A Theoretical Analysis of the Differential Chemical Reaction Results Caused by Chirality Induction.

The theory of electron spin has been proposed for a century, but the study of quantum effects in biological molecules is still in its infancy. Chirality-induced spin selectivity (CISS) is a very modern theory that can explain many biochemical phenomena. In this paper, we propose a new theoretical model based on CISS theory and quantum chemistry theory, which can well explain the theoretical explanation of the chiral selectivity of chiral proteins. Moreover, this theory can predict the spin state of corresponding chiral molecules. Taking the L-DOPA and AADC enzymes as examples, this theoretical model elucidates the AADC enzyme's chiral catalysis selectivity and successfully predicts the spin state of L-DOPA and D-DOPA's valence electrons.

Association between dosing of spironolactone and outcomes in heart failure with preserved ejection fraction patients combined with chronic kidney disease------Balance of efficacy and risk.

Aims: Few studies have compared the association between dosing of spironolactone and outcomes in patients with heart failure with preserved ejection fraction (HFpEF), and whether spironolactone dose could significantly affect the prognosis of HFpEF patients combined with chronic kidney disease (CKD) remains unclear. Our aim was to directly compare 'high vs. low' doses of spironolactone in an attempt to find a benefit-risk-balanced point, and infer an adequate dose for HFpEF with CKD patients. Methods: Overall, 4,321 symptomatic heart failure inpatients were initially screened from January 2013 to December 2019, and all enrolled patients were followed-up for 36 months; After including patients who meet the diagnostic criteria of HFpEF and CKD with ejection fraction > 45% and estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, a total of 387 patients was selected. Primary outcome was a composite of all-cause death, heart failure (HF) hospitalization and non-fatal stroke. The key safety outcome was hyperkalemia rates during the follow-up period. Results: The primary outcome event rates in patients with or without spironolactone were 12.74 and 21.45 per 100 person-years, respectively. Compared with patients not taking spironolactone, the adjusted hazard ratio (HR) [95% confidence interval (CI)] was 0.55 (0.38-0.79) with spironolactone group for primary outcomes. After grouped by the daily dose of spironolactone, low-dose group (≤ 40 mg) was associated with lower relative risk for the primary efficacy outcome [adjusted HR (95% CI) was 0.43 (0.23-0.81), 0.50 (0.33-0.76) and 0.74 (0.36-2.79) with < 40 mg, 40 mg and >40 mg, respectively]. During 3-year follow-up, the risk for hyperkalemia was amplified in the higher dose group (>40 mg) while showed no significant difference compared with low dose group (p = 0.425). Conclusion: HFpEF with CKD patients using spironolactone had lower risk of adverse cardiovascular outcomes. And the use of low-dose spironolactone (≤ 40 mg) showed the best efficacy and safety, therefore we may recommend ≤ 40 mg as the optimal initial dose for these patients. However, this was a relatively small sample size, retrospective study, and further adequately powered randomized trials are needed to verify these results.

Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signaling Pathways.

We have previously developed a cocktail of nine small molecules to convert human fetal astrocytes into neurons, but a nine-molecule recipe is difficult for clinical applications. Here, we identify a chemical formula with only three to four small molecules for astrocyte-to-neuron conversion. We demonstrate that modulation of three to four signaling pathways among Notch, glycogen synthase kinase 3, transforming growth factor ß, and bone morphogenetic protein pathways is sufficient to change an astrocyte into a neuron. The chemically converted human neurons can survive >7 months in culture, fire repetitive action potentials, and display robust synaptic burst activities. Interestingly, cortical astrocyte-converted neurons are mostly glutamatergic, while midbrain astrocyte-converted neurons can yield some GABAergic neurons in addition to glutamatergic neurons. When administered in vivo through intracranial or intraperitoneal injection, the four-drug combination can significantly increase adult hippocampal neurogenesis. Together, human fetal astrocytes can be chemically converted into functional neurons using three to four small molecules, bringing us one step forward for developing future drug therapy.

