A revised Fisher model on analysis of quantitative trait loci with multiple alleles

Zeng et al. (2005) proposed a general two-allele (G2A) model to model bi-allelic quantitative trait loci (QTL). Comparing with the classical Fisher model, the G2A model can avoid using redundant parameters and be fitted directly using standard least square (LS) approach. In this study, we further extend the G2A model to general multi-allele (GMA) model. First, we propose a one-locus GMA model for phase known genotypes based on modeling the inheritance of paternal and maternal alleles. Next, we develop a one-locus GMA model for phase unknown genotypes by treating it as a special case of the phase known one-locus GMA model. Thirdly, we extend the one-locus GMA models to multiple loci. We discuss how the genetic variance components can be analyzed using these GMA models in equilibrium as well as disequilibrium populations. Finally, we apply the GMA model to a published experimental data set

Abnormal Changes of Brain Cortical Anatomy and the Association with Plasma MicroRNA107 Level in Amnestic Mild Cognitive Impairment

MicroRNA107 (Mir107) has been thought to relate to the brain structure phenotype of Alzheimer’s disease. In this study, we evaluated the cortical anatomy in amnestic mild cognitive impairment (aMCI) and the relation between cortical anatomy and plasma levels of Mir107 and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). 20 aMCI and 24 cognitively normal control (NC) subjects were recruited, and T1-weighted MR images were acquired. Cortical anatomical measurements, including cortical thickness (CT), surface area (SA), and local gyrification index (LGI), were assessed. Quantitative RT-PCR was used to examine plasma expression of Mir107, BACE1 mRNA. Thinner cortex was found in aMCI in areas associated with episodic memory and language, but with thicker cortex in other areas. SA decreased in aMCI in the areas associated with working memory and emotion. LGI showed a significant reduction in aMCI in the areas involved in language function. Changes in Mir107 and BACE1 messenger RNA plasma expression were correlated with changes in CT and SA. We found alterations in key left brain regions associated with memory, language, and emotion in aMCI that were significantly correlated with plasma expression of mir107 and BACE1 mRNA. This combination study of brain anatomical alterations and gene information may shed lights on our understanding of the pathology of AD

Structural, cellular and molecular aspects of immune privilege in the testis

The testis presents a special immunological environment, considering its property of immune privilege that tolerates allo- and auto-antigens. Testicular immune privilege was once believed to be mainly based on the sequestration of antigens from the immune system by the blood-testis barrier in the seminiferous epithelium. Substantial evidence supports the view that the combination of physical structure, testicular cells, and cytokines controls immune responses in the testis to preserve the structural and functional integrity of testicular immune privilege. Both systemic immune tolerance and local immunosuppression help maintain the immune privilege status. Constitutive expression of anti-inflammatory factors in testicular cells is critical for local immunosuppression. However, the testis locally generates an efficient innate immune system against pathogens. Disruption of these mechanisms may lead to orchitis and impair fertility. This review article highlights the current understanding of structural, cellular and molecular mechanisms underlying the unique immune environment of the testis, particularly its immune privilege status

A re-formulation of generalized linear mixed models to fit family data in genetic association studies

The generalized linear mixed model (GLMM) is a useful tool for modeling genetic correlation among family data in genetic association studies. However, when dealing with families of varied sizes and diverse genetic relatedness, the GLMM has a special correlation structure which often makes it difficult to be specified using standard statistical software. In this study, we propose a Cholesky decomposition based re-formulation of the GLMM so that the re-formulated GLMM can be specified conveniently via `proc nlmixed' and `proc glimmix' in SAS, or OpenBUGS via R package BRugs. Performances of these procedures in fitting the re-formulated GLMM are examined through simulation studies. We also apply this re-formulated GLMM to analyze a real data set from Type 1 Diabetes Genetics Consortium (T1DGC)

An Intracranial Electroencephalography (iEEG) Brain Function Mapping Tool with an Application to Epilepsy Surgery Evaluation

