Next-Generation Grade and Survival Expression Biomarkers of Human Gliomas Based on Algorithmically Reconstructed Molecular Pathways.

In gliomas, expression of certain marker genes is strongly associated with survival and tumor type and often exceeds histological assessments. Using a human interactome model, we algorithmically reconstructed 7494 new-type molecular pathways that are centered each on an individual protein. Each single-gene expression and gene-centric pathway activation was tested as a survival and tumor grade biomarker in gliomas and their diagnostic subgroups (IDH mutant or wild type, IDH mutant with 1p/19q co-deletion, MGMT promoter methylated or unmethylated), including the three major molecular subtypes of glioblastoma (proneural, mesenchymal, classical). We used three datasets from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas, which in total include 527 glioblastoma and 1097 low grade glioma profiles. We identified 2724 such gene and 2418 pathway survival biomarkers out of total 17,717 genes and 7494 pathways analyzed. We then assessed tumor grade and molecular subtype biomarkers and with the threshold of AUC > 0.7 identified 1322/982 gene biomarkers and 472/537 pathway biomarkers. This suggests roughly two times greater efficacy of the reconstructed pathway approach compared to gene biomarkers. Thus, we conclude that activation levels of algorithmically reconstructed gene-centric pathways are a potent class of new-generation diagnostic and prognostic biomarkers for gliomas.

Latching chains in K-nearest-neighbor and modular small-world networks.

Latching dynamics retrieve pattern sequences successively by neural adaption and pattern correlation. We have previously proposed a modular latching chain model in Song et al. (2014) to better accommodate the structured transitions in the brain. Different cortical areas have different network structures. To explore how structural parameters like rewiring probability, threshold, noise and feedback connections affect the latching dynamics, two different connection schemes, K-nearest-neighbor network and modular network both having modular structure are considered. Latching chains are measured using two proposed measures characterizing length of intra-modular latching chains and sequential inter-modular association transitions. Our main findings include: (1) With decreasing threshold coefficient and rewiring probability, both the K-nearest-neighbor network and the modular network experience quantitatively similar phase change processes. (2) The modular network exhibits selectively enhanced latching in the small-world range of connectivity. (3) The K-nearest-neighbor network is more robust to changes in rewiring probability, while the modular network is more robust to the presence of noise pattern pairs and to changes in the strength of feedback connections. According to our findings, the relationships between latching chains in K-nearest-neighbor and modular networks and different forms of cognition and information processing emerging in the brain are discussed.

Synthesis and Biological Evaluation of a Series of New Hybrid Amide Derivatives of Triazole and Thiazolidine-2,4-dione.

A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the target compounds have been tested. A microbiological assessment of the obtained compounds was carried out on strains of pathogenic fungi C. albicans, C. non-albicans, multidrug-resistant C. auris, Rhizopus arrhizus, Aspergillus spp. and some dermatophytes and other yeasts. The lowest obtained MIC values for target compounds lie between 0.003 µg/mL and 0.5 µg/mL and therefore the compounds are not inferior or several times better than commercial azole drugs. The length of the acylpiperazine linker has a limited effect on antifungal activity. Some bioisosteric analogues were tested in microbiological analysis, but turned out to be weaker than the leader in activity. The highest activity was demonstrated by a compound with para-chlorobenzylidene substituent in the thiazolidine fragment. Molecular modelling was used to predict binding modes of synthesized molecules and rationalize experimentally observed SAR. The leader compound is twice more effective in inhibiting the formation of germ tubes by Candida albicans yeast cells compared to voriconazole. An increased level of Pdr5, an azoles drug efflux pump was observed, but the increase is lower than that caused by azoles. The results can be useful for further development of more powerful and safe antifungal agents.

Uniformly shaped harmonization combines human transcriptomic data from different platforms while retaining their biological properties and differential gene expression patterns.

