bluuebunny/crossref_metadata_2025 huggingface dataset:
Surface laser processing of maraging steel parts manufactured by selective laser melting: effect on pass geometry and hardness
Authors: Bučelis Kęstutis , Škamat Jelena , Černašejus Olegas
Published: June 2022

Due to the possibility to produce the parts with complex internal and external geometries, selective laser melting (SLM) process attracts growing interest in various fields of engineering segments such as aircraft, aerospace, biomedical, automotive, marine industries and tooling. Maraging steels, having excellent weldability and high resistance to thermal fatigue due to the lack of carbon, has showed good suitability for SLM [1]. However, owing to the limited hardness and wear resistance, maraging steels has limited application at the harsh wear conditions [4]. In this study, the possibility to improve the surface characteristics of DIN 1.2709 steel SLM parts by application of laser alloying technology is evaluated. The surface of SLM part was laser processed at various laser spot diameters and varying laser scanning speeds from 500 to 1500 mm⋅min-1, with and without preposition of alloying element. The power density was provided in the range from ~0.8⋅103 W⋅cm-2 to ~51⋅103 W⋅cm-2 and heat input – from 4 to 12 J⋅mm-1. The effect of laser processing parameters and presence of alloying element on the geometry of obtained processed passes and hardness of surface was evaluated. It was determined, that the application of CO2 continuous laser at the parameters of 1 kW laser power, 0.5 mm laser beam spot diameter and laser scanning speed in the range between 500 mm⋅min-1 and 1250 mm⋅min-1 allows obtaining laser pool of acceptable geometry and sizes directly on as-manufactured SLM part surface without any pre-processing. The increasing scanning speed to 1500 mm⋅min-1 or spot size to 2.0 and 3.0 mm results in too small pool depth and unstable pool geometry. The laser processing with preposition of alloying element layer provided surface alloying effect of the maraging steel SLM part. The hardness of processed surface areas ranged between ~600 HV0.2 at the lowest scanning speed and ~1770 HV0.2 at the highest speed, what is from 18% to ~3.5 times higher, as compared with maximum hardness of 1.2709 maraging steel after aging (~58 HRC or ~510 HV).
Neural classifying system for predictive maintenance of rotating devices.
Authors: Balazy P , Gut P , Knap P
Published: June 2022

This paper presents the results of research on a neural classifier system for the recognition of electrical drive disturbances and its speed. The classification task is performed by a convolutional neural network implemented on an artificial intelligence accelerator. The operation of the drive is monitored using intelligent accelerometers. Based on the sensor data, it is possible to create spectrograms of the signal using Short Time Fourier Transformation. Since convolutional neural networks are excellent at recognizing images and detecting objects, the signal spectrograms were used as input data for learning the network. Transfer learning method has been used, to create a model of neural network.
Fluorine-doped graphene as triboelectric material
Authors: Molina-García Miguel Ángel , Sofer Zdeněk , Panda Jaya Kumar , Serri Michele , Salerno Marco , Marras Sergio , Lauciello Simone , Plutnar Jan , Bonaccorso Francesco
Published: June 2022

The optimization of the triboelectric layer is of paramount importance for the improvement of the performance of triboelectric nanogenerators (TENGs). In this work, we present an innovative approach exploiting the addition of highly electronegative fluorine-doped reduced graphene oxide (F-RGO) flakes into a polydimethylsiloxane (PDMS) polymeric matrix acting as the tribonegative frictional layer. The resulting layer (F-RGO/PDMS) is incorporated into a vertical contact-separation mode TENG. The optimization of the F-RGO/PDMS composition, with a F-RGO content of 2%, delivered a ten times higher power density peak compared to a F-RGO-free device. The outstanding enhancement of the power density peak is attributed to the synergistic effect of the high electronegativity of the fluorine atoms and the triboelectric properties of the graphene-based flakes. Endurance tests confirmed the stability of the F-RGO/PDMS system, demonstrating its suitability for long-lasting TENG-based wearable devices.
Quantum researcher mobility: the wonderful wizard of Oz who paid for Dorothy’s visa fees
Authors: Malik Mehul , Agudelo Elizabeth , Kunjwal Ravi
Published: June 2022

