitis Indiana virus strain Mudd-Summers/VSIV) at 5.3 μg/mg of tissue protein, and repressing virus of Nucleoprotein (FluA) at 0.02, RNA-directed RNA polymerase subunit P2 (FluA) at 0.87, and RNA-directed RNA polymerase subunit P3 (FluC) at 6.1 μg/mg of tissue protein, respectively (total 7.0 μg/mg of tissue protein). Thus, repressing power by Flu virus is stronger at 1.7 μg/mg of tissue protein.
Serum of 1y11mo girl has Homeobox protein engrailed-2/Homeobox protein en-2 at 3.1 μg/mg of serum protein. This serum has inducing virus Genome polyprotein (HAV) at 10.7 μg/mg of serum protein, and has no repressing virus of Flu.
Serum of healthy 52y female has Zinc finger homeobox protein 4 at 5.0 μg/mg of serum protein. This serum has inducing virus Large structural protein (hPIV-5/Simian virus 5/SV5) at 4.0 μg/mg of serum protein, and has no repressing virus of Flu.
Healed HepG2 (cultured with fucoidan) has Homeobox protein HMX3/Transcription factor HMX3 at 0.034 μg/mg of cell protein. This cells have inducing virus Protein L (Mumps virus; MuV) at 2.2, and repressing virus of Hemagglutinin (FluA) at 0.4, Nucleoprotein (FluC) at 0.95 μg/mg of cell protein, respectively. Thus, induction power is stronger at 0.8 μg/mg of cell protein.
Hepatoma HepG2 (cultured without fucoidan) has no Homeobox protein. This cell has inducing virus of Nucleoprotein/Nucleocapsid protein/Protein N (MuV) at 0.06, and has inhibiting virus Neuraminidase (FluA) at 0.8 μg/mg of cell protein. Thus, inhibitor power is stronger in this cell.
Fetal hepatocyte Hc cell has no Homeobox protein. This cell has no inducing and repressing virus at all.
Therefore, Fucoidan and/or edible Mozuku seems to be also the best drug for prevention of the birth of morphologically changed babies, since amount of these virus (HAV, VSIV, LIV, hPIV-5, MuV, and Flu virus) may be reduced within 3 weeks of feeding.
Japanese edible Mozuku also seems to be safe to the pregnant women (please see file; Feed by Measure).
Furthermore, added on 1 December 2017
I have further studied for the expression of α-Fetoprotein. α-Fetoprotein (AFP) expression seems to be induced by HHV, Herpesvirus saimiri (SaHV-2), HAV, HCV, Measles virus (MeV), Bluetongue virus (BTV), Influenza A virus (FluA), and Acanthamoeba polyphaga mimivirus (Mimivirus; APMV). α-Fetoprotein expression seems to be repressed by Coronavirus.
Serum of 8mo (with gastritis) has Alpha-Fetoprotein (AFP; 1- of mature; 19- of precursor) at 2.0 μg/mg of serum protein. Her serum has inducer HHV-5, and repressor HCoV. Inducer concentration is higher at 7.7 μg/mg of serum protein.
Serum of 12mo (with cold; the same person as above) has AFP at 0.7 μg/mg of serum protein. Her serum has inducer HHV-6 and APMV, and repressor virus IBV. Inducer concentration is higher at 3.1 μg/mg of serum protein.
Human breast milk (healthy) has AFP at 2.9 μg/mg of milk protein. Her milk has inducers HHV-4, HHV-6B, HHV-7, SaHV-2, and APMV at 92.4 μg/mg of milk protein. Her milk has no repressor virus.
Healthy serum of 33y (male) has AFP at 2.3 μg/mg of serum protein. His serum has inducer virus MeV at 20.4 μg/mg of serum protein. His serum has no repressor virus.
Healthy serum of 52y (fmale) has AFP at 2.2 μg/mg of serum protein. Her serum has inducer virus Bluetongue virus (BTV) at 18.4 μg/mg of serum protein. Her serum has repressor virus HCoV at 10.3 μg/mg of serum protein. Inducer concentration is higher at 8.1 μg/mg of serum protein.
Serum of Gait disorder patient (32y, female) has AFP at 1.5 μg/mg of serum protein. Her serum has inducer virus HCV and HHV-6 at 9.8 μg/mg of serum protein. Her serum has repressor virus Canine coronavirus (CCoV) at 5.9 μg/mg of serum protein. Inducer concentration is higher at 3.9 μg/mg of serum protein.
Serum of light Gait disorder patient (22y, female) has AFP at 1.3 μg/mg of serum protein. Her serum has inducer virus HHV-6 at 2.1 μg/mg of serum protein. Her serum has no repressor virus. Inducer concentration is higher at 2.1 μg/mg of serum protein.
Serum of 1y girl (with biotin deficiency) has AFP at 3.2 μg/mg of serum protein. Her serum has inducer virus HHV-6 and APMV at 21.2 μg/mg of serum protein. Her serum has no repressor virus. Inducer concentration is higher at 21.2 μg/mg of serum protein.
The serum of the same girl (1y4mo) has AFP at 4.7 μg/mg of serum protein. Her serum has inducer virus FluA at 9.0 μg/mg of serum protein. Her serum has no repressor virus. Inducer concentration is higher at 9.0 μg/mg of serum protein.
The serum of the same girl (1y11mo) has AFP at 1.7 μg/mg of serum protein. Her serum has inducer virus HAV and HCV at 18.3 μg/mg of serum protein. Her serum has repressor virus HCoV at 10.5 μg/mg of serum protein. Inducer concentration is higher at 7.8 μg/mg of serum protein.
Serum of 4mo boy (with biotin deficiency) has no AFP. His serum has no inducer and repressor virus.
The serum of the same boy (7mo1w) has no AFP. His serum also has no inducer and repressor virus.
Serum of GSD-1b patient (3y, female; biotin deficiency) has AFP at 1.9 μg/mg of serum protein. Her serum has inducer virus HHV-4 and HHV-6 at 9.9 μg/mg of serum protein. Her serum has repressor virus Murine coronavirus (MCoV) at 11.0 μg/mg of serum protein. Repressor concentration is higher at 1.1 μg/mg of serum protein. Repressing power by MCoV may be weak.
Serum of the same patient (4y1mo; after 2mo of liver transplantation; during biotin therapy) has AFP at 3.8 μg/mg of serum protein. Her serum has inducer virus HCV at 4.0 μg/mg of serum protein. Her serum has no repressor virus. Inducer concentration is higher at 4.0 μg/mg of serum protein.
LC liver tissue (named No.6) has AFP at 23.0 μg/mg of tissue protein. His tissue has inducer virus HHV-1, HHV-5, HCV, FluA, and BTV at 55.0 μg/mg of tissue protein. His tissue has repressor virus Murine coronavirus (MCoV) at 29.1 μg/mg of tissue protein. Inducer concentration is higher at 25.9 μg/mg of tissue protein.
