Sunday, April 17, 2016

Allergy, inflammation, pesticides, pathogens, diseases, domains: Insights and my hypotheses........

Science is undergoing overhaul for good. Pre-established facts are being overthrown. 
 In nature, everything is related. This aspect ought to be focussed while hypothesizing.
#Allergy/inflammation/hormone insights
When similarity is high proteins have isozyme, isoforms. When less, they are different but homology remains.
Check homology between chitin (NAGA-NAGA), peptidoglycan (NAGA-NAMA), cuticle.
Pollen , virus domains and bacterial surface proteins are same.
Virus and cockroach allergen have same domain (kelch, jacalin)
Check similarity between gibberellin, auxin, insect pheromone, animal hormone,
Pathogenesis of pathogens, allergens and venoms are same.........just the latter two can't replicate, so victim might survive. Venom is high dose, so it can coagulate blood and kill.
All irritants provoke immune system and cause neural inflammation, leading to different diseases. Brain malaria, brain dengue, brain fever are nothing but body's immune system trying too hard to get rid of the pathogens and in turn causing harm to the host body itself.
Stress causes strange surface protein formation in bacteria which human antibody can't trap.

Immunodeficiency and autoimmunity is wrong classification. Its better to explain as immune activation-led inflammation.
Pastereulla sp. causes 50K antelope death, can it be by consumption of bad water?
Chymptrypsin can degrade galactouranase
Trypsin can cleave leather, collagen, keratin and can sequester co-factor metals like Ni, Cd.
Lathyrus plant causes neural paralysis by manipulating host protein via its lectins. Any pulse consumed too often will cause the same.
Any form of irritant disturbs host proteases. 
Most critical: Serine-, cysteine-, and metalloproteases (cause charge relay system)
So, lead to allergy, infectious disease, cancer, autoimmune disease

Bacterial ubiquitous protease: AAA proteases, degP (acts as chaperone as well as peptidase) or sortase (cys) ( substrates function as adhesins, internalins, blood clotting and immune evasion factors, and transporters for nutrients )
Bacterial pathogenic protease: clostripain (cys), collagenase (cause gas gangrene), botulinum neurotoxin, tetanus neurotoxin

Serine/threonine-protein kinase (pknA-B)
Ser/Thr phosphatase

Serine protease: chymotrypsin (S1), subtilisin (S8) 

To counter it protease inhibitors are given in the form of drugs or antibiotics. Chemotherapy is nothing but protease inhibitors and DNA gyrase inhibitors (to prevent DNA replication). Venoms, sea cucumber, ginseng etc. do the same. Peptide can be protease inhibitor. Myoactive neuropeptide NGIWY amide was  isolated from the holothurian. Sea urchin Strongylocentrotus purpuratus.
Protease inhibitors: glycoproteins or sulfated polysaccharides
These are present from virus to human. These inhibitors-coding  gene family have undergone duplication in higher animals. 
Serpin superfamily:
all-beta, immunoglobulin (Ig) fold:  (bacteria), chagasin and amoebiasin
Glycoproteins:  Kazal type (viral, fungal , termite, jelly fish, sea cucumber, human,  (SPINK)) or kunitz type (mostly in venoms e.g. spider, tick,  snake). Both types have been found in helminthes and bacteria

Protaese inhibition by: lock-and-key type,  conformational change and consequent kinetic trapping of an enzyme intermediate 

*Mice homozygous for SPINK gene results in postnatal lethality, growth retardation, dehydration, autophagic degeneration of acinar cells resulting in pancreas trophy, small intestine degeneration, and a small spleen.

Glycosylation of proteins occur in diabetes. It inactivates proteins that need to be activated. Protease can help in this scenario. Herbal drug cause glycosylation i.e is make activated protease inactive again. (most proteins are glycoproteins. Loss of glyco part might activate or inactivate the protein). Some hormones are glycoproteins. The allergen is cutting glyco moiety, so hormone can't act. Carbohydrate-degrading domains are known to play a role in fungal pathogenicity.
Non-pathogenicity is only a matter of time.
Person is not exposed to the allergen anymore, but the antibody, already formed is preventing the glycoproteins. Female menstrual cycle disturbance is an example of it. The hormone required for it are being destroyed by the antibody. That's what they call autoimmunity.
Breast infection...a type of its adipose tissue, pollutants are attracted here..
No one can underestimate the power of causes bloom in bare plant, it brings puberty in an innocent child...
Why, women face most allergies in late 20's and early 30's? May be because estrogen level is high at this phase. (LTP (tomato, pulses, fruits), insect, allergy).

