Efectos de los Polimorfismos del Transportador y de los Receptores de Serotonina en la Depresión

Introducción: La serotonina tiene gran implicación en la regulación del estado emocional y la ejecución de tareas cognitivas, de modo que los genes del transportador de serotonina (5-HTT, SLC6A4) y de los receptores de serotonina (HTR1A, HTR1B, HTR2A) se convierten en candidatos adecuados para estudiar los efectos de estos genes y sus variaciones polimórficas en las características de la depresión. Objetivo: Revisión de reportes de investigación que hayan estudiado los efectos de las variantes de los genes del transportador y de los receptores de serotonina en las diferentes características clínicas de la depresión. Métodos: Se realizó una búsqueda en las bases de datos Scopus, Web of Science y PubMed con las palabras clave "depression", AND "polymorphism". Conclusiones: Según la revisión de 54 artículos, se encontró que el alelo corto del polimorfismo de 5-HTTLPR es el factor de riesgo más reportado en relación con el desarrollo de depresión y su gravedad. Las variantes de los genes estudiados (SLC6A4, HTR1A, HTR1B y HTR2A) pueden generar alteraciones morfológicas de estructuras cerebrales.

Introduction: Serotonin is highly implicated in the regulation of emotional state and the execution of cognitive tasks, so much so that the serotonin transporter genes (5-HTT, SLC6A4) and the serotonin receptor genes (HTR1A, HTR1B, HTR2A) have become the perfect candidates when studying the effects that these genes and their polymorphic variations have on depression characteristics. Objective: A review of research reports that have studied the effects of variations in the serotonin transporter and receptor genes on different clinical features of depression. Methods: A search of the Scopus, Web of Science and PubMed databases was conducted using the keywords ("depression" AND "polymorphism"). Conclusions: According to the review of 54 articles, the short allele of the 5-HTTLPR polymorphism was found to be the most reported risk factor related to the development of depression and its severity. Variations in the genes studied (SLC6A4, HTR1A, HTR2A) can generate morphological alterations of brain structures.

Medicated effect of CDKN1B on promoting proliferation of islet β cells in diabetes mellitus / 中国综合临床

The serious decrease in the number of functional β cells is one of the main features in the pathogenesis of diabetes mellitus. CDKN1B is a new kind of regulatory protein, which can bind and inactivate cyclin and cyclin-dependent kinase complex to control the process of cell cycle. It was suggested that down-regulation or deletion of CDKN1B in islet β cells could accelerate the proliferation of islet β cells, thus increasing the number of islet β cells, which is of great significance for treatments of diabetes.

A case of recurrent Miller-Fisher syndrome with multiple anti-ganglioside antibodies / 中国综合临床

Guillain-Barré syndrome (GBS) defines a kind of Immune-mediated acute inflammatory peripheral neuropathy. Miller-Fisher Syndrome (MFS) is a special variant of GBS, with mostly one-way course and rare clinical recurrence. Only a few recurrent cases have been reported in China. Here we report a case of a young male patient with double vision and progressive aggravation of limb numbness, acute onset, with symptoms of upper respiratory tract infection before onset, accompanied by pupil abnormalities and autonomic nervous dysfunction, who was was admitted to our hospital for similar symptoms 3 years ago and was improved by immunotherapy. The patient had a triad of “ataxia, areflexia and ophthalmoplegia”. Cerebrospinal fluid showed protein-cell separation. Serum anti-Sulfatides antibody IgM, anti-GT1a antibody IgG, anti-GQ1b antibody IgG and anti-GM3 IgM were positive. Recurrent MFS was diagnosed and the symptoms improved after immunotherapy. This case suggests that MFS is clinically heterogeneous, a few patients can present with relapse and generally have a better prognosis with immunotherapy. Pre-existing infection and anti-GQ1b antibody production may be predisposing factors for MFS recurrence.

Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics / 药物分析学报

Fexofenadine is useful in various allergic disease treatment.However,the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking.This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmaco-kinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability.Polymorphisms of the organic-anion-transporting-polypeptide(OATP)1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity.Therefore,modeling was performed using fexofenadine oral exposure data according to the OATP1B1-and 2B1-polymorphisms.OATP1B1 and 2B1 were identified as effective covariates of clearance(CL/F)and distribution volume(V/F)-CL/F,respectively,in fexofenadine pharmacokinetic variability.CL/F and average steady-state plasma con-centration of fexofenadine differed by up to 2.17-and 2.20-folds,respectively,depending on the OATP1B1 polymorphism.Among the individuals with different OATP2B1 polymorphisms,the CL/F and V/F differed by up to 1.73-and 2.00-folds,respectively.Ratio of the areas under the curves following single-and multiple-administrations,and the cumulative ratio were significantly different between OATP1B1-and 2B1-polymorphism groups.Based on quantitative prediction comparison through a model-based approach,OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability.Based on the established pharmacokinetic-pharmacodynamic relationship,the difference in fexofenadine efficacy according to genetic poly-morphisms of OATP1B1 and 2B1 was 1.25-and 0.87-times,respectively,and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well.This population phar-macometrics study will be a very useful starting point for fexofenadine precision medicine.

Gene Analysis for the Sebaceous Carcinoma of Scalp by Whole Exome Sequencing / 中山大学学报(医学科学版)

ObjectiveTo reveal the differences of the related pathogenicity gene mutations between sebaceous adenocarcinoma （SC） of scalp and sebaceous adenoma （SA） of scalp on whole exome level. MethodsWhole exome sequencing was performed on a SC sample and a SA sample by Illumina Hiseq 2500 platform. Suspicious single nucleotide variation sites were selected for mutation conservation and functional analysis. SciClone was used to track subclone evolution and clonal map information was obtained for each tumor sample. The high-frequency significant gene mutations in the tumor sample were screened by MutSigCV software， and compared with the known driver genes. ResultsTwo driver genes TFDP1 and ACVR1B harboring mutations in scalp SC compared to SA were found. ConclusionsThe finding of mutation in driver genes TFDP1 and ACVR1B should be confirmed in a large cohort， which might reveal the mechanism of scalp SC development and find a therapeutic target for SC.

A Case Report of Nail-Patella Syndrome / 罕见病研究

Nail-patella syndrome (NPS) is a hereditary rare disease that can involve fingernail, patella, elbow, and iliac bones. In this article, we report a case of a girl-9 and 1 quarter years old who had asthmatic contractures in both elbows, thumbnail hypoplasia in both hands, patellar dislocation of both knees, iliac angle protrusion of both sides, and scoliosis. Whole exome sequencing suggests the presence of a LMX1B NM_002316.4:c.706G > C(p.Ala236Pro) mutation. NPS is an autosomal dominant disease associated with gene mutation of LMX1B, which can be diagnosed by combining the patient′s clinical manifestations and genetic results. The treatment now only targets on symptoms, relieving the localized severe lesion but not cure right now.

Design, synthesis and evaluation of phenoxyacetic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC50 of 0.42 μmol·L-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.

Patent analysis of new target oral drugs for type 2 diabetes mellitus / 中国药房

OBJECTIVE To analyze the patents of new target oral drugs for type 2 diabetes mellitus （T2DM）， and to provide references for the research and development direction and patent layout of new domestic diabetes drugs. METHODS Based on global patent data in the HimmPat database， from multiple perspectives such as the number of patent applications and authorization， development trend， regional distribution and main applicants， statistics and analysis were performed for the patents related to 3 types of new target oral drugs for T2DM， such as glucokinase activator （GKA）， protein tyrosine phosphatase 1B inhibitor （PTP-1B-IN）， and 11β-hydroxysteroid dehydrogenase 1 inhibitor （11β-HSD1-IN）. RESULTS & CONCLUSIONS A total of 1 649 patents of GKA， 709 patents of PTP-1B-IN， 592 patents of 11β-HSD1-IN were obtained， the main applicants were well-known pharmaceutical companies， which possessed the core patents of pharmaceutical compounds. The research on GKA drugs was more mature， with a larger number of patent applications and a more comprehensive enterprise layout. Domestic enterprises， universities and research institutions had advantages in the field of PTP-1B-IN. Domestic enterprises and research institutions can leverage the advantages of traditional Chinese medicine and resources to enhance their research capabilities and improve technological competitiveness through core technology exploration， the exploration of process route， patent layout， industry- university-research cooperation and the establishment of patent pool.

