CN110361345A - Ultraviolet spectra DNA protein phenotypic analysis instrument - Google Patents

Ultraviolet spectra DNA protein phenotypic analysis instrument Download PDF

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CN110361345A
CN110361345A CN201810335499.XA CN201810335499A CN110361345A CN 110361345 A CN110361345 A CN 110361345A CN 201810335499 A CN201810335499 A CN 201810335499A CN 110361345 A CN110361345 A CN 110361345A
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dna protein
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phenotypic analysis
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魏秋英
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    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/33Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using ultraviolet light

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Abstract

According to Einstein theory, the quality for measuring an object is exactly to measure energy therein.Ultraviolet spectra DNA protein phenotypic analysis instrument working principle is measurement DNA, protein energy therein, the apparent electronic spectrum method of early diagnosis of one tumour of early diagnosis of oncology is namely carried out in measurement tumour apparent mass, the difference of cancer phenotype quality can make atom or molecular energy level change, and cause the line displacement of atom spectrum or molecular spectrum.The difference of nuclear spin can cause the variation of spectral fine structure.Cancer apparent mass, momentum is bigger, and it is diagnosing tumour that spectrum specificity wavelength is shorter (p=h/ λ), determines its good, pernicious specific spectra foundation.Seldom there are false positive, apparent these advantages of fingerprint screening in the apparent liquid dna detection of cancer, so that this technology is expected to be used for the early stage screening and prognosis treatment of tumour.Ultraviolet spectra DNA protein phenotypic analysis instrument will be early diagnosed to traditional tumour, and treatment zone carrys out subversiveness change.

Description

Ultraviolet spectra DNA protein phenotypic analysis instrument
Technical field
Cancer feelings are in an emergency, and " 2012 China's tumour registration annual report " is externally issued: " whole nation just has a people to be diagnosed as in every 6 minutes Cancer has 8550 people to become cancer patient daily, just has a people to die of cancer in every seven to eight people." " Nattonal Cancer morbidity situation Sternness, from " cancer county " to " cancer village ", the history and geographical coordinate of Chinese tumor invasion are social development and life side behind Formula many decades change the high-incidence situation of bring cancer.Annual new cancer cases about 3,500,000, because of cancer mortality about 2,500,000.It faces The number of this succession of grey makes us the fear that produces to cancer really, and what is come therewith is again thick air PM2.5.To anticancer institute facing challenges, expert unanimously thinks the mankind at present, is exactly appreciated that the relationship of gene and environment.Reason Does is what solving gene? what does is it different that oncogene from normal gene physicochemical property have? it could thorough beat cancer
The one ultraviolet spectra DNA protein phenotypic analysis instrument of calling in epoch is born.(infrared, Raman, fluorescence, ultraviolet spectra Instrument etc.) it can detect cancer cell isotope spectral effects, and " infrared spectroscopy of clinical tumor diagnosis " new method passes through into Fruit identification-the Chinese Academy of Sciences.In face of such a cancer the situation is tense period, it is in the history of science, the world and a call Analyze the epoch of giant.To clearly recognize cancer, virus, the diseases cause of disease such as apparent and captures treating cancer simultaneously at tumour general character Non- part nothing the matter.The method that Protocols in Molecular Biology achievement is summarized from historical lessons, rises to enough height, seeks help from Philosophy guidance, has finished the best thinking that cancer is exactly cell isotope theory successfully.This understanding implies solution neoplastic problems Method.
Background technique
The essence of cancer: being hereditary disease or epigenetic disease? people once thought that cancer was a kind of genetic disease, And sizable human and material resources and time have been spent to find suitable gene therapy method, however, many evidences show in canceration In the process, epigenetic variation changes prior to DNA sequence dna, and epigenetic relatively easily regulates and controls and reverses, this is pre- anti-cancer Provide new approaches.The especially implementation of cancer gene group sequencing project, so that people start to examine this theory closely again.It is first First, it has been found that gene is activated or inactivates, and is not necessarily to change by DNA sequence dna, and epigenetic regulation is not normal can also be with Gene mutation equally causes carcinogenic consequence.These evidences all show that hereditary (DNA sequence dna change) and epigenetic two ways can To lead to same result.The not normal carcinogenic theoretical basis of epigenetic regulation has been established in these researchs.Recognize epigenetic Key effect in cancer occurrence and development exerts far reaching influence clinical prevention, diagnosis and the treatment to cancer.