Object: Before epilepsy surgeries, intracranial electroencephalography (iEEG) is often employed in function mapping and epileptogenic foci localization. Although the implanted electrodes provide crucial information for epileptogenic zone resection, a convenient clinical tool for electrode position registration and brain function mapping visualization is still lacking. In this study, we developed a Brain Function Mapping (BFM) Tool, which facilitates electrode position registration and brain function mapping visualization, with an application to epilepsy surgeries.Methods: The BFM Tool mainly utilizes electrode location registration and function mapping based on pre-defined brain models from other software. In addition, the electrode node and mapping properties, such as the node size/color, edge color / thickness, mapping method, can be adjusted easily using the setting panel. Moreover, users may manually import / export location and connectivity data to generate figures for further application. The role of this software is demonstrated by a clinical study of language area localization.Results: The BFM Tool helps clinical doctors and researchers visualize implanted electrodes and brain functions in an easy, quick and flexible manner.Conclusions: Our tool provides convenient electrode registration, easy brain function visualization, and has good performance. It is clinical-oriented and is easy to deploy and use. The BFM tool is suitable for epilepsy and other clinical iEEG applications

MicroRNA Machinery Genes as Novel Biomarkers for Cancer

MicroRNAs (miRNAs) directly and indirectly affect tumorigenesis. To be able to perform their myriad roles, miRNA machinery genes, such as Drosha, DGCR8, Dicer1, XPO5, TRBP, and AGO2, must generate precise miRNAs. These genes have specific expression patterns, protein-binding partners, and biochemical capabilities in different cancers. Our preliminary analysis of data from The Cancer Genome Atlas consortium on multiple types of cancer revealed significant alterations in these miRNA machinery genes. Here, we review their biological structures and functions with an eye towards understanding how they could serve as cancer biomarkers

Soil pH is a key determinant of soil fungal community composition in the Ny-Ålesund Region, Svalbard (High Arctic)

This study assessed the fungal community composition and its relationships with properties of surface soils in the Ny-Ålesund Region (Svalbard, High Arctic). A total of thirteen soil samples were collected and soil fungal community was analyzed by 454 pyrosequencing with fungi-specific primers targeting the rDNA internal transcribed spacer (ITS) region. The following eight soil properties were analyzed: pH, organic carbon (C), organic nitrogen (N), ammonium nitrogen (NH4+-N), silicate silicon (SiO42--Si), nitrite nitrogen (NO2--N), phosphate phosphorus (PO43--P) and nitrate nitrogen (NO3--N). A total of 57,952 reads belonging to 541 operational taxonomic units (OTUs) were found. Of these OTUs, 343 belonged to Ascomycota, 100 to Basidiomycota, 31 to Chytridiomycota, 22 to Glomeromycota, 11 to Zygomycota, 10 to Rozellomycota, whereas 24 belonged to unknown fungi. The dominant orders were Helotiales, Verrucariales, Agaricales, Lecanorales, Chaetothyriales, Lecideales, and Capnodiales. The common genera (>8 soil samples) were Tetracladium, Mortierella, Fusarium, Cortinarius, and Atla. Distance-based redundancy analysis (db-rda) and analysis of similarities (ANOSIM) revealed that soil pH (p=0.001) was the most significant factor in determining the soil fungal community composition. Members of Verrucariales were found to predominate in soils of pH 8-9, whereas Sordariales predominated in soils of pH 7-8 and Coniochaetales predominated in soil samples of pH 6-7. The results suggest the presence and distribution of diverse soil fungal communities in the High Arctic, which can provide reliable data for studying the ecological responses of soil fungal communities to climate changes in the Arctic

Genome-wide identification of CAMTA gene family members in Medicago truncatula and their expression during root nodule symbiosis and hormone treatments

Calmodulin-binding transcription activators (CAMTAs) are well-characterized calmodulin-binding transcription factors in the plant kingdom. Previous work shows that CAMTAs play important roles in various biological processes including disease resistance, herbivore attack response and abiotic stress tolerance. However, studies that address the function of CAMTAs during the establishment of symbiosis between legumes and rhizobia are still lacking. This study undertook comprehensive identification and analysis of CAMTA genes using the latest updated M. truncatula genome. All the MtCAMTA genes were expressed in a tissues-specific manner and were responsive to environmental stress-related hormones. The expression profiling of MtCAMTA genes during the early phase of Sinorhizobium meliloti infection was also analyzed. Our data showed that the expression of most MtCAMTA genes was suppressed in roots by S. meliloti infection. The responsiveness of MtCAMTAs to S. meliloti infection indicated that they may function as calcium-regulated transcription factors in the early nodulation signaling pathway. In addition, bioinformatics analysis showed that CAMTA binding sites existed in the promoter regions of various early rhizobial infection response genes, suggesting possible MtCAMTAs-regulated downstream candidate genes during the early phase of S. meliloti infection. Taken together, these results provide basic information about MtCAMTAs in the model legume M. truncatula, and the involvement of MtCAMTAs in nodule organogenesis. This information furthers our understanding of MtCAMTA protein functions in M. truncatula and opens new avenues for continued research