HCC liver tissue (No.6) has AFP at 39.3 μg/mg of tissue protein. His tissue has inducer virus HHV-1, HHV-2, HHV-3, HHV-4, HHV-5, SaHV-2, HCV, FluA, and MeV at 53.1 μg/mg of tissue protein. His tissue has repressor virus HCoV and Porcine transmissible gastroenteric coronavirus (PTGEV; PCoV) at 10.5 μg/mg of tissue protein. Inducer concentration is higher at 42.6 μg/mg of tissue protein.
Liver tissue (with pseudo-liver cancer) has AFP at 32.8 μg/mg of tissue protein. His tissue has inducer virus HCV, FluA, and MeV at 94.1 μg/mg of tissue protein. His tissue has repressor virus HCoV, MCoV, and ACoV at 49.7 μg/mg of tissue protein. Inducer concentration is higher at 44.4 μg/mg of tissue protein.
LC liver tissue (with leprosy) has AFP at 53.5 μg/mg of tissue protein. Her tissue has inducer virus HHV-1, HHV-2, HHV-4, HHV-5, HAV, HCV, FluA, and MeV at 113.8 μg/mg of tissue protein. Her tissue has repressor virus FCoV at 3.4 μg/mg of tissue protein. Inducer concentration is higher at 110.4 μg/mg of tissue protein.
HCC liver tissue (with PBC) has AFP at 36.9 μg/mg of tissue protein. Her tissue has inducer virus HHV-1, HHV-2, HHV-5, HAV, HCV, and FluA at 80.6 μg/mg of tissue protein. Her tissue has no repressor virus. Inducer concentration is higher at 80.6 μg/mg of tissue protein.
Normal fetal hepatocyte Hc has AFP at 2.3 μg/mg of cell protein. This Hc cell has inducer virus of only HCV at 2.2 μg/mg of cell protein. This Hc cell has no repressor virus. Inducer concentration is higher at 2.2 μg/mg of cell protein.
Hepatoma HepG2 (cultured without fucoidan) has only precursor AFP at 11.5 μg/mg of cell protein. This hepatoma cell has inducer virus of HHV-3, HHV-4, HHV-5, HCV, GBV-C, FluA, and APMV at 37.1 μg/mg of cell protein. This hepatoma cell has repressor virus of HCoV at 14.8 μg/mg of cell protein. Inducer concentration is higher at 22.3 μg/mg of tissue protein.
Healed hepatoma HepG2 (cultured with fucoidan at 0.102 mg/mL for three days) has precursor AFP at 1.5 μg/mg of cell protein and AFP at 3.8 μg/mg of cell protein (total AFP becomes to 5.3 μg/mg of cell protein). This healed hepatoma cell has inducer virus of HHV-1, HHV-4, HHV-5, HHV-6, HHV-7, HCV, FluA, and APMV at 20.4 μg/mg of cell protein. This healed hepatoma cell has repressor virus of HCoV at 0.2 μg/mg of cell protein. Inducer concentration is higher at 20.2 μg/mg of tissue protein.
Thus, AFP gene expression is under the control of virus. Up-regulated AFP in some liver cancers may only be due to HCV and HAV, and possible cancer markers seem to give only the illusions.
Amended on 3 December 2017
Further, I have considered about the grief Down syndrome. It seems to be mainly due to infection by Human adenovirus (HAdV). Only three specimens have the Down syndrome cell adhesion molecule (membrane glycoprotein; Hydrophobicity is 0.510, similar to the hydrophobicity to another representative membrane glycoprotein of Growth hormone receptor of 0.499).
Serum of 1y girl (with biotin deficiency, without Down syndrome) has Down syndrome cell adhesion molecule at 9.8 μg/mg of serum protein, and has Maturation protein (HAdV-6) at 7.7 μg/mg of serum protein. Other three biotin-deficient patients (one male and two females) have no Down syndrome cell adhesion molecule and HAdV. But, the leak of this membrane glycoprotein may be due to biotin deficiency. Biotin deficiency leaks membrane protein of Keratin-associated protein (KAP; Hydrophobicity 0.597) in child patients (please see file; JMBT Alopecia).
Male Down syndrome patients is 1.36-fold higher (p < 0.01) than female patients. HAdV infection has no gender difference. We have previously found that the low range persons in biotinidase activity as assessed by lipoyl-para-aminobenzoate (LPAB) as substrate are rich in male children (please see Fig. 6 of the file; Human Serum BIN-LIP). Therefore, Down syndrome patients may have been in biotin-deficient state during fetal period.
Hepatoma HepG2 cell (male; cultured without fucoidan) has Down syndrome cell adhesion molecule at 6.8 μg/mg of cell protein, and has Packaging protein 3 (HAdV-2) at 0.2 μg/mg of cell protein. Healed HepG2 cell (with fucoidan for three days) has Down syndrome cell adhesion molecule at 5.6 μg/mg of cell protein, and has Fiber protein (HAdV-12) and DNA polymerase (HAdV-40) at 1.3 μg/mg of cell protein.
Inducing power for Down syndrome cell adhesion molecule by HAdV-6 seems to be weak as compared to HAdV-2, HAdV-12, and HAdV-40.
Therefore, Fucoidan (sulphated poly-fucose) and/or edible Japanese Mozuku seems to be also the best drug to prevent the birth of Down syndrome baby, since amount of HAdV (dsDNA) may be reduced within 3 weeks of fucoidan therapy, and the fucoidan can normalize the biotinidase/lipoamidase activity (please see file; Anticancer Res). Japanese edible Mozuku also seems to be safe even to the pregnant women.
This new result by us suggests that the "Gene Therapy" is only a pure fabrication.
Furthermore, amended on 10 January 2018
I have recently reported in this ResearchGate that Alopecia patients with biotin deficiency seem to have been co-infected by Bacteriophage or HAdV, and Actinomycete. This co-infection may be due to the reduced innate-immunity in these biotin deficient patients. Reduced level of biotin (vitamin H) seems to reduce the rigidity of the membrane structure to leak the Keratin-associated proteins (KAP) from skin to blood (please see file; JMBT Alopecia 1, and Biotin Asialoprotein Receptor in the case of liver).
Then, another Morphological Disease of Harelip or Cleft lip may be occurred similar mechanism to Alopecia. As has also been recently reported in this ResearchGate that Transcription factors of Homeobox proteins have been up-regulated by some inducing virus (HAV, VSIV, LIV, hPIV-5, MuV), and repressed by Flu virus.
