Search

Over the last decades, rapid technological and scientific advances have led to a merge of molecular sciences and clinical medicine, resulting in a better understanding of disease mechanisms and the development of novel therapies that exploit specific molecular lesions or profiles driving disease. Precision oncology is here used as an example, illustrating the potential of precision/personalized medicine that also holds great promise in other medical fields. Real-world implementation can only be achieved by dedicated healthcare connected centers which amass and build up interdisciplinary expertise reflecting the complexity of precision medicine. Networks of such centers are ideally suited for a nation-wide outreach offering access to precision medicine to patients independent of their place of residence. Two of these multicentric initiatives, Genomic Medicine Sweden (GMS) and the Centers for Personalized Medicine (ZPM) initiative in Germany have teamed up to present and share their views on core concepts, potentials, challenges, and future developments in precision medicine. Together with other initiatives worldwide, GMS and ZPM aim at providing a robust and sustainable framework, covering all components from technology development to clinical trials, ethical and legal aspects as well as involvement of all relevant stakeholders, including patients and policymakers in the field.

Significance: Diabetic heart disease (DHD) is the primary cause of mortality in people with diabetes. A significant contributor to the development of DHD is the disruption of redox balance due to r...

Super enhancers (SEs) are broad enhancer domains usually containing multiple constituent enhancers that hold elevated activities in gene regulation. Disruption in one or more constituent enhancers causes aberrant SE activities that lead to gene dysregulation in diseases. To quantify SE aberrations, differential analysis is performed to compare SE activities between cell conditions. The state-of-art strategy in estimating differential SEs relies on overall activities and neglect the changes in length and structure of SEs. Here, we propose a novel computational method to identify differential SEs by weighting the combinatorial effects of constituent-enhancer activities and locations (i.e., internal dynamics). In addition to overall activity changes, our method identified four novel classes of differential SEs with distinct enhancer structural alterations. We demonstrate that these structure alterations hold distinct regulatory impact, such as regulating different number of genes and modulating gene expression with different strengths, highlighting the differentiated regulatory roles of these unexplored SE features. When compared to the existing method, our method showed improved identification of differential SEs that were linked to better discernment of cell-type-specific SE activity and functional interpretation. We implement an R package, DASE, to facilitate the use of our method.

Considerable advancements have been made in the quantification of biofluid-based biomarkers for traumatic brain injury (TBI), which provide a clinically accessible window to investigate disease mechanisms and progression. Methods with improved analytical sensitivity compared with standard immunoassays are increasingly used, and blood tests are being used in the diagnosis, monitoring, and outcome prediction of TBI. Most work to date has focused on acute TBI diagnostics, while the literature on biomarkers for long-term sequelae is relatively scarce. In this review, we give an update on the latest developments in biofluid-based biomarker research in TBI and discuss how acute and prolonged biomarker changes can be used to detect and quantify brain injury and predict clinical outcome and neuropsychiatric sequelae.

The human health impacts of microplastics exposure remain uncertain, though they are of growing global concern. The strategic use of the adverse outcome pathways (AOPs) framework will permit leveraging of existing knowledge on disease mechanisms of other stressors to improve our understanding of the toxicological impacts of microplastics and enable identification of key biological events within a causal framework linking microplastic exposures to adverse outcomes. Here, the AOP framework is briefly described. Considering that inflammation, oxidative stress and cytotoxicity are among the reported outcomes of microplastics exposure in vitro or in vivo and because these key events form the AOP for tissue injury, an adverse key event preceding tissue dysfunction and disease, the review describes a tiered microplastics testing strategy targeting these events. Minimum considerations for in vitro testing of microplastics are also summarised.

Traumatic brain injury (TBI) is a risk factor for later-life dementia. Clinical and pre-clinical studies have elucidated multiple mechanisms through which TBI may influence or exacerbate multiple pathological processes underlying Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). The National Institutes of Health hosts triennial ADRD Summits to inform a national research agenda, and the 2019 ADRD Summit was the first to highlight "TBI and AD/ADRD Risk" as an emerging topic in the field. A multidisciplinary committee of TBI researchers with relevant expertise reviewed extant literature, identified research gaps and opportunities, and proposed draft research recommendations at the 2019 ADRD Summit. These research recommendations, further refined after broad stakeholder input at the Summit, cover four overall areas: 1) Encourage crosstalk and interdisciplinary collaboration between TBI and dementia researchers; 2) Establish infrastructure to study TBI as a risk factor for AD/ADRD; 3) Promote basic and clinical research examining the development and progression of TBI AD/ADRD neuropathologies and associated clinical symptoms; and 4) Characterize the clinical phenotype of progressive dementia associated with TBI and develop non-invasive diagnostic approaches. These recommendations recognize a need to strengthen communication and build frameworks to connect the complexity of TBI with rapidly evolving AD/ADRD research. Recommendations acknowledge TBI as a clinically and pathologically heterogeneous disease whose associations with AD/ADRDs remain incompletely understood. The recommendations highlight the scientific advantage of investigating AD/ADRD in the context of a known TBI exposure, the study of which can directly inform on disease mechanisms and treatment targets for AD/ADRDs with shared common pathways.

