Recent Trends in Computational Research on Diseases

Recent advances in information technology have brought forth a paradigm shift in science, especially in the biology and medical fields. Statistical methodologies based on high-performance computing and big data analysis are now indispensable for the qualitative and quantitative understanding of experimental results. In fact, the last few decades have witnessed drastic improvements in high-throughput experiments in health science, for example, mass spectrometry, DNA microarray, next generation sequencing, etc. Those methods have been providing massive data involving four major branches of omics (genomics, transcriptomics, proteomics, and metabolomics). Information about amino acid sequences, protein structures, and molecular structures are fundamental data for the prediction of bioactivity of chemical compounds when screening drugs. On the other hand, cell imaging, clinical imaging, and personal healthcare devices are also providing important data concerning the human body and disease. In parallel, various methods of mathematical modelling such as machine learning have developed rapidly. All of these types of data can be utilized in computational approaches to understand disease mechanisms, diagnosis, prognosis, drug discovery, drug repositioning, disease biomarkers, driver mutations, copy number variations, disease pathways, and much more. In this Special Issue, we have published 8 excellent papers dedicated to a variety of computational problems in the biomedical field from the genomic level to the whole-person physiological level

Outlook Magazine, Autumn 2012

https://digitalcommons.wustl.edu/outlook/1187/thumbnail.jp

2018 Touro College & University System Faculty Publications

This is the 2018 edition of the Faculty Publications Book of the Touro College & University System. It includes all eligible 2018 publication citations of faculty within the Touro College & University System, including New York Medical College (NYMC). It was produced as a joint effort of the Touro College Libraries and the Health Sciences Library at NYMC.https://touroscholar.touro.edu/facpubs/1008/thumbnail.jp

The role of unfolded protein deposits in cardiac dysfunction

In this study we investigated the role of unfolded proteins as a toxic insult for cardiomyocytes in idiopathic dilated cardiomyopathy (DCM). We first confirmed the presence of amyloid fibers in DCM cardiomyocytes by histological and ultrastructural analysis, showing their preferentially intracellular distribution. These molecular species seem to coexist with low-complexity β-folded precursors (oligomers) which in our experiments could promote increase of systolic Ca2+ in normal cardiomyocytes and alterations of contractility. Our results suggest that these molecular species trigger the overexpression of UPR components such as GRPs, Chop and Caspase 12. In addition we demonstrated the presence of interactions between presenilins (PS) and Serca2a, suggesting a regulatory role of these Alzheimer’s-related proteins on the Ca2+ pump. The genetic analysis of the presenilin genes in DCM samples identified two undescribed mutations in the promoter of PS1, which appeared to inhibit the expression of the protein. The quantification of the presenilin levels showed a considerable decrease of PS2 associated with an increase of PS1. In order to characterize the protein(s) involved in the aggregasomes, we developed a series of purification protocols, which, unfortunately, did not identify a single protein species. As an alternative approach, we focused on the identification of transcripts differentially expressed in iDCM. Our study introduces an innovative three-group analysis in which we used amyloid samples to eliminate the interference related to the accumulation of unfolded peptides and deriving from the progression of HF. Interestingly we recognized a limited number of iDCM-specific genes, including nestin and DSCR1, which are normally correlated to neural development. In conclusion, our findings open intriguing perspectives to increase our knowledge of the etiology and progression of DCM. However further investigation is required to identify the protein(s) involved in the formation of the aggregasomes and the role of these molecular structures in the etiology of the disease

Improving the domain generalization and robustness of neural networks for medical imaging