Harelip-linked Homeobox protein MSX-1/Hox-7 seems to be up-regulated by Hepatitis A virus (HAV). HAV infection to pregnant mother may be occurred by biotin deficient state, which induces lowered innate immunity. HAV seems to infect preferably to female, and Flu seems to virulently infect to male (harelip seems to be higher in male persons; my unpublished observation). As shown in Alopecia case, Morphological change is also co-induced by biotin deficiency, which leads to instable membrane structures.
Then, I have determined the biotinidase activity of serum of a harelip patient. Human serum biotinidase of normal healthy adult has shown the heat stable character.
Amo V Km Kip Rep Cap
Fresh 27.9 131 5.94 359 59.3 40.7
Heat treated 20.6 109 6.71 501 69.3 37.8
(Heat treatment has been done by incubating fresh serum 4 h at 37 ℃).
On the other hand, serum biotinidase of this adult harelip patient has shown the heat instable characteristics.
Amo V Km Kip Rep Cap
Fresh 18.1 98.7 6.93 391 48.7 29.7
Heat treated 24.9 74.1 3.76 210 19.7 22.1
(units for Amo is s-1*M-1 , V is pmol/min/mg, Km is μM, Kip is μM, Rep is s-1*M*10-3, Cap is sec-1, respectively)
The heat instable biotinidase has been observed in biotin deficient Alopecia patients (please see file; Wide range of Biotin and JMBT alopecia), and this reduced enzyme stability has been attributed to be due to glycochain of biotinidase. Patients possessing labile biotinidase (changed in glycochain structure) cannot respond to several special milk powders for children with allergies contained low levels of biotin. Low level of biotin in the patients leads membrane structure to labile, which induces leaking of membrane protein Keratin-associated proteins (KAP), and alopecia has been induced.
HAV does not give the effect on the biotinidase expression. Thus, the heat labile serum biotinidase in the case of harelip patient and mother may be due to the changed glycochain of biotinidase.
HAV has also been found to up-regulate the glycochain degrading enzymes; i.e.,
LC tissue with leprosy and with HAV (14.4 μg/mg of tissue protein) has Beta-Galactoside alpha-2,6-sialyltransferase 1/Alpha-2,6-ST at 2.4, Glycosylceramidase/Acid beta-glucosidase at 0.28, and N-Acetylglucosamine-6-sulfatase/G6S at 3.2 μg/mg of tissue protein, respectively (total glycochain-related proteins becomes 5.9 μg/mg of tissue protein), and
HCC tissue with PBC and with HAV (24.0 μg/mg of tissue protein) has Beta-Glucuronidase/Beta-Gl/GUS at 3.1, Na+/H+ antiporter, amiloride-sensitive/Sodium/hydrogen exchanger 1 at 11.7, and Uracil-DNA glycosylase 2/UNG/UDG at 4.6 μg/mg of tissue protein, respectively (total glycochain-related proteins becomes 19.4 μg/mg of tissue protein). Another tissues without HAV have small amount of glycochain-related proteins; i.e., fetal hepatocyte Hc cells and LC and HCC tissue of No.6 patient have no glycochain-related proteins, and liver of pseudo-liver cancer has Alpha-L-Iduronidase at 5.1 μg/mg of tissue protein.
Thus, HAV may also have changed the glycochain of biotinidase via the effect of these elevated glycochain-related enzymes. Heat labile biotinidase induces biotin deficiency.
Low level of biotin during pregnancy is very important to induce morphological disorder in mice. Since 1983, Dr. Toshiaki Watanabe (now; Osaka Aoyama University, Faculty of Health Sciences, Ni-ina, Minō-city, Osaka, Japan) has reported that biotin deficiency induces cleft palate in mice but not in rat (Watanabe T. Teratogenic effects of biotin deficiency in mice. J. Nutr. 1983; 113: 574–581, and see file; Dr. Watanabe mouse harelip). I also have found that the serum of male LEW rat has 10-fold higher biotinidase activity than the serum of male C57BL/6 mouse (please see Table 8 of the file; J Chrom B Rat BIN LIP Km); i.e., V of rat serum is 151 pmol/min/mg of protein, but V of mouse serum is only 15.2 pmol/min/mg of protein. Then, serum biotinidase activity is important to harelip formation. The low level of biotin induces labile membrane structure as in the case of Alopecia. Therefore, HAV induces both changed level of Homeobox protein MSX-1 and changed biotinidase in glycochain giving biotin deficiency in the developing harelip-fetal baby, but Flu represses Homeobox protein MSX-1.
Biotin therapy is dangerous to give excess biotin, and does not reduce the amount of HAV and Flu.
Thus, the birth of baby with cleft lip also seems to be prevented by eating the edible Mozuku or Fucoidan (sulphated poly-fucose) to reduce HAV and Flu in the pregnant mother. Feed of adequate nutrition of biotin by measure is also important in the pregnant mother (please see file; Feed by Measure).
Amended on 15 December 2017
I have further studied about the Dementia or Demenz in relation to virus.
Dementia seems to be strongly linked to the infection or co-infection of Retrovirus, HAV, HCV, HHV-5, HHV-6, Coronavirus, Measles virus (MeV), Ebolavirus (EBOV), Togavirus, and Bacterio-phages of Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Haemophilus influenza. Haemophilus influenza uses nicotine (vitamin B3) and heme, and tobacco seems to be important to prevent the vitamin B3 deficiency and Dementia due to Haemophilus influenza.
A healthy serum (52y, female) has Biotinidase (serum-type) at 2.1, Biotinidase (kidney-type) at 0.8, Biotinidase (Fetal/inflammatory-type) at 1.1, Neurogenic locus notch homolog protein 3 at 5.5, Prickle-like protein 2 at 3.4, Protein tweety homolog 3 at 4.3, Ryanodine receptor 1 at 5.0, Tubulin delta chain at 9.8, Adenylhomocysteinase 3 at 6.6, Chondroitin sulfate proteoglycan 5 at 2.7, Semaphorin-6A at 5.5 μg/mg of serum protein, respectively (Total 46.8 μg/mg of serum protein). Her serum has Sulfate transporter CysZ, Uncharacterized ABC transporter ATP-binding protein, and Ribose-5-phosphate isomerase A (Haemophilus influenzae) at 21.4 μg/mg of serum protein and Replicase polyprotein 1a (Human coronavirus 229E; HCoV 229E) at 10.3 μg/mg of serum protein (Total 31.7 μg/mg of serum protein). She may have a high risk to become to be Dementia.
It is found that hepatocellular carcinoma tissue and liver cirrhosis tissue (pre-cancer state) have already been differentiated to mimic the brain (CNS).
Fetal hepatocyte Hc seems to independently develop without influences of virus. Hc has brain-related proteins at 105 μg/mg of cell protein (10.5%), but only few microbirobe protein is present; i.e., Biotin synthetase (Bacillus subtilis) at 2.6, Env polyprotein/Envelope glycoprotein gp160 (HIV-2) at 2.9, and Genome polyprotein (HCV) at 2.2 μg/mg of cell protein, respectively (Total 7.7 μg/mg of cell protein (0.77%)). Therefore, influences by microbes seems to be very low level.