Coding mutations in NUS1 contribute to Parkinson's disease.

Whole-exome sequencing has been successful in identifying genetic factors contributing to familial or sporadic Parkinson's disease (PD). However, this approach has not been applied to explore the impact of de novo mutations on PD pathogenesis. Here, we sequenced the exomes of 39 early onset patients, their parents, and 20 unaffected siblings to investigate the effects of de novo mutations on PD. We identified 12 genes with de novo mutations (MAD1L1, NUP98, PPP2CB, PKMYT1, TRIM24, CEP131, CTTNBP2, NUS1, SMPD3, MGRN1, IFI35, and RUSC2), which could be functionally relevant to PD pathogenesis. Further analyses of two independent case-control cohorts (1,852 patients and 1,565 controls in one cohort and 3,237 patients and 2,858 controls in the other) revealed that NUS1 harbors significantly more rare nonsynonymous variants (P = 1.01E-5, odds ratio = 11.3) in PD patients than in controls. Functional studies in Drosophila demonstrated that the loss of NUS1 could reduce the climbing ability, dopamine level, and number of dopaminergic neurons in 30-day-old flies and could induce apoptosis in fly brain. Together, our data suggest that de novo mutations could contribute to early onset PD pathogenesis and identify NUS1 as a candidate gene for PD.

Notch signaling mediated by TGF-ß/Smad pathway in concanavalin A-induced liver fibrosis in rats.

AIM: To explore the exact interaction between Notch and transforming growth factor (TGF)-ß signaling in liver fibrosis. METHODS: We established a rat model of liver fibrosis induced by concanavalin A. Peripheral blood mononuclear cells (PBMCs) were isolated from the modeled rats, and cultured with γ-secretase inhibitor DAPT and TGF-ß inhibitor for 24 h. The mRNA levels of Notch and TGF-ß signaling were detected by quantitative real-time polymerase chain reaction. Expression of Notch and TGF-ß proteins was analyzed by western blotting. RESULTS: Compared to control rats, Notch and TGF-ß signaling was activated in PBMCs of model rats. Administration of DAPT and TGF-ß inhibitor suppressed Notch and TGF-ß signal transducer in PBMCs of model rats. DAPT reduced mRNA and protein expression of TGF-ß signaling, such as TGF-ß1 and Smad3. TGF-ß inhibitor also downregulated Notch1, Hes1 and Hes5, and mRNA and protein expression of the Notch signaling pathway. CONCLUSION: Notch and TGF-ß signaling play a role in liver fibrosis. TGF-ß signaling upregulates Notch signaling, which promotes TGF-ß signaling.

Employment and financial burden of families with preschool children diagnosed with autism spectrum disorders in urban China: results from a descriptive study.

BACKGROUND: Autism spectrum disorder (ASD) affects many aspects of family life, such as social and economic burden. Little investigation of this phenomenon has been carried out in China. We designed this study to evaluate the employment and financial burdens of families with ASD-diagnosed preschoolers. METHODS: Four hundred and fifty-nine nuclear families of children with ASD, 418 with some other disability (OD) and 424 with typically developing (TD) children were recruited for this study. Employment and financial burdens of families were evaluated using a structured questionnaire; logistic regression was used to examine differences in job change measures by group, and ordinal logistic regression was used to investigate the association between household income and group. RESULTS: Fifty-eight percent of families with ASD children and 19% of families with OD children reported that childcare problems had greatly affected their employment decisions, compared with 9% of families with TD children (p < 0.001). Age of child, parental education and parental age notwithstanding, having a child with ASD and having a child with OD were both associated with increased odds of reporting that childcare greatly interfered with employment (ASD, OR: 15.936; OD, OR: 2.502; all p < 0.001) and decreased the odds of living in a higher-income household (ASD, estimate = -1.271; OD, estimate = -0.569; all p < 0.001). The average loss of annual income associated with having a child with ASD was Chinese RenMinBi (RMB) 44,077 ($7,226), compared with RMB 20,788 ($3,408) for families of OD children. CONCLUSIONS: ASD is associated with severe employment and financial burdens, much more than for OD, in families with preschool children.

