Common Human Diseases Research Articles

The metabolic alterations within the normal appearing brain in patients with Hashimoto\u2019s thyroiditis are correlated with hormonal changes

Hashimoto’s thyroiditis (HT) is the most common autoimmune disease in humans usually associated with subsequent hypothyroidism. The purpose of the study was to assess metabolic alterations within the normal appearing brain in subjects with HT using MR spectroscopy (MRS) and to correlate MRS measurements with hormonal concentrations. Fifty-five HT patients (mean age 43.5 yrs) and 30 healthy controls (mean age 42.5 yrs) were examined with the use of a 1.5 T MR scanner. There were no signs of central nervous system involvement in the studied group. The MRS examinations were performed using the single voxel method. The voxels were placed in the left parietal white matter (PWM) and the posterior cingulate gyrus (PCG). The NAA/Cr, Cho/Cr, and mI/Cr ratios were calculated. The correlations between metabolite ratios and hormonal concentrations (TSH, fT3, fT4) as well as anti-TG and anti-TPO levels were also assessed. We found significantly (p < 0.05) decreased NAA/Cr ratios in PCG and PWM in HT subjects compared to the control group. There were no other significant differences in metabolite ratios. We observed significant positive correlations between the NAA/Cr ratio in PCG as well as the PWM and fT3 level. There was also a significant negative correlation between the Cho/Cr ratio in the PCG and fT4 level. MRS could be a sensitive biomarker capable of depicting early cerebral metabolic disturbances associated with HT. Our findings may indicate the reduction of neuronal activity within the normal appearing brain in patients with HT as well as suggesting that there is a possible biological association between thyroid dysfunction and cerebral metabolic changes.

In a Nutshell: Findings from the Bruneck Study

The Bruneck Study is a prospective community-based study enrolling an age- and sex-stratified random sample of 1,000 men and women. It achieved an extraordinary participation rate of 93.4% and a near-complete long-term follow-up exceeding a quarter of a century (1990–2018). High-quality ascertainment of most common human diseases enables reliable evaluation of: disease epidemiology, overlaps between age-related diseases, and risk factors, and discovery of novel biomarkers. Research priorities include atherosclerosis, cardiovascular disease, aging and longevity, neurological diseases, disorders of the bone, and cancer. This review summarizes the main scientific contributions of the Bruneck Study over the past decades, outlines recent highlights, and gives an outlook of what is planned next.

GLNMDA: a novel method for miRNA-disease association prediction based on global linear neighborhoods

ABSTRACTRecently, increasing studies have shown that miRNAs are involved in the development and progression of various complex diseases. Consequently, predicting potential miRNA-disease associations makes an important contribution to understanding the pathogenesis of diseases, developing new drugs as well as designing individualized diagnostic and therapeutic approaches for different human diseases. Nonetheless, the inherent noise and incompleteness in the existing biological datasets have limited the prediction accuracy of current computational models. To solve this issue, in this paper, we propose a novel method for miRNA-disease association prediction based on global linear neighborhoods (GLNMDA). Specifically, our method obtains a new miRNA/disease similarity matrix by linearly reconstructing each miRNA/disease according to the known experimentally verified miRNA-disease associations. We then adopt label propagation to infer the potential associations between miRNAs and diseases. As a result, GLNMDA achieved reliable performance in the frameworks of both local and global LOOCV (AUCs of 0.867 and 0.929, respectively) and 5-fold cross validation (average AUC of 0.926). Case studies on five common human diseases further confirmed the utility of our method in discovering latent miRNA-disease pairs. Taken together, GLNMDA could serve as a reliable computational tool for miRNA-disease association prediction.

