Local focal adhesion kinase (FAK) is a non-receptor intracellular tyrosine kinase that plays an important role in tumor initiation, development, metastasis and invasion, and is considered to be an important target for the development of antineoplastic drugs. It has both kinase-dependent and non-kinase-dependent scaffolding functions. However, traditional small molecular inhibitors can only inhibit its kinase-dependent activity, so it is difficult to target the kinase-independent scaffolding function. Therefore, there is an urgent need for novel strategies to enhance FAK targeting to lay the foundation for determining the druggability and discovery of FAK inhibitors. Proteolysis targeting chimera (PROTAC) is a new drug development strategy that can recruit E3 ligase to specifically ubiquitinylate target proteins for degradation through the proteasome system. The unique mechanism of action of the PROTAC system could be used to target and degrade the FAK protein, thus eliminating the scaffolding function of FAK. In this review, FAK protein, the signaling pathway, and small molecule inhibitors are briefly described, and the latest research progress in targeting the degradation of FAK using PROTAC technology is summarized.

OBJECTIVETo examine the effect of docosahexaenoic acid (DHA) deficiency in brain on spatial learning and memory in rats.

METHODSSprague Dawley rats were fed with an n-3 fatty acid deficient diet for two generations to induce DHA depletion in brain. DHA in seven brain regions was analyzed using the gas-liquid chromatography. Morris water maze (MWM) was employed as an assessing index of spatial learning and memory in the n-3 fatty acid deficient adult rats of second generation.

RESULTSFeeding an n-3 deficient diet for two generations depleted DHA differently by 39%-63% in the seven brain regions including cerebellum, medulla, hypothalamus, striatum, hippocampus, cortex and midbrain. The MWM test showed that the n-3 deficient rats took a longer time and swam a longer distance to find the escape platform than the n-3 Adq group.

CONCLUSIONThe spatial learning and memory in adult rats are partially impaired by brain DHA depletion.

Animals ; Brain ; metabolism ; Docosahexaenoic Acids ; metabolism ; Maze Learning ; physiology ; Memory ; physiology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the expression of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in children with tetralogy of Fallot (TOF), and to investigate the role of histone acetylation and acetylation-related enzymes in the pathogenesis of TOF.

METHODSMyocardial tissue samples in the TOF group were obtained from 46 children with TOF who underwent radical operation, and myocardial tissue samples in the control group were obtained from 16 children who suffered accidental deaths and had no cardiac anomalies as shown by autopsy. The acetylation of H3K9, H3K18 and H3K27 was evaluated by immunohistochemistry. The mRNA expression of HATs and HDACs in the myocardium was measured by real-time PCR. The correlation between mRNA expression of HATs and HDACs and histone acetylation was analyzed.

RESULTSCompared with the control group, the TOF group showed significantly increased acetylation of H3K9 (P=0.0165) and significantly decreased acetylation of H3K18 (P=0.0048) and H3K27 (P=0.0084). As to 4 HATs and 6 HDACs, the mRNA expression of EP300 and CBP was significantly higher in the TOF group than in the control group (P=0.025; P=0.017), and there was no significant difference in the mRNA expression of other HATs and HDACs between the two groups. The correlation analysis revealed a positive correlation between H3K9 acetylation and mRNA expression of EP300 (r=0.71, P<0.01) and CBP (r=0.72, P<0.01).

CONCLUSIONSUpregulated mRNA expression of EP300 and CBP may be associated with increased H3K9 acetylation, suggesting that EP300 and CBP might affect cardiac development by regulating H3K9 acetylation.

Acetylation ; E1A-Associated p300 Protein ; genetics ; Female ; Histone Acetyltransferases ; genetics ; Histone Deacetylases ; genetics ; Histones ; metabolism ; Humans ; Infant ; Male ; Myocardium ; metabolism ; Peptide Fragments ; genetics ; RNA, Messenger ; analysis ; Sialoglycoproteins ; genetics ; Tetralogy of Fallot ; metabolism

OBJECTIVETo study the role of cerebrovascular hemodynamic indexes (CVHI) changing in stroke and to provide reference for stroke prevention and risk factor study.