Is wisdom teeth eruption related to nerve growth factor?
Inflammation is the cause of all diseases...personalized diet is needed for healthy living.
Catalytic site of protease contain or leach Ni, Mo, Cd or  Zn atoms. So, they become active and unleash immune response.
Due to disulfide arrangement, sulphur-rich proteins (cysteine protease as well) are stable against thermal and enzymatic degradation.
Sulfites in food can cause bronchial constriction, which can cause asthma (e.g preserved fries, namkeen, pizza)
Common acids in fruits: malic acid, tartaric acid, oxalic acid
Para-phenylenediamine (PPD) in ‘black henna’, hair dye, black rubber cause allergy
Polysaccharide (ligand)-----Dectin-1 (receptor) on APC (macrophage, dendritic cell)--- (Syk, NF-κB signaling, and cytokine release) --->TNF-α and IL-6 secretion
Dectin-1 blocking reagent: Laminarin 
Did pesticides or hormones caused protein misfolding (prions) and madcow disease in cattle?
In the 80's and 90's excessive use of pesticides in animal husbandry, led to their neural damage, corpse of which when devored by scavengers (vulture), the latter succumbed. Pesticides caused inflammation in cattle, that caused mad cow disease, causative agent of which was described as prions.....the misfolded proteins.....By devouring the carcass, vulture population almost vanished.
It is possible that the pesticides in food disrupted female reproductive system and caused birth defects, including autism in children.
Do food additives and other food chemicals are mimicing estrogen and causing early puberty in girls?
Dairy farm animals are advertised as free-range grazing cattle...but then mix preservatives in milk..
Pesticides manipulate our serine proteases.  Formaldehyde killed a young instantly.
Facts are emerging that rampant use of pesticides is affecting nervous system of farmers, leading to depression and suicidal tendencies.

Drug resistance in pathogens and cancer in human in outcome one stress.......drug abuse, pollution
deodorant use may be linked to diseases like cancer and Alzheimer's.
Surface antigens: repeat proteins of gram-positive cocci
Internalin: a repeat protein in Listeria
Transcriptional regulation (histidine kinases)
Chemotaxis (methyl-accepting proteins)
Catabolite repression (adenylate cyclases)
Modulation of enzyme activity (diguanylate cyclases and phosphodiesterases)PhoQ histidine kinase, essential for resistance to antimicrobial peptides is present in a variety of enteric pathogens. IS cause over-expression in some Mtb PhoQ.
hyperthermophilic bacteria (i.e. Aquifex and Theromotoga) and archea (e.g. Pyrococcus, Thermococcus, Methanothermus and Sulfolobus). Despite the small set of studied systems, it is clear that super-slow protein unfolding is a dominant strategy to allow these proteins to function at extreme temperatures. 
Repeat sequences are supposed to play a role in protein–protein interactions
Chloramphenicol acetyltransferase attaches an acetyl group to chloramphenicol, which prevents the drug from binding to ribosomes. It leads to drug resistance. In vitro culture-driven picture is a messed up picture.
Because of its excellent blood-brain barrier penetration (superior to any of the cephalosporins), chloramphenicol remains the first-choice treatment for staphylococcal brain abscesses.
Clostridium perfringens enterotoxin gene is on a transposable element
Iron-regulated heparin-binding hemagglutinin capacity of M. tuberculosis

Helicobacter pyroli: CagA to perturb a host cell signaling pathway, and leads to development of peptic ulcer 
Plasmodium falciparum: histidine-rich proteins that facilitate its survival inside red blood cells 
Plant-pathogenic oomycetes: the multifunctional elicitin molecules facilitate infection by triggering host tissue necrosis; serve as a sterol-carrying protein
The elicitin-encoding gene is highly expressed at body temperature than room temperature. Something like this must be happening in Mtb replication. Stimulation of clathrin-mediated endocytosis by the elicitin. 
##Intracellular pathogens
Mycobacterium tuberculosis
Coxiella burnetii
Legionella pneumophila
Brucella abortus