Historically, science has benefited greatly through the mobility of researchers, whether it has been due to large-scale conflict, the search for new opportunities or a lack thereof. Today’s world of strict global immigration policies, exacerbated by the COVID-19 pandemic, places inordinate hurdles on the mobility of all researchers, let alone quantum ones. Exorbitant visa fees, the difficulty of navigating a foreign immigration system, lack of support for researchers’ families, and explicit government policy targeting selected groups of immigrants are all examples of things that have severely impacted the ability of quantum researchers to cross both physical and scientific borders. Here we clearly identify some key problems affecting quantum researcher mobility and discuss examples of good practice on the governmental, institutional, and societal level that have helped, or might help, overcome these hurdles. The adoption of such practices worldwide can ensure that quantum scientists can reach their fullest potential, irrespective of where they were born.
On the energy consumption of online and on-site lectures
Authors: Holas Alexander , Koch Catherine Y , Leibold Joachim , Prendi Alesia , Schlachta Tim P , Sophia Schmid Anna , Schmitt Leonard
Published: June 2022

In this study, the energy consumption of online (streaming or video on demand) lectures is compared with on-site lectures in the case of the Garching campus of the Technical University of Munich (TUM). The energy consumption is calculated using data collected by a survey, own measurements and literature research. On-site lectures at the TUM consume up to two orders of magnitude more energy than digital formats, making any combination of both always more energy intensive than purely online lectures. Transportation turns out to be the factor with the highest energy consumption. In scenarios with a decreased impact of transportation, e.g. regarding universities with dormitories on campus, hybrid or purely on-site lectures can become more favorable in terms of energy consumption, especially if several on-site lectures are attended in one day.
Air pollution exposure and its impacts on everyday life and livelihoods of vulnerable urban populations in South Asia
Authors: Maharjan Amina , Adhikari Sagar , Ahmad Rida , Ahmad Usman , Ali Zulfiqar , Bajracharya Sugat , Baniya Jeevan , Bhattarai Sadikshya , Gautam Amit , Gilmore Elisabeth , Ko Hein Min , Myat Nilar , Myint Theingi , Mahapatra Parth Sarathi , Mishra Arabinda , Singh Chandni
Published: June 2022

Urban populations in South Asia are regularly exposed to poor air quality, especially elevated concentrations of fine particulate matter (PM2.5). However, the potential differential burden for the urban poor has received little attention. Here, we evaluate the links between occupation, patterns of exposure to PM2.5, and the impacts at an individual and household level for vulnerable populations in Lahore (Pakistan), Kathmandu (Nepal), and Mandalay (Myanmar). We conduct personal exposure measurements and detailed interviews, identifying a wide range of impacts at individual and household levels. Low-income populations are concentrated in occupations that expose them to higher concentrations. Individuals report a range of adverse health impacts and limited capacities to reduce exposure. The lost income, compounded with the costs of managing these health impacts and limited opportunities for alternative employment, can deepen the socioeconomic vulnerability for the household. Reducing these risks requires targeted interventions such as improved social safety nets.
Effects of coaxial airflow swirl number on combustion and flame characteristics of methane/air and n-butane/air flames in a miniature-scale swirl burner
Authors: Sheykhbaglou Soroush , Robati Seyed Mostafa
Published: June 2022

In this paper, the effects of coaxial airflow swirl number on blow-out limit, flame characteristics, and emission performance of non-premixed methane/air and n-butane/air flames in a miniature-scale swirl burner are investigated experimentally. Swirl numbers ranging from

0

to

0.72

have been chosen to be examined. It was observed that increasing the vane angle does not increase the blow-out limit monotonically and a swirler with