METHODSFrom 2003 to 2004, participants aged 40 years and above in two communities in Fengxian district were recruited by cluster sampling. Risk factors of stroke and CVHI were investigated and checked during baseline investigation. A total of 10 565 individuals completed the survey and met the inclusion criterion. After baseline investigation, the cohort was followed up for stroke occurrence. Relative risk (RR) of CVHI and common risk factors were estimated by cohort study design.

RESULTSAge of the cohort was (56.2 ± 11.4) years. 4444 (42.1%) were males and 6121 (57.9%) were females. Total follow-up duration was 67 885.7 person-years. A total of 195 stroke cases occurred and incidence density of stroke was 287.2 per 100 000 person-years. Stroke incidence in exposure groups of hypertension, heart disease and alcohol drinking was 3.47% (108/3118), 2.96% (21/710) and 2.50% (47/1882), respectively. The incidence in corresponding non-exposure group was 1.17% (87/7448), 1.77% (174/9855) and 1.70% (148/8683) respectively. There was significant difference between 2 groups (χ(2) value was 62.72, 4.56 and 4.94, respectively, P < 0.05). Stroke incidence in CVHI score < 25, 25 - 49, 50 - 74 and ≥ 75 groups was 9.12% (59/647), 5.68% (44/775), 2.52% (39/1545) and 0.72% (53/7403)(χ(2)trend = 273.57, P < 0.05), respectively. Incidence of stroke in 40 - 49, 50 - 59, 60 - 69, ≥ 70 years age group was 0.22% (8/3565), 1.28% (43/3357), 2.71% (50/1848) and 5.88% (94/1600) (χ(2)trend = 181.48, P < 0.05), respectively. Multiple Cox regression analysis indicated that RR (95%CI) value of hypertension and cigarette smoking was 1.40(1.02 - 1.92) and 1.59(1.19 - 2.12), respectively when comparing with non-exposure group. RR (95%CI) value in CVHI score < 25, 25 - 49 and 50 - 74 points group were 6.15 (4.08 - 9.26), 4.55 (2.98 - 6.96) and 2.68 (1.75 - 4.09), respectively when comparing with the score ≥ 75 points group. RR (95%CI) value in age 50 - 59, 60 - 69 and ≥ 70 years group was 4.61 (2.16 - 9.82), 7.81 (3.67 - 16.60) and 13.49(6.44 - 28.24), respectively when comparing with below 40 years group.

CONCLUSIONCVHI score is the strong independent predictive factor and hypertension, cigarette smoking and age are the independent risk factors of stroke.

Aged ; Brain ; physiopathology ; Cohort Studies ; Female ; Hemodynamics ; Humans ; Male ; Middle Aged ; Risk Factors ; Stroke ; epidemiology ; etiology ; physiopathology

OBJECTIVETo study the changes of amino acids in cerebral spinal fluid (CSF) in children with spastic or athetotic cerebral palsy (CP) by examining CSF levels of glutamic acid (Glu), gamma-aminobutyric acid (GABA) and aspartate (ASP).

METHODSCSF samples were obtained from 13 children with spastic CP, from 14 children with athetotic CP, and from 10 children without central nervous system and infectious diseases (control group). CSF levels of Glu, GABA and ASP were determined by high-performance liquid chromatography.

RESULTSCSF levels of GABA, ASP and Glu in the control group were 13.04+/-2.19, 10.21+/-0.45 and 8.41+/-2.26 micromol/L, respectively. Compared with the control group, CSF GABA levels in the spastic and the athetotic CP groups (8.02+/-2.03 and 10.01+/-2.68 micromol/L respectively) significantly decreased (P<0.01), whereas CSF levels of Glu (20.99+/-8.15 and 28.77+/-17.62 micromol/L respectively) and Asp (13.53+/-3.93 and 14.02+/-2.88 micromol/L respectively) in the spastic and the athetotic CP groups significantly increased (P<0.01). There were statistical differences in the GABA level between the spastic and the athetotic CP groups (P<0.05). In children with spastic CPCSF Glu level was positively correlated to muscle tension.