Solar urticaria is a rare, immunologically-mediated photodermatosis in which activation of cutaneous mast cells is triggered by specific wavelengths of solar electromagnetic radiation. This manifests clinically as the rapid development of cutaneous itch, erythema and wheal formation after several minutes of sun exposure. Disease mechanisms in solar urticaria remain incompletely elucidated and there have been few recent investigations of its pathobiology. Historic passive transfer experiments performed during the twentieth century provide support for a "photoallergy" model of disease pathogenesis, wherein molecular alteration of a putative chromophore by solar electromagnetic radiation produces mast cell activation via an IgE-dependent mechanism. However, this model does not account for several observations made during passive transfer experiments, nor does it explain a range of subsequent clinical and photobiological observations made in solar urticaria patients. Furthermore, increased understanding of the molecular dynamics underpinning cutaneous mast cell responses highlights the need to reformulate our understanding of solar urticaria pathogenesis in the context of this contemporary scientific landscape. In this review, we discuss the current understanding of solar urticaria pathogenesis and, by incorporating recent scientific and clinical observations, develop new hypotheses to drive future investigation into this intriguing disorder.

Improved bioassays have significantly increased the rate of identifying new protein-protein interactions (PPIs), and the number of detected human PPIs has greatly exceeded early estimates of human interactome size. These new PPIs provide a more complete view of disease mechanisms but precise understanding of how PPIs affect phenotype remains a challenge. It requires knowledge of PPI context (e.g. tissues, subcellular localizations), and functional roles, especially within pathways and protein complexes. The previous IID release focused on PPI context, providing networks with comprehensive tissue, disease, cellular localization, and druggability annotations. The current update adds developmental stages to the available contexts, and provides a way of assigning context to PPIs that could not be previously annotated due to insufficient data or incompatibility with available context categories (e.g. interactions between membrane and cytoplasmic proteins). This update also annotates PPIs with conservation across species, directionality in pathways, membership in large complexes, interaction stability (i.e. stable or transient), and mutation effects. Enrichment analysis is now available for all annotations, and includes multiple options; for example, context annotations can be analyzed with respect to PPIs or network proteins. In addition to tabular view or download, IID provides online network visualization. This update is available at http://ophid.utoronto.ca/iid.

Analyzing an appropriate disease model system is important to conduct disease research. Analyzing cells obtained from patient tissues could not only help elucidate the pathological mechanisms and to develop novel therapy but also lead to personalized medicine in the future. However, it is generally difficult to collect and culture neuronal cells from patients suffering from neurodegenerative disorders. Skin fibroblasts are easier to collect than neurons but may not show the expected pathology when disease-relevant genes are not sufficiently expressed. In this article, I describe an in vitro model system that enables the facile analysis of neurological disease mechanisms in patient fibroblast cultures by CRISPR transcriptional activation of endogenous disease-relevant genes. This system introduces an additional platform to analyze neurodegenerative disorders.

Causal mediation analysis aims to characterize an exposure's effect on an outcome and quantify the indirect effect that acts through a given mediator or a group of mediators of interest. With the increasing availability of measurements on a large number of potential mediators, like the epigenome or the microbiome, new statistical methods are needed to simultaneously accommodate high-dimensional mediators while directly target penalization of the natural indirect effect (NIE) for active mediator identification. Here, we develop two novel prior models for identification of active mediators in high-dimensional mediation analysis through penalizing NIEs in a Bayesian paradigm. Both methods specify a joint prior distribution on the exposure-mediator effect and mediator-outcome effect with either (a) a four-component Gaussian mixture prior or (b) a product threshold Gaussian prior. By jointly modelling the two parameters that contribute to the NIE, the proposed methods enable penalization on their product in a targeted way. Resultant inference can take into account the four-component composite structure underlying the NIE. We show through simulations that the proposed methods improve both selection and estimation accuracy compared to other competing methods. We applied our methods for an in-depth analysis of two ongoing epidemiologic studies: the Multi-Ethnic Study of Atherosclerosis (MESA) and the LIFECODES birth cohort. The identified active mediators in both studies reveal important biological pathways for understanding disease mechanisms.

Advanced glycation end products (AGEs) are glycated proteins or lipids derived from complex metabolic pathways involved in the pathophysiology of various diseases, especially diabetes and diabetes-related complications. These compounds are omnipresent in human life, with both endogenous and exogenous sources. Despite the well-elucidated disease mechanisms, little is known about the AGEs/nutrition nexus in the circles of clinical practice recommendations. This review seeks to translate the accumulated knowledge about the biochemistry and pathophysiology of AGEs into a nutritional intervention based on real-world prescriptions.