Introduction: Co-normalization of RNA profiles obtained using different experimental platforms and protocols opens avenue for comprehensive comparison of relevant features like differentially expressed genes associated with disease. Currently, most of bioinformatic tools enable normalization in a flexible format that depends on the individual datasets under analysis. Thus, the output data of such normalizations will be poorly compatible with each other. Recently we proposed a new approach to gene expression data normalization termed Shambhala which returns harmonized data in a uniform shape, where every expression profile is transformed into a pre-defined universal format. We previously showed that following shambhalization of human RNA profiles, overall tissue-specific clustering features are strongly retained while platform-specific clustering is dramatically reduced. Methods: Here, we tested Shambhala performance in retention of fold-change gene expression features and other functional characteristics of gene clusters such as pathway activation levels and predicted cancer drug activity scores. Results: Using 6,793 cancer and 11,135 normal tissue gene expression profiles from the literature and experimental datasets, we applied twelve performance criteria for different versions of Shambhala and other methods of transcriptomic harmonization with flexible output data format. Such criteria dealt with the biological type classifiers, hierarchical clustering, correlation/regression properties, stability of drug efficiency scores, and data quality for using machine learning classifiers. Discussion: Shambhala-2 harmonizer demonstrated the best results with the close to 1 correlation and linear regression coefficients for the comparison of training vs validation datasets and more than two times lesser instability for calculation of drug efficiency scores compared to other methods.

Algorithmically Reconstructed Molecular Pathways as the New Generation of Prognostic Molecular Biomarkers in Human Solid Cancers.

Individual gene expression and molecular pathway activation profiles were shown to be effective biomarkers in many cancers. Here, we used the human interactome model to algorithmically build 7470 molecular pathways centered around individual gene products. We assessed their associations with tumor type and survival in comparison with the previous generation of molecular pathway biomarkers (3022 "classical" pathways) and with the RNA transcripts or proteomic profiles of individual genes, for 8141 and 1117 samples, respectively. For all analytes in RNA and proteomic data, respectively, we found a total of 7441 and 7343 potential biomarker associations for gene-centric pathways, 3020 and 2950 for classical pathways, and 24,349 and 6742 for individual genes. Overall, the percentage of RNA biomarkers was statistically significantly higher for both types of pathways than for individual genes (p < 0.05). In turn, both types of pathways showed comparable performance. The percentage of cancer-type-specific biomarkers was comparable between proteomic and transcriptomic levels, but the proportion of survival biomarkers was dramatically lower for proteomic data. Thus, we conclude that pathway activation level is the advanced type of biomarker for RNA and proteomic data, and momentary algorithmic computer building of pathways is a new credible alternative to time-consuming hypothesis-driven manual pathway curation and reconstruction.

An investigation of codon usage pattern analysis in pancreatitis associated genes.

BACKGROUND: Pancreatitis is an inflammatory disorder resulting from the autoactivation of trypsinogen in the pancreas. The genetic basis of the disease is an old phenomenon, and evidence is accumulating for the involvement of synonymous/non-synonymous codon variants in disease initiation and progression. RESULTS: The present study envisaged a panel of 26 genes involved in pancreatitis for their codon choices, compositional analysis, relative dinucleotide frequency, nucleotide disproportion, protein physical properties, gene expression, codon bias, and interrelated of all these factors. In this set of genes, gene length was positively correlated with nucleotide skews and codon usage bias. Codon usage of any gene is dependent upon its AT and GC component; however, AGG, CGT, and CGA encoding for Arg, TCG for Ser, GTC for Val, and CCA for Pro were independent of nucleotide compositions. In addition, Codon GTC showed a correlation with protein properties, isoelectric point, instability index, and frequency of basic amino acids. We also investigated the effect of various evolutionary forces in shaping the codon usage choices of genes. CONCLUSIONS: This study will enable us to gain insight into the molecular signatures associated with the disease that might help identify more potential genes contributing to enhanced risk for pancreatitis. All the genes associated with pancreatitis are generally associated with physiological function, and mutations causing loss of function, over or under expression leads to an ailment. Therefore, the present study attempts to envisage the molecular signature in a group of genes that lead to pancreatitis in case of malfunction.

Ameliorative Effects of Phytomedicines on Alzheimer's Patients.

