Potential risk factors associated with human encephalitis: application of canonical correlation analysis

<p>Abstract</p> <p>Background</p> <p>Infection of the CNS is considered to be the major cause of encephalitis and more than 100 different pathogens have been recognized as causative agents. Despite being identified worldwide as an important public health concern, studies on encephalitis are very few and often focus on particular types (with respect to causative agents) of encephalitis (e.g. West Nile, Japanese, etc.). Moreover, a number of other infectious and non-infectious conditions present with similar symptoms, and distinguishing encephalitis from other disguising conditions continues to a challenging task.</p> <p>Methods</p> <p>We used canonical correlation analysis (CCA) to assess associations between set of exposure variable and set of symptom and diagnostic variables in human encephalitis. Data consists of 208 confirmed cases of encephalitis from a prospective multicenter study conducted in the United Kingdom. We used a covariance matrix based on Gini's measure of similarity and used permutation based approaches to test significance of canonical variates.</p> <p>Results</p> <p>Results show that weak pair-wise correlation exists between the risk factor (exposure and demographic) and symptom/laboratory variables. However, the first canonical variate from CCA revealed strong multivariate correlation (ρ = 0.71, se = 0.03, p = 0.013) between the two sets. We found a moderate correlation (ρ = 0.54, se = 0.02) between the variables in the second canonical variate, however, the value is not statistically significant (p = 0.68). Our results also show that a very small amount of the variation in the symptom sets is explained by the exposure variables. This indicates that host factors, rather than environmental factors might be important towards understanding the etiology of encephalitis and facilitate early diagnosis and treatment of encephalitis patients.</p> <p>Conclusions</p> <p>There is no standard laboratory diagnostic strategy for investigation of encephalitis and even experienced physicians are often uncertain about the cause, appropriate therapy and prognosis of encephalitis. Exploration of human encephalitis data using advanced multivariate statistical modelling approaches that can capture the inherent complexity in the data is, therefore, crucial in understanding the causes of human encephalitis. Moreover, application of multivariate exploratory techniques will generate clinically important hypotheses and offer useful insight into the number and nature of variables worthy of further consideration in a confirmatory statistical analysis.</p

Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry.

PURPOSE: Retinitis pigmentosa is a Mendelian disease with a very elevated genetic heterogeneity. Most mutations are responsible for less than 1% of cases, making molecular diagnosis a multigene screening procedure. In this study, we assessed whether direct testing of specific alleles could be a valuable screening approach in cases characterized by prevalent founder mutations. METHODS: We screened 275 North American patients with recessive/isolate retinitis pigmentosa for two mutations: an Alu insertion in the MAK gene and the p.Lys42Glu missense in the DHDDS gene. All patients were unrelated; 35 reported Jewish ancestry and the remainder reported mixed ethnicity. RESULTS: We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry. Haplotype analyses revealed that inheritance of the MAK mutation was attributable to a founder effect. CONCLUSION: In contrast to most mutations associated with retinitis pigmentosa-which are, in general, extremely rare-the two alleles investigated here cause disease in approximately one-third of North American patients reporting Jewish ancestry. Therefore, their screening constitutes an alternative procedure to large-scale tests for patients belonging to this ethnic group, especially in time-sensitive situations.Genet Med 17 4, 285-290

Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients

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Selection-Driven Gene Loss in Bacteria

Gene loss by deletion is a common evolutionary process in bacteria, as exemplified by bacteria with small genomes that have evolved from bacteria with larger genomes by reductive processes. The driving force(s) for genome reduction remains unclear, and here we examined the hypothesis that gene loss is selected because carriage of superfluous genes confers a fitness cost to the bacterium. In the bacterium Salmonella enterica, we measured deletion rates at 11 chromosomal positions and the fitness effects of several spontaneous deletions. Deletion rates varied over 200-fold between different regions with the replication terminus region showing the highest rates. Approximately 25% of the examined deletions caused an increase in fitness under one or several growth conditions, and after serial passage of wild-type bacteria in rich medium for 1,000 generations we observed fixation of deletions that substantially increased bacterial fitness when reconstructed in a non-evolved bacterium. These results suggest that selection could be a significant driver of gene loss and reductive genome evolution

A barrier to homologous recombination between sympatric strains of the cooperative soil bacterium Myxococcus xanthus

The bacterium Myxococcus xanthus glides through soil in search of prey microbes, but when food sources run out, cells cooperatively construct and sporulate within multicellular fruiting bodies. M. xanthus strains isolated from a 16 × 16-cm-scale patch of soil were previously shown to have diversified into many distinct compatibility types that are distinguished by the failure of swarming colonies to merge upon encounter. We sequenced the genomes of 22 isolates from this population belonging to the two most frequently occurring multilocus sequence type (MLST) clades to trace patterns of incipient genomic divergence, specifically related to social divergence. Although homologous recombination occurs frequently within the two MLST clades, we find an almost complete absence of recombination events between them. As the two clades are very closely related and live in sympatry, either ecological or genetic barriers must reduce genetic exchange between them. We find that the rate of change in the accessory genome is greater than the rate of amino-acid substitution in the core genome. We identify a large genomic tract that consistently differs between isolates that do not freely merge and therefore is a candidate region for harbouring gene(s) responsible for self/non-self discrimination

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10 &lt;sup&gt;-5&lt;/sup&gt; ). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance

Structural insight into the formation of lipoprotein-β-barrel complexes

The β-barrel assembly machinery (BAM) inserts outer membrane β-barrel proteins (OMPs) in the outer membrane of Gram-negative bacteria. In Enterobacteriacea, BAM also mediates export of the stress sensor lipoprotein RcsF to the cell surface by assembling RcsF–OMP complexes. Here, we report the crystal structure of the key BAM component BamA in complex with RcsF. BamA adopts an inward-open conformation, with the lateral gate to the membrane closed. RcsF is lodged deep within the lumen of the BamA barrel, binding regions proposed to undergo outward and lateral opening during OMP insertion. On the basis of our structural and biochemical data, we propose a push-and-pull model for RcsF export following conformational cycling of BamA, and provide a mechanistic explanation for how RcsF uses its interaction with BamA to detect envelope stress. Our data also suggest that the flux of incoming OMP substrates is involved in the control of BAM activity