A Survey of SNP Data Analysis

Every person differs from every other person regarding their physical appearance, susceptibility to disease, response to medications, and so on. However, 99.9 percent of human DNA is the same. As such, differences in human genomes are very worthy of study. Single-Nucleotide Polymorphisms (SNPs) are the simplest form and most common source of genetic polymorphism. SNPs have been used to successfully identify defective genes that cause Mendelian diseases. However, most common human diseases are complex and are caused by multiple SNPs. Each SNP explains only a small fraction of genetic causes. Experiments on individual SNPs may reveal their non-detectable effects on complex diseases. Pathogenesis is a complicated topic, and it is difficult to correctly predict multiple SNPs. As such, the analysis of SNP data is a critical task in the study of genetic diseases. In this paper, we divide the methods for genome-wide SNP data analysis into two categories: single-trait GenomeWide Association Studies (GWAS) in which pathology is mined from data of a single phenotype, and multiple-trait GWAS which identifies cross-phenotype associations. For single-trait GWAS, we review methods ranging from the simple to the complex, including TEAM, BOOST, AntEpiSeeker, SNPRuler, EDCF, HiSeeker, ORF, MLR-tagging, MSCD, and MIC. For multiple-trait GWAS, we describe methods in terms of their employed regression models, dimension-reduction methods, and meta-analysis methods. We also list the advantages and disadvantages of these methods. Finally, we discuss the future directions of SNP data analysis for genome-wide association.

Epigenome wide association study of SNP\u2013CpG\xa0interactions on changes in triglyceride levels after pharmaceutical intervention: a GAW20 analysis

In the search for an understanding of how genetic variation contributes to the heritability of common human disease, the potential role of epigenetic factors, such as methylation, is being explored with increasing frequency. Although standard analyses test for associations between methylation levels at individual cytosine-phosphate-guanine (CpG) sites and phenotypes of interest, some investigators have begun testing for methylation and how methylation may modulate the effects of genetic polymorphisms on phenotypes. In our analysis, we used both a genome-wide and candidate gene approach to investigate potential single-nucleotide polymorphism (SNP)–CpG interactions on changes in triglyceride levels. Although we were able to identify numerous loci of interest when using an exploratory significance threshold, we did not identify any significant interactions using a strict genome-wide significance threshold. We were also able to identify numerous loci using the candidate gene approach, in which we focused on 18 genes with prior evidence of association of triglyceride levels. In particular, we identified GALNT2 loci as containing potential CpG sites that moderate the impact of genetic polymorphisms on triglyceride levels. Further work is needed to provide clear guidance on analytic strategies for testing SNP–CpG interactions, although leveraging prior biological understanding may be needed to improve statistical power in data sets with smaller sample sizes.

Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis.

Focal adhesion kinase (FAK) is an intensely studied non-receptor tyrosine kinase with roles in cancer and other common human diseases. Despite the large interest in FAK, the in vivo contribution of FAK auto-phosphorylation site tyrosine (Y) 397 to FAK function is incompletely understood. To study FAK Y397 in vivo we analyzed mice with ‘non-phosphorylatable’ Y-to-phenylalanine (F) and ‘phospho-mimicking’ Y-to-glutamate (E) mutations in the germline. We found that FAK Y397F mice die early during embryogenesis with abnormal angiogenesis like FAK kinase-dead mice. When Y397 is mutated to a glutamate mice survive beyond mid-gestation like mice where Y397 is lost by deletion of FAK exon 15. In culture, defects in proliferation, invasion and gene expression were more severe with the FAK Y397F than with the FAK Y397E mutation despite the inability of FAK Y397E to bind SRC. Conditional expression of FAK Y397F or Y397E in unchallenged avascular epidermis, however, resulted in no appreciable phenotype. We conclude that FAK Y397 is required for the highly dynamic tissue remodeling during development but dispensable for normal homeostasis of avascular epidermis. In contrast to the Y397F mutation, FAK Y397E retains sufficient biological activity to allow for development beyond mid-gestation.

Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms.