30
°

vane angle (

0.50

swirl number) results in the greatest blow-out limit. Besides, it was found out that methane outperforms n-butane in the blow-out limit at the same fuel flow rates. The intermittency distribution approach was used to determine flame properties such as lift-off height, length, and width. It was found that the lift-off variation with coaxial airflow Reynolds number at the specified fuel flow rates yields an inverted V-shape for S

n
≥ 0.50. The tip of these plots indicates the airflow rate at which the swirl shows its influence, and after this point, the lift-off height begins to decrease. It was also observed that the airflow related to this point decreases with an increase in the swirl number at a certain fuel flow rate. Furthermore, the results revealed that at high airflow rates, the flame width rises as the swirl number increases. Also, raising the swirl number and airflow Reynolds number reduced the flame length. It was also observed that n-butane/air flames have longer and wider flames than methane/air flames. Additionally, adding swirl to the airflow rate typically reduces

N

O

x

and

CO

concentrations and n-butane/air flames exhibit lower levels of

N

O

x

and higher levels of

CO

than methane/air flames under the same operating conditions.
Advancing the Science of Vaccine Safety During the Coronavirus Disease 2019 (COVID-19) Pandemic and Beyond: Launching an International Network of Special Immunization Services
Authors: Top Karina A , Chen Robert T , Levy Ofer , Ozonoff Al , Carleton Bruce , Crawford Nigel W , Creech C Buddy , Kochhar Sonali , Poland Gregory A , Gutu Kimberley , Cutland Clare L
Published: June 2022

Within 2 years after the start of the coronavirus disease 2019 (COVID-19) pandemic, novel severe acute respiratory syndrome coronavirus 2 vaccines were developed, rigorously evaluated in large phase 3 trials, and administered to more than 5 billion individuals globally. However, adverse events of special interest (AESIs) have been described post-implementation, including myocarditis after receipt of messenger RNA (mRNA) vaccines and thrombosis with thrombocytopenia syndrome after receipt of adenoviral vector vaccines. AESIs are rare (<1 to 10/100 000 vaccinees) and less frequent than COVID-19 complications, though they have associated morbidity and mortality. The diversity of COVID-19 vaccine platforms (eg, mRNA, viral vector, protein) and rates of AESIs both between and within platforms (eg, higher rate of myocarditis after mRNA-1273 vs BNT162b2 vaccines) present an important opportunity to advance vaccine safety science. The International Network of Special Immunization Services has been formed with experts in vaccine safety, systems biology, and other relevant disciplines to study cases of AESIs and matched controls to uncover the pathogenesis of rare AESIs and inform vaccine development.
Global Distribution of O Serotypes and Antibiotic Resistance in Extraintestinal Pathogenic Escherichia coli Collected From the Blood of Patients With Bacteremia Across Multiple Surveillance Studies
Authors: Weerdenburg Eveline , Davies Todd , Morrow Brian , Zomer Aldert L , Hermans Peter , Go Oscar , Spiessens Bart , van den Hoven Thijs , van Geet Gunter , Aitabi Moussa , DebRoy Chitrita , Dudley Edward G , Bonten Marc , Poolman Jan , Geurtsen Jeroen
Published: June 2022

Background

Extraintestinal pathogenic Escherichia coli (ExPEC) is the leading cause of bacteremia worldwide, with older populations having increased risk of invasive bacterial disease. Increasing resistance to first-line antibiotics and emergence of multidrug-resistant (MDR) strains represent major treatment challenges. ExPEC O serotypes are key targets for potential multivalent conjugate vaccine development. Therefore, we evaluated the O serotype distribution and antibiotic resistance profiles of ExPEC strains causing bloodstream infections across 4 regions.

Methods

Blood culture isolates from patients aged ≥60 years collected during 5 retrospective E. coli surveillance studies in Europe, North America, Asia-Pacific, and South America (2011–2017) were analyzed. Isolates were O serotyped by agglutination; O genotyping was performed for nontypeable isolates. Antimicrobial susceptibility testing was also conducted.

Results

Among 3217 ExPEC blood culture isolates, the most ubiquitous O serotype was O25 (n = 737 [22.9%]), followed by O2, O6, O1, O75, O15, O8, O16, O4, O18, O77 group, O153, O9, O101/O162, O86, and O13 (prevalence of ≥1%). The prevalence of these O serotypes was generally consistent across regions, apart from South America; together, these 16 O serotypes represented 77.6% of all ExPEC bacteremia isolates analyzed. The overall MDR frequency was 10.7%, with limited variation between regions. Within the MDR subset (n = 345), O25 showed a dominant prevalence of 63.2% (n = 218).