Pharmacodynamics of human interferon α1b against severe acute respiratory syndrome coronavirus 2 Omicron strain in vitro / 中国生物制品学杂志

@#Objective To evaluate the pharmacodynamics of human interferon(IFN)α1b against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron strain in vitro.Methods Total four drugs human IFNα1b bulk,human IFNα1b eye drops,human IFNα1b spray and Remdesivir were detected for cytotoxicity by CCK-8 assay.The inhibitory effect of human IFNα1b on SARS-CoV-2 Omicron strains(BA.5/BA.2/BA.1)was determined by qPCR.Results Human IFNα1b bulk of the maximum concentration(1 × 107IU/mL)and Remdesivir of the maximum concentration(150 μmol/L)did not achieve half cytotoxicity to Vero cells;The median cytotoxicity concentrations(CC_(50))of human IFNα1b eye drops and human IFNα1b sprays were 29 958 and 37 550 IU/mL,respectively,showing toxicity to Vero cells.The median effective concentrations(EC_(50))of human IFNα1b against virus strains BA.1,BA.2 and BA.5 after incubation for 2 h in advance were 9.30,13.38 and 12.33 IU/mL and those of Remdesivir were 0.314 7,0.291 0 and0.300 3 μmol/L.When incubation with virus simultaneously,the EC_(50)of human IFNα1b to BA.1,BA.2 and BA.5 were19.68,10.91 and 18.84 IU/mL and those of the control drug Remdesivir were 0.320 5,0.274 4 and 0.304 1 μmol/L,respectively.Conclusion At the cell level in vitro,human IFNα1b of very low activity showed a good inhibitory effect on SARS-CoV-2 Omicron strain,which was expected to be a clinical specific drug for the treatment of SARS-CoV-2 Omicron strain infection.

Effect of interleukin-6 on nucleated erythrocytes in lipopolysaccharide-induced preeclampsia rats / 解剖学报

Objective To explore the effect of interleukin (IL)-6 on nucleated erythrocytes in lipopolysaccharide (LPS)-induced preeclampsia rats. Methods ELISA and immunohistochemistry were used to detect the IL-6 in peripheral blood and placenta of preeclampsia and normal pregnancy; Flow cytometry and immunofluorescence were used to detect the maternal nucleated erythrocytes. Pregnant SD rats were randomly divided into 3 groups: the control, LPS and LPS +anti-IL-6 group; IL-6, the proportion of nucleated erythrocytes, JAK2/MEK and PI3K/Akt signal-related genes were detected. Results The IL-6 of preeclampsia was higher than that of normal patients. Compared with the Control group, IL-6, the proportion of nucleated erythrocytes and JAK2, P85, Akt, P65, IL-IB mRNA of LPS group increased, the fetal weight decreased; Compared with the LPS group, IL-6, the proportion of nucleated erythrocytes and JAK2, P85, Akt, P65 and IL-IB mRNA of the LPS + anti-IL-6 group decreased. Conclusion The up-regulation of IL-6 of preeclampsia patients is accompanied by increased nucleated erythrocytes in peripheral blood. Neutralizing IL-6 in vivo may down-regulate JAK2/ PI3K/Akt/NF-KB-signal-mediated IL-IB to protect preeclampsia rats.

Sortilin-induced lipid accumulation and atherogenesis are suppressed by HNF1b SUMOylation promoted by flavone of Polygonatum odoratum / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

