WO2020259189A1 - Application de sox11 comme marqueur de diagnostic de la schizophrénie - Google Patents

Application de sox11 comme marqueur de diagnostic de la schizophrénie Download PDF

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WO2020259189A1
WO2020259189A1 PCT/CN2020/092583 CN2020092583W WO2020259189A1 WO 2020259189 A1 WO2020259189 A1 WO 2020259189A1 CN 2020092583 W CN2020092583 W CN 2020092583W WO 2020259189 A1 WO2020259189 A1 WO 2020259189A1
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sox11
protein
schizophrenia
mrna
sample
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PCT/CN2020/092583
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李立东
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北京太东生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present disclosure relates to the field of biomedical detection, in particular to the application of SOX11 as a diagnostic marker for schizophrenia.
  • Schizophrenia is a chronic disabling disease with complex etiology and high phenotypic heterogeneity. There are often obstacles in perception, thinking, emotion, and behavior, and generally unconscious and intellectual obstacles. At present, it is generally believed that the lifetime prevalence of schizophrenia in the general population is 1%. It often starts in young adults and most of them have a poor prognosis. More than 50% of patients have long-term intermittent mental problems, and about 20% of patients have residuals. Symptoms and lead to mental disability. The unemployment rate of patients with schizophrenia is as high as 80%-90%, the relative risk of suicide increases by 12 times, and the life expectancy is reduced by about 10-20 years.
  • a biomarker refers to a certain characteristic biochemical index in the course of general physiology or pathology or treatment that can be objectively measured and evaluated. Through its measurement, the progress of the organism's current biological process can be known.
  • biomarkers can be DNA, RNA, protein, or metabolites, which are generally obtained from body fluids.
  • the application of biomarkers to schizophrenia can effectively assist the uncertain human factors in the current diagnosis, reduce the rate of error/misdiagnosis, and help guide medication and rehabilitation.
  • biomarkers that can be used to diagnose first-episode schizophrenia, which should be reliable, and should also have good sensitivity and specificity.
  • the present disclosure provides an objective detection method for diagnosing schizophrenia, that is, detecting the expression level of Sox 11 in peripheral blood.
  • the present disclosure relates to the application of SOX11 mRNA or protein quantitative detection agent in preparing reagents or kits for diagnosing schizophrenia.
  • the present disclosure also relates to a method for diagnosing schizophrenia by detecting the expression amount of SOX11 mRNA or protein in a sample of a subject.
  • SOX11 mRNA or protein has high specificity and sensitivity for the diagnosis of schizophrenia, and is a peripheral blood index, which can be easily obtained; single index detection method requires only one index to be measured, which is convenient for future promotion. It can also be combined with other detection methods to get more reliable results.
  • Figure 1 is an example of the expression of SOX11 mRNA in the serum of violent schizophrenia patients and normal people;
  • Figure 2 An embodiment of the present application shows the expression of SOX11 protein in blood samples of violent schizophrenia patients and normal people.
  • the present disclosure relates to the application of SOX11 mRNA or protein quantitative detection agent in preparing reagents or kits for diagnosing schizophrenia.
  • the present disclosure also relates to a quantitative detection agent for SOX11 mRNA or protein, which is used in the diagnosis of schizophrenia.
  • the severity and/or susceptibility of the disorder and/or disease can also be determined based on the difference in expression levels.
  • the marker gene is one of the genes described herein, the degree of increase in the expression level of the marker gene is related to the existence and/or severity of the condition and/or disease.
  • SOX11 is a nuclear transcription factor that belongs to the C subgroup of the HMG-box gene related to SRY (sex determining region on Y-chromosome). This subgroup contains three members: SOX4, SOX11 and SOX12. Human SOX11 is located on chromosome 2p25.3, and the encoded SOX11 protein is 46.7kDa and contains 441 amino acids. The expression of SOX11 is essential for embryonic neurogenesis and tissue remodeling. It is usually expressed in the nervous system during human embryonic development and is necessary for neurite growth and neuron survival.