Huntington disease is an autosomal dominant inherited brain disorder that typically becomes manifest in adulthood. Juvenile-onset Huntington disease refers to approximately 5% of patients with symptom onset before the age of 21 years. The causal factor is a pathologically expanded CAG repeat in the Huntington gene. Age at onset is inversely correlated with CAG repeat length. Juvenile-onset patients have distinct symptoms and signs with more severe pathology of involved brain structures in comparison with disease onset in adulthood. The aim of this review is to compare clinical and pathological features in juvenile- and adult-onset Huntington disease and to explore which processes potentially contribute to the observed differences. A specific focus is placed on molecular mechanisms of mutant huntingtin in early neurodevelopment and the interaction of a neurodegenerative disease and postnatal brain maturation. The importance of a better understanding of pathophysiological differences between juvenile- and adult-onset Huntington disease lies in development and implementation of new therapeutic strategies. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Neurodegenerative disorders are characterized by neuronal loss, usually in late life. But recently, abnormalities of proteins implicated in neurodegenerative disorders have been identified in disorders of childhood, raising the possibility that clues to susceptibility to and prevention of neurodegenerative disorders may be identifiable before symptoms of disease arise. This review leverages these new and evolving findings to test our hypothesis, first proposed in 2010, that proteins implicated in neurodegenerative disorders play important roles in brain development by examining evidence in the peer-reviewed literature published in the past five years for the relevance of these proteins in normal and disease-associated brain development.

Down syndrome (DS) is characterized by a collection of clinical features including intellectual disability, congenital malformations, and susceptibility to infections and autoimmune diseases. While the presence of an extra chromosome 21 is known to cause DS, the precise genetic annotation linked to specific clinical features is largely missing. However, there is growing evidence that two genes located on chromosome 21, IFNAR1 and IFNAR2, play an important role in disease pathogenesis. These genes encode the two subunits of the receptor for type I interferons (IFN-I), a group of potent antiviral and pro-inflammatory cytokines. Human monogenic diseases caused by uncontrolled IFN-I production and response have been well characterized, and they clinically overlap with DS but also have notable differences. Herein, we review the literature characterizing the role of IFN-I in DS and compare and contrast DS to other IFN-mediated conditions. The existing IFN-I literature serves as a rich resource for testable hypotheses to elucidate disease mechanisms in DS and is likely to open novel therapeutic avenues.

One of the biggest infectious diseases for humans in modern history is the COVID-19 pandemic. The disease mechanisms of human viral infections have been modified by virus-virus interaction. This study was carried out to detect the seroprevalence of CMV in COVID-19 patients. A total of 105 cases (58 females and 47 males) with an age range of 17-65 years (mean age 39.52±11.02 years) were included in this study. HCMV-IgG and IgM were determined in subjects' cases. Sixty-five out of 105 (62%) were positive for SARS-CoV-2, while 40 (38%) had negative SARS-CoV-2. Forty-seven (72.3%) and 11 (16.9%) cases out of 65 SARS-CoV-2 positive patients were positive for CMV-IgG and IgM antibodies, respectively. No significant differences were noted between females and males in terms of seroprevalence rates. A high rate of positive CMV-IgG was observed among 40-64 years COVID-19 patients. It is concluded that the seroprevalence of CMV antibodies amongst COVID-19 cases is high in relation to findings in cases without SARSCoV-2.

We compared velocity pulsatility, distensibility, and pulsatility attenuation along the intracranial ICA and MCA between 50 patients with pseudoxanthoma elasticum and 40 controls. Patients with pseudoxanthoma elasticum had higher pulsatility and lower distensibility at all measured locations, except for a similar distensibility at C4. The pulsatility attenuation over the siphon was similar between patients with pseudoxanthoma elasticum and controls. This finding suggests that other disease mechanisms are the main contributors to increased intracranial pulsatility in pseudoxanthoma elasticum.

Continuous cell lines are practical models that are widely used in the study of disease mechanisms and particularly cancers. However, the issue of cell line cross-contamination has existed since the 1960s, despite repeated advocation for cell line authentication by many experts. Furthermore, cell line abuse has been underestimated and underreported. The China Center for Type Culture Collection (CCTCC) received 1373 cell samples for authentication from 2010 to 2019, and has found that the quality of cell lines has improved during this time, offering a positive outlook for the future. This article is protected by copyright. All rights reserved.

Immune-mediated inflammatory diseases are common and clinically diverse. Although they are currently incurable, the therapeutic armamentarium for immune-mediated inflammatory diseases has been transformed in the past two decades. We have moved from the wide application of broad-spectrum immune modulators to the routine use of agents with exquisite specificity, arising from monoclonal and molecular biotechnology and more recently from highly targeted medicinal chemistry. Here we describe key advances and lessons that drove this remarkable progress and thereafter reflect on the next steps in this ongoing journey., In this Perspective, McInnes and Gravallese highlight the remarkable progress made over the past 20 years in treating immune-mediated inflammatory diseases. The available therapies have progressed from broad-spectrum immune modulators to highly targeted biological and small-molecule agents as our understanding of disease mechanisms has advanced.

Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by sustained elevated pulmonary arterial pressures in which the pulmonary vasculature undergoes significant structural and functional remodeling. To better understand disease mechanisms, in this review article we highlight recent insights into the regulation of pulmonary arterial cells by mechanical cues associated with PAH. Specifically, the mechanobiology of pulmonary arterial endothelial cells (PAECs), smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs) has been investigated in vivo, in vitro, and in silico. Increased pulmonary arterial pressure increases vessel wall stress and strain and endothelial fluid shear stress. These mechanical cues promote vasoconstriction and fibrosis that contribute further to hypertension and alter the mechanical milieu and regulation of pulmonary arterial cells.

The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.

The main histopathology of Alzheimer's disease (AD) is featured by the extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aβ plaques, and hence stops the neurodegenerative course in AD.

Introduction Main problems of kidney stone disease are its increasing prevalence and high recurrence rate after calculi removal in almost all areas around the globe. Despite enormous efforts in the past, its pathogenic mechanisms remain unclear and need further elucidations. Proteomics has thus become an essential tool to unravel such sophisticated disease mechanisms at cellular, subcellular, molecular, tissue and whole organism levels. Areas covered This review provides a brief overview of kidney stone disease followed by updates on proteomics for investigating urinary stone modulators, matrix proteins, cellular responses to different types/doses of calcium oxalate (CaOx) crystals, sex hormones and other stimuli, crystal-cell interactions, crystal receptors, secretome, and extracellular vesicles (EVs), all of which lead to better understanding of the disease mechanisms. Finally, the future challenges and translation of these obtained data to the clinic are discussed. Expert opinion/commentary Knowledge from urinary proteomics for exploring the important stone modulators (either inhibitors or promoters) will be helpful for early detection of asymptomatic cases for prompt prevention of symptoms, complications, and new stone formation. Moreover, these modulators may serve as the new therapeutic targets in the future for successful treatment and prevention of kidney stone disease by medications or other means of intervention. Key words Crystal-cell interactions; Crystal receptors; Mass spectrometry; Nephrolithiasis; Proteome; Urinary proteomics; Urolithiasis.

The development and early morphological features of feline hip osteoarthritis (OA) are largely unknown. Tears in the acetabular labrum and at the chondrolabral transition zone are suggested to be important in the pathogenesis of human hip OA, but in cats such lesions have not been described. We investigated associations between computed tomography (CT)-detected joint changes and microscopic articular cartilage lesions, the distribution of detected changes, and histologically evaluated the acetabular margin (AM) in hip joints from 20 cats. Histologic evaluation was undertaken on at least one joint from each cat. CT-detected joint changes and articular cartilage lesions were graded and the histological appearance of CT-detected osteophytes evaluated. The majority of CT-detected lesions and cartilage lesions were mild. Whole-joint CT scores and AM osteophyte CT scores showed moderate to strong correlation with cartilage scores. The odds were higher for presence of CT-detected osteophytes in craniodorsal, cranial, cranioventral, ventral and dorsal AM regions. Peripheral acetabular regions showed higher cartilage lesion grades than central regions. Tears, seen as fissures/clefts, in labral and perilabral tissues were common. CT-detected AM osteophytes morphologically presented as pointed sclerotic bone, spur-shaped bone or rounded chondro-osteophytes. The results suggest that CT is a valuable tool for diagnosing early feline hip OA. CT-detected osteophytes showed variable histologic morphologies, which may implicate different disease mechanisms and/or disease stages. Tears in the AM could represent an early event in feline hip OA and this warrants further investigation.

In this work, we attempt to address a key question in the joint analysis of transcriptomic data: can we correlate the patterns we observe in transcriptomic datasets to known molecular interactions and pathway knowledge to broaden our understanding of disease pathophysiology? We present a systematic approach that sheds light on the patterns observed in hundreds of transcriptomic datasets from over sixty indications by using pathways and molecular interactions as a template. Our analysis employs transcriptomic datasets to construct dozens of disease specific co-expression networks, alongside a human interactome network of protein-protein interactions described in the literature. Leveraging the interoperability between these two network templates, we explore patterns both common and particular to these diseases on three different levels. Firstly, at the node-level, we identify the most and least common proteins in these diseases and evaluate their consistency against the interactome as a proxy for their prevalence in the scientific literature. Secondly, we overlay both network templates to analyze common correlations and interactions across diseases at the edge-level. Thirdly, we explore the similarity between patterns observed at the disease level and pathway knowledge to identify pathway signatures associated with specific diseases and indication areas. Finally, we present a case scenario in the context of schizophrenia, where we show how our approach can be used to investigate disease pathophysiology.