Serum of healthy 1y4mo girl has Biotinidase (serum sequence) at 1.1, Biotinidase (kidney-type) at 1.1, Biotinidase (Fetal/inflammatory-type) at 0.5, Activin receptor type-2B at 2.6, and Cysteine-rich motor neuron 1 protein at 10.6 μg/mg of serum protein, respectively (Total 15.9 μg/mg of serum protein). This serum has Elastin-binding protein ebpS (Staphylococcus aureus) at 8.4, Exodeoxyribonuclease 7 large subunit (Staphylococcus epidermidis) at 12.3 , Uncharacterized 55.3kDa protein in gtrB 5' region (Enterobacteria phage P22) at 5.8 μg/mg of serum protein, respectively (Total 26.5 μg/mg of serum protein). Therefore, this healthy children has low risk to be Dementia.
Hepatoma HepG2 has 19.1% of brain-related proteins, but healed normal HepG2 (with fucoidan for three days of therapy) has 10.6% of them (please see file again; HepG2 Fucoidan).
Hepatoma HepG2 has Serum (liver-type; sBIN) biotinidase, 5'-3' Exoribonuclease 2, Alcohol dehydrogenase 6, Ankyrin repeat domain-containing protein 15/KANK1/KN motif and ankyrin repeat domain-containing protein 1, Ankyrin-2/Brain ankyrin, Chordin-like protein 1/Neuralin-1/Neurogenesin-1, Desmuslin/Synemin, Discs large homolog 4 , Dopamine D4 receptor, Doublecortin domain-containing protein 1/Serine/threonine-protein kinase DCLK1, Down syndrome cell adhesion molecule, Fragile X E mental retardation syndrome protein/AF4/FMR2 family member 2, Glutathione synthetase, Heterogeneous nuclear ribonucleoprotein U, Transcription factor HIVEP2/HIV-EP2/Human immunodeficiency virus type I enhancer-binding protein 2/HIV-1-EP2, Kinesin-like protein KIF3B, L-Lactate dehydrogenase A-like 6A, Myelin transcription factor 1, Myosin-10/Non-muscle myosin heavy chain B, Neural cell adhesion molecule 1/N-CAM-1/CD56, Neurogenin 2, Peroxisomal bifunctional enzyme, Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 , Protein kinase C-binding protein NELL2, Protocadherin-16, Protocadherin-17, Ryanodine receptor 1/RyR1, S-Arrestin/Rod photoreceptor arrestin, Short stature homeobox protein 2, Sodium/hydrogen exchanger 1, Stereocilin, Tankyrase-1, Transmembrane protease serine 5/Spinesin, Usher syndrome type-2A protein/Usherin, Whirlin/Autosomal redessive deafness type 31 protein, WW domain-containing oxidoreductase/Fragile site FRA16D oxidoreductase, X-linked interleukin-1 receptor accessory protein-like 1 (Total 191 μg/mg of cell protein). This cells have Bacillus subtilis, HIV-1, RSV, HIV-2, HHV-5, HCV, GBV-C, and HCoV (Total 59.0 μg/mg of cell protein).
Healed normal HepG2 (with fucoidan for three days of therapy) has Serum (liver-type; sBIN) biotinidase, Urine (kidney-type; uBIN) biotinidase, Amyloid beta A4 protein/Alzheimer disease amyloid protein, Acetylcholine receptor protein subunit delta, Acyl-coenzyme A oxidase 2, peroxisomal, ADAMTS-4/Aggrecanase-1, Aggrecan core protein, Ankyrin-2/Brain ankyrin, Attractin, Cadherin-10, Cadherin-18, Cadherin EGF LAG seven-pass G-type receptor 1/Flamingo homolog 2, Calcium/calmodulin-dependent protein kinase type 1, Chloride intracellular channel 6, Choline transporter-like protein 2/Solute carrier family 44 member 2, Dedicator of cytokinesis protein 9, Dihydrofolate reductase-like protein 1/Dihydrofolate reductase, mitochondrial, Down syndrome cell adhesion molecule, Ectodermal-neural cortex (with BTB-like domain), Glutamate receptor ionotropic, kainate 3/Excitatory amino acid receptor 5, GTP-binding protein 3/Atlastin-1/Brain-specific GTP-binding protein, HIV-EP2, Inositol hexaphosphate kinase 3/InsP6 kinase 3, Integral membrane protein 2B, Iodotyrosine dehalogenase 1/Iodotyrosine deiodinase 1, [F-actin]-methionine sulfoxide oxidase MICAL1/Molecule interacting with CasL protein 1, Nesca/RUN and SH3 domain-containing protein 1, Neuroligin-1, Plexin-B2, Protocadherin alpha 5, 13, Protocadherin-17, Secretory carrier-associated membrane protein 1, Semaphorin-5B, Semaphorin-6A, Semaphorin-6C, Sensory neuron sodium channel 2/Sodium channel protein type 11 subunit alpha, Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial/Short-chain 3-hydroxyacyl-CoA dehydrogenase/3-Hydroxyacyl-CoA dehydrogenase, Transcription factor HES-4, Cytochrome b-c1 complex subunit Rieske, mitochondrial/Ubiquinol-cytochrome c reductase iron-sulphur subunit, mitochondrial (Total 107.8 μg/mg of cell protein). This healed cells have HHV-6, HCoV, HHV-5, HHV-7, BoHV-1, HIV-1, and HCV (Total 22.3 μg/mg of cell protein).
I have included biotinidase in these calculations since biotinidase is an important brain enzyme (please see file; Brain-BIN pig).
Fucoidan seems to normalize the protein expression of the liver cancer cells via reducing HCV and HIV-1 dramatically; i.e., hepatoma has HCV + HIV-1 at 24.7 μg/mg of cell protein, but healed HepG2 has HCV + HIV-1 at 2.7 μg/mg of cell protein.
It is interesting that Amyloid beta A4 protein/Alzheimer disease amyloid protein has been up-regulated in healed HepG2. Therefore, this amyloid protein seems to be an innate immunity protein against virus or invading microbes into CNS, and fucoidan can up-regulate the proteins (or genes) of the innate immunity.
It is noteworthy that fucoidan completely repressed Usher syndrome type-2A protein/Usherin (34.4 μg/mg of cell protein), Protocadherin-16 (23.8 μg/mg of cell protein), Kinesin-like protein KIF3B (14.7 μg/mg of cell protein), and Myosin-10/Non-muscle myosin heavy chain B (10.2 μg/mg of cell protein) via repressing HIV-1 and HCV virus in 3 days. Then, HIV-1 and HCV may be affecting both onto the liver and the CNS.