In order to solve neoplastic problems and various demands, medical market develops miscellaneous practical instrument, and Fourier is red The spectrometers such as external spectrum, Raman spectrum FITR-Rama, uv electron spectrum, fluorescence spectrum they in detection virus, apparent disease It takes the course of its own in terms of disease, knubble biological isotope, tumour spectral effects all successfully confirm cancer cell spectrum to high wave number blue shift Excitation information;DNA secondary structure quantum genetic, hydrogen bond are to maintain and promote the binding force of protein and nucleic acid higher structure to increase By force.FTIR spectrum, Fourier transform-Raman spectroscopy FITR-Rama, uv electron spectrum, tumour fluorescence spectrum are successfully caught It has obtained cancer atom or molecule is in excitation state.Excitation state and ground state have different potential energy curve and balance nuclear separation.Two-dimentional light Modal data successfully confirms the hydrogen excited electronic state of cancer DNA.It lays a good foundation for knubble biological isotope spectral effects model.Light Although spectrometer has all been successfully acquired the specific spectra information of cancer, only know that it does not know its reason.
Cancer is cell isotope.1897 English physicist J.J. Thomson (Joseph John Thomson) have found Electronics, he improves the instrument for surveying electronics within 1912, and using magnetic fields, a kind of magnetic separator has been made (before mass spectrometric Body).When he is measured with neon, no matter how neon is purified, and what is obtained on screen is two parabolas, and one represents matter The neon that amount is 20, another neon that then representation quality is 22.It is here it is the stable isotope of first time discovery, i.e., "dead" Isotope.It after First mass spectrograph is made in the Aston F.W., further proves, neon has different two of atomic mass really Kind isotope, Britain chemist F. Suo Di in 1910 propose a hypothesis, and chemical element is there is relative atomic mass and puts Penetrating property is different and the identical mutation of other physicochemical properties, these mutation should be on the same position of periodic table, referred to as together Position element.It is shortly 206.08 from the relative atomic mass that different radioactive elements obtain a kind of lead, it is another then be 208. It after proposing within 1932 nuclear one Proton of neutron opinion, just further understands fully, isotope is exactly that there is matter for a kind of element Subnumber is identical and several atoms that neutron population is different.The chemical property of isotope is identical, but not due to their neutron population Together, this, which has resulted in each atomic mass, will be different, and be related to nuclear certain physical properties (such as radioactivity), also It is different.Many elements have isotope from boundary.Isotope has plenty of naturally occurring, has plenty of made, some has Radioactivity, some is without radioactivity.These mutation are on the same position of the periodic table of elements, and atomic nucleus proton number phase Together, but neutron number is different, and it is the element of same position in periodic table that they, which still have identical atomic number, so referred to as same position Element.But chemical property is just the same.
Cell carcinogenesis normal anomaly cell is that a series of molecular sequence structures are identical and the apparent INFORMATION OF INCOMPLETE one of functional structure- The dyskaryotic cell of sample, (cancer is nonhistones and the increase of amount of sugar chains, sugar chain contain multiple saliva acidic groups.More sialic acid chains also can Shorten with development.Cancer cell telomere, Telomerase are abnormal, and the virtual inertias quality such as DNA, protein methylation increases), it indulges more The difference that apparent mass difference discloses cancer cell nuclear mass can make atom or molecular energy level change, and cause atom spectrum Or the line displacement of molecular spectrum.The difference of nuclear spin can cause the variation of spectral fine structure.Biology is detected using spectrometer And cell isotope;The isotopic characteristics such as cancer cell, cancer albumen at different levels, oncogene, viral vaccine pass on strain, between stem cell Isotopic characteristic equally has spectroscopic isotope effect between them: can cause cellular elements DNA, RNA at different levels, protein, The line displacement of the spectrum such as enzyme or biological virus molecular spectrum.The difference of nuclear spin can cause the variation of spectral fine structure Scientific method.It is diagnosing tumour, determines its good, pernicious major histological foundation.Molecular biology, which is ignorant of biology, also same position Element, therefore when the aneuploid of cancer cell core DNA is increasing, it is but also difficult to decrypt the difference of cancer and former cancer.Cancer " duplication The discovery of decay " will be cell isotope for cancer cell one cancer of rectification of name.The discovery of cancer cell " cell isotope ", makes people to thin The understanding of karyon structure is stepped to gene (molecular core) depth and is gone a step further.It not only makes tumour concept have new meaning, but also Also biochemistry benchmark will be made to generate great deep change.