Aim To demonstrate the little-known metabolic changes and pathways in patients with colorectal cancer (CRC). Methods We used gas chromatography time-of-flight mass spectrometry (GC-TOF/MS) to perform metabolic profiling of urine samples from 163 consecutive patients with CRC and 111 healthy controls without history of gastrointestinal tumors. The metabolic profiles were assayed using multivariate statistical analysis and one-way analysis of variance, and further analyzed to identify potential marker metabolites related to CRC. The GC-TOF/MS-derived models showed clear discriminations in metabolic profiles between the CRC group and healthy control group. Results We demonstrated that 15 metabolites contributed to the differences. Among them, eleven metabolites were significantly upregulated, while other four metabolites were downregulated in the urine samples of CRC patients compared with healthy controls. Pathway analysis revealed changes in energy metabolism of patients with CRC, which are reflected in the upregulation of glycolysis and amino acid metabolism and the downregulation of lipid metabolism. Our study revealed the metabolic profile of urine from CRC patients and indicated that GC-TOF/MS-based methods can distinguish CRC from healthy controls. Conclusion GC-TOF/MS-based metabolomics has the potential to be developed into a novel, non-invasive, and painless clinical tool for CRC diagnosis, and may contribute to an improved understanding of disease mechanisms.

Coronavirus disease 2019 (COVID-19) is the worst public health crisis of the century. Although we have made tremendous progress in understanding the pathogenesis of this disease, a lot more remains to be learned. Mitochondria appear to be important in COVID-19 pathogenesis because of its role in innate antiviral immunity, as well as inflammation. This article examines pathogenesis of COVID-19 from a mitochondrial perspective and tries to answer some perplexing questions such as why the prognosis is so poor in those with obesity, metabolic syndrome, or type 2 diabetes. Although effective vaccines and antiviral drugs will be the ultimate solution to this crisis, a better understanding of disease mechanisms will open novel avenues for treatment and prevention.

One important challenge in the post-genomic era is to explore disease mechanisms by efficiently integrating different types of biological data. In fact, a single disease is usually caused through multiple genes products such as protein complexes rather than single gene. Therefore, it is meaningful for us to discover protein communities from the protein-protein interaction network and use them for inferring disease-disease associations. In this article, we propose a new framework including protein-protein networks, disease-gene associations and disease-complex pairs to cluster protein complexes and infer disease associations. Complexes discovered by our approach is superior in quality (Sn, PPV and ACC) and clustering quantity than other four popular methods on three PPI networks. A systematic analysis shows that disease pairs sharing more protein complexes (such as Glucose and Lipid Metabolic Disorders) are more similar and overlapping proteins may have different roles in different diseases. These findings can provide clinical scholars and medical practitioners with new ideas on disease identification and treatment.

Among the hematological parameters, neutrophil/lymphocyte ratio (NLR) and platelet/ lymphocyte ratio (PLR) have been associated with inflammatory state, microvascular damage and ischemia. It is well-known that these ratios increase in idiopathic sudden sensorineural hearing loss (ISSHL). In ISSHL, different audiographic features may reflect different disease mechanisms. This study aimed to investigate whether there were differences in NLR and PLR among patient groups with different audiometric configurations. Patients meeting the study inclusion criteria were divided into four groups according to their audiogram configurations. Mean NLR and PLR values of the patient groups were compared among themselves and versus control group. The study was conducted with 166 participants. Mean NLR values were 3.07 ± 2.48, 3.30 ± 2.70, 5.24 ± 3.71, 3.57 ± 3.19 and 1.51 ± 0.68 for ascending, flat, descending and total/subtotal audiometric configuration groups and control group, respectively. Mean PLR values were 145.2 ± 126.7, 130.9 ± 57.8, 192.2 ± 94.4, 143.7 ± 70.8 and 94.1 ± 24.7 for ascending, flat, descending, total/subtotal audiometric configuration groups and control group, respectively. Both NLR and PLR were significantly greater in patients from all configuration groups than in control group (p

Enhancer-promoter interactions (EPIs) in the human genome are of great significance to transcriptional regulation, which tightly controls gene expression. Identification of EPIs can help us better decipher gene regulation and understand disease mechanisms. However, experimental methods to identify EPIs are constrained by funds, time, and manpower, while computational methods using DNA sequences and genomic features are viable alternatives. Deep learning methods have shown promising prospects in classification and efforts that have been utilized to identify EPIs. In this survey, we specifically focus on sequence-based deep learning methods and conduct a comprehensive review of the literature. First, we briefly introduce existing sequence- based frameworks on EPIs prediction and their technique details. After that, we elaborate on the dataset, pre-processing means, and evaluation strategies. Finally, we concluded with the challenges these methods are confronted with and suggest several future opportunities. We hope this review will provide a useful reference for further studies on enhancer-promoter interactions.

