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Neural network and deep-learning algorithms used in QSAR studies: merits and drawbacks.

Drug Discov Today. 2018 Jun 21;:

Authors: Ghasemi F, Mehridehnavi A, Pérez-Garrido A, Pérez-Sánchez H

Abstract
The past two decades are regarded as the golden age of using neural networks (NNs) in chemoinformatics. However, two major issues have arisen concerning their use: redundancy problems when dealing with small data sets, and the large number of compounds with thousands of descriptors, which gives rise to serious overfitting problems. Various NN algorithms, based on feature selection methods and learning algorithms, were devised to avoid these predicaments in drug discovery. Pruning the overfitting problem has emerged as another challenge in recent years, leading to the advent of deep-learning (DL) networks using innovative techniques. Here, we discuss the advantages and disadvantages of the proposed NN algorithms, especially the innovative DL techniques used in ligand-based virtual screening (VS).

PMID: 29936244 [PubMed - as supplied by publisher]

Related Articles

Linear Regression Links Transcriptomic Data and Cellular Raman Spectra.

Cell Syst. 2018 Jun 08;:

Authors: Kobayashi-Kirschvink KJ, Nakaoka H, Oda A, Kamei KF, Nosho K, Fukushima H, Kanesaki Y, Yajima S, Masaki H, Ohta K, Wakamoto Y

Abstract
Raman microscopy is an imaging technique that has been applied to assess molecular compositions of living cells to characterize cell types and states. However, owing to the diverse molecular species in cells and challenges of assigning peaks to specific molecules, it has not been clear how to interpret cellular Raman spectra. Here, we provide firm evidence that cellular Raman spectra and transcriptomic profiles of Schizosaccharomyces pombe and Escherichia coli can be computationally connected and thus interpreted. We find that the dimensions of high-dimensional Raman spectra and transcriptomes measured by RNA sequencing can be reduced and connected linearly through a shared low-dimensional subspace. Accordingly, we were able to predict global gene expression profiles by applying the calculated transformation matrix to Raman spectra, and vice versa. Highly expressed non-coding RNAs contributed to the Raman-transcriptome linear correspondence more significantly than mRNAs in S. pombe. This demonstration of correspondence between cellular Raman spectra and transcriptomes is a promising step toward establishing spectroscopic live-cell omics studies.

PMID: 29936183 [PubMed - as supplied by publisher]

Related Articles

Isoniazid-induced hepatotoxicity and neurotoxicity in rats investigated by 1H NMR based metabolomics approach.

Toxicol Lett. 2018 Jun 21;:

Authors: Ruan LY, Fan JT, Hong W, Zhao H, Li MH, Jiang L, Fu YH, Xing YX, Chen C, Wang JS

Abstract
Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

PMID: 29936297 [PubMed - as supplied by publisher]

Funding Opportunity RFA-AG-19-009 from the NIH Guide for Grants and Contracts. The purpose of this FOA is to solicit applications for the AD/ADRD Health Care Systems Research Collaboratory (Collaboratory, henceforth) to improve care for persons with dementia (PWD) and their caregivers through health systems. Health and long-term systems for this FOA are defined broadly and include organizations providing care across settings to include primary and specialty outpatient care, acute inpatient care, skilled nursing and other rehabilitation facilities, residential long-term care, and home and community-based services. Organizations may be traditional health care systems (e.g., health maintenance organizations, or HMOs), health insurance companies, managed care plans, home health care providers, memory clinics, nursing homes, assisted living facilities, outpatient clinics, federally-designated health centers, hospitals, and other providers of acute and long-term care. The Collaboratory will: 1) serve as a national resource to promote development of pragmatic trials and demonstration projects to improve care and health outcomes for PWD and their caregivers; 2) support pilot pragmatic trials within the Collaboratory; 3) develop and disseminate technical and policy guidelines and best practices for effectively conducting AD/ADRD research studies in partnership with health care systems; 4) work collaboratively with researchers to provide technical support for scaling up pilot studies, and; 5) disseminate best practices for engaging stakeholders, conducting ethical research in the special circumstances of dementia care, and involving long-term and acute-care providers.

Related Articles

The A-Z of Zika drug discovery.

Drug Discov Today. 2018 Jun 20;:

Authors: Mottin M, Borba JVVB, Braga RC, Torres PHM, Martini MC, Proenca-Modena JL, Judice CC, Costa FTM, Ekins S, Perryman AL, Andrade CH

Abstract
Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond.

PMID: 29935345 [PubMed - as supplied by publisher]

Related Articles

Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.