  • SOX11 is clinically believed to be related to certain tumors, for example, it is overexpressed in more than 90% of mantle cell lymphomas (MCL), including the rare Cyclin D1 negative cases; in the vast majority of B and T lymphoblastic leukemias / Lymphoma and half of childhood Burkitt lymphoma also have strong expression; in some hairy cell leukemias may have weak expression.
  • MCL mantle cell lymphomas
  • the expression of SOX11 is also speculated to be related to the survival of high-grade epithelial ovarian cancer.
  • SOX11 is closely related to the nervous system, there is no related report of SOX11 as a schizophrenia marker in the prior art. At present, there are very few reports on the expression level of SOX 11 gene or the role of related gene mutations in human mental diseases, and reports related to its mechanism regulation are even rarer.
  • the inventors of the present disclosure unexpectedly discovered that the levels of SOX11 mRNA (such as SOX11 mRNA in peripheral blood) or protein levels in patients with mental illness and control populations have significant differences; the diagnosis can be performed alone/in combination with other molecular markers, and the results are objective and reliable. It has a good application prospect in the diagnosis of schizophrenia patients.
  • schizophrenic disorder refers to a series of mental disorders including schizophrenia and related psychosis.
  • the term is intended to specifically include schizophrenia (generally including first-episode schizophrenia or relapsed schizophrenia), schizophrenia-like schizophrenia, affective schizophrenia, delusional disorder, short-term mental disorder and short-term mental disorder, such as mental As defined in the Diagnostic and Statistical Manual of Disorders, 4th Edition (DSM-IV-TR).
  • the schizophrenia is violent.
  • Symptoms of aggressive behavior that are common in violent schizophrenia Patients who have psychotic symptoms are likely to have aggressive behavior.
  • psychiatric patients suffering from schizophrenia, paranoid psychosis and affective psychosis are the high-risk groups of violent behavior.
  • Quantitative detection agent for SOX11 mRNA in the present disclosure should not only be understood as a detection agent for SOX11 mRNA, but should include other detection reagents known to those skilled in the art that can reflect the expression level of SOX11 mRNA.
  • the expression of SOX11 mRNA can be indirectly detected by quantitatively detecting the cDNA obtained by reverse transcription of SOX11 mRNA.
  • SOX11 mRNA and SOX11 protein can be referred to as “markers”, “marker genes” (specifically SOX11 mRNA), “biochemical markers”, and “marker polypeptides” ( Specifically refers to SOX11 protein), “schizophrenia markers”. It specifically refers to a molecule to be used as a target for the analysis of a patient's experimental sample.
  • the SOX11 mRNA used as a marker in the present disclosure is expected to include its full-length ribonucleotide sequence, or naturally-occurring variants, or full-length sequences and fragments of variants, especially fragments that can be detected and determined for specific sequences .
  • it comprises at least 7, 8, 9, 10, 11, 12, 15 or 20 consecutive ribonucleotides of the full-length ribonucleotide sequence.
  • the SOX11 protein used as a marker in the present disclosure is expected to include naturally-occurring variants of the protein and fragments of the protein or the variants, particularly immunologically detectable fragments.
  • the immunologically detectable fragment contains, for example, at least 5, 6, 7, 8, 9, 10, 11, 12, 15 or 20 consecutive amino acids of the marker polypeptide.
  • the expression "SOX11 protein” includes the complete protein sequence of SOX11 and the marker polypeptide defined above.
  • ribonucleotides/proteins/polypeptides released by cells or ribonucleotides present in the extracellular matrix may be damaged (for example, during inflammation), and may be degraded or Cut into fragments like this.
  • mRNA, protein or fragments thereof may also be present as part of the complex.
  • Such a complex can also be used as a marker in the sense of the present disclosure.
  • the marker polypeptide or variants thereof may carry post-translational modifications.
  • post-translational modifications are glycosylation, acylation and/or phosphorylation.
  • “Naturally occurring variants” should be understood to mean that higher animal genes are usually accompanied by high frequency polymorphisms. There are also many molecules that produce isotypes that contain mutually different amino acid sequences during splicing. Any gene associated with a schizophrenia-related disease that has an activity similar to that of the marker gene is included in the marker gene, even if it has a nucleotide sequence difference due to polymorphism or isotype.