INTRODUCTION: Alzheimer's disease (AD) is a progressive, neurodegenerative disease that severely affects individuals' cognitive abilities, memory, and quality of life. It affects the elderly population, and there is no permanent prevention or cures available to date, treatments mainly aiming to alleviate the symptoms as and when they appear. Alternate therapeutic approaches are being researched constantly, and there is a growing focus on phytomedicine, herbal medicine, organic compounds, and ayurvedic compounds for the treatment of AD. METHODS: The current study aims to provide an extensive review of these plants against AD from the currently existing literature. Most relevant keywords like Alzheimer's Disease, phytomedicines, ethnic medicines, the role of phytomedicine in neuroprotection, common phytomedicines against AD, etc., were used to select the plants and their metabolites effective in treating AD. The study focuses on six plants: Panax ginseng, Ginkgo biloba, Bacopa monnieri, Withania somnifera, Curcuma longa, and Lavandula angustifolia. Their active components have been studied along with neuroprotective properties, and evidence of in-vitro, pre-clinical, and clinical studies conducted to prove their therapeutic potential against the disease have been presented. RESULTS: All plants envisaged in the study show potential for fighting against AD to varying degrees. Their compounds have shown therapeutic effects by reversing the neurological changes such as clearing Aß plaque and neurofibrillary tangle formation, and ameliorative effects against neurodegeneration through processes including improving concentration, memory, cognition and learning, higher working and cue memory, improved spatial memory, inhibition of NF-κB expression, inhibiting the release of pro-inflammatory cytokines, inhibition of AChE and lipid peroxidase enzymes, and reduction of interleukin levels and tumor necrosis factor-alpha. CONCLUSION: The present review is a comprehensive and up-to-date analysis supported by the evidentiary proofs from pre-clinical studies, meta-analyses, and review papers related to natural phytochemicals' impact on neurodegenerative disorders like AD.

Evaluation of New Antimicrobial Agents Based on tris(1H-Indol-3-yl)methylium Salts: Activity, Toxicity, Suppression of Experimental Sepsis in Mice.

The antimicrobial activity and toxicity of three novel synthetic antibacterial agents containing tris(1H-indol-3-yl)methylium fragment were studied in vitro and in vivo. All compounds in vitro revealed high activity (minimal inhibitory concentration (MIC) 0.13-1.0 µg/mL) against bacteria that were either sensitive or resistant to antibiotics, including multidrug-resistant clinical isolates. The derivatives combining high antimicrobial activity with relatively low cytotoxicity against human donor fibroblasts HPF-hTERT were subjected to further testing on mice. In vivo they revealed fairly good tolerance and relatively low toxicity. Acute toxicity was evaluated, and the main indicators of toxicity, including LD50 and LD10, were determined. A study of compounds in vivo showed their efficiency in the model of staphylococcal sepsis in mice. The efficiency of compounds may be due to the ability of indolylmethylium salts to form pores in the cytoplasmic membrane of microbial cells and thereby facilitate the penetration of molecules into the pathogen.

Antifungal Thiazolidines: Synthesis and Biological Evaluation of Mycosidine Congeners.

Novel derivatives of Mycosidine (3,5-substituted thiazolidine-2,4-diones) are synthesized by Knoevenagel condensation and reactions of thiazolidines with chloroformates or halo-acetic acid esters. Furthermore, 5-Arylidene-2,4-thiazolidinediones and their 2-thioxo analogs containing halogen and hydroxy groups or di(benzyloxy) substituents in 5-benzylidene moiety are tested for antifungal activity in vitro. Some of the synthesized compounds exhibit high antifungal activity, both fungistatic and fungicidal, and lead to morphological changes in the Candida yeast cell wall. Based on the use of limited proteomic screening and toxicity analysis in mutants, we show that Mycosidine activity is associated with glucose transport. This suggests that this first-in-class antifungal drug has a novel mechanism of action that deserves further study.

OncoboxPD: human 51 672 molecular pathways database with tools for activity calculating and visualization.

