Compressed Sparse FM-Index: Fast Sequence Alignment Using Large K-Steps.

The FM-index is a data structure used in genomics for exact search of input sequences over large reference genomes. Algorithms based on the FM-index show an irregular memory access pattern, resulting in a memory bound problem. We analyze a recent implementation of the FM-index and highlight existing throughput-memory trade-offs, showing that memory requirements limit implementation of large k-steps. We propose COFI, a COmpressed FM-Index for large K-steps. COFI enables a 15-step FM-index using less than 16 GB for a human genome reference of 3 giga base pairs. An algorithm based on this new layout is evaluated on both a Knights Landing (KNL) and an Skylake-based system (SKX). We achieve average speed-ups of 1.46× and 1.39×, respectively, with respect to an state-of-the-art FM-index implementation that is already well optimized.

MEPSA: minimum energy pathway analysis for energy landscapes.

UNLABELLED: From conformational studies to atomistic descriptions of enzymatic reactions, potential and free energy landscapes can be used to describe biomolecular systems in detail. However, extracting the relevant data of complex 3D energy surfaces can sometimes be laborious. In this article, we present MEPSA (Minimum Energy Path Surface Analysis), a cross-platform user friendly tool for the analysis of energy landscapes from a transition state theory perspective. Some of its most relevant features are: identification of all the barriers and minima of the landscape at once, description of maxima edge profiles, detection of the lowest energy path connecting two minima and generation of transition state theory diagrams along these paths. In addition to a built-in plotting system, MEPSA can save most of the generated data into easily parseable text files, allowing more versatile uses of MEPSA's output such as the generation of molecular dynamics restraints from a calculated path. AVAILABILITY AND IMPLEMENTATION: MEPSA is freely available (under GPLv3 license) at: http://bioweb.cbm.uam.es/software/MEPSA/ CONTACT: pagomez@cbm.csic.es. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

NFFinder: an online bioinformatics tool for searching similar transcriptomics experiments in the context of drug repositioning.

Drug repositioning, using known drugs for treating conditions different from those the drug was originally designed to treat, is an important drug discovery tool that allows for a faster and cheaper development process by using drugs that are already approved or in an advanced trial stage for another purpose. This is especially relevant for orphan diseases because they affect too few people to make drug research de novo economically viable. In this paper we present NFFinder, a bioinformatics tool for identifying potential useful drugs in the context of orphan diseases. NFFinder uses transcriptomic data to find relationships between drugs, diseases and a phenotype of interest, as well as identifying experts having published on that domain. The application shows in a dashboard a series of graphics and tables designed to help researchers formulate repositioning hypotheses and identify potential biological relationships between drugs and diseases. NFFinder is freely available at http://nffinder.cnb.csic.es.

NMF-mGPU: non-negative matrix factorization on multi-GPU systems.

BACKGROUND: In the last few years, the Non-negative Matrix Factorization ( NMF ) technique has gained a great interest among the Bioinformatics community, since it is able to extract interpretable parts from high-dimensional datasets. However, the computing time required to process large data matrices may become impractical, even for a parallel application running on a multiprocessors cluster. In this paper, we present NMF-mGPU, an efficient and easy-to-use implementation of the NMF algorithm that takes advantage of the high computing performance delivered by Graphics-Processing Units ( GPUs ). Driven by the ever-growing demands from the video-games industry, graphics cards usually provided in PCs and laptops have evolved from simple graphics-drawing platforms into high-performance programmable systems that can be used as coprocessors for linear-algebra operations. However, these devices may have a limited amount of on-board memory, which is not considered by other NMF implementations on GPU. RESULTS: NMF-mGPU is based on CUDA ( Compute Unified Device Architecture ), the NVIDIA's framework for GPU computing. On devices with low memory available, large input matrices are blockwise transferred from the system's main memory to the GPU's memory, and processed accordingly. In addition, NMF-mGPU has been explicitly optimized for the different CUDA architectures. Finally, platforms with multiple GPUs can be synchronized through MPI ( Message Passing Interface ). In a four-GPU system, this implementation is about 120 times faster than a single conventional processor, and more than four times faster than a single GPU device (i.e., a super-linear speedup). CONCLUSIONS: Applications of GPUs in Bioinformatics are getting more and more attention due to their outstanding performance when compared to traditional processors. In addition, their relatively low price represents a highly cost-effective alternative to conventional clusters. In life sciences, this results in an excellent opportunity to facilitate the daily work of bioinformaticians that are trying to extract biological meaning out of hundreds of gigabytes of experimental information. NMF-mGPU can be used "out of the box" by researchers with little or no expertise in GPU programming in a variety of platforms, such as PCs, laptops, or high-end GPU clusters. NMF-mGPU is freely available at https://github.com/bioinfo-cnb/bionmf-gpu .

Ictal EEG-fMRI in localization of epileptogenic area in patients with refractory neocortical focal epilepsy.