Rickettsia conorii
Diseases are geographical, largely based on diet and lifestyle . 
Asians have vitiligo, and diabetes. But no peanut allergy or Alzheimer disease. Also, cancer death was less, though pollution is causing cancer even in villages. Peanut is native to Indian subcontinent, so people their have evolved to metabolize it, so there is no issue of allergy or anaphylaxis. 
High instance s diabetes might be due to cereal-based diet. Eating too much sugar will activate carbohydrate cleaving enzymes. these enzymes will disturb glycoproteins. Signalling system goes awry. Moderation is the answer. Diabetes and hormonal disturbance is tied together. Thats why diabetic woman can't conceive. Diabetic people have low sexual drive, as the hormones for the stimulation are getting destroyed.
In Western  countries, instances of Alzheimer, Parkinson, multiple sclerosis, autism, cancer is high. Cheese and  alcohol seem to be the culprit. Cheese is serine and tyrosine rich, so might be manipulating serine, tyrosine protease and serine/tyrosine receptors in brain. Alcohol causes liver cirrhosis, so enzymes can't be formed.

Diseases: Heart: Acute myocardial infarction
Lungs: Chronic obstructive pulmonary disease (COPD)
Neural: Autism
Fungal: Aspergillosis
Bacteria: Tuberculosis
Cystic fibrosis: A disease of cells producing mucus, sweat and digestive juice (lungs, liver, pancreas)

Alzheimer's: Processed foods produce toxins, they cause inflammation,  build-up of plaques, impaired cognitive function. Processed foods such as white breads, pasta, processed meats and cheeses cause inflammation.

Autism: Causes of autism might be:Pesticides (other endocrine disruptors), Alcohol, Drugs (anti-depressants). Study approaches: Microbiome of faeces, Brain imaging, Behavioral study
Vitiligo: Caucasian families with co-segregation of vitiligo and Hashimoto thyroiditis
Pfeiffer syndrome is strongly associated with mutations of Fibroblast growth factor receptor 1 and 2 hypnic jerk is an involuntary twitch which occurs just as a person is beginning to fall asleep.
Disease-causing mutations: His to alanine; Phe to glycine
#mutagenesis results,  pharmacophore data
Increased circulating galaninL levels in serum contribute to the development of metabolic syndrome
Matrix molecules, i.e. collagens and proteoglycans. Defective hydroxylation of collagen cause scurvy.
Intermediate filaments (IF) 
type I: acidic cytokeratins
type II: basic cytokeratins
type III: vimentin, desmin, glial fibrillary acidic protein (GFAP), peripherin, and plasticin
type IV: neurofilaments L, H and M, alpha-internexin and nestin
type V: nuclear lamins A, B1, B2 and C
Mutations in long coiled-coil proteins causes diseases

Mutations in BRCA1 result in truncated proteins

95% of the cases of chronic myelogenous leukemia contain the Philadelphia chromosome, which is a translocation of part of chromosome 22 to chromosome 9. 
BRCA1: Hereditary breast cancer, hereditary ovarian cancer

 kinase activators, including epidermal growth factor (EGF) and the tumor promoting phorbol ester 12-O-tetradecanylphorbol-13-acetate (TPA)
Antibiotics affect host: G protein-coupled receptors,  intracellular calcium signals,  membrane cholesterol distribution.
Proton pump (H2) inhibitors can prevent acid production
Hydrocortisone prevents itching, eczema, psoriasis
Glucosamine and chondroitin sulfate is needed for joint health

Chromothripsis: Chromosomal rearrangement due to DNA damage in micronuclei
Most health issues start a vicious circle in us.
Pyrimidines: cytosine, thymine, and uracil
Urines: adenine, guanine
CG bond
AT bond, AU bond
Y: Any pyrimidine (C, T)
Out of 4 bases, A and C are methylated
Differential networks have recently been introduced as a powerful way to study the dynamic rewiring capabilities of an interactome in response to changing environmental conditions or stimuli. 
Paralogous genes are homologous genes that occur within one species and have diverged after a duplication event. 