  • RNA quantitative detection reagents can be selected from reagents known to those skilled in the art, such as nucleic acids that can hybridize to the RNA and labeled with fluorescent labels; in common cases, RNA detection reagents can be selected from RT-PCR primers, and Used to amplify the product of RT-PCR-cDNA primers.
  • the SOX11 mRNA quantitative detection agent includes a reagent suitable for at least one of the following methods:
  • the SOX11 mRNA quantitative detection agent is a probe or primer that can specifically bind to SOX11 mRNA or SOX11 cDNA.
  • the marker gene may include homologues of other species except human. Therefore, unless explicitly stated, the expression “marker gene” refers to a homolog of a marker gene unique to a species or an exogenous marker gene that has been introduced into an individual. Similarly, it should be understood that "a homolog of a marker gene” can be used as a probe to hybridize to a human marker gene under stringent conditions. Such stringent conditions are known to those skilled in the art (who can select appropriate conditions to produce the same stringency through experiment or experience).
  • a polynucleotide containing the nucleotide sequence of the marker gene or the complementary strand of the nucleotide sequence of the marker gene and having a nucleotide sequence of at least 15 nucleotides can be used as a primer or a probe. Therefore, the "complementary strand” refers to one strand of double-stranded DNA composed of A:T (U for RNA) and G:C base pairs relative to the other strand.
  • complementary means not only a sequence that is completely complementary to a region of at least 15 consecutive nucleotides, but also a sequence having at least 40% in some cases, 50% in some cases, and 60% in some cases. %, 70% in some cases, 80% in some cases, 90% in some cases, and in some cases 95% or higher nucleotide sequence homology. The degree of homology between nucleotide sequences can be determined using an algorithm such as BLAST.
  • polynucleotides can be used as probes for detecting marker genes or as primers for amplifying marker genes.
  • polynucleotides When used as primers, polynucleotides generally comprise 15 bp to 100 bp, and in certain embodiments 15 bp to 35 bp of nucleotides.
  • DNA When used as a probe, DNA contains the entire nucleotide sequence of the marker gene (or its complementary strand), or a partial sequence thereof having at least 15 bp nucleotides.
  • the 3'region must be complementary to the marker gene, and the 5'region can be linked to a restriction endonuclease recognition sequence or tag.
  • Polynucleotide can be DNA or RNA.
  • oligonucleotide means a polynucleotide having a relatively low degree of polymerization. Oligonucleotides are also included in polynucleotides.
  • Northern hybridization dot blot hybridization, or DNA microarray technology can be used for detection of disorders and/or diseases using hybridization technology.
  • gene amplification techniques such as the RT-PCR method can be used. By using the PCR amplification monitoring method in the gene amplification step of RT-PCR, the expression of marker genes can be analyzed more quantitatively.
  • the probe or primer has a detectable label.
  • the detection target (reverse transcript of DNA or RNA) is hybridized with a probe labeled with a fluorescent dye and a quencher that absorbs fluorescence.
  • a probe labeled with a fluorescent dye and a quencher that absorbs fluorescence.
  • Taq polymerase degrades the probe with its 5'-3' exonuclease activity
  • the fluorescent dye and the quencher are separated from each other, thereby detecting fluorescence.
  • Real-time detection of fluorescence By simultaneously measuring a standard sample in which the copy number of the target is known, the cycle number (in which PCR amplification is linear) can be used to determine the copy number of the target in the subject sample.
  • the cycle number in which PCR amplification is linear
  • the PCR amplification monitoring method can be performed using any appropriate method.
  • the quantitative detection agent for SOX11 mRNA is a qRT-PCR primer for SOX11 mRNA
  • the upstream primer is agcaagaaatgcggcaagc, as shown in SEQ ID NO:1
  • the downstream primer is atccagaaacacgcacttgac, as shown in SEQ ID NO: shown in 2.
  • the quantitative detection agent for SOX11 protein is a reagent required to specifically measure SOX11 protein.