Down syndrome cell adhesion molecule (cause of Down syndrome) is not changed; i.e., from 6.8 μg/mg of cell protein (without fucoidan) to 5.6 μg/mg of cell protein (with fucoidan) in HepG2. Packaging protein 3 (HAdV-2) is present at 0.2 μg/mg of cell protein (without fucoidan), but DNA polymerase (HAdV-40) at 0.9 μg/mg of cell protein (with fucoidan) and Fiber protein/Protein IV (HAdV-12) at 0.4 μg/mg of cell protein (with fucoidan) are present, This increased result indicates that HAdV (dsDNA) is not reduced within 3 day's therapy, and three weeks of fucoidan treatment may be necessary to reduce HAdV (cause of the Down syndrome). Then, the Down syndrome cell adhesion molecule may not be linked to the cause of Dementia.
Therefore, fucoidan is also effective to prevent the Dementia by fucoidan therapy for three weeks (please see file; Feed by Measure).
Effect of fucoidan on bacteria has already been reported by Dr. Suwaree Kitikiew, Dr. Jiann-Chu Chen et al. (please see file; Fucoidan bacteria).
Added on 25 December 2017
Furthermore, I have studied about the knee osteoarthrosis. The knee osteoarthrosis has become to be an important disease of the aged in Japan and also in the world. Therefore, I have searched the infectious origin of knee osteoarthrosis.
It is found that Influenza virus (Flu), Vaccinia virus (VACV), Herpes virus (HHV), and Vibrio cholera have tendency to co-infect. FluB is found in female and FluC is found in male, but FluA infects to both genders. Flu and VACV up-regulate brain-related proteins, and Vaccines against Flu and VACV seem to be very dangerous to induce brain diseases via side-effect. Further, VACV and HHV seem to up-regulate the knee collagens and knee-related proteins, and seem to induce the knee osteoarthrosis.
Liver of pseudo-liver cancer (male) has Collagen alpha 1 (VIII) chain/Endothelial collagen at 5.9, Collagen alpha 2 (IV) chain at 16.0, Alpha-L-Iduronidase at 5.1, N-Acetylglucosamine-6-sulfatase/G6S at 1.9, Syndecan-2/Basement membrane-specific heparan sulfate proteoglycan core protein/HSPG at 1.2, Serine/threonine-protein kinase receptor R5/ALK-3 at 1.7, and Bone morphogenetic protein 7/Osteogenic protein 1 at 21.3 μg/mg of tissue protein (total; 54.0 μg/mg of tissue protein). This tissue has proteins of HHV-1 at 40.4 μg/mg of tissue protein and Protein L2 (VACV) at 14.2 μg/mg of tissue protein (total; 54.6 μg/mg of tissue protein).
LC tissue with leprosy (female) has Collagen alpha-1(XV) chain/Restin at 11.5, Heparin cofactor II/HC-II/HLS2 at 1.3, Kallman syndrome protein/KAL1/Anosmin-1 at 3.9, Metalloproteinase inhibitor 1/TIMP-1/EPA at 1.6, N-Acetylglucosamine-6-sulfatase/G6S at 3.2, Elastin/Tropoelastin at 16.6 μg/mg of tissue protein (total; 38.1 μg/mg of tissue protein). This tissue has proteins of VACV at 20.0 μg/mg of tissue protein and of HHV at 19.6 μg/mg of tissue protein (total; 39.6 μg/mg of tissue protein).
HCC tissue with PBC (female) has Collagen alpha-1(V) chain/Collagen alpha-1(V) chain isoform 1 preproprotein at 16.3, Cytokeratin 2E/Keratin, type II cytoskeletal 2 epidermal at 8.8, Cytokeratin 15/Keratin, type I cytoskeletal 15 at 1.0, Androgen receptor/Nuclear receptor subfamily 3, group C, member 4 at 7.1, Beta-Glucuronidase/Beta-Gl at 3.1, Integrin alpha-V/CD51/Vitronectin receptor alpha subunit at 18.1 μg/mg of tissue protein, respectively (total; 54.4 μg/mg of tissue protein). This tissue has proteins of VACV at 8.6, HHV at 36.6, HBV at 2.2, and B-Lymphotropic polyoma virus (LPyV) at 1.5 μg/mg of tissue protein, respectively (total; 48.9 μg/mg of tissue protein).
LC tissue (named No.6, male) has Collagen alpha 5(IV) chain at 12.5, Procollagen alpha 1(II) chain at 11.1, Integrin alpha-V/Vitronectin receptor alpha subunit/CD51 at 0.38, Serine/threonine protein kinase receptor R5/Bone morphogenetic protein receptor type-1A/ALK-3 at 2.2, and Fibrillin-1 at 17.3 μg/mg of tissue protein, respectively (total; 43.5 μg/mg of tissue protein). This tissue has proteins of VACV at 7.7 μg/mg of tissue protein and HHV at 36.3 μg/mg of tissue protein (total; 44.0 μg/mg of tissue protein).
HCC tissue (named No.6, male) has Collagen alpha 1(IX) chain at 4.4, Collagen alpha-1(XV) chain/Restin at 1.4, 72 KD type IV collagenase/MMP-2 at 0.3, 78 KD glucose regulated protein at 8.1, Bone morphogenetic protein 2 at 8.9, Mucin 2/Intestinal mucin-2 at 10.6 μg/mg of tissue protein, respectively (total; 33.7 μg/mg of tissue protein). This tissue has proteins of VACV at 24.5 μg/mg of tissue protein and proteins of Herpesvirus Saimiri (SaHV-2) and HHV at 8.2 μg/mg of tissue protein (total; 32.7 μg/mg of tissue protein).
Fetal hepatocyte Hc has Collagen alpha-5 (VI) chain (not present in the knee tissue) at 3.7 μg/mg of cell protein, and does not have HHV and VACV.
Hepatoma HepG2 (15y, Caucasoid, male) has no collagen, but has Breast tumor novel factor 1/Chordin-like protein 2 at 0.97, Integrin beta-8 at 0.3, and WW domain-containing oxidoreductase/Fragile site FRA16D oxidoreductase/Short chain dehydrogenase/reductase family 41C member 1 at 0.47 μg/mg of cell protein (total; 1.7 μg/mg of cell protein). This cell has HHV at 5.2 μg/mg of cell protein and VACV at 3.6 μg/mg of cell protein (total; 8.8 μg/mg of cell protein).