Fasudil hydrochloride protects neurons in rat hippocampal CA1 region through inhibiting GluR6-MLK3-JNKs signal pathway.

Fasudil hydrochloride (FH), a Rho kinase (ROCK) inhibitor, has been reported to prevent cerebral ischemia in vivo from increasing cerebral blood flow and inhibiting inflammatory responses. However, it is uncertain by what mechanism a ROCK inhibitor can directly protect neurons against ischemic damage. The present study was designed to evaluate whether FH decreased the increased phosphorylation of glutamate receptor 6 (GluR6) and its downstream in GluR6-MLK3-JNKs signal transduction pathway following global transient cerebral ischemia, as a result of protecting against neuronal apoptosis and death. Transient cerebral ischemia was induced by the Pulsinelli-Brierley four-vessel occlusion method. FH (15 mg/kg) was administered to rats by intraperitoneal injection 30 min before ischemia. The phosphorylation and protein expression of GluR6 at 6 h during reperfusion were detected using immunoprecipitation and immunoblotting analysis. The phosphorylation and protein expression of Mixed lineage kinase 3 (MLK3) at ischemia/reperfusion (I/R) 6 h and c-Jun N-terminal kinase (JNK) at I/R 3 d were detected using immunoblotting analysis, respectively. The same method was used to detect the expression of caspase-3 at I/R 6 h. Furthermore, we also use TUNEL staining and Cresyl violet staining to examine the survival neurons in rat hippocampal CA1 regions after 3 and 5 d reperfusion, respectively. Our study indicated that FH could inhibit the increased phosphorylation of GluR6 and MLK3 and the expression of caspase-3 at peaked 6 h of reperfusion and the phosphorylation of JNK (3 d) (p < 0.5). The results of TUNEL staining and Cresyl violet showed that the number of surviving pyramidal neurons in rats hippocampal CA1 subfield increased markedly in FH-treated rats compared with ischemic groups after 3 or 5 d of reperfusion following ischemia (p < 0.5). These results suggested that FH, as a ROCK inhibitor, may be partly responsible for its protective effects against such damage by taking part in GluR6-MLK3-JNKs signaling pathway which modulates ischemic damage. Taken together, this is the first study investigating Rho and ROCK as the upstream of GluR6 taking part in GluR6-MLK3-JNKs signal transduction pathway following cerebral ischemia.

Assembly of the FKBP51-PHLPP2-AKT signaling complex in cerebral ischemia/reperfusion injury in rats.

The imbalance of cell pro-death and pro-survival signaling pathways determines the neuronal fate during cerebral ischemia/reperfusion (I/R) injury. However, the biological mechanisms regulating the balance between activation of the pro-death or the pro-survival signaling pathways remain unclear. In this study, a rat model of I/R injury was established using four-vessel occlusion followed by different times of reperfusion. I/R injury did not affect the level of FK506 binding protein 51 (FKBP51), PH domain and leucine rich repeat protein phosphatases (PHLPP)-2, and AKT, but induced assembly of the FKBP51-PHLPP2-AKT signaling complex, as indicated by the enhancement of interactions among these compounds following reperfusion. Using an antisense oligonucleotide, PHLPP2 expression was effectively inhibited. Critically, the inhibition of PHLPP2 prohibited the interactions of FKBP51, PHLPP2 and AKT, reversed the decrease of p-AKT expression and increased the expression of p-JNKs and p-c-Jun elicited by I/R injury. In addition, PHLPP2 inhibition reversed I/R-injury-induced Caspase-3 cleavage and loss of pyramid neurons in the CA1 region of hippocampus. The results of the current study indicate that the assembly of the FKBP51-PHLPP2-AKT signaling complex plays a critical role in mediating cell death in I/R injury. The inhibition of PHLPP2 via antisense oligonucleotide treatment may be an effective method to prohibit the assembly of the FKBP51-PHLPP-AKT signaling complex, thus balancing the cell pro-survival and pro-death signaling pathways ultimately mitigating cell death in I/R injury.

