Type 1 hereditary hemochromatosis (HH) is an autosomal, recessive genetic entity with systemic iron overload. Iron homeostasis disorders develop as a result of
gene mutations, which are associated ...with hepcidin arthropathy or osteoporosis and may cause permanent disability in HH patients despite a properly conducted treatment with phlebotomies. In this study, selected parameters of calcium and phosphate metabolism were analyzed in combination with the assessment of bone mineral density (BMD) disorders in patients from northern Poland with clinically overt
-HH. BMD was determined by a dual-energy X-ray absorptiometry (DXA) test with the use of the trabecular bone score (TBS) function. The study included 29 HH patients (mean age = 53.14 years) who were compared with 20 healthy volunteers. A significantly lower TBS parameter and serum 25-OH-D3 concentration, a higher concentration of intact parathormone and more a frequent occurrence of joint pain were found in HH patients compared with the control group. In HH patients, the diagnosis of liver cirrhosis was associated with lower serum 25-OH-D3 and osteocalcin concentrations. In HH, DXA with the TBS option is a valuable tool in the early assessment of the bone microarchitecture and fracture risk. A supplementation of vitamin D, monitoring its concentration, should be considered especially in HH patients with liver damage and liver cirrhosis.
- Nematodes Caenorhabditis elegans (C. elegans) have been used as model organisms in a wide variety of biological studies, especially those intended to obtain a better understanding of aging and ...age-associated diseases. This paper focuses on automating the analysis of C. elegans imagery to classify the muscle age of nematodes based on the known and well established IICBU dataset. Unlike many modern classification methods, the proposed approach relies on deep learning techniques, specifically on convolutional neural networks (CNNs), to solve the problem and achieve high classification accuracy by focusing on non-handcrafted self-learned features. Various networks known from the ImageNet Large Scale Visual Recognition Challenge (ILSVRC) have been investigated and adapted for the purposes of the C. elegans muscle aging dataset by applying transfer learning and data augmentation techniques. The proposed approach of unfreezing different numbers of convolutional layers at the feature extraction stage and introducing different structures of newly trained fully connected layers at the classification stage, enable to better fine-tune the selected networks. The adjusted CNNs, as featured in this paper, have been compared with other state-of-art methods. In anti-aging drug research, the proposed CNNs would serve as a very fast and effective age determination method, thus leading to reductions in time and costs of laboratory research.
The study was undertaken to compare the diagnostic performance of diffusion kurtosis imaging (DKI) with the standard monoexponential (ME) apparent diffusion coefficient (ADC) model in the detection ...of significant prostate cancer (PCa), using whole-mount histopathology of radical prostatectomy specimens as a reference standard.
155 patients with prostate cancer had undergone multiparametric magnetic resonance imaging (mpMRI) at 3T before prostatectomy. Quantitative diffusion parameters-the apparent diffusion coefficient corrected for non-Gaussian behavior (D
), kurtosis (K), ADC
, and ADC
were correlated with Gleason score and compared between cancerous and benign tissue and between GS ≤ 3 + 3 and GS ≥ 3 + 4 tumors.