Unlike superficial fungal infections of the skin and nails, which are the most common fungal diseases in humans, invasive fungal infections carry high morbidity and mortality, particularly those associated with biofilm formation on indwelling medical devices. Therapeutic management of these complex diseases is often complicated by the rise in resistance to the commonly used antifungal agents. Therefore, the availability of accurate susceptibility testing methods for determining antifungal resistance, as well as discovery of novel antifungal and antibiofilm agents, are key priorities in medical mycology research. To direct advancements in this field, here we present an overview of the methods currently available for determining (i) the susceptibility or resistance of fungal isolates or biofilms to antifungal or antibiofilm compounds and compound combinations; (ii) the in vivo efficacy of antifungal and antibiofilm compounds and compound combinations; and (iii) the in vitro and in vivo performance of anti-infective coatings and materials to prevent fungal biofilm-based infections.

Cachexia and Sarcopenia in Companion Animals: An Under‐Utilized Natural Animal Model of Human Disease

AbstractWhile laboratory small animal models of cachexia and sarcopenia are well‐suited and critical for studying mechanisms and early pre‐clinical phases for potential treatments, they are not similar enough to the human conditions to always be good predictors for results in human clinical trials. As a result, translational failures can occur when large‐scale human clinical trials are conducted on drugs, even when they appear promising in pre‐clinical studies in rodent models. What is needed is a way to more efficiently and successfully translate information gained from basic science and rodent research into human clinical trials that produce effective approved drugs. Naturally‐occurring cachexia and sarcopenia in companion animals is a more representative model of human disease that can serve as a stepping stone between basic science and human clinical trials. Many of the common diseases of humans also affect companion animals, particularly pet dogs and cats. Pet dogs and cats commonly develop heart failure, cancer, and kidney disease, as well as acute trauma or illness. The population of elderly companion animals also is increasing as pets' lifespans have become longer. As a result, both cachexia and sarcopenia are very common in companion animals. Studying these conditions in dogs and cats – either in colonies or in animal clinical trials ‐ can help to identify successful treatments that can benefit both humans and companion animals.

Resistance of uropathogens to antibacterial agents: Emerging threats, trends and treatments.

Urinary tract infections are among the most common infectious diseases in humans. Today, resistance to nearly all antimicrobial classes is dramatically growing, and extremely drug-resistant or even pan-drug resistant pathogens are increasingly isolated around the world. It is foreseen that in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. Carbapenemase-producing Enterobacteriaceae, multidrug- resistant Enterococci and fluoroquinolone resistance determinants in both Gram-negative and Gram-positive uropathogens are among the greatest emergencies. In this article, the major emerging threats of particular interest to urologists are reviewed, worldwide resistance trends are illustrated, and novel and older - but still active - recommended drugs are summarized.

Isolation and identification of Streptococcus mutans from dental caries patients at Thi-Qar province/Iraq

Dental caries is one of an important common human infectious disease that can lead to loss of tooth structure, it is occur due to the metabolic activation of the plague microorganisms especially Streptococcus mutans bacterium. Eighteen samples from saliva and dental plaque were collected from patients with dental caries active at ages from (7-25) years from Specialized dental hospital and dental clinics at Thi-Qar province during the period from November to December 2016.Thirty-three isolates belong Streptococcus mutans were identified by cultural methods, biochemical tests and Api 20 Strep. system, while twenty-eight isolates identified by using Polymerase Chain Reaction (PCR) technique and sequencing of 16S rRNA gene with 507 bp, whereas by using 16S rRNA gene the result confirmed that these isolates were belong to Streptococcus mutans. The aim of study is Isolation and identification of Streptococcus mutans bacterium from the dental caries and dental biofilm patients at Thi-Qar province by of 16S rRNA gene.

Predicting miRNA-disease association based on inductive matrix completion.