Prevalence of systemic lupus erythematosus and risk factors in rural areas of Anhui Province.

Systemic lupus erythematosus (SLE) is a severe complex rheumatic disease, but good estimate of its prevalence and risk factors is lacking in China. The aim of the study was to explore the prevalence of SLE and risk factors in rural areas of Anhui Province of China. Eleven counties were randomly selected in Anhui Province, and then, 15% of the villages in selected counties were randomly sampled as study sites. Patients with SLE were identified through two phases. Based on the cases identified, a population-based case-control study was designed to examine risk factors associated with SLE. A total of 1,253,832 individuals and identified 471 SLE cases were surveyed. Crude and age-standardized prevalence were estimated at 37.56 and 36.03 per 100,000 persons, respectively. Gender difference in the prevalence of SLE was significant (P = 4.62 × 10(-76)), and the age-standardized prevalence was 6.17 for males and 67.78 for females per 100,000 persons. The distribution of SLE prevalence was significant by age group (P = 1.78 × 10(-53)), and the peak prevalence was observed at 40-50 years. Multiple environmental factors were associated with SLE, including birth conditions, sweet food, cooking oil, taste, fruit consumption, sunlight exposure, quality of sleep, physical activities, drinking water, residence, negative life events, hepatitis B vaccine, age of menarche, and age at birth of first child (P < 0.05). Our large population-based epidemiological survey estimated the prevalence of SLE at 37.56 per 100,000 persons. Multiple environmental factors were associated with the development of SLE.

EZH2 genetic variants affect risk of gastric cancer in the Chinese Han population.

Enhancer of zeste 2 (EZH2) gene encodes a histone methyltransferase that constitutes the catalytic component of the polycomb repressive complex-2 (PRC2) to initiate epigenetic silencing of genes. It is reported that the expression level of EZH2 in gastric cancer tissue was highly correlated with tumor progression, however, whether EZH2 genetic variants were associated with the risk of gastric cancer remains yet unknown. In this study, we conducted a genotyping analysis for EZH2 in 311 cases of gastric cancer and 425 controls from the Chinese Han population. We found five single nucleotide polymorphisms (SNP; rs12670401, rs6464926, rs2072407, rs734005, and rs734004) of EZH2 gene were significantly associated with the risk of gastric cancer. Of which, the rs12670401 with the minor allele C and rs6464926 with the minor allele T revealed strong associations with increased gastric cancer risk [P = 0.009, adjusted odds ratio (aOR) = 1.327, 95% CI = 1.075-1.683 and P = 0.012, aOR = 1.310, 95% CI = 1.059-1.619]. The other three SNPs, rs2072407, rs734005, and rs734004 contributed to significantly reduced risk of gastric cancer (P = 0.033, aOR = 0.787, 95% CI = 0.633-0.981, P = 0.045, aOR = 0.799, 95% CI = 0.642-0.995 and P = 0.048, aOR = 0.803, 95% CI = 0.645-0.999), respectively. We further found that rs12670401 and rs6464926 were in a strong LD while rs2072407, rs734005, and rs734004 were in another. Haplotype analysis of the five SNPs showed that haplotype CCTCT reduced the risk of gastric cancer (P = 0.031 and aOR = 0.784), while haplotype GTCTC significantly elevated the risk of gastric cancer (P = 0.011 and aOR = 1.310). We concluded that EZH2 variants were significantly associated with gastric cancer risk. Our results for the first time provided new insight into susceptibility factors of EZH2 gene variants in carcinogenesis of gastric cancer of the Chinese Han population.

TNIP1/ANXA6 and CSMD1 variants interacting with cigarette smoking, alcohol intake affect risk of psoriasis.