Casting aside cancer is that cell isotopic theory is not gone into seriously, and when which kind of spectrometer no matter we use to tumour cell, (they can Can be oncogene, be also possible to cancer DNA, oncoprotein) when being measured, purify in any case, cancer obtains but on the screen It is two parabolas different from normal cell, one is represented as the cancer cell of apparently methylation quality, and another then represents just The noble cells of Chang Zhiliang.Here it is the specific spectra curves of unstable bioisotope-cancer cell of first time discovery.
Summary of the invention
Tumour DNA protein isotope spectral effects model comes into being, and DNA and protein are that two kinds of important biologies are big Molecular substance, their collective effects together form the frame of life.The agent of vital movement, all life activity all from DNA protein is not opened.They play an important role in the vital movement of organism.DNA is made of deoxynucleotide, is The central genetic substance of organism.Protein is made of amino acid, is generally used for energy storage and energy supply, and special such as enzyme, which has, urges Change function.There is no DNA protein just without life.Therefore, it is closely connected with life and with various forms of vital movements Substance together.Each of body cell and all important compositions and function have the participation of DNA protein.Therefore DNA The normal anomaly physicochemical property of protein is directly related to cell function.The line displacement of cancer DNA, protein molecule spectrum.Core is certainly The difference of rotation is the scientific theory basis for the variation for causing spectral fine structure.Ultraviolet spectra DNA protein phenotypic analysis instrument energy The line displacement of cancer DNA, protein molecule spectrum are captured, the apparent momentum of cancer, quality is bigger, and spectrum specificity wavelength is shorter (p=h/ λ), is diagnosing tumour, determines its good, pernicious major spectral foundation.
Isotope spectral effects are the bases of isotope analysis and isotopic separation.It can disclose chemical structure substantially not In the case where change, cause the change of physics, those chemical constants, thus can be disclosed deeper into ground material microstructure and property it Between relationship.Isotope spectrometer is in the 1940s once for the nuclear physics important element isotope such as uranium, deuterium, heavy water point It has ever made significant contribution in analysis, separation.20th century, life science was it has also been found that their isotope such as cancer, virus, stem cell Cell, the change in the case where their sequential structure is constant only by apparent modification constant can also cause DNA conformation, stabilization Property, the expression and closing of controlling gene.DNA protein bio isotope and cell isotope equally also have spectroscopic isotope Effect detects biology and cell isotope using spectrometer;Isotopic characteristic between proto-oncogene, oncogene, viral vaccine Pass on strain isotopic characteristic, isotopic characteristic between stem cell equally have spectroscopic isotope effect between them: can cause The line displacement of the spectrum such as cellular elements DNA, RNA at different levels, protein, enzyme or biological virus molecular spectrum.Nuclear spin is not It together, is the scientific instrument for causing the variation of spectral fine structure.Ultraviolet spectra DNA protein phenotypic analysis instrument, is life science Research can not puzzled scarce critical equipment.Major contribution will be made in the analysis of 21 century bioisotope, separation.Ultraviolet spectra DNA protein phenotypic analysis instrument equipment is simple, easy to operate, and deep by hospital, patient likes.