It has been shown that microRNAs (miRNAs) play key roles in variety of biological processes associated with human diseases. In Consideration of the cost and complexity of biological experiments, computational methods for predicting potential associations between miRNAs and diseases would be an effective complement. This paper presents a novel model of Inductive Matrix Completion for MiRNA-Disease Association prediction (IMCMDA). The integrated miRNA similarity and disease similarity are calculated based on miRNA functional similarity, disease semantic similarity and Gaussian interaction profile kernel similarity. The main idea is to complete the missing miRNA-disease association based on the known associations and the integrated miRNA similarity and disease similarity. IMCMDA achieves AUC of 0.8034 based on leave-one-out-cross-validation and improved previous models. In addition, IMCMDA was applied to five common human diseases in three types of case studies. In the first type, respectively, 42, 44, 45 out of top 50 predicted miRNAs of Colon Neoplasms, Kidney Neoplasms, Lymphoma were confirmed by experimental reports. In the second type of case study for new diseases without any known miRNAs, we chose Breast Neoplasms as the test example by hiding the association information between the miRNAs and Breast Neoplasms. As a result, 50 out of top 50 predicted Breast Neoplasms-related miRNAs are verified. In the third type of case study, IMCMDA was tested on HMDD V1.0 to assess the robustness of IMCMDA, 49 out of top 50 predicted Esophageal Neoplasms-related miRNAs are verified. The code and dataset of IMCMDA are freely available at https://github.com/IMCMDAsourcecode/IMCMDA. Supplementary data are available at Bioinformatics online.

Distinct Infant Immune Phenotypes Determine Childhood Disease Trajectories

Deregulated immune responses to environmental triggers may propagate disease by eliciting chronic inflammatory disease trajectories. To address relations between early immune competence and development of common childhood diseases in humans, we performed a large-scale immunological profiling in 18-month-old infants and linked ex vivo functional immune response phenotypes to development of disease until school-age. Several distinct and non-overlapping response phenotypes were identified to selectively associate with development of asthma, allergic rhinoconjunctivitis, or atopic dermatitis. These findings pinpoint the diversity of immune responses between infants in early life and its importance in relation to the development of common childhood diseases.

Artificial strain of human prions created in vitro

The molecular mechanism that determines under physiological conditions transmissibility of the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD) is unknown. We report the synthesis of new human prion from the recombinant human prion protein expressed in bacteria in reaction seeded with sCJD MM1 prions and cofactor, ganglioside GM1. These synthetic human prions were infectious to transgenic mice expressing non-glycosylated human prion protein, causing neurologic dysfunction after 459 and 224 days in the first and second passage, respectively. The neuropathology, replication potency, and biophysical profiling suggest that a novel, particularly neurotoxic human prion strain was created. Distinct biological and structural characteristics of our synthetic human prions suggest that subtle changes in the structural organization of critical domains, some linked to posttranslational modifications of the pathogenic prion protein (PrPSc), play a crucial role as a determinant of human prion infectivity, host range, and targetting of specific brain structures in mice models.

Non-plaque-induced gingival diseases.

While plaque-induced gingivitis is one of the most common human inflammatory diseases, several non-plaque-induced gingival diseases are less common but often of major significance for patients. The non-plaque-induced gingival lesions are often manifestations of systemic conditions, but they may also represent pathologic changes limited to gingival tissues. A classification is proposed, based on the etiology of the lesions and includes: Genetic/Developmental disorders; Specific infections; Inflammatory and immune conditions and lesions; Reactive processes; Neoplasms; Endocrine, Nutritional and metabolic diseases; Traumatic lesions; and Gingival pigmentation.

Non–plaque‐induced gingival diseases

While plaque-induced gingivitis is one of the most common human inflammatory diseases, several non-plaque-induced gingival diseases are less common but often of major significance for patients. The non-plaque-induced gingival lesions are often manifestations of systemic conditions, but they may also represent pathologic changes limited to gingival tissues. A classification is proposed, based on the etiology of the lesions and includes: Genetic/Developmental disorders; Specific infections; Inflammatory and immune conditions and lesions; Reactive processes; Neoplasms; Endocrine, Nutritional and metabolic diseases; Traumatic lesions; and Gingival pigmentation.

Streptococcus sanguinis biofilm formation & interaction with oral pathogens.