OncoboxPD (Oncobox pathway databank) available at https://open.oncobox.com is the collection of 51 672 uniformly processed human molecular pathways. Superposition of all pathways formed interactome graph of protein-protein interactions and metabolic reactions containing 361 654 interactions and 64 095 molecular participants. Pathways are uniformly classified by biological processes, and each pathway node is algorithmically functionally annotated by specific activator/repressor role. This enables online calculation of statistically supported pathway activation levels (PALs) with the built-in bioinformatic tool using custom RNA/protein expression profiles. Each pathway can be visualized as static or dynamic graph, where vertices are molecules participating in a pathway and edges are interactions or reactions between them. Differentially expressed nodes in a pathway can be visualized in two-color mode with user-defined color scale. For every comparison, OncoboxPD also generates a graph summarizing top up- and downregulated pathways.

Experimental and Meta-Analytic Validation of RNA Sequencing Signatures for Predicting Status of Microsatellite Instability.

Microsatellite instability (MSI) is an important diagnostic and prognostic cancer biomarker. In colorectal, cervical, ovarian, and gastric cancers, it can guide the prescription of chemotherapy and immunotherapy. In laboratory diagnostics of susceptible tumors, MSI is routinely detected by the size of marker polymerase chain reaction products encompassing frequent microsatellite expansion regions. Alternatively, MSI status is screened indirectly by immunohistochemical interrogation of microsatellite binding proteins. RNA sequencing (RNAseq) profiling is an emerging source of data for a wide spectrum of cancer biomarkers. Recently, three RNAseq-based gene signatures were deduced for establishing MSI status in tumor samples. They had 25, 15, and 14 gene products with only one common gene. However, they were developed and tested on the incomplete literature of The Cancer Genome Atlas (TCGA) sampling and never validated experimentally on independent RNAseq samples. In this study, we, for the first time, systematically validated these three RNAseq MSI signatures on the literature colorectal cancer (CRC) (n = 619), endometrial carcinoma (n = 533), gastric cancer (n = 380), uterine carcinosarcoma (n = 55), and esophageal cancer (n = 83) samples and on the set of experimental CRC RNAseq samples (n = 23) for tumors with known MSI status. We found that all three signatures performed well with area under the curve (AUC) ranges of 0.94-1 for the experimental CRCs and 0.94-1 for the TCGA CRC, esophageal cancer, and uterine carcinosarcoma samples. However, for the TCGA endometrial carcinoma and gastric cancer samples, only two signatures were effective with AUC 0.91-0.97, whereas the third signature showed a significantly lower AUC of 0.69-0.88. Software for calculating these MSI signatures using RNAseq data is included.

N-(Hydroxyalkyl) Derivatives of tris(1H-indol-3-yl)methylium Salts as Promising Antibacterial Agents: Synthesis and Biological Evaluation.

The wide spread of pathogens resistance requires the development of new antimicrobial agents capable of overcoming drug resistance. The main objective of the study is to elucidate the effect of substitutions in tris(1H-indol-3-yl)methylium derivatives on their antibacterial activity and toxicity to human cells. A series of new compounds were synthesized and tested. Their antibacterial activity in vitro was performed on 12 bacterial strains, including drug resistant strains, that were clinical isolates or collection strains. The cytotoxic effect of the compounds was determined using an test with HPF-hTERT (human postnatal fibroblasts, immortalized with hTERT) cells. The activity of the obtained compounds depended on the carbon chain length. Derivatives with C5-C6 chains were more active. The minimum inhibitory concentration (MIC) of the most active compound on Gram-positive bacteria, including MRSA, was 0.5 µg/mL. Compounds with C5-C6 chains also revealed high activity against Staphylococcus epidermidis (1.0 and 0.5 µg/mL, respectively) and moderate activity against Gram-negative bacteria Escherichia coli (8 µg/mL) and Klebsiella pneumonia (2 and 8 µg/mL, respectively). However, they have no activity against Salmonella cholerasuis and Pseudomonas aeruginosa. The most active compounds revealed higher antibacterial activity on MRSA than the reference drug levofloxacin, and their ratio between antibacterial and cytotoxic activity exceeded 10 times. The data obtained provide a basis for further study of this promising group of substances.