Healed HepG2 (15y, Caucasoid, male; by fucoidan for three days) has knee-related proteins of 25-Hydroxyvitamin D-1 alpha hydroxylase, mitochondrial/Cytochrome P450 subfamily XXVIIB polypeptide 1 at 1.4, ADAMTS-4/Aggrecanase-1/A disintegrin and metallo- proteinase with thrombospondin motifs 4 at 1.9, Aggrecan core protein at 3.5, Alpha-N-Acetylglucosaminidase/NAG at 9.1, Epiphycan/Dermatan sulphate proteoglycan 3 at 0.42, Gelatinase B/Matrix metalloproteinase-9 at 2.8, Hyaluronan synthase 3 at 1.7, Hyaluronidase-3 at 0.6, Matrix metalloproteinase-19 at 1.3, UDP-glucuronic acid/UDP-N-acetylgalactosamine transporter/UDP-GlcA/UDP-GalNAc transporter/Solute carrier family 35 member D1 at 0.55, and Vacuolar ATP synthase subunit D homolog at 0.39 μg/mg of cell protein, respectively (total; 23.7 μg/mg of cell protein). This cell has HHV at 30.0 μg/mg of cell protein and VACV at 0.65 μg/mg of cell protein (total; 30.7 μg/mg of cell protein).
These results strongly suggest that knee osteoarthrosis is caused by co-infection of HHV and VACV. VACV and HHV seem to be present as latent state. It is known that HHV has high ability of immune escape, and HHV vaccine and HIV-1 vaccine have not yet been made. It is interesting that vaccine against VACV (Vaccination) only can induce VACV into latent state, and VACV are widely present in our biological specimens. It is interesting that fucoidan does not reduced dsDNA virus of HHV and VACV within three days. However, these enveloped dsDNA viruses would be reduced by fucoidan treatment for three weeks (please see file; Fucoidan dsDNA virus, in Japanese).
Amended on 11 January 2018
I would like to add an important point about biochemistry.
Human enzyme (human serum biotinidase; please see file; Thiol type BIN) is very different from the Bacterial enzyme (bacterial biotinidase) of Streptococcus (Enterococcus) faecalis 10C1 (ATCC 11700) (please see paper; Koivusalo, M., Elorriaga, C., Kaziro, Y., & Ochoa, S. (1963) J. Biol. Chem. 238,1038-1042.).
Furthermore amended on 12 January 2018
Human milk does have Biotinidase (please see file; Compa mBIN), but Bovine milk does not have Biotinidase at all.
Therefore, the reversed reaction of peptides by the human milk biotinidase becomes an important issue. Bovine milk may have the β-Casomorphin derived from bovine β-Casein. But, the bovine-milk β-Casomorphin may not be working in the human baby. Then, the bovine milk may not iduce the sleep in the human babies.
Human milk seems to synthesize Enkephalin from major human milk proteins of RING finger protein 86/Tripartite motif-containing protein 2/UBE2D1-dependent E3 ubiquitin-protein ligase (which has FM and FL peptides) at 55.0 μg/mg of milk protein, Vacuolar protein sorting-associated protein 13B (which has GG and YGG peptides) at 55.0 μg/mg of milk protein, and Tetraspanin-14 (which has many FL peptides) at 33.8 μg/mg of milk protein. Reversed reaction of human milk biotinidase seems to be able to synthesize Enkephalins (YGGFM and YGGFL).
Sleep-inducing peptide (WAGGDASGE; gene has not yet been found) may also be synthesized by human milk biotinidase; i.e., human milk has Laminin subunit alpha-5 (which has AGGD peptide) at 10.1 μg/mg of milk protein and Mucin-5AC (which has ASGE peptide) at 2.7 μg/mg of milk protein. Bonding of W-A can be synthesized by milk biotinidase (milk biotinidase is present at 10.0 μg/mg of human milk protein or 1% of milk proteins), and Sleep-inducing peptide (W-AGGD-ASGE) seems to be synthesized in human milk without using any mRNA (or gene).
Thus, abundant human milk biotinidase in the human breast milk seems to be used to synthesize opioid-neuropeptides, and this enzyme may contribute to human babies to sleep sufficiently giving the state of an Italian maxim “I bambini che dormono tanto crescono bene” (please see also file; The Fascio Effect).
Therefore, notorious Central Dogma (from DNA, RNA, to protein) may not be working in the Humans.
Thus, biotinidase seems to be an essential machinery for protein biosynthesis, and biotinidase leaking into urine from the kidney in early IDDM (insulin-dependent Diabetes Mellitus) is surely the important phenomenon (please see file; Dr. Terentyeva Urine BIN) to induce the Diabetic nephropathy. In order to prevent Diabetic nephropathy, adequate biotin and fucoidan treatments seem to be effective, since Insulin-Dependent Diabetes Mellitus (IDDM) seems to be induced by Paramyxoviridae such as Mumps virus (MuV) and Measles virus (MeV) as declared above.
Furthermore, biotinidase activity has not been detected in Nematodes (Ascaridida) of Anisakis (our unpublished observation with Dr. Takayuki Watanabe (now Teikyo University of Science, 2-2-1 Senju-Sakuragi, Adachi-ku, Tokyo)). Anisakis is known to synthesize proteins in accordance with procaryotic operon theory. This important finding suggests that biotinidase is surely important for eucaryote, which biosynthesizes proteins via the reversed reactions of biotinidase and proteases.
Further, added on 20 January 2018.
I have searched procaryotic-type protein-biosynthesis-related protein of cellular tRNA ligases, and only cancer cell of HepG2 has Glutamine-tRNA ligase/Glutaminyl-tRNA synthetase at 3.8 μg/mg of cell protein (only 0.4% among the cell proteins). Normal fetal Hc and Healed HepG2 (by fucoidan) have no cellular tRNA ligase. This has suggested that protein synthesis is occurring other than the notorious Central Dogma in the eucaryotes.
Protein biosynthesis by the reversed reaction of proteases (original idea of Dr. Hans Neurath) and biotinidase in the eucaryote seems to be important, I have searched the amount of protein-synthetic proteins (proteases and biotinidase) and protein-degradating proteins (labeled or tagged by ubiquitin (UbI) and hydrolyzed by proteasomes in the eucaryote).