This study aims to investigate the impact of hepatocyte nuclear factor 1β (HNF1b) on macrophage sortilin-mediated lipid metabolism and aortic atherosclerosis and explore the role of the flavone of Polygonatum odoratum (PAOA-flavone)-promoted small ubiquitin-related modifier (SUMO) modification in the atheroprotective efficacy of HNF1b. HNF1b was predicted to be a transcriptional regulator of sortilin expression via bioinformatics, dual-luciferase reporter gene assay, and chromatin immunoprecipitation. HNF1b overexpression decreased sortilin expression and cellular lipid contents in THP-1 macrophages, leading to a depression in atherosclerotic plaque formation in low-density lipoprotein (LDL) receptor-deficient (LDLR-/-) mice. Multiple SUMO1-modified sites were identified on the HNF1b protein and co-immunoprecipitation confirmed its SUMO1 modification. The SUMOylation of HNF1b protein enhanced the HNF1b-inhibited effect on sortilin expression and reduced lipid contents in macrophages. PAOA-flavone treatment promoted SUMO-activating enzyme subunit 1 (SAE1) expression and SAE1-catalyzed SUMOylation of the HNF1b protein, which prevented sortilin-mediated lipid accumulation in macrophages and the formation of atherosclerotic plaques in apolipoprotein E-deficient (ApoE-/-) mice. Interference with SAE1 abrogated the improvement in lipid metabolism in macrophage cells and atheroprotective efficacy in vivo upon PAOA-flavone administration. In summary, HNF1b transcriptionally suppressed sortilin expression and macrophage lipid accumulation to inhibit aortic lipid deposition and the development of atherosclerosis. This anti-atherosclerotic effect was enhanced by PAOA-flavone-facilitated, SAE1-catalyzed SUMOylation of the HNF1b protein.

Correlation between PAFAH1B3 Expression Level and Risk of Disease Progression After Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients / 中国实验血液学杂志

OBJECTIVE@#To investigate the association between the expression level of platelet-activating factor acetylhydrolase 1B3 (PAFAH1B3 ) gene in bone marrow CD138+ cells of patients with multiple myeloma (MM) treated with autologous hematopoietic stem cell transplantation (AHSCT) and the prognosis within 2 years.@*METHODS@#147 MM patients treated with AHSCT in The First and The Second Affiliated Hospital of Nantong University from May 2014 to May 2019 were included in the study. Expression level of PAFAH1B3 mRNA in bone marrow CD138+ cells of the patients was detected. Patients with disease progression or death during 2 years of follow-up were included in progression group, and the rest were included in good prognosis group. After comparing the clinical data and PAFAH1B3 mRNA expression levels of the two groups, the patients were divided into high PAFAH1B3 expression group and low PAFAH1B3 expression group based on the median PAFAH1B3 mRNA expression level of the enrolled patients. Progression-free survival rate (PFSR) between the two groups was compared by the Kaplan-Meier method. The related factors of prognosis within 2 years were analyzed by univariate analysis and multivariate COX regression analysis.@*RESULTS@#At the end of follow-up, there were 13 patients lost to follow-up. Finally, 44 patients were included in the progression group and 90 patients were included in the good prognosis group. Age in the progression group was higher than that in the good prognosis group, the proportion of patients with CR+VGPR after transplantation in the progression group was lower than that in the good prognosis group, and there was a statistical difference between two groups in the cases distribution of ISS stage (all P<0.05). PAFAH1B3 mRNA expression level and the proportion of patients with LDH>250U/L in the progression group were higher than those in the good prognosis group, and platelet count in the progression group was lower than that in the good prognosis group (all P<0.05). Compared with the low PAFAH1B3 expression group, the 2-year PFSR of the high PAFAH1B3 expression group was significantly lower (log-rank χ2=8.167, P=0.004). LDH>250U/L (HR=3.389, P=0.010), PAFAH1B3 mRNA expression (HR=50.561, P=0.001) and ISS stage Ⅲ(HR=1.000, P=0.003) were independent risk factors for prognosis in MM patients, and ISS stage Ⅰ (HR=0.133, P=0.001) was independent protective factor.@*CONCLUSION@#The expression level of PAFAH1B3 mRNA in bone marrow CD138+ cells is related to the prognosis of MM patients treated with AHSCT, and detecting PAFAH1B3 mRNA expression can bring some information for predicting PFSR and prognostic stratification of patients.