Synthesis and antimicrobial activity of 3,4-bis(arylthio)maleimides.

A series of 3,4-bis(arylthio)maleimides were synthesized and their antimicrobial activity was evaluated against Gram-positive and Gram-negative bacteria, including multidrug resistant (MDR) strains and some fungi. Most compounds turned out to be highly active, activity being dependent on substituents on phenyl rings.

FLOating-Window Projective Separator (FloWPS): A Data Trimming Tool for Support Vector Machines (SVM) to Improve Robustness of the Classifier.

Here, we propose a heuristic technique of data trimming for SVM termed FLOating Window Projective Separator (FloWPS), tailored for personalized predictions based on molecular data. This procedure can operate with high throughput genetic datasets like gene expression or mutation profiles. Its application prevents SVM from extrapolation by excluding non-informative features. FloWPS requires training on the data for the individuals with known clinical outcomes to create a clinically relevant classifier. The genetic profiles linked with the outcomes are broken as usual into the training and validation datasets. The unique property of FloWPS is that irrelevant features in validation dataset that don't have significant number of neighboring hits in the training dataset are removed from further analyses. Next, similarly to the k nearest neighbors (kNN) method, for each point of a validation dataset, FloWPS takes into account only the proximal points of the training dataset. Thus, for every point of a validation dataset, the training dataset is adjusted to form a floating window. FloWPS performance was tested on ten gene expression datasets for 992 cancer patients either responding or not on the different types of chemotherapy. We experimentally confirmed by leave-one-out cross-validation that FloWPS enables to significantly increase quality of a classifier built based on the classical SVM in most of the applications, particularly for polynomial kernels.

Feature Detection in Visual Cortex during Different Functional States.

Cortical activity exhibits distinct characteristics in different functional states. In awake behaving animals it shows less synchrony, while in rest or sleeping state cortical activity is most synchronous. Previous studies showed that switching between functional states can change the efficiency of flowing sensory information. Switching between functional states can be triggered by releasing neuromodulators which affect neurotransmitter release probability and depolarization of cortical neurons. In this work we focus on studying primary visual area V1, by using firing rate ring model with short-term synaptic depression (STD). We show that reconstruction of visual features from V1 activity depends on the functional state, with best precision achieved at the state with intermediate release probability. We suggest that this regime corresponds to the state of maximal visual attention.

Pattern retrieval in a three-layer oscillatory network with a context dependent synaptic connectivity.

We propose a network solution for memory pattern retrieval in an oscillatory network based on a context dependent Hebbian connectivity. The model is composed of three interacting layers of spiking neurons with excitatory and inhibitory synaptic connections. Information patterns are stored in the memory using a symmetric Hebbian matrix and can be retrieved in response to a definite stimulus pattern. The patterns are encoded as distributions of phases of the oscillatory network units. We include in the network architecture an intermediate layer of excitable (non-oscillatory) interneurons. This layer provides a kind of pre-processing by filtering the in-phase or the anti-phase components of the input pattern. Then, only a part of Hebbian connections defined by the input (a "context dependent connectivity") is further used for the memory retrieval. Being supplied with an oscillatory clock signal the interneurons drive the signal propagation pathways in the feedforward architecture and, hence, reduce the number of effective connections needed for the retrieval. The oscillation phase stability problem for the in-phase and anti-phase locking modes is investigated. Information characteristics and efficiency of the context dependent retrieval are discussed and compared with traditional oscillatory associative memory models.

An analysis of reasons for failed back surgery syndrome and partial results after different types of surgical lumbar nerve root decompression.