As this kind of incurable disease of cancer, absolutely accuracy tumor markers completely currently not yet, be because We also do not recognize that cancer is nucleus DNA lesion clearly, and simple only pursuit tumor marker protein matter, hormone, enzyme etc. are this kind of Cytoplasm chemical substance is detected with molecular biology method, however these tumor markers, their naturally occurring " defects " Be because they be all cytoplasm chemical marker, cannot exact early expression nucleus DNA lesion, so just making our faces It is servile to cancer.Pathology DNA is diagnosed, also morphologic features and disease under the microscope multifarious vulnerable to Tumour DNA , unavoidably there is certain parting inconsistency in the influence for managing the judgement of doctor's subjective factor.In addition, even if identical parting, point Grade shows entirely different therapeutic response and prognosis due to the difference of its DNA phenotype with tumour by stages.As it can be seen that according to excellent The malignant tumour hierarchy plan that gesture principle carries out has one in terms of reflection tumor histology's feature, biological behaviour and prognosis Fixed limitation is not able to satisfy the requirement in tumor individual therapy for diagnosing tumor fining.Therefore, in traditional tumour On the basis of histological typing, carries forward vigorously and compel by the diagnosis of the molecular fractionation of core tumour of Tumour DNA protein Phenotypic examination In the eyebrows and eyelashes-Chinese Medical Association's pathology branch academic meeting paper compilation.Present Tumour DNA phenotype spectral quantum grading diagnosis Relative to the progress that oncomolecularbiology method has had Hen big, therefore urgently need to develop DNA phenotype amount of spectrum Sub- instrument early diagnoses tumour, promotes the well-being of mankind.
Specific embodiment
Ultraviolet spectra DNA protein phenotypic analysis instrument can detect tumour-specific spectral signatures object, with 80% or more Sensibility and specificity when its appearance is applied to clinically, is able to satisfy this several standards, first is that sensibility is high: tumour spectrum Percentage existing for specificity is very high, second is that spectrum is specific: can distinguish the tumor grade energy of patient and normal person Power froms the perspective of that tumour-specific spectral signatures object should all be not present in normal person from the angle of normal person, is negative.It is nothing Number physician, scientist's dream hide the early diagnosis of tumor tool that oneself asks, and detection circular list DNA ratio ctDNA ratio CTC is earlier.Classification It is quantitative more accurate.It is more more excellent than detection tumor markers table circulating protein matter, it is that tumor nuclear medicine liquid biopsy is indispensable Equipment.(table DNA letter is released;Table DNA and ctDNA difference is Tumour DNA methylation, acetylation, glycopolypeptide multimer amino lactose knot Structure content increases, and the increase of poly amino lactose is converted along with cell from benign form to mailgnant form, and ctDNA is DNA structure sequence Column variation.Table DNA is the apparent information change of DNA.Institute all shows hereditary (DNA sequence dna change) and two kinds of sides of epigenetic on evidence Formula can result in tumour result)
It is tested by self-test, it has been found that ultraviolet spectra DNA protein phenotypic analysis instrument is a outstanding tumor blood Circulating DNA detection device, single serology circular list DNA detection, function is just very powerful, 20 normal human serum samples In, just detect 3 early stage positive patients.The equipment accuracy and specificity respectively reach 76% or 85%.Though sensibility is 50%, this may be not stringent in relation to (before sample should select cancer patients surgery with selection sample;Tumor markers concentration Gao Shicai Collection, if collection of specimens is improper, the error and mistake that are introduced when being difficult to and make up in collect specimen best instrument and equipment Accidentally).Health experience can find big quality in serum in time, and big energy acidic circulation DNA, this is possible from tumour with before The viruses such as oncogene-human papilloma virus (abbreviation HPV), big quality in serum, big energy acid dna.It is killing siberian crabapple The important factor of system, therefore be the great early warning of early detection cancer.Big quality, big energy acid dna is than our normal cells The much higher energy level of DNA, with common DNA, protein not in a level, therefore in serum various globulin classes change only It can cause the change of amount of DNA, it is impossible to which the displacement of interference effect optic spectrum line changes.
The inertia mass of substance is that its energy intension measures an Einstein, and DNA virtual inertia quality is exactly DNA energy Estimate.Ultraviolet specrophotometer is a powerful for measuring hydrogen bond energy.Spectrum in molecule, the absorption of electronic area mainly by The sum of fundamental frequencies and frequency multiplication of the groups such as C-H, O-H, N-H, C=O, which absorb, to be formed, and tumour spectral wavelength specificity is mobile in terms of shortwave 3-5 millimicrons quite mutually with energy be every gram molecule be the card of 2-3 thousand, (1,000 block 1 g can be made waterborne to be upgraded to 1000 DEG C of heat), Tumour DNA ultraviolet spectra phenotypic analysis instrument can easily capture tumour spectrum Specific marker, extensively For the early stage screening of tumour, treatment.