BACKGROUND: Psoriasis is a common multi-factorial skin disease, in which gene-gene and gene-environment interactions may affect the onset, manifestation and clinical course. OBJECTIVE: To investigate the underlying gene-environment interaction among several established susceptibility genes, cigarette smoking and alcohol intake. METHODS: Using a two-stage case-control design, we searched for pairwise interactions between cigarette smoking and alcohol intake respectively with 9 single nucleotide polymorphisms (SNPs) at ERAP1, PTTG1, CSMD1, GJB2, SERPINB8, ZNF816A and TNIP1/ANXA6 that have been associated with risk for psoriasis in 7,223 subjects. Multiple logistic regression analysis was used for data analysis. RESULTS: Significant interactions were found for alcohol intake with rs3762999 (p=0.0257) and rs999556 (p=0.0071) at TNIP/ANXA6; and for cigarette smoking with rs7007032 (p=0.0023) and rs10088247 (p=0.0023) at CSMD1. CONCLUSION: This study provides empirical evidence for the gene-environment interactions between TNIP1/ANXA6 and alcohol use, CSMD1 and cigarette smoking, highlighting the importance of gene-environment interactions in the pathogenesis of psoriasis.

[Effects of sodium aescinate on the apoptosis-related genes in lung injury induced by intestinal ischemia reperfusion in rats].

OBJECTIVE: To investigate the relationship between apoptosis-related genes and lung injury induced by intestinal ischemia reperfusion and to explore the effects and its possible mechanism of sodium aescinate. METHODS: Rat model of intestinal I/R injury was established with clamping of the superior mesenteric artery for 60 min and then clamping was relieved for 60 min. Twenty-four SD rats were randomly divided into three groups with eight rats in each: sham group, intestinal ischemia/reperfusion group (I/R group) and sodium aescinate group (SA + I/R group). Lung wet/dry weight ratio, lung coefficient and Superoxide dismutase (SOD), malondialdehyde (MDA) in plasma and lung tissue were measured, as well as the expression levels of Bcl-2 and Bax proteins in lung tissue were examined using immunohistochemical method. RESULTS: Compared with sham group, lung wet/dry weight ratio, lung coefficient and MDA in plasma and lung tissue were significantly increased, and while the activity of SOD in plasma and lung tissue were decreased significantly in I/R group. At the same time, the protein expression level of Bcl-2 and Bax were significantly increased. But Bax protein expression was much greater than that of Bcl-2, the ratio of Bcl-2 to Bax was decreased significantly in I/R group than that in sham group. Compared with I/R group, lung wet/dry weight ratio, lung coefficient and MDA in plasma and lung tissue were significantly decreased, and while the activity of SOD in serum and lung tissue were significantly increased in SA + I/R group. At the same time, Bax protein expression was significantly decreased, both Bcl-2 protein expression and the ratio of Bcl-2 to Bax were significantly increased in SA + I/R group than that in I/R group. CONCLUSION: Lung injury induced by intestinal ischemia reperfusion is correlated with abnormal expression levels of Bcl-2 and Bax protein which is caused by oxidative injury. Sodium aescinate can protect the lung injury induced by intestinal ischemia/reperfusion (I/R), which may be mediated by inhibiting lipid peroxidation, upregulating Bcl-2 gene protein expression, improving the ratio of Bcl-2/ Bax to inhibit lung apoptosis.

Psoriasis regression analysis of MHC loci identifies shared genetic variants with vitiligo.

Psoriasis is a common inflammatory skin disease with genetic components of both immune system and the epidermis. PSOR1 locus (6q21) has been strongly associated with psoriasis; however, it is difficult to identify additional independent association due to strong linkage disequilibrium in the MHC region. We performed stepwise regression analyses of more than 3,000 SNPs in the MHC region genotyped using Human 610-Quad (Illumina) in 1,139 cases with psoriasis and 1,132 controls of Han Chinese population to search for additional independent association. With four regression models obtained, two SNPs rs9468925 in HLA-C/HLA-B and rs2858881 in HLA-DQA2 were repeatedly selected in all models, suggesting that multiple loci outside PSOR1 locus were associated with psoriasis. More importantly we find that rs9468925 in HLA-C/HLA-B is associated with both psoriasis and vitiligo, providing first important evidence that two major skin diseases share a common genetic locus in the MHC, and a basis for elucidating the molecular mechanism of skin disorders.