Impulsive and Compulsive Behaviors in Parkinson’s Disease

Background: Impulsive and compulsive behaviors (ICBs) are a heterogeneous group of conditions that may be caused by long-term dopaminergic replacement therapy (DRT) of Parkinson's disease (PD). The spectrum of ICBs includes dopamine dysregulation syndrome (DDS), punding and impulsive control disorders (ICDs).Contents: We made a detailed review regarding the epidemiology, pathology, clinical characteristics, risk factors, diagnosis as well as treatment of ICBs.Results: The prevalence of ICBs in PD patients is approximately 3-4% for DDS, 0.34-4.2% for punding and 6-14% for ICDs, with higher prevalence in Western populations than in Asian. Those who take high dose of Levodopa are more prone to have DDS, whereas ICDs are markedly associated with dopamine agonists (DAs). Different subtypes of ICBs share many risk factors such as male gender, higher Levodopa equivalent daily dose (LEDD), younger age at PD onset, history of alcoholism, impulsive or novelty-seeking personality. The Questionnaire for Impulsive-Compulsive Disorder in Parkinson’s Disease-Rating Scale (QUIP-RS) seems to be a rather efficacious instrument to obtain relevant information from patients and caregivers. Treatment of ICBs is still a great challenge for clinicians. Readjustment of DRT remains the primary method. Atypical antipsychotics, antidepressants, amantadine, and psychosocial interventions are also prescribed in controlling episodes of psychosis caused by compulsive DRT, but attention should be drawn to balance ICBs symptoms and motor disorders. Moreover, deep brain stimulation of the subthalamic nucleus (STN-DBS) might be a potential method in controlling ICBs.Conclusions: The exact pathophysiological mechanisms of ICBs in PD remains poorly understood. Further researches are needed not only to study the pathogenesis, prevalence, features and risk factors of ICBs, but to find efficacious therapy for patients with these devastating consequences

Boosted influenza-specific T cell responses after H5N1 pandemic live attenuated influenza virus (pLAIV) vaccination

Background: In a phase I clinical trial, a H5N1 pandemic live attenuated influenza virus (pLAIV) VN2004 vaccine bearing avian influenza H5N1 HA and NA genes on the A/Ann Arbor cold-adapted vaccine backbone displayed very restricted replication. We evaluated T cell responses to H5N1 pLAIV vaccination and assessed pre-existing T cell responses to to determine whether they were associated with restricted replication of the H5N1 pLAIV. Method: ELISPOT assays were performed using pools of overlapping peptides spanning the entire H5N1 proteome and the hemagglutinin (HA) proteins of relevant seasonal H1N1 and H3N2 viruses. We tested stored PBMCs from 21 study subjects who received two doses of the H5N1 pLAIV. The PBMCs were collected 1 day before and 7 days after the first and second pLAIV vaccine doses, respectively. Result: T cell responses to conserved internal proteins M and NP were significantly boosted by vaccination (p=0.036). In addition, H5N1 pLAIV appeared to preferentially stimulate and boost pre-existing seasonal influenza virus HA-specific T cell responses that showed low cross-reactivity with the H5 HA. We confirmed this observation by T cell cloning and identified a novel HA-specific epitope. However, we did not find any evidence that pre-existing T cells prevented pLAIV replication and take. Conclusion: We found that cross-reactive T cell responses could be boosted by pLAIV regardless of the induction of antibody. The impact of the original antigenic sin phenomenon in a subset of volunteers, with preferential expansion of seasonal influenza-specific but not H5N1-specific T cell responses merits further investigation