Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p_meta-Euro = 2.08 × 10⁻¹⁰), transmembrane protein 39A (TMEM39A; rs1132200; p_meta-all = 8.62 × 10⁻⁹), and 17q21 (rs1453560; p_meta-all = 3.48 × 10⁻¹⁰) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10⁻⁸ < p_meta-Euro < 9.99 × 10⁻⁵) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.     

In silico study of interaction between rice proteins enhanced disease susceptibility 1 and phytoalexin deficient 4, the regulators of salicylic acid signalling pathway

Enhanced disease susceptibility 1 (EDS1), a plant-specific protein has homology with the eukaryotic lipase in their N-terminal halves and a unique domain at its C-termini. EDS1 is known to be an important regulator of biotic stress and an essential component of basal immunity. EDS1 interacts with its positive co-regulator phytoalexin deficient 4 (PAD4), resulting in mobilization of the salicylic acid defence pathway. Limited information regarding this interaction in rice is available. To study this interaction, a model of EDS1 and PAD4 proteins from rice was generated and validated with Accelrys DS software version 3.1 using bioinformatics interface. The in silico docking between the two proteins showed a significant protein-protein interaction between rice EDS1 and PAD4, suggesting that they form a dimeric protein complex, which, similar to that in Arabidopsis, is perhaps also important for triggering the salicylic acid signalling pathway in plants.     

Analysis of the multicopper oxidase gene regulatory network of Aeromonas hydrophila

Multicopper oxidase (MCO) is an enzyme which involves in reducing the oxygen in a four electron reduction to water with concomitant one electron oxidation of reducing the substrate. We have generated the 3-D structure of MCO by homology modeling and validated on the basis of free energy while 90.4 % amino acid residues present in allowed regions of Ramachandran plot. The screening of potential hazardous aromatic compounds for MCO was performed using molecular docking. We obtained Sulfonaphthal, Thymolphthalein, Bromocresol green and Phloretin derivatives of phenol and aromatic hydrocarbon were efficient substrates for MCO. The phylogeny of MCO reveals that other bacteria restrain the homologous gene of MCO may play an important role in biodegradation of aromatic compounds. We have demonstrated the gene regulatory network of MCO with other cellular proteins which play a key role in gene regulation. These findings provide a new insight for oxidization of phenolic and aromatic compounds using biodegradation process for controlling environmental pollution.     

Intermittent hypoxia regulates stem-like characteristics and differentiation of neuroblastoma cells

Background

Neuroblastomas are the most common extracranial solid tumors in children. Neuroblastomas are derived from immature cells of the sympathetic nervous system and are characterized by clinical and biological heterogeneity. Hypoxia has been linked to tumor progression and increased malignancy. Intermittent hypoxia or repeated episodes of hypoxia followed by re-oxygenation is a common phenomenon in solid tumors including neuroblastoma and it has a significant influence on the outcome of therapies. The present study focuses on how intermittent hypoxia modulates the stem-like properties and differentiation in neuroblastoma cells.

Methods and Findings

Cell survival was assessed by clonogenic assay and cell differentiation was determined by morphological characterization. Hypoxia-inducible genes were analyzed by real-time PCR and Western blotting. Immunofluorescence, real-time PCR and Western blotting were utilized to study stem cell markers. Analysis of neural crest / sympathetic nervous system (SNS) markers and neuronal differentiation markers were done by real-time PCR and Western blotting, respectively. Intermittent hypoxia stimulated the levels of HIF-1α and HIF-2 α proteins and enhanced stem-like properties of neuroblastoma cells. In intermittent hypoxia-conditioned cells, downregulation of SNS marker genes and upregulation of genes expressed in the neural crest were observed. Intermittent hypoxia suppressed the retinoic acid-induced differentiation of neuroblastoma cells.

Conclusions

Our results suggest that intermittent hypoxia enhances stem-like characteristics and suppresses differentiation propensities in neuroblastoma cells.     

The impact of taxon sampling on phylogenetic inference: a review of two decades of controversy

Over the past two decades, there has been a long-standing debate about the impact of taxon sampling on phylogenetic inference. Studies have been based on both real and simulated data sets, within actual and theoretical contexts, and using different inference methods, to study the impact of taxon sampling. In some cases, conflicting conclusions have been drawn for the same data set. The main questions explored in studies to date have been about the effects of using sparse data, adding new taxa, including more characters from genome sequences and using different (or concatenated) locus regions. These questions can be reduced to more fundamental ones about the assessment of data quality and the design guidelines of taxon sampling in phylogenetic inference experiments. This review summarizes progress to date in understanding the impact of taxon sampling on the accuracy of phylogenetic analysis.     

Stromatoporoid-grade and other sponge fossils from the upper Krol Formation of the Lesser Himalaya (India) Implications for the biotic evolution around the Precambrian-Cambrian boundary interval

Summary A study of fossils in thin sections of a sample from the uppermost Krol E Member in the Mussoorie Hills of the Lesser Himalaya, India, proves the existence of morphologically differentiated calcified sponges within the Precambrian-Cambrian boundary time interval. The sponges, described as Mussooriella kroli n.g., n.sp. and Maldeotaina composita n.g., n.sp. indicate the presence of different organization grades at the Precambrian-Cambrian interval. Mussooriella had a calcareous skeleton consisting of skeletal elements composed of an inner laminated part and a distinct peripheral layer with knobs. Maldeotaina is characterized by a stromatoporoid-grade growth pattern following a thalamid-grade pattern. The stromatoporoidgrade part of the skeletons reminds strongly on skeletal elements common in labechiid Ordovician and younger stromatoporoids. Maldeotaina also shows criteria of Early Cambrian fossils, originally described as stromatoporoids and later excluded from this group and transferred to archaeocyaths. These similarities point to an Early Cambrian age of the fossil-bearing horizon in the topmost Krol E Member. Growth cavities with crypts indicate that the sponges might have contributed to the formation of small metazoan reefs-like structures. Although the study is based on limited material and many interpretations are still tentative, a thorough documentation of the preliminary results seems reliable considering the high potential of the fossils of the upper Krol Formation important source in understanding of early metazoan differentiation.     

The influence of iron,sulphite and paraformaldehyde on the formation of 2.3 butanediol in the cultures of bacillus polymyxa

Summary InB. polymyxa cultures containing sucrose as the substrate the amount of 2.3 butanediol decreases between 10 and 30 days of fermentation but after 30 days, the formation of the glycol increases. If iron or sulphite ions are present in the culture ofB. polymyxa the yield of 2.3 butanediol is small in the first 10 days, as compared to the control culture but it gradually increases with the increase of the period of fermentation. This increase was observed upto 50 days. In the culture containing paraformaldehyde 2.3 butanediol is not formed. The sugar consumption in the cultures is high only during the first ten days of fermentation and after that though there is enough sugar present, it is not utilised and the amount of 2.3 butanediol goes on increasing. It appears that 2.3 butanediol is formed from some intermediate material formed during the period of high sugar consumption. Later the increase of 2.3 butanediol is due to its formation from the intermediate compound.