Variants in MHC, LCE and IL12B have epistatic effects on psoriasis risk in Chinese population.

BACKGROUND: Psoriasis has long been considered as a complex disease, and gene-gene or gene-environment interactions may jointly influence the etiology for psoriasis. OBJECTIVE: We evaluated the associations of single nucleotide polymorphisms (SNPs) in MHC region, and determined the epistasis and combined effects of MHC locus and IL12B, LCE on risk for psoriasis. METHODS: We genotyped SNP rs1265181 (MHC) in 5067 cases and 6404 controls, combining with the prior GWAS data (1139 cases and 1132 controls), we explored the genetic interaction among MHC locus, LCE and IL12B by using logistic regression analysis. We evaluated the combined effects of MHC locus and two non-MHC loci in the combined sample of 6206 cases and 7536 controls. RESULTS: Extremely high significance of association was detected between rs1265181 and psoriasis (p combined < 10E--300, OR = 16.52, 95% CI: 15.28-18.44). We observed significant interactions between MHC and LCE (p = 0.0016) and between MHC and IL12B (p = 0.0036). The risk increased some 26-fold in individuals with risk alleles in both MHC and LCE as compared with those without risk alleles, and individual carrying risk alleles of MHC and IL12B has around 36-fold higher risk of psoriasis than those with protective alleles. CONCLUSIONS: This study provides evidence for the epistatic effects between MHC locus and LCE, IL12B genes. Besides, we suggest that MHC might be the main effect gene on the risk for psoriasis. This data may contribute to our understanding of psoriasis genetic interactions and account for the additional risk of certain patients to develop psoriasis.

Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.

We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).

The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients.

Vitiligo is a common skin and hair depigmentary disorder that results from selective destruction of melanocytes. It occurs in a typical multifactorial, polygenic inheritance. Several studies have indicated that vitiligo is associated with some autoimmune diseases. In this paper we examined 6,516 vitiligo patients including clinical characteristics, familial involvement, and their association with other autoimmune diseases. Compared with sporadic vitiligo probands, familial vitiligo probands have earlier age onset and longer disease duration. The prevalences of four autoimmune diseases namely rheumatoid arthritis, chronic urticaria, alopecia areata and psoriasis, were significantly elevated in generalized vitiligo probands and their first-degree relatives. The prevalences of chronic urticaria, rheumatoid arthritis, psoriasis were much higher in familial generalized vitiligo probands. In addition, the prevalences of diabetes mellitus and asthma were also higher in familial vitiligo probands. These findings indicate that generalized vitiligo may share common genetic aetiologic links with other autoimmune diseases, and the genetic component of familial generalized vitiligo is stronger.

(2E,5E)-2,5-Bis(3,4,5-trimethoxy-benzyl-idene)cyclo-penta-none.

The title compound, C(25)H(28)O(7), was prepared by the base-catalysed reaction of 3,4,5-trimethoxy-benzaldehyde with cyclo-penta-none. The mol-ecule has crystallographic twofold rotation symmetry and adopts an E-configuration about the central olefinic bonds. The two benzene rings and the central cyclo-penta-none ring are almost coplanar [dihedral angle = 4.7 (2)°].

1,5-Dimethyl-4-[(E)-3-phenoxy-benzyl-ideneamino]-2-phenyl-1H-pyrazol-3(2H)-one.

The title Schiff base, C(24)H(21)N(3)O(2), adopts an E configuration with respect to the central C=N bond. The pyrazole ring and the central benzene ring attached to the imino group are almost coplanar. The phenyl ring attached to the pyrazole unit is twisted by 39.3 (2)° with respect to the pyrazole ring plane. The phen-oxy benzene ring makes a dihedral angle of 79.8 (2)° with the central benzene ring.