  • the reagent (specific binding agent) required to specifically measure the SOX11 protein is, for example, a ligand or receptor (if present) of the SOX11 protein, agglutination that binds to the SOX11 protein Protein, aptamers that bind to SOX11 protein, or antibodies and antibody fragments that bind to SOX11 protein.
  • Specific binding agent having an affinity of at least 10 7 l / mol for its corresponding target molecule.
  • Specific binding agent to its target molecule for example, 10 8 l / mol, e.g., affinity or 10 9 l / mol of.
  • specific means that other biomolecules present in the sample do not significantly bind to the specific binding agent of the SOX11 protein.
  • the level of binding to biomolecules other than the target molecule produces a binding affinity that is at most only 10% or less, only 5 percent of the affinity to the target molecule, respectively. % Or less, only 2% or less, or only 1% or less.
  • the specific binding agent will simultaneously meet the aforementioned minimum criteria for affinity and specificity.
  • the detection agent capable of specifically binding to the SOX11 polypeptide is an antibody or an antibody fragment.
  • antibody includes polyclonal antibodies and monoclonal antibodies, and the term “antibody fragment” includes antigen compound binding fragments of these antibodies, including Fab, F(ab') 2 , Fd, Fv, scFv, bispecific antibodies and antibodies The smallest recognition unit, and single-chain derivatives of these antibodies and fragments, such as scFv-Fc, etc.
  • the type of antibody can choose IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, IgD.
  • antibody includes naturally-occurring antibodies and non-naturally-occurring antibodies, including, for example, chimeric, bifunctional, humanized, and human antibodies, and related synthetic antibodies. Isoforms.
  • antibody can be used interchangeably with "immunoglobulin”.
  • the antibodies or antibody fragments can be obtained by immunizing with SOX11 protein or fragments thereof as antigens.
  • the immunized subjects can include humans and all livestock (such as domestic animals and pets) and wild animals and poultry.
  • Birds which include, without limitation, cattle, horses, cows, pigs, sheep, goats, rats, mice, dogs, cats, rabbits, camels, donkeys, deer, minks, chickens, ducks, geese, turkeys, and cockfighting Wait.
  • the antibody or antibody fragment is labeled with an indicator that shows signal strength.
  • the kit further includes one or more detection agents for schizophrenia markers.
  • the schizophrenia markers described herein can be combined with other risk factors for schizophrenia.
  • additional risk factors are selected from SNPs, microsatellites, or indel polymorphisms.
  • the kit further includes reverse transcription reagents, blood extraction reagents, internal reference primers, fluorescent substances for indicating the amount of DNA synthesis, qPCR reaction buffer, dNTPs, DNA polymerase , One or more of the water.
  • the internal reference primer is selected from primers of GAPDH, tubulin or actin.
  • the water is nuclease-free water, such as reverse osmosis water, distilled water, deionized water, and reverse osmosis water .
  • the DNA polymerase is selected from Taq, Bst, Vent, Phi29, Pfu, Tru, Tth, T11, Tac, Tne, Tma, Tih, Tf1, Pwo, Kod, Sac, Sso , Poc, Pab, Mth, Pho, ES4 DNA polymerase, Klenow fragment.
  • the blood extraction reagent is selected from an anticoagulant (for example, citric acid or its salt, EDTA or its salt), lymphocyte separation solution and the like.
  • an anticoagulant for example, citric acid or its salt, EDTA or its salt
  • the present disclosure also provides a method for diagnosing schizophrenia (especially violent schizophrenia) in a human individual, the method comprising:
  • step (a) Obtain a sample containing SOX11 mRNA or protein of the subject; (b) Measure the expression of SOX11 mRNA or protein in the sample, (c) Optionally, measure one or more other spirits in the sample The concentration of the schizophrenia marker; (d) the measurement result of step (b) and the measurement result of optional step (c) are used to diagnose schizophrenia.
  • step a) in step a), the above-mentioned reagents required for specific and quantitative measurement of SOX11 mRNA/protein are used for measurement.
  • subject refers to any animal, including mammals, such as but not limited to primates (such as humans), rodents (such as mice, rats, rabbits), dogs, cats, pigs, cows, Sheep, horse.
