Prediction of Candidate Primary Immunodeficiency Disease Genes Using a Support Vector Machine Learning Approach

Screening and early identification of primary immunodeficiency disease (PID) genes is a major challenge for physicians. Many resources have catalogued molecular alterations in known PID genes along with their associated clinical and immunological phenotypes. However, these resources do not assist in identifying candidate PID genes. We have recently developed a platform designated Resource of Asian PDIs, which hosts information pertaining to molecular alterations, protein-protein interaction networks, mouse studies and microarray gene expression profiling of all known PID genes. Using this resource as a discovery tool, we describe the development of an algorithm for prediction of candidate PID genes. Using a support vector machine learning approach, we have predicted 1442 candidate PID genes using 69 binary features of 148 known PID genes and 3162 non-PID genes as a training data set. The power of this approach is illustrated by the fact that six of the predicted genes have recently been experimentally confirmed to be PID genes. The remaining genes in this predicted data set represent attractive candidates for testing in patients where the etiology cannot be ascribed to any of the known PID genes.

Theoretical Investigation on the Effect of Different Nitrogen Donors on Intramolecular Se center dot center dot center dot N Interactions

The effect of different donor nitrogen atoms on the strength and nature of intramolecular Se center dot center dot center dot N interactions is evaluated for organoselenium compounds having N,N-dimethylaminomethyl (dime), oxazoline (oxa) and pyridyl (py) substituents. Quantum chemical calculations on three series of compounds [2-(dime)C6H4SeX (1a-g), 2-(oxa)C6H4SeX (2a-g), 2- (py)C6H4SeX (3-ag); X=Cl, Br, OH, CN, SPh, SePh, CH3] at the B3LYP/6-31G(d) level show that the stability of different conformers depends on the strength of intramolecular nonbonded Se center dot center dot center dot N interactions. Natural bond orbital (NBO), NBO deletion and atoms in molecules (AIM) analyses suggest that the nature of the Se center dot center dot center dot N interaction is predominantly covalent and involves nN ->sigma*(Se-X) orbital interaction. In the three series of compounds, the strength of the Se center dot center dot center dot N interaction decreases in the order 3>2>1 for a particular X, and it decreases in the order Cl > Br > OH>SPh approximate to CN approximate to SePh>CH3 for all the three series 1-3. However, further analyses suggest that the differences in strength of Se center dot center dot center dot N interaction in 1-3 is predominantly determined by the distance between the Se and N atoms, which in turn is an outcome of specific structures of 1, 2 and 3, and the nature of the donor nitrogen atoms involved has very little effect on the strength of Se center dot center dot center dot N interaction. It is also observed that Se center dot center dot center dot N interaction becomes stronger in polar solvents such as CHCl3, as indicated by the shorter r(Se center dot center dot center dot N) and higher E-Se center dot center dot center dot N values in CHCl3 compared to those observed in the gas phase.

Location of Pathogenic Bacteria during Persistent Infections: Insights from an Analysis Using Game Theory

Bacterial persistent infections are responsible for a significant amount of the human morbidity and mortality. Unlike acute bacterial infections, it is very difficult to treat persistent bacterial infections (e.g. tuberculosis). Knowledge about the location of pathogenic bacteria during persistent infection will help to treat such conditions by designing novel drugs which can reach such locations. In this study, events of bacterial persistent infections were analyzed using game theory. A game was defined where the pathogen and the host are the two players with a conflict of interest. Criteria for the establishment of Nash equilibrium were calculated for this game. This theoretical model, which is very simple and heuristic, predicts that during persistent infections pathogenic bacteria stay in both intracellular and extracellular compartments of the host. The result of this study implies that a bacterium should be able to survive in both intracellular and extracellular compartments of the host in order to cause persistent infections. This explains why persistent infections are more often caused by intracellular pathogens like Mycobacterium and Salmonella. Moreover, this prediction is in consistence with the results of previous experimental studies.

Prediction of individual genetic risk to prostate cancer using a polygenic score

BACKGROUND Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction. Prostate 75:1467–1474, 2015. © 2015 Wiley Periodicals, Inc.