CONCLUSIONSCSF excitatory amino acid levels increased, while CSF inhibitory amino acid levels decreased in children with CP. There were differences for CSF amino acid levels in different types of CP. The changes of amino acid levels may contribute to the pathogenesis of CP.

Amino Acids ; cerebrospinal fluid ; Cerebral Palsy ; cerebrospinal fluid ; physiopathology ; Child, Preschool ; Chromatography, High Pressure Liquid ; Female ; Humans ; Male ; Muscle Tonus

BACKGROUND: Postoperative anticoagulant therapy after hip and knee arthroplasties has been included in the perioperative management guidelines. However, the application of anticoagulant drugs accompanies with the risk of bleeding. Routine coagulation tests provide limited information about the quality of clots because they identify only the first stage of clotting, while thrombelastography provides a comprehensive assessment of coagulation function. But its practicality remains controversial and the research for bleeding after joint replacement is little reported. OBJECTIVE: To explore the distribution of thrombelastography parameters (time to initial fibrin formation, clotting time, α angle, and maximum amplitude) and to analyze the correlation of the four parameters with postoperative blood loss, thereby providing guidance for improving the safety and effectiveness of anticoagulant therapy. METHODS: Totally 148 patients with detection of thrombelastogram after arthroplasty from August 2015 to March 2017 in Sun Yat-sen Memorial Hospital, Sun Yat-sen University were enrolled, including 76 cases of total hip arthroplasty and 72 cases of total knee arthroplasty. Thrombelastography data were collected on day 1 postoperatively, and the perioperative blood loss was calculated. Structural equation modeling of each group was constructed to investigate the relationship of four parameters and total blood loss. RESULTS AND CONCLUSION: (1) In the structural equation modeling of hip and knee arthroplasties, the root mean square error of approximation was less than 0.08, goodness-of-fit index, adjusted goodness-of-fit index, normed fit index and comparative fit index was all higher than 0.9, and Parsi-mony goodness-of-fit index was less than 2, so the theoretical model was matched with the data. (2) There was a correlation of postoperative hemorrhage with time to initial fibrin formation, clotting time, α angle, and maximum amplitude. (3) That is to say, thrombelastogram can be used as an efficient tool in predicting bleeding after hip and knee arthroplasties. Future study based on this research will further verify the correlation and provide more information for its clinical practice.

Intrauterine infection is an important cause of some birth defects worldwide. The most common pathogens include rubella virus, cytomegaloviurs, ureaplasma urealyticum, toxoplasma, etc. General information about these pathogens in epidemiology, consequence of birth defects, and the possible mechanisms in the progress of birth defects, and the interventions to prevent or treat these pathogens' infections are described. The infections caused by rubella virus, cytomegaloviurs, ureaplasma urealyticum, toxoplasma, etc. are common, yet they are proved to be fatal during the pregnant period, especially during the first trimester. These infections may cause sterility, abortion, stillbirth, low birth weight, and affect multiple organs that may induce loss of hearing and vision, even fetal deformity and the long-term effects. These pathogens' infections may influence the microenvironment of placenta, including levels of enzymes and cytokines, and affect chondriosome that may induce the progress of birth defect. Early diagnosis of infections during pregnancy should be strengthened. There are still many things to be settled, such as the molecular mechanisms of birth defects, the effective vaccines to certain pathogens. Birth defect researches in terms of etiology and the development of applicable and sensitive pathogen detection technology and methods are imperative.
Animals ; Congenital Abnormalities ; etiology ; Female ; Humans ; Infant, Newborn ; Placenta Diseases ; complications ; Pregnancy ; Pregnancy Complications, Infectious ; Pregnancy Outcome ; Pregnancy Trimester, First ; Rubella ; complications ; Toxoplasma ; pathogenicity ; Ureaplasma urealyticum ; pathogenicity