Two, tumour spectrum specificity can be used as the exclusive specificity of tumour cell marker, be widely used in the morning of tumour Phase screening, is supplied to reference for clinicians.
Present lesion detection is general problem is that cancer markers are not specific enough.It is " most of swollen for what is explored before Tumor markers, normal cell can also generate, therefore be not the exclusive specificity of tumour cell.It means that they are often It is not bery special, it is ideal." liquid biopsy then passes through more special tumour fingerprint in search blood and other body fluid, to overcome this The defect of aspect.Epigenetics (bioisotope spectrometer) " liquid biopsy " technology can be used as tumor screening tool, spectrum In molecule, the absorption of electronic area is mainly by C-H, O-H, N-H, and the sum of fundamental frequencies of the groups such as C=O, which absorbs to absorb with frequency multiplication, to be formed, tumour Spectral wavelength specificity moved in terms of shortwave 5 millimicrons quite mutually with energy be every gram molecule be 2-3 thousand card, (1,000 cards can make 1 g of heat waterborne for being upgraded to 1000 DEG C), virus, oncogene excitation state quantum, DNA, protein complex Fastness and hard-decomposed, all depends on this.Cancer nucleoprotein matter wave phenomenon, the former Russian scholar is in " nucleic acid structure and its biology Activity " in already reported (1948).It can be worth as gene barrier height-gene valve, be the amount of nucleus degree of stability Degree.Oncogene matter wave is theoretical, and cancer cell quantum and momentum relationship, it is exactly the pass of famous de Broglie wavelength and momentum System, which is exactly Einstein-de Broglie equation known to us together with ω=hv.Using it, we can understand aobvious Show cancer markers specificity, for distinguishing the classification of various cancers and the curative effect degree of cancer patient.It is supplied to clinician With reference to.
One blood routine spectroscopic isotope technology of ultraviolet spectra DNA protein phenotypic analysis instrument is imitated using biological spectrum isotope It answers analytic approach to have studied Healthy People, tumor patient blood, serum, lymph respectively, waits Cellular spectroscopics isotopic properties.Research knot Fruit shows that the ultraviolet absorption spectrum of human serum about has an extremely strong absorption peak near 230nm, and blood is in 275nm, serum proteins There is a stronger absorption peak in 279nm, has absorption paddy in 252nm.Analysis serum shows cancer and former cancer isotope spectral effects; Ultraviolet absorption spectrum is variant.Cancer patient trough DNA position mean 253-255nm, the 252 (P of average value of healthy person wave trough position < 0.01).(coincidence rate 88.2%) and healthy person should be less than 253nm (coincidence rate 81.8%).Healthy human blood 275nm, tumour 5nm, blood samples of patients 278 has a stronger absorption peak etc. (P < 0.01).Absorption peak hyperchromicity Tm increment near 414nm Height is the significant contribution of tumor patient red blood cell G/C content, methylation.These DNA protein spectral differences are for cancer spectrum On the qualitative and quantitative analysis of early diagnosis and oncotherapy prognosis, with important theoretical value and its clinical screening application valence Value.
