Testing Genetic Association With Rare Variants in Admixed Populations: Rare Variant Analysis in Admixed Populations

Recent studies suggest that rare variants play an important role in the etiology of many traits. Although a number of methods have been developed for genetic association analysis of rare variants, they all assume a relatively homogeneous population under study. Such an assumption may not be valid for samples collected from admixed populations such as African Americans and Hispanic Americans as there is a great extent of local variation in ancestry in these populations. To ensure valid and more powerful rare variant association tests performed in admixed populations, we have developed a local ancestry-based weighted dosage test, which is able to take into account local ancestry of rare alleles, uncertainties in rare variant imputation when imputed data are included, and the direction of effect that rare variants exert on phenotypic outcome. We used simulated sequence data to show that our proposed test has controlled type I error rates, whereas naïve application of existing rare variants tests and tests that adjust for global ancestry lead to inflated type I error rates. We showed that our test has higher power than tests without proper adjustment of ancestry. We also applied the proposed method to a candidate gene study on low-density lipoprotein cholesterol. Our results suggest that it is important to appropriately control for potential population stratification induced by local ancestry difference in the analysis of rare variants in admixed populations

The Zn(II)2Cys6-Type Transcription Factor ADA-6 Regulates Conidiation, Sexual Development, and Oxidative Stress Response in Neurospora crassa

Conidiation and sexual development are critical for reproduction, dispersal and better-adapted survival in many filamentous fungi. The Neurospora crassa gene ada-6 encodes a Zn(II)2Cys6-type transcription factor, whose deletion resulted in reduced conidial production and female sterility. In this study, we confirmed the positive contribution of ada-6 to conidiation and sexual development by detailed phenotypic characterization of its deletion mutant and the complemented mutant. To understand the regulatory mechanisms of ADA-6 in conidiation and sexual development, transcriptomic profiles generated by RNA-seq from the Δada-6 mutant and wild type during conidiation and sexual development were compared. During conidial development, differential expressed genes (DEGs) between the Δada-6 mutant and wild type are mainly involved in oxidation-reduction process and single-organism metabolic process. Several conidiation related genes are positively regulated by ADA-6, including genes that positively regulate conidiation (fluffy and acon-3), and genes preferentially expressed during conidial development (eas, con-6, con-8, con-10, con-13, pcp-1, and NCU9357), as the expression of these genes were lower in the Δada-6 mutant compared to wild type during conidial development. Phenotypic observation of deletion mutants for other genes with unknown function down-regulated by ada-6 deletion revealed that deletion mutants for four genes (NCU00929, NCU05260, NCU00116, and NCU04813) produced less conidia than wild type. Deletion of ada-6 resulted in female sterility, which might be due to that ADA-6 affects oxidation-reduction process and transmembrane transport process, and positively regulates the transcription of pre-2, poi-2, and NCU05832, three key genes participating in sexual development. In both conidiation and the sexual development process, ADA-6 regulates the transcription of cat-3 and other genes participating in reactive oxygen species production according to RNA-seq data, indicating a role of ADA-6 in oxidative stress response. This was further confirmed by the results that deletion of ada-6 led to hypersensitivity to oxidants H2O2 and menadione. Together, these results proved that ADA-6, as a global regulator, plays a crucial role in conidiation, sexual development, and oxidative stress response of N. crassa

Review Article Advances in the Treatment of Ischemic Diseases by Mesenchymal Stem Cells

Ischemic diseases are a group of diseases, including ischemic cerebrovascular disease, ischemic cardiomyopathy (ICM), and diabetic foot as well as other diseases which are becoming a leading cause of morbidity and mortality in the whole world. Mesenchymal stem cells (MSCs) have been used to treat a variety of ischemic diseases in animal models and clinical trials. Lots of recent publications demonstrated that MSCs therapy was safe and relieved symptoms in patients of ischemic disease. However, many factors could influence therapeutic efficacy including route of delivery, MSCs' survival and residential rate in vivo, timing of transplantation, particular microenvironment, and patient's clinical condition. In this review, the current status, therapeutic potential, and the detailed factors of MSCs-based therapeutics for ischemic cerebrovascular disease, ICM, and diabetic foot are presented and discussed. We think that MSCs transplantation would constitute an ideal option for patients with ischemic diseases

Clinicopathological Features and Prognostic Factors of Colorectal Neuroendocrine Neoplasms