Objective To summarize the epidemiological and clinical features of infectious diseases of the central nervous system(CNS)by a single-center analysis.Methods A retrospective analysis was conducted on the data of 1247 cases of CNS infectious diseases diagnosed and treated in the First Medical Center of PLA General Hospital from 2001 to 2020.Results The data for this group of CNS infectious diseases by disease type in descending order of number of cases were viruses 743(59.6％),Mycobacterium tuberculosis 249(20.0％),other bacteria 150(12.0％),fungi 68(5.5％),parasites 18(1.4％),Treponema pallidum 18(1.4％)and rickettsia 1(0.1％).The number of cases increased by 177 cases(33.1％)in the latter 10 years compared to the previous 10 years(P<0.05).No significant difference in seasonal distribution pattern of data between disease types(P>0.05).Male to female ratio is 1.87︰1,mostly under 60 years of age.Viruses are more likely to infect students,most often at university/college level and above,farmers are overrepresented among bacteria and Mycobacterium tuberculosis,and more infections of Treponema pallidum in workers.CNS infectious diseases are characterized by fever,headache and signs of meningeal irritation,with the adductor nerve being the more commonly involved cranial nerve.Matagenomic next-generation sequencing improves clinical diagnostic capabilities.The median hospital days for CNS infectious diseases are 18.00(11.00,27.00)and median hospital costs are ￥29,500(￥16,000,￥59,200).The mortality rate from CNS infectious diseases is 1.6％.Conclusions The incidence of CNS infectious diseases is increasing last ten years,with complex clinical presentation,severe symptoms and poor prognosis.Early and accurate diagnosis and standardized clinical treatment can significantly reduce the morbidity and mortality rate and ease the burden of disease.

Coronary Angiography ; Coronary Vessel Anomalies ; diagnostic imaging ; therapy ; Embolization, Therapeutic ; methods ; Fistula ; congenital ; diagnostic imaging ; therapy ; Heart Ventricles ; abnormalities ; diagnostic imaging ; Humans ; Male ; Middle Aged

OBJECTIVETo investigate the association between rs9722 polymorphisms in the S100B gene and hand, foot and mouth disease (HFMD) caused by enterovirus 71.

METHODSA total of 124 HFMD children with enterovirus 71 infection were enrolled as subjects, and 56 healthy children were enrolled as control group. The rs9722 polymorphisms in the S100B gene were detected for both groups, and the serum level of S100B protein was measured for 74 HFMD children.

RESULTSThe rs9722 locus of the S100B gene had three genotypes, CC, CT, and TT, and the genotype frequencies were in accordance with Hardy-Weinberg equilibrium. Compared with the control group, the HFMD group had significant increases in the frequencies of TT genotype and T allele (P<0.01). Children with severe HFMD caused by enterovirus 71 infection had significantly higher frequencies of TT genotype and T allele than those with moderate or mild HFMD (P<0.05). Compared with the cured patients, the patients with poor prognosis had significant increases in the frequencies of TT genotype and T allele in the rs9722 locus of the S100B gene (P<0.05). Among the 74 children with HFMD, the children with TT genotype had the highest serum level of S100B protein, and those with CC genotype had the lowest level (P<0.01).

CONCLUSIONST allele in the rs9722 locus of the S100B gene might be a risk factor for severe HFMD caused by enterovirus 71 infection.

Child, Preschool ; Enterovirus A, Human ; Enterovirus Infections ; complications ; Female ; Genotype ; Hand, Foot and Mouth Disease ; etiology ; genetics ; Humans ; Infant ; Male ; Polymorphism, Genetic ; S100 Calcium Binding Protein beta Subunit ; genetics