Fetal hepatocyte Hc has Fetal-Inflammatory-biotinidase at 0.3, Milk biotinidase at 1.7, Liver-type serum-biotinidase at 1.9, and Kidney-type urine-biotinidase at 1.9 μg/mg of cell protein (total biotinidase 5.8 μg/mg of cell protein). Fetal hepatocyte Hc also has protein-synthetic proteins (proteases) of Chymase/Mast cell protease I at 12.9, LON peptidase N-terminal domain and RING finger protein 1/RING finger protein 191 at 7.2, Metalloreductase STEAP2/Protein up-regulated in metastatic prostate cancer at 5.7, and Vitamin K-dependent protein C/Protein C at 5.0 μg/mg of cell protein (total proteases 30.8 μg/mg of cell protein). Total protein-synthetic proteins including biotinidase becomes to be 36.6 μg/mg of cell protein or 3.7% among cell proteins. On the other hand, protein-degradating proteins (UbI-related proteins) are present as follows; i.e., Dyslexia susceptibility 1 candidate gene 1 protein/Dynein assembly factor 4, axonemal at 17.1, Erasin/UBX domain-containing protein 4 at 4.8, and LON peptidase N-terminal domain and RING finger protein 1/RING finger protein 191 at 7.2 μg/mg of cell protein (total UbI-related proteins 29.1 μg/mg of cell protein). Total protein-degradating proteins becomes to be 29.1 μg/mg of cell protein or 2.9% among cell proteins. Therefore, normal non-cancer cells has similar amount of protein-synthetic proteins and protein-degradation proteins. Normal fetal-hepatocyte Hc cells seem to biosynthesize cellular proteins at 1.3-fold slightly higher synthesis.
Cancer hepatoma HepG2 (cultured without fucoidan) has only Liver-type serum-biotinidase at 18.2 μg/mg of cell protein, and has proteases of ADAMTS-19/A disintegrin and metalloproteinase with thrombospondin motifs 19 at 5.6, ADAMTS-13/A disintegrin and metalloproteinase with thrombospondin motifs 13/von Willebrand factor-cleaving protease at 9.2, Brain-specific serine protease 4 at 0.9, Endoplasmic reticulum aminopeptidase 1/Aminopeptidase PILS at 0.53, Nardilysin/N-arginine dibasic convertase at 14.0, Syntaxin-12 at 0.23, Transmembrane protease serine 5/Spinesin at 1.3, and Suppressor of tumorigenicity protein 14 at 2.7 μg/mg of cell protein (total proteases 34.5 μg/mg of cell protein). Total protein-synthetic proteins including biotinidase becomes to be 52.7 μg/mg of cell protein or 5.3% among cell proteins. On the other hand, protein-degradating proteins (UbI-related proteins) are present as follows; i.e., Cyclin-F isoform 1/G2/mitotic-specific cyclin-F at 4.5, E3 ubiquitin-protein ligase TRIM33/Transcription intermediary factor 1-gamma/Tripartite motif-containing protein 28 at 3.9, F-box only protein 46 at 1.6, RING finger protein 123/E3 ubiquitin-protein ligase RNF123 at 3.4, U4/U6,U5 tri-snRNP-associated protein 2 at 0.4, and Zinc finger Ran-binding domain-containing protein 1/Ubiquitin thioesterase ZRANB1 at 0.76 μg/mg of cell protein (total UbI-related proteins 14.6 μg/mg of cell protein). Total protein-degradating proteins becomes to be 14.6 μg/mg of cell protein or 1.5% among cell proteins. Therefore, cancer cells have 2-fold reduced amount of protein-degradation proteins, and cancer cells seem to biosynthesize cellular proteins actively at 3.5-fold higher synthesis.
On the other hand, healed HepG2 (cultured with fucoidan) has Liver-type serum-biotinidase at 9.8 μg/mg of cell protein and Kidney-type urine-biotinidase at 4.8 μg/mg of cell protein (total biotinidase 14.6 μg/mg of cell protein). Healed HepG2 (cultured with fucoidan) also has protein-synthetic proteins (proteases) of ADAMTS-4/Aggrecanase-1/A disintegrin and metalloproteinase with thrombospondin motifs 4 at 1.9, ADAMTS-like protein 2 at 3.6, Cathepsin F at 0.08, Dipeptidyl-peptidase 1/Cathepsin C at 0.09, Endothelin-converting enzyme-like 1 at 8.5, Gelatinase B/Matrix metalloproteinase-9 at 2.8, Matrix metalloproteinase-19 at 1.3, Neprilysin at 1.2, Neuroligin-1 at 5.2, and Serine protease TADG-15/Suppressor of tumorigenicity 14 protein at 1.2 μg/mg of cell protein (total proteases 25.9 μg/mg of cell protein). Total protein-synthetic proteins including biotinidase becomes to be 40.5 μg/mg of cell protein or 4.1% among cell proteins. On the other hand, protein-degradating proteins (UbI-related proteins) are present as follows; i.e., 26S Protease regulatory subunit 6B/Tat-binding protein 7/Proteasome 26S subunit ATPase 4 at 1.6, Arginyl-tRNA--protein transferase 1/Arginyltransferase 1 at 1.49, Deubiquitinating enzyme 29 and Deubiquitinating enzyme 19 at 12.2, Hepatocyte growth factor-regulated tyrosine kinase substrate at 1.9, HIV-1 Nef-interacting protein/Virion-associated nuclear shuttling protein at 4.1, Leukemia-associated protein 5/E3 ubiquitin-protein ligase TRIM13/RING finger protein 77 at 0.51, Proteasome subunit beta type-1/Macropain subunit C5 at 0.26, and Tumor necrosis factor type 1 receptor-associated protein 2/26S proteasome non-ATPase regulatory subunit 2/Protein 55.11 at 1.05 μg/mg of cell protein (total UbI-related proteins 23.1 μg/mg of cell protein). Total protein-degradating proteins becomes to be 23.1 μg/mg of cell protein or 2.3% among cell proteins. Therefore, healed non-cancer HepG2 cells by fucoidan have re-gained similar balance of protein-synthetic proteins and protein-degradation proteins. Healed HepG2 cells seem to biosynthesize cellular proteins at 1.8-fold higher synthesis.
Cancer cells seem to biosynthesize proteins more actively than protein degradation.
Further added protein synthesis issue on 22 January 2018.
Normal liver tissue (pseudo liver-cancer) has cellular t-RNA ligase of Bifunctional aminoacyl-tRNA synthetase/Bifunctional glutamate/proline--tRNA ligase at 10.9 μg/mg of tissue protein, but this protein seems to be a protection protein against invation of virus. This normal liver tissue (pseudo liver-cancer) has Liver-type serum-biotinidase at 22.7 μg/mg of cell protein and Kidney-type urine-biotinidase at 16.0 μg/mg of tissue protein (total biotinidase 38.7 μg/mg of tissue protein). This normal liver tissue (pseudo liver-cancer) also has protein-synthetic proteins (proteases) of Acylamino-acid-releasing enzyme/APH at 2.0, Beta-Secretase 1 at 3.9, Complement factor I at 2.0, and Mitochondrial intermediate peptidase/MIP at 2.7 μg/mg of tissue protein, respectively (total proteases 10.6 μg/mg of tissue protein). Total protein-synthetic proteins including biotinidase becomes to be 49.3 μg/mg of tissue protein or 4.9% among tissue proteins. On the other hand, protein-degradating proteins (UbI-related proteins) are present as follows; i.e., E3 Ubiquitin protein ligase Praja-1/RING finger protein 70/PJA1 at 21.1, TAT-binding protein-1/TBP-1/26S protease regulatory subunit 6A at 2.3, and Ubiquitin carboxyl-terminal hydrolase 36/Ubiquitin thioesterase 36 at 7.4 μg/mg of tissue protein, respectively (total UbI-related proteins 30.8 μg/mg of tissue protein). Total protein-degradating proteins becomes to be 30.8 μg/mg of tissue protein or 3.1% among tissue proteins. Therefore, normal liver tissue (pseudo liver-cancer) has similar amount of protein-synthetic proteins and protein-degradation proteins. Normal liver tissue (pseudo liver-cancer) seems to biosynthesize cellular proteins at 1.6-fold slightly higher synthesis.