  • mammals such as but not limited to primates (such as humans), rodents (such as mice, rats, rabbits), dogs, cats, pigs, cows, Sheep, horse.
  • the sample is a body fluid of the subject, such as blood, serum or plasma and cerebrospinal fluid, tissue or tissue lysate, cell culture supernatant, semen, saliva sample, Or other appropriate samples containing SOX11 mRNA/protein, such as peripheral blood;
  • a body fluid of the subject such as blood, serum or plasma and cerebrospinal fluid, tissue or tissue lysate, cell culture supernatant, semen, saliva sample, Or other appropriate samples containing SOX11 mRNA/protein, such as peripheral blood;
  • the sample is total RNA extracted from peripheral blood
  • the method is an in vitro method.
  • diagnosis includes assessing the susceptibility to schizophrenia, the severity of schizophrenia, or the diagnosis of schizophrenia along with other indicators/conditions, or the prognostic assessment of schizophrenia.
  • the method of diagnosing a schizophrenia disorder may include an additional step including reporting the susceptibility to at least one entity selected from the group consisting of an individual, an individual’s guardian, an individual’s agent, a genetic service provider, a doctor, a medical institution And medical insurance companies.
  • entity selected from the group consisting of an individual, an individual’s guardian, an individual’s agent, a genetic service provider, a doctor, a medical institution And medical insurance companies.
  • other single entities including any of the aforementioned entities, can be targeted by such reports, and the same applies to any combination of the aforementioned entities.
  • the marker gene when the marker gene is one of the genes described herein, its symptoms at least suggest an increase or decrease in the expression level of the marker in subjects who are susceptible to the disorder and/or disease It indicates that the symptoms are mainly caused by the condition and/or disease.
  • testing can be used to determine whether the condition and/or disease has improved in the subject.
  • the method described herein can be used to judge the therapeutic effect of the treatment for the condition and/or disease.
  • the marker is one of the markers described herein (especially SOX11 mRNA/protein)
  • an increase or decrease in the expression level of the marker gene in a subject who has been diagnosed with the disorder and/or disease means The disease has moved forward.
  • the present disclosure provides a method for diagnosing schizophrenia, including:
  • the method includes
  • step (d) Use the measurement result of step (b) and the measurement result of step (c) to diagnose schizophrenia.
  • the method includes
  • the expression level of SOX11 mRNA or protein in the subject sample is lower than the expression level of SOX11 mRNA or protein in the control sample is an indication of schizophrenia.
  • control sample is a sample from a healthy subject or a sample from a non-schizophrenic subject.
  • the present disclosure also provides a method for judging the therapeutic effect of schizophrenia, including
  • the expression level of SOX11 mRNA or protein in the subject sample after treatment is lower than the expression level of SOX11 mRNA or protein in the subject sample before treatment is an indication that schizophrenia continues to progress or the treatment effect is not good.
  • the subject is a mammal, such as a primate, such as a human.
  • the sample is at least one of blood, serum, plasma, cerebrospinal fluid, tissue, tissue lysate, cell culture supernatant, semen, or saliva sample, such as peripheral blood.
  • the SOX11 mRNA measurement is performed by qRT-PCR using SOX11 mRNA primers.
  • the upstream primer of the SOX11 mRNA primer is shown in SEQ ID NO:1, and the downstream primer is shown in SEQ ID NO: shown in 2.
  • the schizophrenia is violent schizophrenia.
  • the schizophrenic patients came from a hospital specializing in schizophrenia (Ankang Hospital of the Public Security Department of Jilin province) and a family member in Siping City, Jilin province who suffered from schizophrenia. A total of 46 people were violent schizophrenia patients. Normal people come from normal members of the same family in Siping and other normal people who have nothing to do with this family, a total of 39 people. This study has been reviewed by the Medical Ethics Committee of Ankang Hospital of the Public Security Department of Jilin province, and the clinical trial protocol is ethical. Both the case group and the control group were formally informed in writing.