Deep neural networks are powerful tools to process medical images, with great potential to accelerate clinical workflows and facilitate large-scale studies. However, in order to achieve satisfactory performance at deployment, these networks generally require massive labeled data collected from various domains (e.g., hospitals, scanners), which is rarely available in practice. The main goal of this work is to improve the domain generalization and robustness of neural networks for medical imaging when labeled data is limited. First, we develop multi-task learning methods to exploit auxiliary data to enhance networks. We first present a multi-task U-net that performs image classification and MR atrial segmentation simultaneously. We then present a shape-aware multi-view autoencoder together with a multi-view U-net, which enables extracting useful shape priors from complementary long-axis views and short-axis views in order to assist the left ventricular myocardium segmentation task on the short-axis MR images. Experimental results show that the proposed networks successfully leverage complementary information from auxiliary tasks to improve model generalization on the main segmentation task. Second, we consider utilizing unlabeled data. We first present an adversarial data augmentation method with bias fields to improve semi-supervised learning for general medical image segmentation tasks. We further explore a more challenging setting where the source and the target images are from different data distributions. We demonstrate that an unsupervised image style transfer method can bridge the domain gap, successfully transferring the knowledge learned from labeled balanced Steady-State Free Precession (bSSFP) images to unlabeled Late Gadolinium Enhancement (LGE) images, achieving state-of-the-art performance on a public multi-sequence cardiac MR segmentation challenge. For scenarios with limited training data from a single domain, we first propose a general training and testing pipeline to improve cardiac image segmentation across various unseen domains. We then present a latent space data augmentation method with a cooperative training framework to further enhance model robustness against unseen domains and imaging artifacts.Open Acces

Grand Celebration: 10th Anniversary of the Human Genome Project

In 1990, scientists began working together on one of the largest biological research projects ever proposed. The project proposed to sequence the three billion nucleotides in the human genome. The Human Genome Project took 13 years and was completed in April 2003, at a cost of approximately three billion dollars. It was a major scientific achievement that forever changed the understanding of our own nature. The sequencing of the human genome was in many ways a triumph for technology as much as it was for science. From the Human Genome Project, powerful technologies have been developed (e.g., microarrays and next generation sequencing) and new branches of science have emerged (e.g., functional genomics and pharmacogenomics), paving new ways for advancing genomic research and medical applications of genomics in the 21st century. The investigations have provided new tests and drug targets, as well as insights into the basis of human development and diagnosis/treatment of cancer and several mysterious humans diseases. This genomic revolution is prompting a new era in medicine, which brings both challenges and opportunities. Parallel to the promising advances over the last decade, the study of the human genome has also revealed how complicated human biology is, and how much remains to be understood. The legacy of the understanding of our genome has just begun. To celebrate the 10th anniversary of the essential completion of the Human Genome Project, in April 2013 Genes launched this Special Issue, which highlights the recent scientific breakthroughs in human genomics, with a collection of papers written by authors who are leading experts in the field

Mendeliaarsete haiguste ülegenoomne diagnostika: kromosomaalsest mikrokiibi analüüsist järgmise põlvkonna sekveneerimiseni

