SuperCUT, an unsupervised multimodal image registration with deep learning for biomedical microscopy.

Numerous imaging techniques are available for observing and interrogating biological samples, and several of them can be used consecutively to enable correlative analysis of different image modalities with varying resolutions and the inclusion of structural or molecular information. Achieving accurate registration of multimodal images is essential for the correlative analysis process, but it remains a challenging computer vision task with no widely accepted solution. Moreover, supervised registration methods require annotated data produced by experts, which is limited. To address this challenge, we propose a general unsupervised pipeline for multimodal image registration using deep learning. We provide a comprehensive evaluation of the proposed pipeline versus the current state-of-the-art image registration and style transfer methods on four types of biological problems utilizing different microscopy modalities. We found that style transfer of modality domains paired with fully unsupervised training leads to comparable image registration accuracy to supervised methods and, most importantly, does not require human intervention.

Riverine Microplastic Quantification: A Novel Approach Integrating Satellite Images, Neural Network, and Suspended Sediment Data as a Proxy.

Rivers transport terrestrial microplastics (MP) to the marine system, demanding cost-effective and frequent monitoring, which is attainable through remote sensing. This study aims to develop and test microplastic concentration (MPC) models directly by satellite images and indirectly through suspended sediment concentration (SSC) as a proxy employing a neural network algorithm. These models relied upon high spatial (26 sites) and temporal (198 samples) SSC and MPC data in the Tisza River, along with optical and active sensor reflectance/backscattering. A feedforward MLP neural network was used to calibrate and validate the direct models employing k-fold cross-validation (five data folds) and the Optuna library for hyperparameter optimization. The spatiotemporal generalization capability of the developed models was assessed under various hydrological scenarios. The findings revealed that hydrology fundamentally influences the SSC and MPC. The indirect estimation method of MPC using SSC as a proxy demonstrated higher accuracy (R2 = 0.17-0.88) than the direct method (R2 = 0-0.2), due to the limitations of satellite sensors to directly estimate the very low MPCs in rivers. However, the estimation accuracy of the indirect method varied with lower accuracy (R2 = 0.17, RMSE = 12.9 item/m3 and MAE = 9.4 item/m3) during low stages and very high (R2 = 0.88, RMSE = 7.8 item/m3 and MAE = 10.8 item/m3) during floods. The worst estimates were achieved based on Sentinel-1. Although the accuracy of the MPC models is moderate, it still has practical applicability, especially during floods and employing proxy models. This study is one of the very initial attempts towards MPC quantification, thus more studies incorporating denser spatiotemporal data, additional water quality parameters, and surface roughness data are warranted to improve the estimation accuracy.

Investigation of the Antiremodeling Effects of Losartan, Mirabegron and Their Combination on the Development of Doxorubicin-Induced Chronic Cardiotoxicity in a Rat Model.

Despite the effectiveness of doxorubicin (DOXO) as a chemotherapeutic agent, dose-dependent development of chronic cardiotoxicity limits its application. The angiotensin-II receptor blocker losartan is commonly used to treat cardiac remodeling of various etiologies. The beta-3 adrenergic receptor agonist mirabegron was reported to improve chronic heart failure. Here we investigated the effects of losartan, mirabegron and their combination on the development of DOXO-induced chronic cardiotoxicity. Male Wistar rats were divided into five groups: (i) control; (ii) DOXO-only; (iii) losartan-treated DOXO; (iv) mirabegron-treated DOXO; (v) losartan plus mirabegron-treated DOXO groups. The treatments started 5 weeks after DOXO administration. At week 8, echocardiography was performed. At week 9, left ventricles were prepared for histology, qRT-PCR, and Western blot measurements. Losartan improved diastolic but not systolic dysfunction and ameliorated SERCA2a repression in our DOXO-induced cardiotoxicity model. The DOXO-induced overexpression of Il1 and Il6 was markedly decreased by losartan and mirabegron. Mirabegron and the combination treatment improved systolic and diastolic dysfunction and significantly decreased overexpression of Smad2 and Smad3 in our DOXO-induced cardiotoxicity model. Only mirabegron reduced DOXO-induced cardiac fibrosis significantly. Mirabegron and its combination with losartan seem to be promising therapeutic tools against DOXO-induced chronic cardiotoxicity.

Substitutional Diversity-Oriented Synthesis and In Vitro Anticancer Activity of Framework-Integrated Estradiol-Benzisoxazole Chimeras.