  • the blood samples were processed with red blood cell lysate to obtain white blood cells; total RNA was extracted from the above peripheral blood white blood cell samples; SOX11 was specifically transcribed into cDNA using the total RNA as a template, and real-time quantitative PCR (qPCR) technology was used to detect the mRNA expression level of SOX11 , Compare the level of SOX11 in the blood of schizophrenia patients and normal people.
  • qPCR real-time quantitative PCR
  • the Western blot method was used to detect the protein level expression in the samples of schizophrenia patients and normal people.
  • the specific methods are as follows:
  • Glue Wash the glass plate, dry it, and install the vertical electrophoresis plate. Separate gel was prepared according to the formula, 7ml of each gel was poured into a vertical electrophoresis plate, anhydrous ethanol was gently added for liquid sealing, and the gel was allowed to stand at room temperature for 30 minutes to solidify, then the anhydrous ethanol was poured out and dried with absorbent paper. Prepare concentrated glue according to the formula, pour 3ml of each piece of glue into the separating glue, insert a comb, and let it stand at room temperature for 30 minutes to solidify;
  • Electrophoresis Perform electrophoresis at 80V constant voltage, when bromophenol blue runs into the separation gel, switch to 120V constant voltage electrophoresis, and wait until the bromophenol blue dye runs to the bottom of the gel;
  • Electric transfer Install in the electric transfer glue folder in the following order: anode ⁇ sponge layer ⁇ filter paper three layers ⁇ NC (PVDF) membrane ⁇ gel ⁇ filter paper three layers ⁇ sponge layer ⁇ cathode, remove the glue, membrane and filter paper Clamp the air bubbles between them and move them into the electroporation tank, inject electroporation buffer, and electroporate at 200mA constant current on ice for 2 hours;
  • PVDF PVDF
  • SOX11 mRNA or protein has high specificity and sensitivity for the diagnosis of schizophrenia, and is a peripheral blood index, which can be easily obtained; single index detection method requires only one index to be measured, which is convenient for future promotion. It can also be combined with other detection methods to get more reliable results.

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Abstract

L'invention concerne une application de SOX11 en tant que marqueur de diagnostic pour la schizophrénie; spécifiquement, l'invention concerne l'application d'un ARNm SOX11 ou d'un agent de détection quantitative de protéine dans la préparation d'un réactif ou d'un kit pour diagnostiquer la schizophrénie.
PCT/CN2020/092583 2019-06-27 2020-05-27 Application de sox11 comme marqueur de diagnostic de la schizophrénie WO2020259189A1 (fr)

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CN201910569911 2019-06-27
CN201910602071.1A CN110241204A (zh) 2019-07-05 2019-07-05 Sox11作为精神分裂症诊断标记物的应用
CN201910602071.1 2019-07-05

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN104271748A (zh) * 2012-02-02 2015-01-07 得克萨斯州大学系统董事会 表达异源肿瘤相关抗原的腺病毒
CN110241204A (zh) * 2019-07-05 2019-09-17 北京太东生物科技有限公司 Sox11作为精神分裂症诊断标记物的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104271748A (zh) * 2012-02-02 2015-01-07 得克萨斯州大学系统董事会 表达异源肿瘤相关抗原的腺病毒
CN110241204A (zh) * 2019-07-05 2019-09-17 北京太东生物科技有限公司 Sox11作为精神分裂症诊断标记物的应用

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Title
CHENG-PENG SUN ET AL.: "Association of SOX11 Polymorphisms in distal 3'UTR with Susceptibility for Schizophrenia", J CLIN LAB ANAL, 23 March 2020 (2020-03-23), XP055772918, DOI: 20200717155730PX *
JAY, P. ET AL.: "Human SOX-11 mRNA, complete cds", NON-OFFICIAL TRANSLATION: GENBANK, NUCLEIC ACID SEQUENCE DATABASE, 20 September 1996 (1996-09-20), DOI: 20200717212524Y *
SHA L ET AL.: "SOX11 target genes: implications for neurogenesis and neuropsychiatric illness", ACTA NEUROPSYCHIATRICA, vol. 24, 31 December 2012 (2012-12-31), XP055772921, DOI: 20200717212541Y *

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