PURPOSE: To evaluate the usefulness of ictal electroencephalography (EEG)-combined functional magnetic resonance imaging ( MRI) (EEG-fMRI) in localizing epileptogenic zone in refractory neocortical focal epilepsy. METHODS: From the EEG-fMRI database of our institution including 62 adult patients, 14 (age 18-46 years) experienced some ictal event during the test. Data were segmented into 10-s blocks, and the results were analyzed by contrasting each block to the contiguous 10-s block from the onset of seizure onward, in all cases. In seizures lasting >10 s (five cases), a supplementary analysis was performed, contrasting each block to a baseline condition, in the framework of the general linear model (GLM) of analysis. Regions of activations were compared to results from the different techniques performed during presurgical evaluation, such as SISCOM, positron emission tomography (PET), and invasive subdural EEG monitoring. KEY FINDINGS: Regarding the structural MRI findings, nine cases presented some lesion, with blood oxygen level- dependent (BOLD) signal activation placed in the same location in eight of them (89%). SISCOM studies were performed in 11 patients; 5 were concordant with the increase in BOLD signal in a sublobar level, whereas in 3 cases the concordance was in a lobar level. Eleven patients underwent PET studies, being also concordant in a sublobar level in four of them and in a lobar level in four additional cases. Finally, invasive EEG evaluation was performed in three patients and all of them had the seizure-onset zone in the initial area of BOLD activation. SIGNIFICANCE: This study adds relevant information to support the integration of EEG-fMRI in the multidisciplinary presurgical workup in patients with refractory epilepsy.

Are patients referred for presurgical evaluation drug resistant according to the new consensus definition? A study in a tertiary center.

We performed a retrospective chart review of the last consecutive 40 patients admitted in our Epilepsy Unit for presurgical evaluation to find out if they met criteria for drug resistant epilepsy according to the recently published consensus definition. 276 drug trials had been performed in the 40 patients. In total, 196 trials were considered "uninformative" versus 80 informative and adequate trials. Finally, a firm diagnosis of drug resistant epilepsy could be made only in 13/40 patients (32.5%, 90% confidence interval for proportion 21.7-45.5%), due to insufficient information regarding previous drug trials. The definition should be spread among general neurologists for earlier and more complete referrals.

Sequential analysis of fMRI images: A new approach to study human epileptic networks.

PURPOSE: The aim of this study was to introduce a new approach for analysis of functional magnetic resonance imaging (fMRI) data in order to illustrate the temporal development of the blood oxygenation level-dependent (BOLD) signal changes induced by epileptic seizures. METHOD: In order to sequentially analyze the fMRI images acquired during epileptic seizures, a continuous series of echo planar imaging (EPI) scans covering the complete period of a seizure was acquired. Data were segmented into 10-s blocks. Each block, representing a unique experimental condition, was contrasted with a neutral (no seizure) baseline condition. Visual comparison of the activations from one block to the next highlighted the course of activations and deactivations during the seizure event. This analysis was applied to three independent seizures of one patient with peri-rolandic epilepsy secondary to chronic encephalitis: one seizure before epilepsy surgery and two after unsuccessful tailored resection. Observations were compared to results from invasive subdural electroencephalography (EEG) monitoring, single-photon emission computed tomography (SPECT) coregistered to MRI (SISCOM), and independent component analysis (ICA), a model-free method of BOLD-signal analysis. RESULTS: The initial increase in BOLD signal occurred 10-40 s before clinical onset in the same location compared to the seizure-onset zone determined by invasive subdural evaluation and SISCOM. Sequential involvement of cortical and subcortical structures was in agreement with SISCOM, intracranial EEG recordings, and ICA results. DISCUSSION: In selected patients, sequential analysis of changes in BOLD signal induced by epileptic seizures might represent a useful approach for investigating the temporal development of brain activity during epileptic seizures, thereby allowing imaging of those cerebral structures involved in seizure generation and propagation.

Identifying the structures involved in seizure generation using sequential analysis of ictal-fMRI data.

UNLABELLED: The aim of this study was to investigate if sequential analysis of BOLD signal changes induced by seizures is useful for preoperative identification of the site of seizure onset in patients with pharmaco-resistant focal epilepsy. METHOD: We analyzed BOLD raw data from 5 patients with focal medically refractory epilepsy who experienced partial seizures during fMRI as part of a preoperative evaluation. To sequence the changes in BOLD signal seizure-induced, each seizure epoch was divided into groups of five consecutive images (ten-second blocks). t-maps were calculated continuously from 120 s before the onset of clinical/EEG seizure onwards by comparing two consecutive groups of five images. Time lag between each comparison was 2 s. Relative changes in BOLD signal between two consecutive groups of five images along the seizure epoch were determined. Results were compared with those of subtraction ictal SPECT coregistered with MRI (SISCOM) and intracranial EEG (2 patients). RESULTS: A typical seizure was registered in each patient. After sequential analysis, a well-localized and statistically significant (t: 7-14) area of signal increase was consistently found at seizure initiation in each patient. This area invariably preceded the onset of clinical/electrical seizure by several seconds (6-52 s); was concordant with SISCOM results in all but one patient; and overlapped with the ictal onset zone determined by intracranial EEG in those 2 patients who underwent invasive-EEG recordings. Complete resection of this initial area of signal increase resulted in seizure remission. Three out of four patients who underwent epilepsy surgery remained seizure-free. CONCLUSION: Sequential analysis of ictal-fMRI data may be useful to precisely and non-invasively delineate the ictal onset zone within the brain; and provide insights into the cerebral substrates involved in the generation and propagation of seizures.