Väitekirja elektrooniline versioon ei sisalda publikatsiooneHaruldaste pärilike haiguste diagnostika ja ravi keskne paradigma on täpse molekulaarse haiguspõhjuse (mutatsiooni) tuvastamine igal patsiendil. See on aluseks nii patsiendi ravile, perekonna nõustamisele kui ka sünnieelsele diagnostikale. Kui traditsiooniliselt on geneetiliste haiguste diagnostika olnud võimalik vaid üksikute geenide kaupa, siis tänapäevased tehnoloogiad võimaldavad uurida kõiki enam kui 20 000 geeni korraga. Kuigi teaduses on kromosoomiuuringuteks kasutatavad mikrokiibid ja kõigi geenide järjestamist võimaldavad järgmise põlvkonna sekveneerimisanalüüsid juba ennast hästi tõestanud, on kliinilisse kasutusse rakendamisel vajalik neid metoodikaid teaduslikult analüüsida, et leida igale patsiendile parim uuringustrateegia. Käesoleva uuringuga selgitati nii kromosoomikiipidelt sageli leitud ebaselge tähendusega muutuste, homosügootsete alade, kliinilist tähendust. Näidati, et kolmandik sellistest regioonidest on patsientidel korduvad ja seega tõenäoliselt haigust mittepõhjustavad. Samuti leiti, et üksikud homosügootsed alad sisaldavad harva patsiendi haigusega seostatavat geeni, ent kui selline geen tuvastatakse, on väga tõenäoline leida sealt ka geneetilise haiguse põhjus. Teine osa doktoritööst käsitles suurte geenipaneelide sekveneerimise tulemuslikkust tavapärases kliinilises töös. Töö tulemusena selgus, et ligi 5000 pärilike haigustega seostatud geeni paneeli uuringu tulemuslikkus on võrreldav kõikide geenide ehk eksoomi analüüsiga. Uuringusse kaasatud 501 patsiendist leiti kindel geneetiline haiguspõhjus 132-l (26%). Ligi pooled muutused olid varem kirjeldamata. Doktoritöö viimases osas käsitleti kahte haigusjuhtu. Esiteks kirjeldati maailmas teist korda KPTN geeni mutatsioone intellektipuude põhjusena. Teine haigusjuht, kus lihashaigust põdeva poisi haiguspõhjusena tuvastati uudne MYH7 geeni defekt, laiendas MYH7-seoseliste lihashaiguste teadaolevat kliinilist ja geneetilist spektrit.The fundamental paradigm of diagnostics and care of patients with rare inherited disorders is the detection of specific molecular causes (mutations) associated with the disorder in every patient. This makes the best treatment, counselling, and prenatal diagnostics possible. Traditionally, genetic diagnostics relied on single gene testing. Modern technologies, however, make simultaneous investigation of more than 20,000 genes possible. Although chromosomal microarrays and next-generation sequencing of entire genomes have already found their place in the research, implementation of these techniques to clinical diagnostics needs further studies before the most optimal testing strategies can be established for patients. This study clarified the clinical role of homozygous chromosomal regions – findings of unclear significance frequently detected by chromosomal microarrays. It was shown that a third of such findings are recurrent between patients, and thus are likely benign. In addition, identification of a candidate gene matching a patient’s symptoms from a homozygous region is very rare; however, if such a gene was found, the mutation would likely be detected. The second part of the study focused on the clinical utility of sequencing a panel of nearly 5,000 disease-associated genes. The results indicated that the large gene panel has a similar diagnostic yield as whole exome sequencing. Out of 501 cases included in this study, a molecular cause of the disorder was detected in 132 cases (26%). Nearly a half of the detected mutations were previously unreported. The last part of the dissertation reported on two patients – the second report in the medical literature on KPTN¬ gene mutations causing intellectual disability, and a boy with muscle disorder, in whom a novel mutation in the MYH7 gene was detected. This MYH7 mutation was confirmed to cause novel molecular effects on the gene transcript, thus expanding the clinical and genetic spectra of MYH7-related disorders

Transcriptional Regulation of Cardiac Development and Disease

This reprint contains original research and review articles describing recent advances in our understanding of the transcriptional regulation of cardiac development and disease mechanisms. All articles were originally published in the International Journal of Molecular Sciences (IJMS)

Cardiac Arrhythmias

The most intimate mechanisms of cardiac arrhythmias are still quite unknown to scientists. Genetic studies on ionic alterations, the electrocardiographic features of cardiac rhythm and an arsenal of diagnostic tests have done more in the last five years than in all the history of cardiology. Similarly, therapy to prevent or cure such diseases is growing rapidly day by day. In this book the reader will be able to see with brighter light some of these intimate mechanisms of production, as well as cutting-edge therapies to date. Genetic studies, electrophysiological and electrocardiographyc features, ion channel alterations, heart diseases still unknown , and even the relationship between the psychic sphere and the heart have been exposed in this book. It deserves to be read

Lapseeas alanud pärilike neuromuskulaarsete haiguste molekulaargeneetiliste ja morfoloogiliste uuringutulemuste võrdlus