Hybridization of steroids and other pharmacophores often modifies the bioactivity of the parent compounds, improving selectivity and side effect profile. In this study, estradiol and 3'-(un)substituted benzisoxazole moieties were combined into novel molecules by structural integration of their aromatic rings. Simple estrogen starting materials, such as estrone, estradiol and estradiol-3-methylether were used for the multistep transformations. Some of the heterocyclic derivatives were prepared from the estrane precursor by a formylation or Friedel-Crafts acylation-oximation-cyclization sequence, whereas others were obtained by a functional group interconversion strategy. The antiproliferative activities of the synthesized compounds were assessed on various human cervical, breast and prostate cancer cell lines (HeLa, MCF-7, PC3, DU-145) and non-cancerous MRC-5 fibroblast cells. Based on the primary cytotoxicity screens, the most effective cancer-selective compounds were selected, their IC50 values were determined and their apoptosis-inducing potential was evaluated by quantitative real-time PCR. Pharmacological studies revealed a strong structure-function relationship, where derivatives with a hydroxyl group on C-17 exhibited stronger anticancer activity compared to the 17-acetylated counterparts. The present study concludes that novel estradiol-benzisoxazole hybrids exert remarkable cancer cell-specific antiproliferative activity and trigger apoptosis in cancer cells.

Estradiol-Based Salicylaldehyde (Thio)Semicarbazones and Their Copper Complexes with Anticancer, Antibacterial and Antioxidant Activities.

A series of novel estradiol-based salicylaldehyde (thio)semicarbazones ((T)SCs) bearing (O,N,S) and (O,N,O) donor sets and their Cu(II) complexes were developed and characterized in detail by 1H and ¹³C nuclear magnetic resonance spectroscopy, UV-visible and electron paramagnetic resonance spectroscopy, electrospray ionization mass spectrometry and elemental analysis. The structure of the Cu(II)-estradiol-semicarbazone complex was revealed by X-ray crystallography. Proton dissociation constants of the ligands and stability constants of the metal complexes were determined in 30% (v/v) DMSO/H2O. Estradiol-(T)SCs form mono-ligand complexes with Cu(II) ions and exhibit high stability with the exception of estradiol-SC. The Cu(II) complexes of estradiol-TSC and its N,N-dimethyl derivative displayed the highest cytotoxicity among the tested compounds in MCF-7, MCF-7 KCR, DU-145, and A549 cancer cells. The complexes do not damage DNA according to both in vitro cell-free and cellular assays. All the Cu(II)-TSC complexes revealed significant activity against the Gram-positive Staphylococcus aureus bacteria strain. Estradiol-TSCs showed efficient antioxidant activity, which was decreased by complexation with Cu(II) ions. The exchange of estrone moiety to estradiol did not result in significant changes to physico-chemical and biological properties.

Temperature-Induced Change of Water Structure in Aqueous Solutions of Some Kosmotropic and Chaotropic Salts.

The hydrogen bond structure of water was examined by comparing the temperature dependent OH-stretching bands of water and aqueous NaClO4, KClO4, Na2SO4, and K2SO4 solutions. Results called attention to the role of cations on top of the importance of anions determining the emerging structure of a multi-layered system consisting single water rings or multi-ring water-clusters.

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease.

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-ß/SMAD signaling pathway in our RIHD model.

Novel Phonography-Based Measurement for Fetal Breathing Movement in the Third Trimester.

The detailed assessment of fetal breathing movement (FBM) monitoring can be a pre-indicator of many critical cases in the third trimester of pregnancy. Standard 3D ultrasound monitoring is time-consuming for FBM detection. Therefore, this type of measurement is not common. The main goal of this research is to provide a comprehensive image about FBMs, which can also have potential for application in telemedicine. Fifty pregnancies were examined by phonography, and nearly 9000 FBMs were identified. In the case of male and female fetuses, 4740 and 3100 FBM episodes were detected, respectively. The measurements proved that FBMs are well detectable in the 20-30 Hz frequency band. For these episodes, an average duration of 1.008 ± 0.13 s (p < 0.03) was measured in the third trimester. The recorded material lasted for 16 h altogether. Based on these measurements, an accurate assessment of FBMs could be performed. The epochs can be divided into smaller-episode groups separated by shorter breaks. During the pregnancy, the rate of these breaks continuously decreases, and episode groups become more contiguous. However, there are significant differences between male and female fetuses. The proportion of the episodes which were classified into minimally 10-member episode groups was 19.7% for males and only 12.1% for females, even at the end of the third trimester. In terms of FBM detection, phonography offers a novel opportunity for long-term monitoring. Combined with cardiac diagnostic methods, it can be used for fetal activity assessment in the third trimester and make measurement appreciably easier than before.