Background. Limited research is available regarding colorectal NENs and the prognostic factors remain controversial. Materials and Methods. A total of 68 patients with colorectal NENs were studied retrospectively. Clinical characteristics and prognosis between colonic and rectal NENs were compared. The Cox regression models were used to evaluate the predictive capacity. Results. Of the 68 colorectal NENs patients, 43 (63.2%) had rectal NENs, and 25 (36.8%) had colonic NENs. Compared with rectal NENs, colonic NENs more frequently exhibited larger tumor size (P<0.0001) and distant metastasis (P<0.0001). Colonic NENs had a worse prognosis (P=0.027), with 5-year overall survival rates of 66.7% versus 88.1%. NET, NEC, and MANEC were noted in 61.8%, 23.5%, and 14.7% of patients, respectively. Multivariate analyses revealed that tumor location was not an independent prognostic factor (P=0.081), but tumor size (P=0.037) and pathological classification (P=0.012) were independent prognostic factors. Conclusion. Significant differences exist between colonic and rectal NENs. Multivariate analysis indicated that tumor size and pathological classification were associated with prognosis. Tumor location was not an independent factor. The worse outcome of colonic NENs observed in clinical practice might be due not only to the biological differences, but also to larger tumor size in colonic NENs caused by the delayed diagnosis

Determinants of never-treated status in rural versus urban contexts for individuals with schizophrenia in a population-based study in China

Background A goal of China’s 2012 National Mental Health Law is to improve access to services and decrease urban versus rural disparities in services. However, pre-reform data is needed for objective evaluation of these reforms’ effectiveness. Accordingly, this study compares the pre-reform utilization of medical services for the treatment of schizophrenia in rural and urban communities in China. Methods In a large community-based study in four provinces representing 12% of China’s population conducted from 2001 to 2005, we identified 326 individuals with schizophrenia (78 never treated). Comparing those living in urban (n = 86) versus rural (n = 240) contexts, we used adjusted Poisson regression models to assess the relationship of ‘never treated’ status with family-level factors (marital status, family income, and number of co-resident family members) and illness severity factors (age of onset, symptom severity and functional impairment). Results Despite similar impairments due to symptoms, rural patients were less likely to have received intensive mental health services (i.e., use psychiatric inpatient services), and appeared more likely to be ‘never treated’ or to only have received outpatient care. Among rural patients, only having more than four co-resident family members was independently associated with ‘never-treated’ status (RR = 0.34; 95% CI, 0.12–0.94; p = 0.039). Among urban patients, only older age of onset was independently associated with ‘never-treated’ status (RR = 1.06; 95% CI 1.02–1.10, p = 0.003). Conclusions Identifying differential drivers of service utilization in urban and rural communities is needed before implementing policies to improve the utilization and equity of services and to define metrics of program success

From the 50 Cent Army to Spoof Productions : China’s Internet Censorship as A Way towards Harmonization

China has captured global attention due to its rapid development of Internet infrastructure owing to the introduction of economic reform and marketization over the recent decades. The Internet regulation in China also has its Chinese characteristics. China has long been an authoritarian country whose censorship tradition is deep seated in its historical background and political entity. It has spawned a prosperous Internet culture to ironize the censorship action itself, netizens willingly use “to harmonize” as a synonym of “to censor”. My thesis aims to investigate the complex view of China’s Internet regulation and its Chinese characteristics, and how the censorship is practiced to secure the harmonious socialist society, from both existing research and news media. By investigating existing literature, I unfold the governmental development of the massive cyberspace surveillance and the ways in which the censorship works. On the basis of the theoretical understanding of China’s Internet regulation, my research continues to explore the specific cases of censorship programmes happened in the 2010s represented by news reporting, i.e. anniversaries of the Tiananmen Protest, Occupy the Central, the 50 Cents Army and the banned Internet spoofs, in order to see how China’s Internet censorship was portrayed in the real cases. The research primarily adopts case study and content analysis methodology, carefully identifies novel censorship phenomena appeared during the recent decade to embody the harmonization censorship processes. This paper serves to encapsulate the intricate Chinese Internet regulation system for both Chinese and western scholars, and most significantly, for the young generation of Chinese Internet consumers, to gain an improved understanding of the status quo of China’s cyberspace landscape

Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles

Fungi transcriptionally upregulate expression of azole efflux pumps and ergosterol biosynthesis pathway genes when exposed to antifungal agents that target ergosterol biosynthesis. To date, these transcriptional responses have been shown to be dependent on the presence of the azoles and/or depletion of ergosterol. Using an inducible promoter to regulate Neurospora crassa erg11, which encodes the major azole target, sterol 14α-demethylase, we were able to demonstrate that the CDR4 azole efflux pump can be transcriptionally activated by ergosterol biosynthesis inhibition even in the absence of azoles. By analyzing ergosterol deficient mutants, we demonstrate that the transcriptional responses by cdr4 and, unexpectedly, genes encoding ergosterol biosynthesis enzymes (erg genes) that are responsive to azoles, are not dependent on ergosterol depletion. Nonetheless, deletion of erg2, which encodes C-8 sterol isomerase, also induced expression of cdr4. Deletion of erg2 also induced the expression of erg24, the gene encoding C-14 sterol reductase, but not other tested erg genes which were responsive to erg11 inactivation. This indicates that inhibition of specific steps of ergosterol biosynthesis can result in different transcriptional responses, which is further supported by our results obtained using different ergosterol biosynthesis inhibitors. Together with the sterol profiles, these results suggest that the transcriptional responses by cdr4 and erg genes are associated with accumulation of specific sterol intermediate(s). This was further supported by the fact that when the erg2 mutant was treated with ketoconazole, upstream inhibition overrode the effects by downstream inhibition on ergosterol biosynthesis pathway. Even though cdr4 expression is associated with the accumulation of sterol intermediates, intra- and extracellular sterol analysis by HPLC-MS indicated that the transcriptional induction of cdr4 did not result in efflux of the accumulated intermediate(s). This study demonstrates, by detailed genetic and chemical analysis, that transcriptional responses by a major efflux pump and genes of the ergosterol biosynthesis pathway to ergosterol biosynthesis inhibitors can be independent of the presence of the drugs and are linked with the accumulation of ergosterol intermediate(s)

Can the memory of an object be enhanced by imagining its loss?

Previous investigations examining salient memories have demonstrated that personal memories that are important to individuals and contain emotional information are better remembered than neutral events.Using behavioral and brain-imaging experiments,the present studies explored whether the previous finding was applicable imagined loss.In a behavioral experiment,a free recall paradigm was used to compare the memory performance of individuals who imagined loss with that of individuals who imagined importance.The superior memory performance conferred by imagining loss was constrained to ordinary items of low to medium importance and did not generalize to vital items.Moreover,brain imaging evidence revealed that the activation in certain brain regions was stronger when participants were imagining the loss of ordinary items of low to medium importance compared to vital items.These brain regions included cognitive effort-related areas(such as the parietal cortex and middle prefrontal cortex) and areas related to emotional experiences and emotion-related memories(such as the amygdala,parahippocampal gyrus,and posterior cingulate gyrus).Our study provides a new way of exploring the superior memory performance when imagining loss and enriches the literature on memory enhancement by contributing to a deeper understanding of the psychological mechanisms related to the imagining of vital losses

Can contrast effects regulate emotions? A follow-up study of vital loss decisions.

Although many studies focus on the how contrast effects can impact cognitive evaluations, the question of whether emotions are regulated by such contrast effects is still the subject of considerable debate, especially in the study of loss-related decisions. To address this gap in the literature, we designed three decision making loss conditions: (i) both losses are trivial (TT), (ii) one loss is trivial and the other loss is vital (TV), or (iii) one loss is trivial and the other loss is routine (TR). In study 1, which compared the difference between the negative emotion ratings in TT and TV, we found that negative emotions were affected by the contrast effects. In study 2, which compared the difference between the importance of trivial options in TT and TV, we found that the contrast effects differentially changed the importance of trivial options in the two conditions, which in turn down-regulated negative emotions. In study 3, the impact of decision difficulty was controlled by predetermining the items to be lost. In this study, we found that, when comparing the differences between the negative emotions of losing trivial options in TV and TR, the contrast effects still modulated the loss-related emotions. We concluded that the contrast effects could down-regulate emotions. To our knowledge, this is the first demonstration that contrast effects can alleviate negative affect in loss-related decision making. This study will enrich and extend the literature on emotion regulation theory, and it will provide a new cost-effective mitigation strategy for regulating negative emotions