Ultraviolet spectra DNA protein phenotypic analysis instrument uses apparent electronics " liquid biopsy " diagnostic techniques, main advantage Have a following: 1. ultraviolet spectra DNA protein Phenotypic examination instrument identify blood routine isotope technology, and (one bleeds tumour blood routine Early stage screening) benign tumors, malignant spectra technical indicator are determined by spectroscopic isotope effect, it is swollen to carry out the screening of blood routine early stage When tumor (when blood routine physical examination), only one need to be taken to bleed or other body fluid, be a kind of noninvasive convenient and fast sampling mode.Ultraviolet light Compose DNA protein phenotypic analysis instrument;One bleeds tumour blood routine early stage screening, and a point drop Blood Law, rapid serum method can be fast Speed is accurately diagnosed.Sensitivity, the accuracy of early diagnosis can be increased substantially in conjunction with tumor cells marker detection.2. Real-time and timeliness.Liquid biopsy extraction can different time respectively to patient sample, guarantee detect every time real-time, Timeliness.Bioisotope spectrometer (apparent electronics Biopsy) complements each other with traditional biopsy technology, safe nothing Risk.3. comprehensive, what liquid biopsy sample represented is the summation of multiple target cell information, overcomes tumor tissue section Dyskaryosis one-sidedness.4. apparent spectral is analyzed, the quick of the sensitive accurate of is easy to operate, and usability is strong.It is scientific research, hospital, clinical doctor Product raw, that tumor patients in heilongjiang is badly in need of.5, cell isotopic equilibrium anticancer therapy is exchanged with each other position between cell isotopic molecule Reaction cell isotope exchange reaction, its main feature is that reaction is reversible.Cell DNA, albumen is light, heavy isotope (cell table Appearance quality is different) between forward reaction reach balance, referred to as cell isotopic equilibrium, be the drug for uniquely capableing for the treatment of cancer, Bioisotope spectrometer can monitor the bilateral level of cell isotope, quickly utterly destroy cancer cell.Apparent liquid biopsy this A little advantages carry out subversiveness to conventional cancer treatment zone so that this technology is expected to be used for the early stage screening and prognosis treatment of tumour It changes, digs and develop with Tumour DNA ultraviolet spectra phenotypic analysis instrument technology, 21 century will be a bioisotope application again Century arrives.

Claims (4)

1. ultraviolet spectra DNA protein phenotypic analysis instrument mainly tests and analyzes Tumour DNA protein phenotype matter according to right 1 Amount changes and causes the analysis instrument of DNA protein energy variation.Tumour DNA protein phenotype quality refers to Tumour DNA methyl Change, acetylation, glycopolypeptide multimer amino lactose structural content increases, and the increase of poly amino lactose is along with cell from benign form It is converted to mailgnant form, is the outer culvert measurement of Tumour DNA protein spectral Specific marker character mutation.
2. the inertia mass of substance is that its energy intension measures an Einstein, and DNA phenotype quality is exactly DNA energy according to right 2 Amount is estimated.Ultraviolet specrophotometer is a powerful for measuring hydrogen bond energy level.The DNA protein phenotype hydrogen that can be measured The absorbing state in bonding electron area, mainly by C-H, O-H, N-H, the sum of fundamental frequencies and frequency multiplication of the groups such as C=O, which absorb, to be formed, Tumour DNA egg White matter phenotype quality increase is to promote the enhancing of protein and nucleic acid higher structure binding force, and the tumour spectrum of blue spectral shift is special The leading factor of the property marker origin cause of formation.Therefore ultraviolet spectra DNA protein phenotypic analysis instrument can detect DNA hydrogen bond energy level, be point The scientific instrument analysed Tumour DNA protein phenotype mass change and DNA protein energy is caused to change.
3. according to 1,2, the requirement of right 3, ultraviolet specrophotometer is laboratory measurement instrument and ultraviolet spectra DNA protein phenotype Analyzer is that medical instrument is ultraviolet specrophotometer+ultraviolet spectra DNA protein phenotypic analysis software, technology and theoretical institute The medical instrument of composition.Ultraviolet spectra DNA protein phenotypic analysis instrument has unique ultraviolet spectra DNA protein phenotypic analysis Software scientific basis and patented technology, any ultraviolet specrophotometer must not upgrade to ultraviolet spectra on this basis DNA protein phenotypic analysis instrument.
4. being required according to right 4, ultraviolet spectra DNA protein phenotypic analysis instrument mainly tests and analyzes Tumour DNA protein table Type mass change and cause DNA protein energy change analysis instrument, principle of instrument category quantum biophysics scope.It is ultraviolet Spectrophotometric determination DNA experimental protein room Biochemical Research does not upgrade in this range, any ultraviolet specrophotometer, utilizes two It ties up spectral information and carries out medicine, Tumour DNA protein phenotypic analysis beats the ultraviolet spectra DNA protein phenotypic analysis instrument trade mark, Ultraviolet spectra phenotypic analysis is carried out to Tumour DNA protein, have profit purpose should all belong to infringement range.
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Application publication date: 20191022