Congenit Anom (Kyoto). 2018 Jun 23;:

Authors: Rahman SB, Mir A, Ahmad N, Haider SH, Malik SA, Nasir M

Abstract
Non-bullous congenital ichthyosiform erythroderma (NCIE) is characterized by skin scaling with erythema. In this study, two Pakistani families with NCIE are genetically characterized through Whole Exome and Sanger sequencing to identify molecular basis of the disease. We identified a nonsense homozygous c.2026C>T mutation of ALOXE3, causing premature termination of the eLOX3 protein (p.Q676X). In silico studies predicted impaired enzymatic activity of the premature truncated eLOX3, leading to abnormal synthesis of specific hepoxilin derivatives, essential for epidermal barrier formation. It is the first ever study reporting homozygotes of p.Q676X mutation in ethnically distinct two Pakistani families; otherwise, heterozygotes of the said mutation have been reported in South Asian population only. Hence, mutation seems to be region-specific and may be useful for molecular diagnosis of NCIE. Moreover, our findings should help in genetic counseling and career screening. This article is protected by copyright. All rights reserved.

PMID: 29935003 [PubMed - as supplied by publisher]

Related Articles

Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy.

Neuromuscul Disord. 2018 May 21;:

Authors: Findlay AR, Harms MB, Pestronk A, Weihl CC

Abstract
Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246Thr homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies.

PMID: 29934118 [PubMed - as supplied by publisher]

Related Articles

Genomic Landscapes of EBV-Associated Nasopharyngeal Carcinoma vs. HPV-Associated Head and Neck Cancer.

Cancers (Basel). 2018 Jun 21;10(7):

Authors: Ngan HL, Wang L, Lo KW, Lui VWY

Abstract
: Epstein-Barr virus-positive nasopharyngeal carcinoma (EBV(+) NPC), and human papillomavirus-positive head and neck squamous cell carcinoma (HPV(+) HNSCC) are two distinct types of aggressive head and neck cancers with early age onsets. Their recently identified genomic landscapes by whole-exome sequencing (WES) clearly reveal critical roles of: (1) inflammation via NF-kB activation, (2) survival via PI3K aberrations, and perhaps (3) immune evasion via MHC loss in these cancers as summarized in this review. Immediate outcomes of these WES studies include the identification of potential prognostic biomarkers, and druggable events for these cancers. The impact of these genomic findings on the development of precision medicine and immunotherapies will be discussed. For both of these cancers, the main lethality comes from metastases and disease recurrences which may represent therapy resistance. Thus, potential curing of these cancers still relies on future identification of key genomic drivers and likely druggable events in recurrent and metastatic forms of these intrinsically aggressive cancers of the head and neck.

PMID: 29933636 [PubMed]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/06/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles

Publisher Correction: Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.

Nat Med. 2018 Jun 22;:

Authors: Romani L, Oikonomou V, Moretti S, Iannitti RG, D'Adamo MC, Villella VR, Pariano M, Sforna L, Borghi M, Bellet MM, Fallarino F, Pallotta MT, Servillo G, Ferrari E, Puccetti P, Kroemer G, Pessia M, Maiuri L, Goldstein AL, Garaci E

Abstract
In the version of this article originally published, the amino acid sequence for Tα1 described in the Online Methods is incorrect. The sequence is described as "Ac-SDAAVDTSSEITTJDLKEKKEVVEEAEN-OH". It should be "Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN-OH". The error has been corrected in the HTML and PDF versions of this article.

PMID: 29934535 [PubMed - as supplied by publisher]

Related Articles

Author Correction: Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.

Nat Med. 2018 Jun 22;:

Authors: Romani L, Oikonomou V, Moretti S, Iannitti RG, D'Adamo MC, Villella VR, Pariano M, Sforna L, Borghi M, Bellet MM, Fallarino F, Pallotta MT, Servillo G, Ferrari E, Puccetti P, Kroemer G, Pessia M, Maiuri L, Goldstein AL, Garaci E

Abstract
In the version of this article originally published, some labels in Fig. 1f are incorrect. The "β-actin" labels on the second and fourth rows of blots should instead be "β-tubulin". The error has been corrected in the HTML and PDF versions of this article.

PMID: 29934534 [PubMed - as supplied by publisher]

Related Articles

Quantitative assessment of individual populations within polymicrobial biofilms.