Postictal psychosis: a retrospective study in patients with refractory temporal lobe epilepsy.

UNLABELLED: Postictal psychosis (PIP) represents 25% of the psychoses seen in epileptic patients. A high frequency of bilateral independent epileptiform activity has been observed in patients with PIP. The objective of this study was to determine the frequency of PIP in patients with temporal lobe epilepsy (TLE) who underwent video-EEG monitoring and to investigate possible differences between PIP and control patients. METHODS: Clinical, electroencephalographic and neuroimaging data of 5 PIP patients with TLE were compared with data of 50 patients with TLE without psychotic antecedents. Patients with a past history of interictal psychosis were excluded. RESULTS: From 55 patients, 5 were patients with PIP and 50 controls. 31 (62%) were men, 9 (16.4%) had a previous history of encephalitis and 6 (10.9%) of status epilepticus. The mean age was 42.2 years (S.D. 12.93). Mean age at epilepsy onset was 16.95 years (S.D. 12.93) and mean seizure frequency 5seizures/month (S.D. 1.87). The frequency of PIP was 5/55 (9.1%). Previous history of status epilepticus was more frequent in PIP patients than in controls (p: 0.019). PIP patients more frequently had a non-lateralizing ictal EEG than controls (p: 0.001). Bitemporal lobe dysfunction revealed by neuropsychological studies was greater than expected by the observed lesion on MRI studies in patients with PIP. Moreover, the presurgical study was less conclusive in PIP than in control patients (p: 0.049). CONCLUSIONS: PIP is observed in up to 9% of patients with TLE undergoing video-EEG monitoring and most often develops in patients with bitemporal lobe dysfunction.

Assessment of migration of HIV-1-loaded dendritic cells labeled with 111In-oxine used as a therapeutic vaccine in HIV-1-infected patients.

Monocyte-derived dendritic cells (DCs) loaded with heat-inactivated HIV are used in therapeutic immunizations. It is not known whether they migrate in vivo to lymph nodes. We used an (111)In-oxine-labeled DC (ILDC) method to visualize the migration of DCs. The activity, time and incubation medium were investigated to obtain the highest cellular viability and radiolabeling yield. A trypan-blue exclusion test was used to determine the cellular viability. In five patients, 2 x 10(6) ILDCs were injected subcutaneously in the arm. An initial dynamic study was performed during the first 5 min after injection. This was followed by static acquisitions at several time points, using a high-resolution (general electric) gamma-camera and quantifying the activity at regions of interest drawn on the injection point. The sensitivity of the gamma-camera was evaluated. The highest number of viable DCs (>83%) and the best radiolabeling yield (>70%) were obtained with 1.11 MBq (111)In-oxine, after 10 min of incubation at 37 degrees C in sodium chloride solution 0.9%. We did not observe migration of ILDCs to local lymph nodes in any patient. However, focal uptake at the place of injection continued during the study period. We observed a higher than expected loss of activity from the injection point (median A(t)/A(0) = 0.60 at day 2), which correlated with an increase in total cytotoxic T lymphocytes (CD8(+) and granzyme B(+) cells) in the lypmphoid tissue observed after immunization (R(2) = 0.92, p = 0.03). If more than 20,000 ILDCs had migrated, they could have been detected. In future trials, a higher number of DCs or alternative methods should be used to assess the migration of DCs to lymph nodes.

Therapeutic immunization with dendritic cells loaded with heat-inactivated autologous HIV-1 in patients with chronic HIV-1 infection.

Therapeutic immunization with autologous monocyte-derived dendritic cells (DCs) loaded with heat-inactivated autologous human immunodeficiency virus type 1 (HIV-1) in 12 patients with chronic HIV-1 infection who were receiving highly active antiretroviral therapy (HAART) was feasible, safe, and well tolerated. Virus was obtained during an initial interruption of HAART (hereafter, "stop 1") so that DCs could be pulsed. After immunization and a second interruption of HAART (hereafter, "stop 2"), set-point plasma viral load (PVL; 24 weeks after stop 2) decreased > or =0.5 log(10) copies/mL relative to baseline PVL in 4 of 12 patients. We observed a significant lengthening in mean doubling time of PVL rebound and significant decreases in the area under the curve and the mean peak of PVL rebound after stop 2, compared with those after stop 1. This response was associated with changes in HIV-1-specific CD4(+) lymphoproliferative and CD8(+) T cell responses. These changes were not observed in a group of nonimmunized control patients.