Caries and periodontitis are the two most common human dental diseases and are caused by dysbiosis of oral flora. Although commensal microorganisms have been demonstrated to protect against pathogens and promote oral health, most previous studies have addressed pathogenesis rather than commensalism. Streptococcus sanguinis is a commensal bacterium that is abundant in the oral biofilm and whose presence is correlated with health. Here, we focus on the mechanism of biofilm formation in S. sanguinis and the interaction of S. sanguinis with caries- and periodontitis-associated pathogens. In addition, since S. sanguinis is well known as a cause of infective endocarditis, we discuss the relationship between S. sanguinis biofilm formation and its pathogenicity in endocarditis.

Retromer associates with the cytoplasmic amino-terminus of polycystin-2

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic human disease, with around 12.5 million people affected worldwide. ADPKD results from mutations in either PKD1 or PKD2, which encode the atypical G-protein coupled receptor polycystin-1 (PC1) and the transient receptor potential channel polycystin-2 (PC2), respectively. Although altered intracellular trafficking of PC1 and PC2 is an underlying feature of ADPKD, the mechanisms which govern vesicular transport of the polycystins through the biosynthetic and endosomal membrane networks remain to be fully elucidated. Here, we describe an interaction between PC2 and retromer, a master controller for the sorting of integral membrane proteins through the endo-lysosomal network. We show that association of PC2 with retromer occurs via a region in the PC2 cytoplasmic amino-terminal domain, independently of the retromer-binding Wiskott-Aldrich syndrome and scar homologue (WASH) complex. Based on observations that retromer preferentially interacts with a trafficking population of PC2, and that ciliary levels of PC1 are reduced upon mutation of key residues required for retromer association in PC2, our data are consistent with the identification of PC2 as a retromer cargo protein.This article has an associated First Person interview with the first author of the paper.

Triptolide: A new star for treating human malignancies.

In recent years, cancer has become the most common human disease worldwide, and great attentions have been paid to clarifying the carcinogenesis and identifying new effective antitumor therapy. Although great progress has been made in this research field, human malignant diseases could still not be radically cured. Thunder god vine is a herbal medicine, which has proved to exert efficient antitumor activity in various human cancers such as lung cancer, pancreatic cancer, and colon cancer. In vivo and in vitro experiments showed that thunder god vine extract triptolide could inhibit tumor cell proliferation, cell migration, and cell invasion. Here, we overviewed the functional role of triptolide in human malignancies and its promising therapeutic potential in treating such deadly diseases.

Cytokines, Antibodies, and Histopathological Profiles during Giardia Infection and Variant-Specific Surface Protein-Based Vaccination.

Giardiasis is one of the most common human intestinal diseases worldwide. Several experimental animal models have been used to evaluate Giardia infections, with gerbils (Meriones unguiculatus) being the most valuable model due to their high susceptibility to Giardia infection, abundant shedding of cysts, and pathophysiological alterations and signs of disease similar to those observed in humans. Here, we report cytokine and antibody profiles both during the course of Giardia infection in gerbils and after immunization with a novel oral vaccine comprising a mixture of purified variant-specific surface proteins (VSPs). Transcript levels of representative cytokines of different immune profiles as well as macro- and microtissue alterations were assessed in Peyer's patches, mesenteric lymph nodes, and spleens. During infection, cytokine responses showed a biphasic profile: an early induction of Th1 (gamma interferon [IFN-γ], interleukin-1β [IL-1β], IL-6, and tumor necrosis factor [TNF]), Th17 (IL-17), and Th2 (IL-4) cytokines, together with intestinal alterations typical of inflammation, followed by a shift toward a predominant Th2 (IL-5) response, likely associated with a counterregulatory mechanism. Conversely, immunization with an oral vaccine comprising the entire repertoire of VSPs specifically showed high levels of IL-17, IL-6, IL-4, and IL-5, without obvious signs of inflammation. Both immunized and infected animals developed local (intestinal secretory IgA [S-IgA]) and systemic (serum IgG) humoral immune responses against VSPs; however, only infected animals showed evident signs of giardiasis. This is the first comprehensive report of cytokine expression and anti-Giardia antibody production during infection and VSP vaccination in gerbils, a reliable model of the human disease.