[89 Zr]Oxinate4 is a Positron Emission Tomography (PET) tracer for cell radiolabeling that can enable imaging techniques to help better understand cell trafficking in various diseases. Although several groups have synthetized this compound for use in preclinical studies, there is no available data regarding the production of [89 Zr]Oxinate4 for human use. In this report, we describe the detailed production of [89 Zr]Oxinate4 under USP and autologous leukocyte radiolabeling under USP . The final product presented high radiochemical purity and stability at 24 h post synthesis (>99%) and passed in all quality control assays required for clinical use. [89 Zr]Oxinate4 did not compromise the white blood cells viability and did not show considerable cellular efflux up to 3 h post labeling. The translation of this technique into human use can provide insight into several disease mechanisms since [89 Zr]Oxinate4 has the potential to label any cell subset of interest.

Surgeons are not trained to decipher the pathogenesis of diseases, which they operate on. They are used to repair, remove, or replace defective tissues and organs. Yet, we often see typical pathomorphological or pathophysiological phenomena, characteristic of a specific disorder that can only be observed during surgery. Such patterns would not be recognized easily by current imaging techniques, and their visibility would require a living organism. In modern terminology, one could call them “surgical biomarkers”. Many disease entities, today, are still not completely deciphered regarding initial links of their pathogenesis, despite decades of experimental and clinical research. In such disorders, characteristically named “idiopathic”, surgical observations may be helpful to clarify disease mechanisms, two of which we offer here for one of these disease entities, namely pulmonary hypertension.

In a woman with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) followed for 15 years, we observed magnetic resonance imaging white matter hyperintensities that vanished in the anterior temporal poles while the brain volume decreased unexpectedly. These imaging changes were transient and detected when the patient was being treated by valproic acid for stabilizing mood disturbances. This intriguing case supports that mechanisms underlying white matter hyperintensities can vary from one brain area to another and that important modifications of water influx into the brain tissue might be involved in some imaging features of CADASIL.

Sporadic cerebral small vessel disease (cSVD) is primarily attributed to heritability and vascular risk factors. Still, our understanding of the causative factors in cSVD lesion burden in the brain is far from complete. This is exemplified by this case of identical twins with remarkably similar vascular risk profiles, where one twin had developed severe cSVD on neuroimaging with cognitive deficits, while the other twin had no cSVD. This case highlights the need to search for further causes of cSVD, also beyond genetic and conventional vascular risk factors. Identification of other potential risk factors or disease mechanisms should be a priority for cSVD research to improve our understanding, prevention and treatment of this common cause of vascular brain injury with major clinical consequences.

Motivation Inferring the direct relationships between biomolecules from omics datasets is essential for the understanding of biological and disease mechanisms. Gaussian Graphical Model (GGM) provides a fairly simple and accurate representation of these interactions. However, estimation of the associated interaction matrix using data is challenging due to a high number of measured molecules and a low number of samples. Results In this article, we use the thermodynamic entropy of the non-equilibrium system of molecules and the data-driven constraints among their expressions to derive an analytic formula for the interaction matrix of Gaussian models. Through a data simulation, we show that our method returns an improved estimation of the interaction matrix. Also, using the developed method, we estimate the interaction matrix associated with plasma proteome and construct the corresponding GGM and show that known NAFLD-related proteins like ADIPOQ, APOC, APOE, DPP4, CAT, GC, HP, CETP, SERPINA1, COLA1, PIGR, IGHD, SAA1 and FCGBP are among the top 15% most interacting proteins of the dataset. Availability and implementation The supplementary materials can be found in the following URL: http://dynamic-proteome.utmb.edu/PrecisionMatrixEstimater/PrecisionMatrixEstimater.aspx. Supplementary information Supplementary data are available at Bioinformatics online.

In recent years, phase separation has been increasingly reported to play a pivotal role in a wide range of biological processes. Due to the close relationships between cancer and disorders in intracellular physiological function, the identification of new mechanisms involved in intracellular regulation has been regarded as a new direction for cancer therapy. Introducing the concept of phase separation into complex descriptions of disease mechanisms may provide many different insights. Here, we review the recent findings on the phase separation of cancer‐related proteins, describing the possible relationships between phase separation and key proteins associated with cancer and indicate possible regulatory modalities, especially drug candidates for phase separation, which may provide more effective strategies for cancer therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder, with a highly variable prevalence worldwide. Recent evidence, however, has shown an increase in prevalence in the Asia Pacific region. Nevertheless, most of the published literature has focused mainly on Western populations, and only few clinical trials have included subgroups of other ethnic populations. Reasons for the observed ethnic and geographical differences in AD are not well established. This calls into question the need for a better understanding of AD pathogenesis and inter-ethnic differences in clinical and immuno-phenotypes. These differences may reflect inherent variability in disease mechanisms between populations, which in turn may impact upon treatment responses such as biologics that are currently tailored mainly to a specific immuno-phenotype (T-helper type 2 dominant). In this article, we reviewed existing literature on the prevalence of AD globally, highlighting differences, if any, in the clinical and immuno-phenotypes of AD between different ethnicities. We discussed genetic and environmental factors that affect AD in different populations and therapeutic considerations. Our review highlights AD as a disease with ethnic-dependent clinical and immunological heterogeneity and calls for greater inclusion of ethnic diversity in future research in order to develop targeted treatments.