Sci Rep. 2018 Jun 22;8(1):9494

Authors: Lopes SP, Azevedo NF, Pereira MO

Abstract
Selecting appropriate tools providing reliable quantitative measures of individual populations in biofilms is critical as we now recognize their true polymicrobial and heterogeneous nature. Here, plate count, quantitative real-time polymerase chain reaction (q-PCR) and peptide nucleic acid probe-fluorescence in situ hybridization (PNA-FISH) were employed to quantitate cystic fibrosis multispecies biofilms. Growth of Pseudomonas aeruginosa, Inquilinus limosus and Dolosigranulum pigrum was assessed in dual- and triple-species consortia under oxygen and antibiotic stress. Quantification methods, that were previously optimized and validated in planktonic consortia, were not always in agreement when applied in multispecies biofilms. Discrepancies in culture and molecular outcomes were observed, particularly for triple-species consortia and antibiotic-stressed biofilms. Some differences were observed, such as the higher bacterial counts obtained by q-PCR and/or PNA-FISH (≤4 log10 cells/cm2) compared to culture. But the discrepancies between PNA-FISH and q-PCR data (eg D. pigrum limited assessment by q-PCR) demonstrate the effect of biofilm heterogeneity in method's reliability. As the heterogeneity in biofilms is a reflection of a myriad of variables, tailoring an accurate picture of communities´ changes is crucial. This work demonstrates that at least two, but preferentially three, quantification techniques are required to obtain reliable measures and take comprehensive analysis of polymicrobial biofilm-associated infections.

PMID: 29934504 [PubMed - in process]

Related Articles

CFTR modulator theratyping: Current status, gaps and future directions.

J Cyst Fibros. 2018 Jun 19;:

Authors: Clancy JP, Cotton CU, Donaldson SH, Solomon GM, VanDevanter DR, Boyle MP, Gentzsch M, Nick JA, Illek B, Wallenburg JC, Sorscher EJ, Amaral MD, Beekman JM, Naren AP, Bridges RJ, Thomas PJ, Cutting G, Rowe S, Durmowicz AG, Mense M, Boeck KD, Skach W, Penland C, Joseloff E, Bihler H, Mahoney J, Borowitz D, Tuggle KL

Abstract
BACKGROUND: New drugs that improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with discreet disease-causing variants have been successfully developed for cystic fibrosis (CF) patients. Preclinical model systems have played a critical role in this process, and have the potential to inform researchers and CF healthcare providers regarding the nature of defects in rare CFTR variants, and to potentially support use of modulator therapies in new populations.
METHODS: The Cystic Fibrosis Foundation (CFF) assembled a workshop of international experts to discuss the use of preclinical model systems to examine the nature of CF-causing variants in CFTR and the role of in vitro CFTR modulator testing to inform in vivo modulator use. The theme of the workshop was centered on CFTR theratyping, a term that encompasses the use of CFTR modulators to define defects in CFTR in vitro, with application to both common and rare CFTR variants.
RESULTS: Several preclinical model systems were identified in various stages of maturity, ranging from the expression of CFTR variant cDNA in stable cell lines to examination of cells derived from CF patients, including the gastrointestinal tract, the respiratory tree, and the blood. Common themes included the ongoing need for standardization, validation, and defining the predictive capacity of data derived from model systems to estimate clinical outcomes from modulator-treated CF patients.
CONCLUSIONS: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.

PMID: 29934203 [PubMed - as supplied by publisher]

Related Articles

The choice of lung function reference equation affects clinical trial eligibility: Results from a cystic fibrosis cohort.

J Cyst Fibros. 2018 Jun 19;:

Authors: Mathiesen IH, Ronit A, Pressler T

PMID: 29934202 [PubMed - as supplied by publisher]

Related Articles

Extracellular pH and lung infections in cystic fibrosis.

Eur J Cell Biol. 2018 Jun 18;:

Authors: Massip-Copiz MM, Santa-Coloma TA

Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by CFTR mutations. It is characterized by high NaCl concentration in sweat and the production of a thick and sticky mucus, occluding secretory ducts, intestine and airways, accompanied by chronic inflammation and infections of the lungs. This causes a progressive and lethal decline in lung function. Therefore, finding the mechanisms driving the high susceptibility to lung infections has been a key issue. For decades the prevalent hypothesis was that a reduced airway surface liquid (ASL) volume and composition, and the consequent increased mucus concentration (dehydration), create an environment favoring infections. However, a few years ago, in a pig model of CF, the Na+/K+ concentrations and the ASL volume were found intact. Immediately a different hypothesis arose, postulating a reduced ASL pH as the cause for the increased susceptibility to infections, due to a diminished bicarbonate secretion through CFTR. Noteworthy, a recent report found normal ASL pH values in CF children and in cultured primary airway cells, challenging the ASL pH hypothesis. On the other hand, recent evidences revitalized the hypothesis of a reduced ASL secretion. Thus, the role of the ASL pH in the CF is still a controversial matter. In this review we discuss the basis that sustain the role of CFTR in modulating the extracellular pH, and the recent results sustaining the different points of view. Finding the mechanisms of CFTR signaling that determine the susceptibility to infections is crucial to understand the pathophysiology of CF and related lung diseases.