LC tissue with leprosy has no viral tRNA ligases. This LC tissue has Valyne--tRNA synthetase/VALRS at 22.2 μg/mg of tissue protein, but this protein may be also a protection protein against invation of virus. This LC tissue has Liver-type serum-biotinidase at 23.0 μg/mg of cell protein and Kidney-type urine-biotinidase at 13.0 μg/mg of tissue protein (total biotinidase 36.0 μg/mg of tissue protein). This LC tissue also has protein-synthetic proteins (proteases) of Aminopeptidase N/Membrane alanyl aminopeptidase/GP150/CD13 at 4.9, Bone morphogenetic protein 1/BMP-1 at 5.0, Carboxypeptidase B/Pancreas-specific protein at 0.66, Cathepsin B at 3.2, Coagulation factor V/Activated protein C cofactor at 5.5, Elastase 3A, pancreatic at 0.66, Elastase IIIB/Chymotrypsin-like elastase family member 3B/Protease E at 0.66, Haptoglobin-2 at 2.4, and Protein C/Autoprothrombin IIA/Vitamin K-dependent protein C at 3.6 μg/mg of tissue protein, respectively (total proteases 39.6 μg/mg of tissue protein). Total protein-synthetic proteins including biotinidase becomes to be 62.6 μg/mg of tissue protein or 6.3% among tissue proteins. On the other hand, protein-degradating protein (UbI-related protein) is only present as follows; i.e., Protein MSS1/26S protease regulatory subunit 7 at 2.1μg/mg of tissue protein. Total protein-degradating protein becomes to be 2.1 μg/mg of cell protein or 0.21% among cell proteins. Therefore, this LC tissue has 30-fold reduced amount of protein-degradation proteins, and LC tissue may already be pre-cancer state with respect to protein metabolism.
LC tissue (named as No.6) has no cellular and viral tRNA ligases. This LC tissue has Liver-type serum-biotinidase at 25.6 μg/mg of cell protein and Kidney-type urine-biotinidase at 15.2 μg/mg of tissue protein (total biotinidase 40.8 μg/mg of tissue protein). This LC tissue also has protein-synthetic proteins (proteases) of Complement C2 at 1.3 μg/mg of tissue protein and Insulin-degrading enzyme/Insulinase/IDE at 4.0 μg/mg of tissue protein (total proteases 5.3 μg/mg of tissue protein). Total protein-synthetic proteins including biotinidase become to be 46.1 μg/mg of tissue protein or 4.6% among tissue proteins. On the other hand, protein-degradating protein (UbI-related protein) is only present as follows; i.e., Ubiquitin-like modifier-activating enzyme 1/Ubiquitin-activating enzyme E1/A1S9 protein at 1.1 μg/mg of tissue protein and Macropain subunit C9/Proteasome subunit alpha type-4 at 0.16 μg/mg of tissue protein. Total protein-degradating protein becomes to be 1.26 μg/mg of tissue protein or 0.13% among tissue proteins. Therefore, this LC tissue has 35-fold reduced amount of protein-degradation proteins, and this LC tissue may also be in the pre-cancer state with respect to protein metabolism.
HCC tissue (named as No.6) has no viral tRNA ligases. This HCC tissue has Bifunctional aminoacyl-tRNA synthetase at 8.4 μg/mg of tissue protein, and this protein may be a resistant protein against Vesicular stomatitis Indiana virus strain Mudd-Summers/VSIV. This HCC tissue has Liver-type serum-biotinidase at 25.4 μg/mg of cell protein and Kidney-type urine-biotinidase at 9.5 μg/mg of tissue protein (total biotinidase 34.9 μg/mg of tissue protein). This HCC tissue also has protein-synthetic proteins (proteases) of 72 KD type IV collagenase/MMP-2 at 0.3, Aminopeptidase N/Microsomal aminopeptidase/GP150 at 2.6, Coagulation factor V at 5.6, Complement factor D/Adipsin at 0.21, Elastase IIIA/Protease E at 0.18, and Insulinase/IDE at 13.3 μg/mg of tissue protein (total proteases 22.0 μg/mg of tissue protein). Total protein-synthetic proteins including biotinidase become to be 56.9 μg/mg of tissue protein or 5.7% among tissue proteins. On the other hand, protein-degradating protein (UbI-related protein) is only present as follows; i.e., Breast cancer type 1 susceptibility protein/RING finger protein 53 at 7.4 μg/mg of tissue protein and E3 ubiquitin-protein ligase CBL/Proto-oncogene c-CBL at 0.055 μg/mg of tissue protein (Total protein-degradating protein becomes to be 7.455 μg/mg of tissue protein or 0.75% among tissue proteins). Therefore, this cancer-HCC tissue seems to biosynthesize cellular proteins actively at 7.6-fold higher synthesis as compared to normal livers.
HCC tissue (with PBC) has no viral and ellular tRNA ligases. This HCC tissue has Liver-type serum-biotinidase at 11.5 μg/mg of cell protein and Kidney-type urine-biotinidase at 8.3 μg/mg of tissue protein (total biotinidase 19.8 μg/mg of tissue protein). This HCC tissue also has protein-synthetic proteins (proteases) of Acylamino-acid-releasing enzyme/APH at 6.7, Aminopeptidase N/GP150 at 5.4, Proprotein convertase subtilisin/kexin type 6/Subtilisin/kexin-like protease PACE4 at 14.7 μg/mg of tissue protein (total proteases 26.8 μg/mg of tissue protein). Total protein-synthetic proteins including biotinidase become to be 46.6 μg/mg of tissue protein or 4.7% among tissue proteins. On the other hand, protein-degradating protein (UbI-related protein) is only present as follows; i.e., Ubiquitin carboxyl-terminal hydrolase isozyme L3/Ubiquitin thioesterase L3 at 3.0 μg/mg of tissue protein (Total protein-degradating protein becomes to be 3.0 μg/mg of tissue protein or 0.30% among tissue proteins). Therefore, this cancer-HCC tissue seems to biosynthesize cellular proteins actively at 15.7-fold higher synthesis as compared to normal livers.
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