BACKGROUND: Despite the evident progress in treating vertebral column degenerative diseases, the rate of a so-called "failed back surgery syndrome" associated with pain and disability remains relatively high. However, this term has an imprecise definition and includes several different morbid conditions following spinal surgery, not all of which directly illustrate the efficacy of the applied technology; furthermore, some of them could even be irrelevant. OBJECTIVE: To evaluate and systematize the reasons for persistent pain syndromes following surgical nerve root decompression. STUDY DESIGN: Prospective, nonrandomized, cohort study of 138 consecutive patients with radicular pain syndromes, associated with nerve root compression caused by lumbar disc herniation, and resistant to conservative therapy for at least one month. The minimal period of follow-up was 18 months. SETTING: Hospital outpatient department, Russian Federation METHODS: Pre-operatively, patients were examined clinically, applying the visual analog scale (VAS), Oswestry Disability Index (ODI), magnetic resonance imaging (MRI), discography and computed tomography (CT). According to the disc herniation morphology and applied type of surgery, all participants were divided into the following groups: for those with disc extrusion or sequester, microdiscectomy was applied (n = 65); for those with disc protrusion, nucleoplasty was applied (n = 46); for those with disc extrusion, nucleoplasty was applied (n = 27). After surgery, participants were examined clinically and the VAS and ODI were applied. All those with permanent or temporary pain syndromes were examined applying MRI imaging, functional roentgenograms, and, to validate the cause of pain syndromes, different types of blocks were applied (facet joint blocks, paravertebral muscular blocks, transforaminal and caudal epidural blocks). RESULTS: Group 1 showed a considerable rate of pain syndromes related to tissue damage during the intervention; the rates of radicular pain caused by epidural scar and myofascial pain were 12.3% and 26.1% respectively. Facet joint pain was found in 23.1% of the cases. Group 2 showed a significant rate of facet joint pain (16.9%) despite the minimally invasive intervention. The specificity of Group 3 was the very high rate of unresolved or recurred nerve root compression (63.0%); in other words, in the majority of cases, the aim of the intervention was not achieved. The results of the applied intervention were considered clinically significant if 50% pain relief on the VAS and a 40% decrease in the ODI were achieved. LIMITATIONS: This study is limited because of the loss of participants to follow-up and because it is nonrandomized; also it could be criticized because the dynamics of numeric scores were not provided. CONCLUSION: The results of our study show that an analysis of the reasons for failures and partial effects of applied interventions for nerve root decompression may help to understand better the efficacy of the interventions and could be helpful in improving surgical strategies, otherwise the validity of the conclusion could be limited because not all sources of residual pain illustrate the applied technology efficacy. In the majority of cases, the cause of the residual or recurrent pain can be identified, and this may open new possibilities to improve the condition of patients presenting with failed back surgery syndrome.

Spiking signatures of spontaneous activity bursts in hippocampal cultures.

Dense dissociated hippocampal cultures are known to generate spontaneous bursting electrical activity which can be recorded by multielectrode arrays. We have analyzed spatio-temporal profiles of the distribution of spikes in the bursts recorded after 2 weeks in vitro. We have found a statistically significant similarity between the spiking patterns in sequential bursting events, we refer to these spiking patterns as spiking signatures. Such spiking signatures may appear in different parts of the bursts, including the activation patterns - the first spike times in the bursts, and deactivation patterns - the last spike times in the bursts. Moreover, these patterns may display apparent time scaling, e.g., they may be replayed in the subsequent bursts at different speeds, while preserving the spiking order. We discuss how such properties of the bursts may be associated with the formation of repeatable signaling pathways in cultured networks in vitro.

Search for inhibitors of bacterial and human protein kinases among derivatives of diazepines[1,4] annelated with maleimide and indole cycles.

Aminomethylation of 9b,10-dihydro-1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino-[1,7-a]indole-1,3(2H)-diones or 1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-diones resulted in dialkylaminomethyl derivatives. Alkylation of the nitrogen atom of maleimide moiety of polyannelated diazepines with 1,3-dibromopropane and subsequent reaction with thiourea or its N-alkyl derivatives gave isothiourea-carrying compounds. The compounds containing isothiourea moiety were active against individual human serine/threonine and tyrosine kinases at low micromolar concentrations. Dialkylaminomethyl derivatives of diazepines sensitized Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting serine/threonine kinase(s) mediated aphVIII phosphorylation.