The mean values of all diffusion parameters (D
, K, ADC
, ADC
) were significantly different both between malignant and benign tissue and between GS ≤ 3 + 3 and GS ≥ 3 + 4 tumors. Although the kurtosis model was better fitted to DWI data, the diagnostic performance in receiver operating characteristic (ROC) analysis of DKI and the standard ADC model in the detection of significant PCa was similar in the peripheral zone (PZ) and in peripheral and transitional zones (TZ) together. In conclusion, our study was not able to demonstrate a clear superiority of the kurtosis model over standard ADC in the diagnosis of significant PCa in PZ and in both zones combined.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
MicroRNAs (miRs) are short, evolutionarily conserved noncoding RNAs that canonically downregulate expression of target genes. The miR family composed of miR-204 and miR-211 is among the most highly ...expressed miRs in the retinal pigment epithelium (RPE) in both mouse and human and also retains high sequence identity. To assess the role of this miR family in the developed mouse eye, we generated two floxed conditional KO mouse lines crossed to the RPE65-ERT2-Cre driver mouse line to perform an RPE-specific conditional KO of this miR family in adult mice. After Cre-mediated deletion, we observed retinal structural changes by optical coherence tomography; dysfunction and loss of photoreceptors by retinal imaging; and retinal inflammation marked by subretinal infiltration of immune cells by imaging and immunostaining. Single-cell RNA sequencing of diseased RPE and retinas showed potential miR-regulated target genes, as well as changes in noncoding RNAs in the RPE, rod photoreceptors, and Müller glia. This work thus highlights the role of miR-204 and miR-211 in maintaining RPE function and how the loss of miRs in the RPE exerts effects on the neural retina, leading to inflammation and retinal degeneration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mutations in many visual cycle enzymes in photoreceptors and retinal pigment epithelium (RPE) cells can lead to the chronic accumulation of toxic retinoid byproducts, which poison photoreceptors and ...the underlying RPE if left unchecked. Without a functional ATP-binding cassette, sub-family A, member 4 (ABCA4), there is an elevation of all-
-retinal and prolonged buildup of all-
-retinal adducts, resulting in a retinal degenerative disease known as Stargardt-1 disease. Even in this monogenic disorder, there is significant heterogeneity in the time to onset of symptoms among patients. Using a combination of molecular techniques, we studied
knockout (simulating human noncoding disease variants) and
knock-in mice (simulating human misfolded, catalytically inactive protein variants), which serve as models for Stargardt-1 disease. We compared the two strains to ascertain whether they exhibit differential responses to agents that affect cytokine signaling and/or ceramide metabolism, as alterations in either of these pathways can exacerbate retinal degenerative phenotypes. We found different degrees of responsiveness to maraviroc, a known immunomodulatory CCR5 antagonist, and to the ceramide-lowering agent AdipoRon, an agonist of the ADIPOR1 and ADIPOR2 receptors. The two strains also display different degrees of transcriptional deviation from matched WT controls. Our phenotypic comparison of the two distinct
mutant-mouse models sheds light on potential therapeutic avenues previously unexplored in the treatment of Stargardt disease and provides a surrogate assay for assessing the effectiveness for genome editing.
The aim of the studies is to show that graphical bioinformatics methods are good tools for the description of genome sequences of viruses. A new approach to the identification of unknown virus ...strains, is proposed.
Biological sequences have been represented graphically through 2D and 3D-Dynamic Representations of DNA/RNA Sequences - theoretical methods for the graphical representation of the sequences developed by us previously. In these approaches, some ideas of the classical dynamics have been introduced to bioinformatics. The sequences are represented by sets of material points in 2D or 3D spaces. The distribution of the points in space is characteristic of the sequence. The numerical parameters (descriptors) characterizing the sequences correspond to the quantities typical of classical dynamics.
Some applications of the theoretical methods have been briefly reviewed. 2D-dynamic graphs representing the complete genome sequences of SARS-CoV-2 are shown.
It is proved that the 3D-Dynamic Representation of DNA/RNA Sequences, coupled with the random forest algorithm, classifies successfully the subtypes of influenza A virus strains.
Hereditary haemochromatosis (HH) is a disease characterised by the excessive absorption of iron and its deposition in various organs. Late complications of this disease include cirrhosis, ...hepatocellular carcinoma, and endocrine disorders. Data from the literature on thyroid disorders in patients with HH are inconsistent and ambiguous, and no research has been done to determine the relationship between excessive accumulation of iron and the thyroid morphology. Therefore, the aim of this study was to characterise thyroid function and ultrasound images in patients with clinically overt hereditary haemochromatosis.
We studied 40 patients who were diagnosed with hereditary haemochromatosis with one of the mutations of the HFE gene and iron deposits in liver in specimen from liver biopsies (graded G2 to G4) or in MRI. To assess thyroid function, ultrasound examinations of the thyroid gland were performed and serum TSH concentrations were measured.
We showed in our study that patients with HH have been diagnosed with thyroid focal lesions statistically less frequent than in the control group. We did not reveal any statistically significant difference in TSH concentration between patients with HH and the general population. However, patients with more severe iron deposits in liver showed lower TSH concentration.
Our results indicate lower incidence of focal lesions in thyroid gland in a group of patients with clinically overt hereditary haemochromatosis.