Terahertz electric field modulated mode coupling in graphene-metal hybrid metamaterials.

Taking advantage of the tunable conductivity of graphene under high terahertz (THz) electric field, a graphene-metal hybrid metamaterial consisting of an array of three adjoined orthogonally oriented split-ring resonators (SRRs) is proposed and experimentally demonstrated to show a maximum modulation depth of 23% in transmission when the THz peak field reaches 305 kV/cm. The transmission of the sample is dominated by the antisymmetric and symmetric resonant modes originating from the strong magneto-inductive and conductive coupling among the three SRRs, respectively. Numerical simulations and model calculations based on a coupled oscillator theory were performed to explain the modulation process. It is found that the graphene coating impairs the resonances by increasing the damping of the modes and decreasing the coupling between the SRRs whereas the strong THz field restores the resonances by decreasing the conductivity of graphene.

[Automated measurement of biomarkers for the diagnosis of acute myocardial infarction]. / Automatizáltan mérheto biomarkerek az akut myocardialis infarctus diagnosztikájában.

INTRODUCTION: Cardiac biomarkers have a prominent role in the diagnosis of acute myocardial infarction. AIM: The aim of the authors was to study the diagnostic effectiveness of automated measurement of cardiac biomarkers. METHOD: Myeloperoxidase, high-sensitivity C-reactive protein, myoglobin, heart-type fatty acid binding protein, creatine kinase, creatine kinase MB, high-sensitivity troponin I and T were measured. RESULTS: The high-sensitivity troponin I was the most effective (area under curve: 0.86; 95% confidence interval: 0.77-0.95; p<0.001) for the diagnosis of acute myocardial infarction. Considering a critical value of 0.35 ng/mL, its sensitivity and specificity were 81%, and 74%, respectively. Combined evaluation of the high-sensitivity troponin T and I, chest pain, and the electrocardiogram gave the best results for separation of acute myocardial infarction from other diseases (correct classification in 62.5% and 98.9% of patients, respectively). CONCLUSIONS: Until a more sensitive and specific cardiac biomarker becomes available, the best method for the diagnosis of acute myocardial infarction is to evaluate electrocardiogram and biomarker concentration and to repeat them after 3-6 hours.

[Isolated aspartate aminotransferase elevation in a young, healthy person. Case report]. / Izolált aszpartát-aminotranszferáz-emelkedés fiatal, egészséges egyénben.

The authors present diagnostic methods used in a young healthy person who had isolated aspartate aminotransferase elevation. Polyethylene glycol precipitation test, aspartate aminotransferase serum electrophoresis and immunofixation were performed for measuring the macro-aspartate aminotransferase. It was found that aspartate aminotransferase activity in the patient was almost completely eliminated after precipitation of immunoglobulins with polyethylene glycol. In addition, aspartate aminotransferase migrated in the control samples to the anode while in the patient towards the cathode. Finally, a wider and more intense staining band was visible in the region of immunoglobulin A in the patient sample on the immunofixation gel as compared to the control sample. The authors conclude that that increased aspartate aminotransferase activity was due to macro formation. The elevated level of immunoglobulin A and selective increase of polyclonal immunoglobulin A (κ and λ light chains) indicated that the macro format was created by immunoglobulin A bound to aspartate aminotransferase.

Role of the kisspeptin-KISS1R axis in the pathogenesis of chronic kidney disease and uremic cardiomyopathy.

The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction's echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13's influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.

A proposed novel method for CHD screening by fetal heart murmur detection using phonocardiography.

The paper presents a novel screening method to indicate congenital heart diseases (CHD) which otherwise would remain undetected because of their low level. Therefore, not belonging to the high-risk population, they are omitted from the regular fetal monitoring with ultrasound echocardiography. Based on the fact that CHDs are morphological defects of the heart causing turbulent blood flow, this turbulence appears as a murmur, which can be detected by phonocardiography (PCG). The proposed method applies measurements on the maternal abdomen and from the recorded sound signal a sophisticated processing determines the fetal heart murmur. The paper describes the problems and the additional advantages of the PCG method including the possibility of measurements at home and its combination with the prescribed regular cardiotocographic (CTG) monitoring. The proposed screening process implemented on a telemedicine system provides an enhanced safety against hidden cardiac diseases.

[Comparison of seven estimated glomerular filtration rate equations in kidney patients]. / Hét, becsült glomerulusfiltrációs ráta egyenletének összehasonlítása vesebetegekben.