Type II beta-turn conformation of pivaloyl-L-prolyl-a-aminoiso-butyryl-N-methylamide: Theoretical, spectroscopic and X-ray studies

Pivaloyl-L-Pro-Aib-N-methylamihdaes been shown to possess one intramolecular hydrogen bond in (CD&SO solution, by 'H-nmr methods, suggesting the existence of p-turns, with Pro-Aib as the corner residues. Theoretical conformational analysis suggests that Type II P-turn conformations are about 2 kcal mol-' more stable than Type 111 structures. A crystallographic study has established the Type I1 /%turn in the solid state. The molecule crystallizes in the space group P21 with a = 5.865 8, b = 11.421 A, c = 12.966 A, /3 = 97.55", and 2 = 2. The structure has been refined to a final R value of 0.061. The Type I1 p-turn conformation is stabilized by an intramolecular 4 - 1 hydrogen bond between the methylamide NH and the pivaloyl CO group. The conformational angles are @pro= -57.8", $pro = 139.3', @Aib = 61.4', and $Ajb = 25.1'. The Type 11 /%turn conformation for Pro-Aib in this peptide is compared with the Type I11 structures observed for the same segment in larger peptides.

Theoretical Studies of Hard Filling in Loop Heat Pipes

Loop heat pipe is a passive two-phase heat transport device that is gaining importance as a part of spacecraft thermal control systems and also in applications (such as in avionic cooling and submarines). Hard fill of a loop heat pipe occurs when the compensation chamber is full of liquid. A theoretical study is undertaken to investigate the issues underlying the loop beat pipe hard-fill phenomenon. The results of the study suggest that the mass of charge and the presence of a bayonet have significant impact on the loop heat pipe operation. With a largern mass of charge, a loop heat pipe hard fills at a lower heat load. As the heat load increases, there is a steep rise in the loop heat pipe operating temperature. In a loop heat pipe with a saturated compensation chamber, and also in a hard-filled loop heat pipe without a bayonet, the temperature of the compensation chamber and that of the liquid core are nearly equal. When a loop heat pipe with a bayonet hard fills, the compensation chamber and the evaporator core temperatures are different.

Therapeutic hypothermia after cardiac arrest : Studies on neurological and cardiological outcome and prediction of outcome in hypothermia-treated patients resuscitated from out-of-hospital cardiac arrest

The outcome of the successfully resuscitated patient is mainly determined by the extent of hypoxic-ischemic cerebral injury, and hypothermia has multiple mechanisms of action in mitigating such injury. The present study was undertaken from 1997 to 2001 in Helsinki as a part of the European multicenter study Hypothermia after cardiac arrest (HACA) to test the neuroprotective effect of therapeutic hypothermia in patients resuscitated from out-of-hospital ventricular fibrillation (VF) cardiac arrest (CA). The aim of this substudy was to examine the neurological and cardiological outcome of these patients, and especially to study and develop methods for prediction of outcome in the hypothermia-treated patients. A total of 275 patients were randomized to the HACA trial in Europe. In Helsinki, 70 patients were enrolled in the study according to the inclusion criteria. Those randomized to hypothermia were actively cooled externally to a core temperature 33 ± 1ºC for 24 hours with a cooling device. Serum markers of ischemic neuronal injury, NSE and S-100B, were sampled at 24, 36, and 48 hours after CA. Somatosensory and brain stem auditory evoked potentials (SEPs and BAEPs) were recorded 24 to 28 hours after CA; 24-hour ambulatory electrocardiography recordings were performed three times during the first two weeks and arrhythmias and heart rate variability (HRV) were analyzed from the tapes. The clinical outcome was assessed 3 and 6 months after CA. Neuropsychological examinations were performed on the conscious survivors 3 months after the CA. Quantitative electroencephalography (Q-EEG) and auditory P300 event-related potentials were studied at the same time-point. Therapeutic hypothermia of 33ºC for 24 hours led to an increased chance of good neurological outcome and survival after out-of-hospital VF CA. In the HACA study, 55% of hypothermia-treated patients and 39% of normothermia-treated patients reached a good neurological outcome (p=0.009) at 6 months after CA. Use of therapeutic hypothermia was not associated with any increase in clinically significant arrhythmias. The levels of serum NSE, but not the levels of S-100B, were lower in hypothermia- than in normothermia-treated patients. A decrease in NSE values between 24 and 48 hours was associated with good outcome at 6 months after CA. Decreasing levels of serum NSE but not of S-100B over time may indicate selective attenuation of delayed neuronal death by therapeutic hypothermia, and the time-course of serum NSE between 24 and 48 hours after CA may help in clinical decision-making. In SEP recordings bilaterally absent N20 responses predicted permanent coma with a specificity of 100% in both treatment arms. Recording of BAEPs provided no additional benefit in outcome prediction. Preserved 24- to 48-hour HRV may be a predictor of favorable outcome in CA patients treated with hypothermia. At 3 months after CA, no differences appeared in any cognitive functions between the two groups: 67% of patients in the hypothermia and 44% patients in the normothermia group were cognitively intact or had only very mild impairment. No significant differences emerged in any of the Q-EEG parameters between the two groups. The amplitude of P300 potential was significantly higher in the hypothermia-treated group. These results give further support to the use of therapeutic hypothermia in patients with sudden out-of-hospital CA.