In neurodegenerative diseases a select set of neuron population displays early vulnerability and undergo progressive degeneration. The heterogeneity of the cerebral cortex and the heterogeneity of patient populations diagnosed with the same disease offer many challenges for developing effective and long-term treatment options. Currently, patients who are considered to have a “rare” disease are left with no hopes for cure, and many of the neurodegenerative diseases progress fast without any effective solutions. However, as our understanding of disease mechanisms evolve, we begin to realize that the boundaries between diseases are not as sharp as once believed. There are many patients who develop disease due to common underlying causes and mechanisms. As we move forward with drug discovery effort, it becomes obvious that we will have to shift our focus from finding a cure for a disease, to finding solutions to the disease causing cellular mechanisms so that patients can be treated by mechanism-based strategies. This paradigm shift will lay the foundation for personalized medicine approaches for neurodegenerative disease patients as well as patients diagnosed with a rare disease.

Acute kidney injury (AKI) is one of the most frequent complications of sepsis. Because sepsis and AKI synergistically worsen the outcomes of critically ill patients, better therapeutics against septic AKI urgently are required. In addition to the complexity of disease mechanisms of both sepsis and AKI, there is substantial regional variation in clinical practice, which further hampers the development of new treatments for septic AKI. To overcome this problem, evidence accumulation is necessary for building the foundation for developing novel septic AKI treatments. This review provides a summary of updated evidence regarding septic AKI from Asian regions.

Atrioventricular heart valves, that is, the mitral valve and the tricuspid valve, play vital roles in our cardiovascular system. Disease of these valves is, therefore, a significant source of morbidity and mortality. Unfortunately, current treatment options are suboptimal with significant rates of failure. It was only recently that we have begun to appreciate that the atrioventricular heart valve leaflets are not just passive flaps, but actively (mal)adapting tissues. This discovery sheds new light on disease mechanisms and provides, thus, possible pathways to new treatments. In this current opinion piece, we examine the state of our knowledge about the (mal)adaptive mechanisms (physiological and pathological growth and remodeling) of the atrioventricular heart valves. Furthermore, we review the evidence that suggests that valve maladaptation may be a target for pharmacological treatment of diseased valves which, in the future, could transform clinical practice.

Exosomes are small extracellular vesicles released by almost all cell types in physiological and pathological conditions. The exosomal potential to unravel disease mechanisms, or to be used as a source of biomarkers, is being explored, in particularly in the field of neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world and exosomes appear to have a relevant role in disease pathogenesis. This review summarizes the current knowledge on exosome contributions to AD as well as their use as disease biomarker resources or therapeutic targets. The most recent findings with respect to both protein and miRNA biomarker candidates for AD, herein described, highlight the state of the art in this field and encourage the use of exosomes derived from biofluids in clinical practice in the near future.

In the last 15 years, single-cell technologies have become robust and indispensable tools to investigate cell heterogeneity. Beyond transcriptomic, genomic and epigenome analyses, technologies are constantly evolving, in particular toward multi-omics, where analyses of different source materials from a single cell are combined, and spatial transcriptomics, where resolution of cellular heterogeneity can be detected in situ. While some of these techniques are still being optimized, single-cell RNAseq has commonly been used because the examination of transcriptomes allows characterization of cell identity and, therefore, unravel previously uncharacterized diversity within cell populations. Most endocrine organs have now been investigated using this technique, and this has given new insights into organ embryonic development, characterization of rare cell types, and disease mechanisms. Here, we highlight recent studies, particularly on the hypothalamus and pituitary, and examine recent findings on the pancreas and reproductive organs where many single-cell experiments have been performed.

The aim of this paper is to review esophageal electrical impedance technologies and to discuss the use of these technologies for physiological measurements, diagnostics, and therapy of esophageal disease. In order to develop a better understanding of the pathophysiology of and improve the diagnosis of esophageal disorders, such as gastroesophageal reflux disease (GERD) and achalasia, several new diagnostic tests, including intraluminal impedance, esophageal mucosal impedance, and the functional luminal imaging probe, have been developed. These technologies have proven valuable for assessment of the esophagus in recent years. They provide information on esophageal flow properties, mucosal integrity, lumen shape, and distensibility in esophageal disorders, in particular for GERD and achalasia. Despite their promise and novel clinical studies, the potential of these technologies has been far from realized. New multidisciplinary approaches will contribute to our understanding and interpretation of esophageal impedance data and disease mechanisms.

A mathematical model of amyloid fiber formation is described that is able to simply specify different rates of fiber breakage at internal versus end regions. This Note presents the derivation of the relevant equations and provides results showing the dramatic effects of position biased fiber breakage on the kinetics of amyloid growth.