Väitekirja elektrooniline versioon ei sisalda publikatsioonePärilike neuromuskulaarsete haiguste (NMH-de) alla kuuluvad seljaaju motoneuronite, närvide, närv-lihas ülekande ja lihaste talitluse häired, mis on põhjustatud ühe geeni veast. Nende haiguste diagnoosimisel on lisaks patsiendi haigusloole ja läbivaatusele abiks erinevad instrumentaalsed uuringud, sealhulgas lihasbiopsia. Lihaskoe analüüsimiseks kasutatakse mitmeid erinevaid värvinguid ja tehnikaid, mis võimaldavad näha lihaskiudude struktuuri, keemilisi ja ensümaatilisi omadusi ning erinevate valkude olemasolu või puudumist. Lihaskoe histoloogilised muutused on ajalooliselt olnud aluseks mitmete pärilike NMH-de tuvastamisele ja diagnoosimisele ning andnud suuna, milliseid geene uurida. Kuid tänapäeval on võimalik ühe analüüsiga (kogu eksoomi sekveneerimine) uurida kõiki geene korraga, mis on näidanud ka head diagnostilist efektiivsust. Seega on lihasbiopsia roll NMH-de diagnostikas muutumas. Käesolevasse uuringusse kaasati 70 päriliku NMH või mitokondriaalse haiguse kahtlusega patsienti, kellest 44-l kinnitus geneetiline diagnoos. Uuringust selgus, et lihasbiopsia mängis diagnostilises protsessis olulist rolli paljudel juhtudel, kusjuures 15 patsiendi lihaskoes esinesid spetsiifilised histoloogilised muutused. Mitmel juhul oli lihasbiopsia vajalik mitokondriaalses DNA-s esinevate muutuste tuvastamiseks. Lisaks andsid lihaskoest tehtud uuringud väärtuslikku lisainformatsiooni paljudel juhtudel, kus geneetilisel analüüsil leiti varem kirjeldamata geenivariant, tuvastati muutused kandidaatgeenis või kus leide polnudki. Näiteks ühel lihasdüstroofiaga patsiendil avastasime muutused uudses JAG2 geenis, mille haigusseoselisus kinnitus rahvusvahelise koostöö tulemusena. Uurides geenide ja teatud valkude avaldumist selle patsiendi lihaskoes, saime viite, et haiguse teke võib olla seotud lihase tüvirakkude talitluse häirumisega. Samas enamikel peamiselt kesknärvisüsteemi mõjutava haigusega patsientidel ei andnud lihasbiopsia informatsiooni juurde. Lisaks kirjeldati SPATA5 geeni defekti seost mitokondrite talitluse ja närvijätkete kasvu häiretega ning ühte patsienti, kellel oli kahtlus kongenitaalsele müopaatiale, kuid diagnoositi hoopis PRPS1 geeniga seotud puriinide ainevahetushaigus.Hereditary neuromuscular disorders (NMDs) include spinal motor neuron, nerve, neuromuscular junction, and muscle diseases caused by a single gene defect. In addition to the patient's disease history and examination, the diagnosis of NMDs can be reached using various instrumental investigations, including muscle biopsy. Several different stains and techniques are used to analyze muscle tissue, showing the structure and chemical and enzymatic properties of muscle fibers and the presence or absence of various proteins. Histological changes in muscle tissue have historically been the basis for identifying and diagnosing several hereditary NMDs and have provided guidance on which genes to study. However, nowadays, it is possible to study all genes at once with one analysis (whole exome sequencing), which has also shown good diagnostic efficiency. Thus, the role of muscle biopsy in NMD diagnostics is changing. The present study included 70 patients with a suspected hereditary NMD or mitochondrial disease, of whom 44 received a genetic diagnosis. The study found that muscle biopsy played a vital role in the diagnostic process in many cases, with 15 patients having specific histological changes in the muscle tissue. In several cases, a muscle biopsy was necessary to detect changes in mitochondrial DNA. In addition, studies of muscle tissue provided valuable additional information in many cases with previously undescribed gene variants, changes in a candidate gene, or without genetic findings. For example, in one patient with muscular dystrophy, we discovered changes in the new JAG2 gene and confirmed its disease association owing to international cooperation. Of note, by studying the expression of genes and specific proteins in the muscle tissue of this patient, we got an indication that the development of the disease may be related to the dysfunction of muscle stem cells. However, muscle biopsy did not provide additional information in most patients with a disease affecting the central nervous system. Lastly, the dissertation described the association of SPATA5 gene defect with mitochondrial dysfunction and nerve growth impairment and one patient with a suspected congenital myopathy, eventually diagnosed with PRPS1 gene-related inborn error of purine metabolism.https://www.ester.ee/record=b552434