CYP1B1-derived epoxides modulate the TRPA1 channel in chronic pain

Pain is often debilitating, and current treatments are neither universally efficacious nor without risks. Transient receptor potential (TRP) ion channels offer alternative targets for pain relief, but little is known about the regulation or identities of endogenous TRP ligands that affect inflammation and pain. Here, transcriptomic and targeted lipidomic analysis of damaged tissue from the mouse spinal nerve ligation (SNL)-induced chronic pain model revealed a time-dependent increase in Cyp1b1 mRNA and a concurrent accumulation of 8,9-epoxyeicosatrienoic acid (EET) and 19,20-EpDPA post injury. Production of 8,9-EET and 19,20-EpDPA by human/mouse CYP1B1 was confirmed in vitro, and 8,9-EET and 19,20-EpDPA selectively and dose-dependently sensitized and activated TRPA1 in overexpressing HEK-293 cells and Trpa1-expressing/AITC-responsive cultured mouse peptidergic dorsal root ganglia (DRG) neurons. TRPA1 activation by 8,9-EET and 19,20-EpDPA was attenuated by the antagonist A967079, and mouse TRPA1 was more responsive to 8,9-EET and 19,20-EpDPA than human TRPA1. This latter effect mapped to residues Y933, G939, and S921 of TRPA1. Intra-plantar injection of 19,20-EpDPA induced acute mechanical, but not thermal hypersensitivity in mice, which was also blocked by A967079. Similarly, Cyp1b1-knockout mice displayed a reduced chronic pain phenotype following SNL injury. These data suggest that manipulation of the CYP1B1-oxylipin-TRPA1 axis might have therapeutic benefit.

Role of melatonin receptor 1B gene polymorphism and its effect on the regulation of glucose transport in gestational diabetes mellitus / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Melatonin receptor 1B (MT2, encoded by the MTNR1B gene), a high-affinity receptor for melatonin, is associated with glucose homeostasis including glucose uptake and transport. The rs10830963 variant in the MTNR1B gene is linked to glucose metabolism disorders including gestational diabetes mellitus (GDM); however, the relationship between MT2-mediated melatonin signaling and a high birth weight of GDM infants from maternal glucose abnormality remains poorly understood. This article aims to investigate the relationship between rs10830963 variants and GDM development, as well as the effects of MT2 receptor on glucose uptake and transport in trophoblasts. TaqMan-MGB (minor groove binder) probe quantitative real-time polymerase chain reaction (qPCR) assays were used for rs10930963 genotyping. MT2 expression in the placenta of GDM and normal pregnant women was detected by immunofluorescence, western blot, and qPCR. The relationship between MT2 and glucose transporters (GLUTs) or peroxisome proliferator-activated receptor γ (PPARγ) was established by western blot, and glucose consumption of trophoblasts was measured by a glucose assay kit. The results showed that the genotype and allele frequencies of rs10830963 were significantly different between GDM and normal pregnant women (P<0.05). The fasting, 1-h and 2-h plasma glucose levels of G-allele carriers were significantly higher than those of C-allele carriers (P<0.05). Besides, the protein and messenger RNA (mRNA) expression of MT2 in the placenta of GDM was significantly higher than that of normal pregnant women (P<0.05). Melatonin could stimulate glucose uptake and GLUT4 and PPARγ protein expression in trophoblasts, which could be attenuated by MT2 receptor knockdown. In conclusion, the rs10830963 variant was associated with an increased risk of GDM. The MT2 receptor is essential for melatonin to raise glucose uptake and transport, which may be mediated by PPARγ.

Role of Mitophagy in Myocardial Ischemia/Reperfusion Injury and Chinese Medicine Treatment / 中国结合医学杂志

Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury (MIRI). Moderate mitophagy can remove damaged mitochondria, inhibit excessive reactive oxygen species accumulation, and protect mitochondria from damage. However, excessive enhancement of mitophagy greatly reduces adenosine triphosphate production and energy supply for cell survival, and aggravates cell death. How dysfunctional mitochondria are selectively recognized and engulfed is related to the interaction of adaptors on the mitochondrial membrane, which mainly include phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced kinase 1/Parkin, hypoxia-inducible factor-1 α/Bcl-2 and adenovirus e1b19k Da interacting protein 3, FUN-14 domain containing protein 1 receptor-mediated mitophagy pathway and so on. In this review, the authors briefly summarize the main pathways currently studied on mitophagy and the relationship between mitophagy and MIRI, and incorporate and analyze research data on prevention and treatment of MIRI with Chinese medicine, thereby provide relevant theoretical basis and treatment ideas for clinical prevention of MIRI.