Liquid–liquid phase separation has drawn attention as many neurodegeneration or cancer-associated proteins are able to form liquid membraneless compartments (condensates) by liquid–liquid phase separation. Furthermore, there is rapidly growing evidence that disease-associated mutation or post-translational modification of these proteins causes aberrant location, composition or physical properties of the condensates. It is ambiguous whether aberrant condensates are always causative in disease mechanisms, however they are likely promising potential targets for therapeutics. The conceptual framework of liquid–liquid phase separation provides opportunities for novel therapeutic approaches. This review summarises how the extensive recent advances in understanding control of nucleation, growth and composition of condensates by protein post-translational modification has revealed many possibilities for intervention by conventional small molecule enzyme inhibitors. This includes the first proof-of-concept examples. However, understanding membraneless organelle formation as a physical chemistry process also highlights possible physicochemical mechanisms of intervention. There is huge demand for innovation in drug development, especially for challenging diseases of old age including neurodegeneration and cancer. The conceptual framework of liquid–liquid phase separation provides a new paradigm for thinking about modulating protein function and is very different from enzyme lock-and-key or structured binding site concepts and presents new opportunities for innovation.

Acute kidney injury (AKI) is common in critically ill children and adults, and sepsis-associated AKI (SA-AKI) is the most frequent cause of AKI in the ICU. To date, no mechanistically targeted therapeutic interventions have been identified. High-throughput “omic” technologies (e.g. genomics, proteomics, metabolomics, etc.) offer a new angle of approach to achieve this end. In this review, we provide an update on the current understanding of SA-AKI pathophysiology. Omic technologies themselves are briefly discussed to facilitate interpretation of studies using them. We next summarize the body of SA-AKI research to date that has employed omic technologies. Importantly, omic studies are helping to elucidate a pathophysiology of SA-AKI centered around cellular stress responses, metabolic changes, and dysregulation of energy production that underlie its clinical features. Finally, we propose opportunities for future research using clinically relevant animal models, integrating multiple omic technologies, and ultimately progressing to translational human studies focusing therapeutic strategies on targeted disease mechanisms.

The search for disease mechanisms and treatments is one of the biggest collaborative efforts in science. These researchers are significant contributors. The search for disease mechanisms and treatments is one of the biggest collaborative efforts in science. These researchers are significant contributors.

Cells, basic units of living structures and functions, build up a complicated small world, and their order and complexity resemble a small universe. The detailed understanding and elucidation of the matter transport and energy conversion mechanisms within a single cell will expand our knowledge about the origin and evolution of life, the disease mechanisms and much more. In past decades, single-cell analysis has been rapidly and significantly improved and various methodologies have been developed to reveal the complexity of mass, energy, and information within single cells. In this review, we focused on the methods developed in recent years for single-cell analysis, including electrochemical method, optical method, and mass spectrometry method. We reviewed the recent advances and representative studies in this research field, and also discussed the strengths and limitations of each method. Finally, we presented the existing technical challenges and further directions for single-cell analysis.

Genetic variants in brain-expressed voltage-gated sodium channels (SCNs) have emerged as one of the most frequent causes of Mendelian forms of epilepsy and neurodevelopmental disorders (NDDs). This review explores the biological concepts that underlie sodium channel NDDs, explains their phenotypic heterogeneity, and appraises how this knowledge may inform clinical practice. We observe that excitatory/inhibitory neuronal expression ratios of sodium channels are important regulatory mechanisms underlying brain development, homeostasis, and neurological diseases. We hypothesize that a detailed understanding of gene expression, variant tolerance, location, and function, as well as timing of seizure onset can aid the understanding of how variants in SCN1A, SCN2A, SCN3A, and SCN8A contribute to seizure aetiology and inform treatment choice. We propose a model in which variant type, development-specific gene expression, and functions of SCNs explain the heterogeneity of sodium channel associated NDDs. Understanding of basic disease mechanisms and detailed knowledge of variant characteristics have increasing influence on clinical decision making, enabling us to stratify treatment and move closer towards precision medicine in sodium channel epilepsy and NDDs. WHAT THIS PAPER ADDS: Sodium-channel disorder heterogeneity is explained by variant-specific gene expression timing and function. Gene tolerance and location analyses aid sodium channel variant interpretation. Sodium-channel variant characteristics can contribute to clinical decision making.

Pancreatic Ductal Adenocarcinoma (PDAC) is regarded as one of the most lethal cancer types for its challenges associated with early diagnosis and resistance to standard chemotherapeutic agents, thereby leading to a poor five-year survival rate. The complexity of the disease calls for a multidisciplinary approach to better manage the disease and improve the status quo in PDAC diagnosis, prognosis, and treatment. To this end, the application of quantitative tools can help improve the understanding of disease mechanisms, develop biomarkers for early diagnosis, and design patient-specific treatment strategies to improve therapeutic outcomes. However, such approaches have only been minimally applied towards the investigation of PDAC, and we review the current status of mathematical modeling works in this field.