Orthologous genes are homologous genes that diverged after a speciation event.
Protein expansion is primarily due to indels in intrinsically disordered regions
PCR amplification is one of the major sources of duplicates, which are usually introduced during sequencing library amplification.
Chromatin immunoprecipitation (ChIP) methodology: examine gene regulation in living cells
Plasmid isolation: CsCl/ethidium bromide gradient ultracentrifugation
Protein sizing: Western blot analysis
Localisation: immuno-histochemical staining
Aberrant or additional reactive bands: Southern blotting

Chimeric transcript detection: by RT-PCR
At high GC, coverage drops
Indel events most frequently occur in surface-exposed loops.
Human body contains about 1013 human cells and  about 1014 bacterial, fungal, and protozoan cells.
About 45% of human genome is transposable element.
Human genome size is 3,234.83Mb (almost 3 billion bases)
1.5% of the genome is CDS (20k-25K)
Each of the 23 chromosome has pseudogenes:  59 (chr 18) -1,130 (chr 1)
Confirmed protein range: 2,012 (in chromosome 1)- 45 (in   Y chromosome)
X chromosome codes for 815 genes
mtDNA has genes for only 13 proteins
Most variation s in chr 2 and 1
Longest chr: 1, 2
Shortest chr: mtDNA, 21, 22, 19, Y, 20
Large-scale sequencing efforts: 1000 Genomes, ExAC (Exome Aggregation Consortium), Scripps Wellderly, UK10K
Reference Variant Store (RVS) stores 400 million distinct variants observed in more than 80,000 human samples. (https://​rvs.​u.​hpc.​mssm.​edu/​)
Exhaustive annotation using tools such as snpEff, ANNOVAR, or VEP
Predictions of deleteriousness by SIFT, PolyPhen2, PROVEAN
Curated variantdatabases such as dbSNP, ClinVar, HGMD, OMIM, COSMIC
GEMINI: A software package  for exploring variation in personal genomes and family based genetic studies .
Well-studied disease genes and mutations
Breast cancer: BRCA2 (chr 13)
Cystic fibrosis: CFTR (chr 7)
Ctochrome b: MTCYB (mtDNA)
Hemoglobin: HBB (chr 11)

miRNA: Regulator of gene expression

snRNA: Small nuclear RNA (processes pre-mRNA and regulates transcription factors)
snoRNA: Small nucleolar RNA

After myosin and actin, titin is the third most abundant protein in human muscle

#Proteins/ Domains
Some proteins are fast-evolving 
Domains are common currencies of protein function that nature rearranges to create novel activities. (function and evolutionary aspect can be learnt from them).Domains do not generally appear de novo but my shuffling and rearrangement of existing domains. Cache_2 is predicted to originate from GAF-PAS fold. Domain-swap analysis revealed that the COOH-terminal leucine-rich repeat.
Flo11 flocculin belongs to a family of proteins involved in invasive growth, cell-cell adhesion, and mating, many of which can substitute for each other under abnormal conditions. Flo11 flocculin in yeast gives the cell a wide range of phenotypes (multicellular structures such as biofilms, flors, or filaments), depending on the strain and the environmental conditions. Does it happen in Mtb too? Sure. If its present in virus and cockroach it must be in bacteria too.
All recognition-related proteins are glycosylated (they bind to mannose or other carbohydrates). explains the cell-cell interaction capacity of FLO11-expressing cells.
Insoluble and inactive proteins are co-produced due to codon bias, protein folding, phosphorylation, glycosylation, mRNA stability and promoter strength.
Not only enzymes, even adhesins are pH dependent.
Also, the enzymes are hypothetical, as need cofactors to be active. Culture medium might be lacking in them.
Heparinase need substrate to be activated. (may not activate in vitro)
These are called transposases in the case of DNA elements and integrases in the case of the best-characterized RNA elements, the retroviruses and retrotransposons.
ATPase are cell-surface, membrane traversing proteins

coiled coil proteins: c-Fos,c-jun,tropomyosin

N-terminal amino acid of a protein is an important determinant of its half-life
CpG motifs are considered pathogen-associated molecular patterns (PAMPs). CpG PAMP is recognized by the pattern recognition receptor (PRR) Toll-Like Receptor 9 (TLR9), which is constitutively expressed only in B cells and plasmacytoid dendritic cells (pDCs) 

Protein families have arisen during evolution by gene duplication and divergence

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