Echinacoside hampers malignant progression of breast cancer MCF-7 cells by modulating AKR1B10/ERK signal transduction / 中国中药杂志

This study analyzes the impact of echinacoside(ECH) in the proliferation, metastasis and adriamycin(ADR) resistance of breast cancer(BC) MCF-7 cells via the modulation of aldo-keto reductase family 1 member 10(AKR1B10)/extracellular signal-regulated kinase(ERK) pathway. The chemical structure of ECH was firstly confirmed. MCF-7 cells were treated with different concentration(0, 10, 20, 40 μg·mL~(-1)) of ECH for 48 h. Western blot was used to analyze expression of AKR1B10/ERK pathway-associated proteins and cell counting kit-8(CCK-8) assay to determine cell viability. MCF-7 cells were collected and classified into control group, ECH group, ECH + Ov-NC group, and ECH + Ov-AKR1B10 group. Then Western blot was employed to analyze the expression of AKR1B10/ERK pathway-associated proteins. CCK-8 and 5-ethynyl-2'-deoxyuridine(EdU) assay were used to examine cell proliferation. Cell migration was appraised with scratch assay, Transwell assay, and Western blot. Eventually, MCF-7 cells were treated with ADR for 48 h to induce ADR resistance. Cell viability was tested by CCK-8 assay and cell apoptosis was estimated based on terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL) assay and Western blot. Based on Protein Data Bank(PDB) and molecular docking, the binding affinity of ECH to AKR1B10 was assessed. Various doses of ECH decreased the expression of AKR1B10/ERK pathway-associated proteins in a dose-dependent manner and declined cell viability compared with the control group. Compared with the control group, 40 μg·mL~(-1) ECH blocked the AKR1B10/ERK pathway in MCF-7 cells and inhibited the proliferation, metastasis and ADR resistance of the cells. Compared with the ECH + Ov-NC group, ECH + Ov-AKR1B10 group showed the recovery of some biological behaviors of MCF-7 cells. ECH also targeted AKR1B10. ECH can inhibit the proliferation, metastasis, and ADR resistance of BC cells by blocking AKR1B10/ERK pathway.

Molecular dynamics simulation of force-regulated interaction between talin and Rap1b / 生物医学工程学杂志

The binding of talin-F0 domain to ras-related protein 1b (Rap1b) plays an important role in the formation of thrombosis. However, since talin is a force-sensitive protein, it remains unclear whether and how force regulates the talin-F0/Rap1b interaction. To explore the effect of force on the binding affinity and the dynamics mechanisms of talin-F0/Rap1b, molecular dynamics simulation was used to observe and compare the changes in functional and conformational information of the complex under different forces. Our results showed that when the complex was subjected to tensile forces, there were at least two dissociation pathways with significantly different mechanical strengths. The key event determining the mechanical strength difference between the two pathways was whether the β4 sheet of the F0 domain was pulled away from the original β1-β4 parallel structure. As the force increased, the talin-F0/Rap1b interaction first strengthened and then weakened, exhibiting the signature of a transition from catch bonds to slip bonds. The mechanical load of 20 pN increased the interaction index of two residue pairs, ASP 54-ARG 41 and GLN 18-THR 65, which resulted in a significant increase in the affinity of the complex. This study predicts the regulatory mechanism of the talin-F0/Rap1b interaction by forces in the intracellular environment and provides novel ideas for the treatment of related diseases and drug development.

The A allele of the rs759853 single nucleotide polymorphism in the AKR1B1 gene confers risk for diabetic kidney disease in patients with type 2 diabetes from a Brazilian population