A theoretical model for the magnetic helicity of solar active regions

Active regions on the solar surface are known to possess magnetic helicity, which is predominantly negative in the northern hemisphere and positive in the southern hemisphere. Choudhuri et al. [Choudhuri, A.R. On the connection between mean field dynamo theory and flux tubes. Solar Phys. 215, 31–55, 2003] proposed that the magnetic helicity arises due to the wrapping up of the poloidal field of the convection zone around rising flux tubes which form active regions. Choudhuri [Choudhuri, A.R., Chatterjee, P., Nandy, D. Helicity of solar active regions from a dynamo model. ApJ 615, L57–L60, 2004] used this idea to calculate magnetic helicity from their solar dynamo model. Apart from getting broad agreements with observational data, they also predict that the hemispheric helicity rule may be violated at the beginning of a solar cycle. Chatterjee et al. [Chatterjee, P., Choudhuri, A.R., Petrovay, K. Development of twist in an emerging magnetic flux tube by poloidal field accretion. A&A 449, 781–789, 2006] study the penetration of the wrapped poloidal field into the rising flux tube due to turbulent diffusion using a simple 1-d model. They find that the extent of penetration of the wrapped field will depend on how weak the magnetic field inside the rising flux tube becomes before its emergence. They conclude that more detailed observational data will throw light on the physical conditions of flux tubes just before their emergence to the photosphere.

CAE-based prediction of projectile residual velocity for impact on single and multi-layered metallic armour plates

The present, paper deals with the CAE-based study Of impact of jacketed projectiles on single- and multi-layered metal armour plates using LS-DYNA. The validation of finite element modelling procedure is mainly based on the mesh convergence study using both shell and solid elements for representing single-layered mild steel target plates. It, is shown that the proper choice of mesh density and the strain rate-dependent material properties are essential for all accurate prediction of projectile residual velocity. The modelling requirements are initially arrived at by correlating against test residual velocities for single-layered mild steel plates of different depths at impact velocities in the ran.-c of approximately 800-870 m/s. The efficacy of correlation is adjudged, in terms of a 'correlation index', defined in the paper: for which values close to unity are desirable. The experience gained for single-layered plates is next; used in simulating projectile impacts on multi-layered mild steel target plates and once again a high degree of correlation with experimental residual velocities is observed. The study is repeated for single- and multi-layered aluminium target plates with a similar level of success in test residual velocity prediction. TO the authors' best knowledge, the present comprehensive study shows in particular for the first time that, with a. proper modelling approach, LS-DYNA can be used with a great degree of confidence in designing perforation-resistant single and multi-layered metallic armour plates.