PMID: 29933921 [PubMed - as supplied by publisher]

Related Articles

Assessment of liver disease in cystic fibrosis.

Paediatr Respir Rev. 2018 May 18;:

Authors: Davison S

Abstract
Liver disease in cystic fibrosis has many causes, with biliary fibrosis due to abnormal CFTR protein predominating. Assessment requires aetiology to be defined. Biliary fibrosis may progress to cirrhosis and portal hypertension, which although initially asymptomatic, may cause varices and splenomegaly. Monitoring progression includes clinical and ultrasound assessment with endoscopic assessment of varices for those at risk. Extrapolated primarily from longitudinal assessment of viral hepatitis in adults, non-invasive elastography has a potential role. Evidence is lacking to support intervention strategies, but ursodeoxycholic acid and ligation of varices are widely applied. Indication and timing of liver transplantation are not clearly defined. Multidisciplinary approach is needed to tailor assessment and guide management.

PMID: 29933897 [PubMed - as supplied by publisher]

A novel framework for biomedical entity sense induction.

J Biomed Inform. 2018 Jun 20;:

Authors: Lossio-Ventura JA, Bian J, Jonquet C, Roche M, Teisseire M

Abstract
BACKGROUND: Rapid advancements in biomedical research have accelerated the number of relevant electronic documents published online, ranging from scholarly articles to news, blogs, and user-generated social media content. Nevertheless, the vast amount of this information is poorly organized, making it difficult to navigate. Emerging technologies such as ontologies and knowledge bases (KBs) could help organize and track the information associated with biomedical research developments. A major challenge in the automatic construction of ontologies and KBs is the identification of words with its respective sense(s) from a free-text corpus. Word-sense induction (WSI) is a task to automatically induce the different senses of a target word in the different contexts. In the last two decades, there have been several efforts on WSI. However, few methods are effective in biomedicine and life sciences.
METHODS: We developed a framework for biomedical entity sense induction using a mixture of natural language processing, supervised, and unsupervised learning methods with promising results. It is composed of three main steps: 1) a polysemy detection method to determine if a biomedical entity has many possible meanings; 2) a clustering quality index-based approach to predict the number of senses for the biomedical entity; and 3) a method to induce the concept(s) (i.e., senses) of the biomedical entity in a given context.
RESULTS: To evaluate our framework, we used the well-known MSH WSD polysemic dataset that contains 203 annotated ambiguous biomedical entities, where each entity is linked to 2 to 5 concepts. Our polysemy detection method obtained an F-measure of 98%. Second, our approach for predicting the number of senses achieved an F-measure of 93%. Finally, we induced the concepts of the biomedical entities based on a clustering algorithm and then extracted the keywords of reach cluster to represent the concept.
CONCLUSIONS: We have developed a framework for biomedical entity sense induction with promising results. Our study results can benefit a number of downstream applications, for example, help to resolve concept ambiguities when building Semantic Web KBs from biomedical text.

PMID: 29935347 [PubMed - as supplied by publisher]

The pediatric acenocoumarol dosing algorithm: The Children Anticoagulation and Pharmacogenetics Study.

J Thromb Haemost. 2018 Jun 23;:

Authors: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJM, Appel IM, Tamminga RYJ, le Cessie S, Swen JJ, van der Straaten T, de Boer A, Maitland-van der Zee AH

Abstract
BACKGROUND: The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the right dose for a patient, however not for acenocoumarol.
OBJECTIVES: To develop dosing algorithms for pediatric patients on acenocoumarol with and without genetic information.
METHODS: The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as ≥3 consecutive International Normalized Ratio measurements within therapeutic range over a period of ≥3 weeks.
RESULTS: In total 175 patients were included in the study of whom 86 patients had a stable period and no missing clinical information (clinical cohort; median age 8.9 years and 49% female). Of 80 of these 86 patients genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. By adding the genotypes of VKORC1, CYP2C9, and CYP2C18 to the algorithm it increased to 61.8%.
CONCLUSIONS: These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability. This article is protected by copyright. All rights reserved.

PMID: 29935043 [PubMed - as supplied by publisher]

Related Articles

Liquid biopsies to optimize therapeutic efficacy in unresponsive lung cancer patients.

Expert Opin Drug Metab Toxicol. 2018 Jun 22;:

Authors: Santarpia M, Funel N, Ali A, Giovannetti E

PMID: 29933706 [PubMed - as supplied by publisher]

42 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/06/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.