ABSTRACT Objective: The AKR1B1 gene encodes an enzyme that catalyzes the reduction of glucose into sorbitol. Chronic hyperglycemia in patients with diabetes mellitus (DM) leads to increased AKR1B1 affinity for glucose and, consequently, sorbitol accumulation. Elevated sorbitol increases oxidative stress, which is one of the main pathways related to chronic complications of diabetes, including diabetic kidney disease (DKD). Accordingly, some studies have suggested the rs759853 polymorphism in the AKR1B1 gene is associated with DKD; however, findings are still contradictory. The aim was to investigate the association of the rs759853 polymorphism in the AKR1B1 gene and DKD. Materials and methods: The sample comprised 695 patients with type 2 DM (T2DM) and DKD (cases) and 310 patients with T2DM of more than 10 years' duration, but no DKD (controls). The polymorphism was genotyped by real-time PCR. Results: Allelic and genotype frequencies of this polymorphism did not differ significantly between groups. However, the A/A genotype was associated with risk for DKD after adjustment for gender, triglycerides, BMI, presence of hypertension and diabetic retinopathy, and duration of DM, under both recessive (P = 0.048) and additive (P = 0.037) inheritance models. Conclusion: Our data suggest an association between the AKR1B1 rs759853A/A genotype and risk for DKD in Brazilians T2DM patients.

A case of Coffin-Siris syndrome type 1 due to 6q25.3 deletion / 中华神经科杂志

Clinical data and genetic mutation characteristics of a patient with Coffin-Siris syndrome by 6q25.3 deletion were summarized. The child was a 7-year and 6-month old girl who had feeding difficulties, repeated infection, language and motor retardation, low intelligence, laryngeal cartilage dysplasia, thick eyebrows, sparse teeth, hairy back, hyperactivity and aggressive behavior, seizures and ataxia. There was no abnormality in chromosomal karyotype analysis by proband; genomic copy number variant sequencing (CNV-seq) indicated approximately 4.27 Mb heterozygous deletion in chromosome 6q25.3 region, with 17 genes including ARID1B gene, father maternal CNV-seq showing no abnormalities. Trio-whole-exome sequencing showed the proband missed all exons 1-20 of the ARID1B gene, with wild-type parents. The proband had severe clinical symptoms and haplodose insufficiency which was the genetic etiology.

Analysis of solute carrier organic anion transporter family member 1b1 and apolipoprotein E genes in a population from southern Yunnan / 中国基层医药

Objective:To analyze the distribution of solute carrier organic anion transporter family member 1b1 ( SLCO1B1) and apolipoprotein E ( ApoE) genes in a population from southern Yunnan. Methods:The data of 104 patients who received treatment in Southern Central Hospital of Yunnan Province (The First People's Hospital of Honghe State) between May 2019 and June 2020 were collected. The distribution of SLCO1B1 and ApoE genes and their relationship with nationality, sex, and age were analyzed and compared between different regions. Results:The percentage of patients carrying *1a/*1a, *1a/*1b, *1b/*1b, *1a/*15, *1b/*15, five phenotypes of SLCO1B1 gene, in the population from southern Yunnan was 4.81%, 32.69%, 42.31%, 12.50% and 7.69% respectively. Phenotypes *1a/*5, *5/*5, *5/*15 and *15/*15 were not detected. Normal metabolic phenotype of SLCO1B1 accounted for 79.81%, and intermediate metabolic phenotype of SLCO1B1 accounted for 20.19%. Weak metabolic phenotype was not detected. The percentage of patients carrying E2/E2, E2/E3, E3/E3, E3/E4, E4/E4, five phenotypes of ApoE gene in the population from southern Yunnan was 0.96%, 16.35%, 70.19%, 11.54% and 0.96% respectively. E2/E4 phenotype was not detected. The percentage of patients with ApoE protective phenotype, ApoE normal phenotype, and ApoE risk phenotype was 17.31%, 70.19% and 12.50% respectively. The observed polymorphism mutation frequency of SLCO1B1 and ApoE genes was consistent with the Hardy-Weinberg equilibrium ( P > 0.05), suggesting constancy and a population representation. The Fisher test showed that SLCO1B1 gene distribution differed significantly between ethnic minorities and Han nationality in southern Yunnan ( P = 0.013). There was no significant difference in SLCO1B1 gene distribution between different sexes and between different ages (all P > 0.05). There was no significant difference in ApoE gene distribution between ethnic minorities and Han nationality, between different sexes, and between different ages in the population from southern Yunnan (all P > 0.05). Conclusion:SLCO1B1 gene distribution is related to nationality in the population from southern Yunnan, but it is unrelated to sex and age. ApoE gene distribution is unrelated to nationality, sex and age.