INTRODUCTION: The degree of glomerular filtration rate determines the stages of chronic renal disease and, therefore, knowledge on its estimation is essential. AIMS: Two standardized creatinine based estimated glomerular filtration rate equations and five equations based on the immunoturbidimetric determination of cystatin C were compared. METHODS: The distribution of the analytes and the equations, their relations, as well as the differences among the estimated glomerular filtration rates and their chronic kidney disease stages assignments were studied. RESULTS: The equations based on cystatin C classified more patient into stage 1, while the creatinine based ones more into stages 2, 3 and 4. The equations published as Grubb1, Grubb2 and Larsson classified more patients while the equations created by Tan and Sjöström classified fewer into stage 5 compared to the creatinine based equations. The equations of Grubb1 and Grubb2 resulted in the most similar stage assignment. The occurrence of stages between 3 and 5 was the lowest using the equation of Sjöström. CONCLUSIONS: The different equations for the estimation of glomerular filtration rate modify significantly the chronic kidney disease stage assignment which may have an influence on the treatment and outcome measures of the patients.

Machine learning-based detection and mapping of riverine litter utilizing Sentinel-2 imagery.

Despite the substantial impact of rivers on the global marine litter problem, riverine litter has been accorded inadequate consideration. Therefore, our objective was to detect riverine litter by utilizing middle-scale multispectral satellite images and machine learning (ML), with the Tisza River (Hungary) as a study area. The Very High Resolution (VHR) images obtained from the Google Earth database were employed to recognize some riverine litter spots (a blend of anthropogenic and natural substances). These litter spots served as the basis for training and validating five supervised machine-learning algorithms based on Sentinel-2 images [Artificial Neural Network (ANN), Support Vector Classifier (SVC), Random Forest (RF), Naïve Bays (NB) and Decision Tree (DT)]. To evaluate the generalization capability of the developed models, they were tested on larger unseen data under varying hydrological conditions and with different litter sizes. Besides the best-performing model was used to investigate the spatio-temporal variations of riverine litter in the Middel Tisza. According to the results, almost all the developed models showed favorable metrics based on the validation dataset (e.g., F1-score; SVC: 0.94, ANN: 0.93, RF: 0.91, DT: 0.90, and NB: 0.83); however, during the testing process, they showed medium (e.g., F1-score; RF:0.69, SVC: 0.62; ANN: 0.62) to poor performance (e.g., F1-score; NB: 0.48; DT: 0.45). The capability of all models to detect litter was bounded to the pixel size of the Sentinel-2 images. Based on the spatio-temporal investigation, hydraulic structures (e.g., Kisköre Dam) are the greatest litter accumulation spots. Although the highest transport rate of litter occurs during floods, the largest litter spot area upstream of the Kisköre Dam was observed at low stages in summer. This study represents a preliminary step in the automatic detection of riverine litter; therefore, additional research incorporating a larger dataset with more representative small litter spots, as well as finer spatial resolution images is necessary.

A comparative study on the metal complexes of an anticancer estradiol-hydroxamate conjugate and salicylhydroxamic acid.

Hydroxamic acids bearing an (O,O) donor set are well-known metal-chelating compounds with diverse biological activities including anticancer activity. Since steroid conjugation with a pharmacophoric moiety may have the potential to improve this effect, a salicylhydroxamic acid-estradiol hybrid molecule (E2HA) was synthesized. Only minimal effect of the conjugation on the proton dissociation constants was observed in comparison to salicylhydroxamic acid (SHA). The complexation with essential metal ions (iron, copper) was characterized, since E2HA may exert its cytotoxicity through the binding of these ions in cells. UV-visible spectrophotometric and pH-potentiometric titrations revealed the formation of high-stability complexes, while the Fe(III) preference over Fe(II) was proved by cyclic voltammetry and spectroelectrochemical measurements. Complex formation with half-sandwich Rh(III)(η5-Cp*) and Ru(II)(η6-p-cymene) organometallic cations was also studied as it may improve the anticancer effect and the pharmacokinetic profile of the ligand. At equimolar concentration the speciation is complicated because of the presence of mononuclear and binuclear complexes. The complexes readily react with small molecules e.g. glutathione, 1-methylimidazole and nucleosides, having major effect on solution speciation, namely mixed-ligand complex formation and ligand displacement occur. These processes serve as models for the interactions with biomolecules in the body. E2HA exerted moderate anticancer activity (IC50 = 25-59 µM) in the tested three human cancer cell lines (Colo205, Colo320 and MCF-7), while being non-toxic on non-cancerous MRC-5 cells. Meanwhile, SHA was inactive in the same cells. Complexation with half-sandwich Rh(III) and Ru(II) cations had only a minor improvement on the cytotoxic effect of E2HA.