CsrA interacting small RNAs in Haemophilus spp genomes: a theoretical analysis

The csrA is a carbon storage regulator gene that encodes a protein with multiple RNA interaction sites. Bacterial non-coding small RNAs like csrB, csrC and their counterparts in diverse bacterial genus are identified to control the regulatory activities of CsrA and its orthologs. An attempt has been made in this study to identify 'novel' non-coding small RNAs that are involved in the regulatory activities of csrA gene. All CsrA-interacting small RNAs are computationally fingerprinted to have multiple occurrence of 7-nucleotide CsrA interacting repeats [CAGGA(U/A/C)G] along with a 18-nucleotide upstream binding site. However, in several of the genomes like Haemophilus spp, the upstream binding site is not identified. The current methodology overcomes this difficulty by identifying small RNA-specific orphan transcriptional units within the intergenic regions of the genome. The results could identify all known CsrA-interacting small RNAs in E. coli, Vibrio cholerae and Pseudomonas aeruginosa genomes and additionally has picked six new possible CsrA-interacting small RNA regions in E. coli. Our computational analysis indicates that known rygD and rprA sRNAs in E. coli could possibly interact with CsrA proteins. The study is extended to three of the Haemophilus genomes that could identify seven new possible CsrA interacting small RNAs.

Acute renal failure in critically ill patients : With special reference to prediction of outcome

Acute renal failure (ARF) is a clinical syndrome characterized by rapidly decreasing glomerular filtration rate, which results in disturbances in electrolyte- and acid-base homeostasis, derangement of extracellular fluid volume, and retention of nitrogenous waste products, and is often associated with decreased urine output. ARF affects about 5-25% of patients admitted to intensive care units (ICUs), and is linked to high mortality and morbidity rates. In this thesis outcome of critically ill patients with ARF and factors related to outcome were evaluated. A total of 1662 patients from two ICUs and one acute dialysis unit in Helsinki University Hospital were included. In study I the prevalence of ARF was calculated and classified according to two ARF-specific scoring methods, the RIFLE classification and the classification created by Bellomo et al. (2001). Study II evaluated monocyte human histocompatibility leukocyte antigen-DR (HLA-DR) expression and plasma levels of one proinflammatory (interleukin (IL) 6) and two anti-inflammatory (IL-8 and IL-10) cytokines in predicting survival of critically ill ARF patients. Study III investigated serum cystatin C as a marker of renal function in ARF and its power in predicting survival of critically ill ARF patients. Study IV evaluated the effect of intermittent hemodiafiltration (HDF) on myoglobin elimination from plasma in severe rhabdomyolysis. Study V assessed long-term survival and health-related quality of life (HRQoL) in ARF patients. Neither of the ARF-specific scoring methods presented good discriminative power regarding hospital mortality. The maximum RIFLE score for the first three days in the ICU was an independent predictor of hospital mortality. As a marker of renal dysfunction, serum cystatin C failed to show benefit compared with plasma creatinine in detecting ARF or predicting patient survival. Neither cystatin C nor plasma concentrations of IL-6, IL-8, and IL-10, nor monocyte HLA-DR expression were clinically useful in predicting mortality in ARF patients. HDF may be used to clear myoglobin from plasma in rhabdomyolysis, especially if the alkalization of diuresis does not succeed. The long-term survival of patients with ARF was found to be poor. The HRQoL of those who survive is lower than that of the age- and gender-matched general population.

Fuzzy-logic-based health monitoring and residual-life prediction for composite helicopter rotor

A health-monitoring and life-estimation strategy for composite rotor blades is developed in this work. The cross-sectional stiffness reduction obtained by physics-based models is expressed as a function of the life of the structure using a recent phenomenological damage model. This stiffness reduction is further used to study the behavior of measurable system parameters such as blade deflections, loads, and strains of a composite rotor blade in static analysis and forward flight. The simulated measurements are obtained using an aeroelastic analysis of the composite rotor blade based on the finite element in space and time with physics-based damage modes that are then linked to the life consumption of the blade. The model-based measurements are contaminated with noise to simulate real data. Genetic fuzzy systems are developed for global online prediction of physical damage and life consumption using displacement- and force-based measurement deviations between damaged and undamaged conditions. Furthermore, local online prediction of physical damage and life consumption is done using strains measured along the blade length. It is observed that the life consumption in the matrix-cracking zone is about 12-15% and life consumption in debonding/delamination zone is about 45-55% of the total life of the blade. It is also observed that the success rate of the genetic fuzzy systems depends upon the number of measurements, type of measurements and training, and the testing noise level. The genetic fuzzy systems work quite well with noisy data and are recommended for online structural health monitoring of composite helicopter rotor blades.