The pathogenesis of inflammatory bowel diseases (IBD) seems to be associated with alterations of immunoregulation. Several lines of evidence suggest that estrogens play a role in the modulation of ...immune responses and may be related to the etiology of IBD. The purpose of this work was to examine the involvement of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα), estrogen receptor β (ERβ) and ERα spliced variants ERα36 and ERα46 in Crohn's disease (CD) and ulcerative colitis (UC). The studied group included 73 patients with IBD and 31 sex and age-related controls. No differences in serum levels of 17β-estradiol nor of CYP1A1 and SULT1E1 enzymes involved in estrogen catabolism were stated. The expression pattern of estrogen receptors in tissue samples was quantified using real-time PCR and Western blotting. Statistically significant up-regulation of GPER and ERα in both CD and UC as well as down-regulation of ERβ in CD patients was found. However, differences in the expression of estrogen receptors in CD and UC have been identified, depending on the sex and age of patients. In men, up-regulation of GPER, ERα and ERα46 expression was shown in CD and UC patients. In women under 50 years of age, GPER protein level increased in UC whereas ERβ expression tended to decrease in CD and UC patients. In turn, in women over 50 the protein level of ERα increased in UC while ERβ expression decreased in CD patients. Dysregulation of estrogen receptors in the intestinal mucosa of patients with CD and UC indicates that estrogen signaling may play a role in the local immune response and maintain epithelial homeostasis in a gender- and age-dependent manner.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Estrogens exert immunomodulatory action in many autoimmune diseases. Accumulating evidence highlights the meaningful impact of estrogen receptors in physiology and pathophysiology of the colon. ...However, the significance of G protein-coupled estrogen receptor (GPER) on Crohn's disease (CD), one of the inflammatory bowel disease (IBD) types, is still elusive. Our study revealed GPER overexpression at the mRNA and protein levels in patients with CD. To evaluate the effects of GPER activation/inhibition on colitis development, a murine 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced model of CD was used. We showed that activation of GPER reduces mortality, improves macroscopic and microscopic scores and lowers C-reactive protein (CRP) level. The impact of estrogen signaling on the suppression of the intestinal inflammation was proved by immunohistochemistry. It was demonstrated that GPER activation is accompanied by modulation of extracellular-signal regulated kinase (ERK) signaling pathway and expression level of genes involved in signal transmission and immune response as well as the expression of some microRNAs (miR-145, miR-148-5p and miR-592). Our study revealed that the membrane-bound estrogen receptor GPER mediates anti-inflammatory action and seems to be a potent therapeutic target in maintaining remission in CD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and ...inflammatory pain.
Methods
The anti‐inflammatory activity of selective GPR18 agonist, PSB‐KK‐1415, and antagonist, PSB‐CB5, was characterized in semi‐chronic and chronic mouse models of colitis induced by 2,4,6‐trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor‐α (TNF‐α) and interleukin‐6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real‐time PCR. The anti‐nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain.
Key Results
In semi‐chronic colitis, PSB‐KK‐1415 reduced macroscopic score (1.79 ± 0.22 vs. 2.61 ± 0.48), expression of TNF‐α (1.89 ± 0.36 vs. 2.83 ± 0.64), and microscopic score (5.00 ± 0.33 vs. 6.45 ± 0.40), all compared to mice with colitis. In chronic colitis, PSB‐KK‐1415 decreased macroscopic score (3.33 ± 1.26 vs. 4.00 ± 1.32) and MPO activity (32.23 ± 8.51 vs. 41.33 ± 11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB‐KK‐1415 decreased the number of pain‐induced behaviors in both, controls (32.60 ± 2.54 vs. 58.00 ± 6.24) and inflamed mice (60.83 ± 2.85 vs. 85.00 ± 5.77) compared to animals without treatment with PSB‐KK‐1415 (P < 0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77 ± 1.46 vs. 2.38 ± 0.66, p = 0.87).
Conclusions & Inferences
We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.
A recently deorphanized receptor, GPR18 showed to act with several endogenous cannaboinoid ligands. Among several potent functionalities the receptor activation also leads to the induction of anti‐infammatory and antinociceptive action. By using highly selective agonist of GPR18, PSB‐KK‐1415 we achieved an inflammation alleviation in two mouse models of colitis and a reduction in pain‐induced behaviors in mouse model of inflammatory pain.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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