Medicinal-Chemistry-Driven Approach to 2-Substituted Benzoxazole-Estradiol Chimeras: Synthesis, Anticancer Activity, and Early ADME Profile.

The efficient synthesis of novel estradiol-based A-ring-fused oxazole derivatives, which can be considered as benzoxazole-steroid domain-integrated hybrids containing a common benzene structural motif, is described. The target compounds were prepared from steroidal 2-aminophenol precursors by heterocycle formation or functional group interconversion (FGI) strategies. According to 2D projection-based t-distributed stochastic neighbor embedding (t-SNE), the novel molecules were proved to represent a new chemical space among steroid drugs. They were characterized based on critical physicochemical parameters using in silico and experimental data. The performance of the compounds to inhibit cell proliferation was tested on four human cancer cell lines and non-cancerous cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency (LLE) values, cancer cell selectivity, and apoptosis-triggering features. Pharmacological tests and LLE metric revealed that some derivatives, especially the 2-(4-ethylpiperazin-1-yl)oxazole derivative exhibit strong anticancer activity and trigger the apoptosis of cancer cells with relatively low promiscuity risk similarly to the structurally most closely-related and intensively studied anticancer agent, 2-methoxy-estradiol.

Image-based and machine learning-guided multiplexed serology test for SARS-CoV-2.

We present a miniaturized immunofluorescence assay (mini-IFA) for measuring antibody response in patient blood samples. The method utilizes machine learning-guided image analysis and enables simultaneous measurement of immunoglobulin M (IgM), IgA, and IgG responses against different viral antigens in an automated and high-throughput manner. The assay relies on antigens expressed through transfection, enabling use at a low biosafety level and fast adaptation to emerging pathogens. Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the model pathogen, we demonstrate that this method allows differentiation between vaccine-induced and infection-induced antibody responses. Additionally, we established a dedicated web page for quantitative visualization of sample-specific results and their distribution, comparing them with controls and other samples. Our results provide a proof of concept for the approach, demonstrating fast and accurate measurement of antibody responses in a research setup with prospects for clinical diagnostics.

The kisspeptin-1 receptor antagonist peptide-234 aggravates uremic cardiomyopathy in a rat model.

Uremic cardiomyopathy is characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis. Dysregulation of the kisspeptin receptor (KISS1R)-mediated pathways are associated with the development of fibrosis in cancerous diseases. Here, we investigated the effects of the KISS1R antagonist peptide-234 (P234) on the development of uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (i) Sham, (ii) chronic kidney disease (CKD) induced by 5/6 nephrectomy, (iii) CKD treated with a lower dose of P234 (ip. 13 µg/day), (iv) CKD treated with a higher dose of P234 (ip. 26 µg/day). Treatments were administered daily from week 3 for 10 days. At week 13, the P234 administration did not influence the creatinine clearance and urinary protein excretion. However, the higher dose of P234 led to reduced anterior and posterior wall thicknesses, more severe interstitial fibrosis, and overexpression of genes associated with left ventricular remodeling (Ctgf, Tgfb, Col3a1, Mmp9), stretch (Nppa), and apoptosis (Bax, Bcl2, Casp7) compared to the CKD group. In contrast, no significant differences were found in the expressions of apoptosis-associated proteins between the groups. Our results suggest that the higher dose of P234 hastens the development and pathophysiology of uremic cardiomyopathy by activating the fibrotic TGF-ß-mediated pathways.

Neuregulin-1ß Improves Uremic Cardiomyopathy and Renal Dysfunction in Rats.

Chronic kidney disease is a global health problem affecting 10% to 12% of the population. Uremic cardiomyopathy is often characterized by left ventricular hypertrophy, fibrosis, and diastolic dysfunction. Dysregulation of neuregulin-1ß signaling in the heart is a known contributor to heart failure. The systemically administered recombinant human neuregulin-1ß for 10 days in our 5/6 nephrectomy-induced model of chronic kidney disease alleviated the progression of uremic cardiomyopathy and kidney dysfunction in type 4 cardiorenal syndrome. The currently presented positive preclinical data warrant clinical studies to confirm the beneficial effects of recombinant human neuregulin-1ß in patients with chronic kidney disease.