Conclusions

Predominant O serotypes among ExPEC bacteremia isolates are widespread across different regions. O25 was the most prevalent O serotype overall and particularly dominant among MDR isolates. These findings may inform the design of multivalent conjugate vaccines that can target the predominant O serotypes associated with invasive ExPEC disease in older adults.
Transcriptional Analysis for Tuberculosis in Pregnant Women From the PRegnancy Associated Changes In Tuberculosis Immunology (PRACHITi) Study
Authors: Mathad Jyoti S , Queiroz Artur T L , Bhosale Ramesh , Alexander Mallika , Naik Shilpa , Kulkarni Vandana , Andrade Bruno B , Gupta Amita
Published: June 2022

A new tuberculosis (TB) diagnostic cartridge assay, which detects a 3-gene TB signature in whole blood, was not diagnostic in women with maternal TB disease in India (area under the curve [AUC] = 0.72). In a cohort of pregnant women, we identified a novel gene set for TB diagnosis (AUC = 0.97) and one for TB progression (AUC = 0.96).
Cardiac progenitor cell-derived extracellular vesicles skew human macrophages towards a pro-inflammatory phenotype
Authors: Carmo Viola AM , Vader P , De Jager SCA , Sluijter JPG
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This research is support by the European Research Council (ERC) consolidator grant EVICARE (ERC-2016-COG-725229).

Background

Repair of damaged heart tissue upon myocardial infarction remains a major challenge. Transplantation of cardiac progenitor cells (CPCs) has been studied as a potential regenerative therapy, but recent studies have shown that the cardioprotective effect of CPCs is mediated by the release of extracellular vesicles (EVs). The benefits of CPC-derived EVs have mostly been associated with stimulation of angiogenesis and inhibition of cell death. Although macrophages have been suggested to be key for cardiac repair, the effect of CPC-EVs on macrophage polarization is poorly explored.

Purpose

Here, we hypothesized that CPC-derived EVs can modulate the inflammatory response after myocardial infarction by interacting with macrophages.

Methods

EVs were isolated from serum-starved CPCs by ultrafiltration followed by size exclusion chromatography. Human monocytes were isolated from the blood of healthy donors and differentiated into macrophages with M-CSF. Macrophages were subsequently stimulated with LPS + IFNy or with IL4 in order to induce an inflammatory M1 and reparative M2 phenotype, respectively. A third group of macrophages were cultured in media without LPS, IFNy or IL4 to resemble naive M0 macrophages. The obtained macrophages were exposed to CPC-EVs and analyzed by flow cytometry, bulk RNA sequencing and confocal microscopy to assess macrophage phenotype changes. Gene candidates were selected based on the p-value and fold-change, and validated by RT-PCR. Small molecule inhibitors were used to further investigate the mechanism by which CPC-EVs are taken up by macrophages and the pathways involved in macrophage response.

Results

Stimulation of macrophages with CPC-EVs enhanced the expression of the pro-inflammatory marker CD80, while slightly decreasing the anti-inflammatory marker CD206, in M0 and M2 macrophages. CPC-EV-stimulated macrophages also adopted a morphology that reflects the inflammatory macrophage. In line with these findings, bulk RNA sequencing on M0 and M2 polarized macrophages revealed upregulation of genes involved in inflammatory response, including cytokine and both type I and II interferon signaling. EV exposure did not significantly affect gene expression in M1 polarized macrophages. Ongoing investigations will provide in-depth insight into the mechanism by which CPC-EVs induce this response in macrophages.

Conclusion

Our data suggests that CPC-EVs are able to induce macrophage polarization towards an inflammatory phenotype, which might have implications for CPC-EV treatment after myocardial infarction. This underlines an urgent need to understand the molecular mechanisms underlying the immunomodulatory effect of CPC-derived EVs before moving into a clinical setting.
Platelets amino acids spectrum and coagulation in patients with atherosclerosis
Authors: Melnychuk I , Kramarova VN , Lizogub VG
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): O.O.Bogomolets National Medical University

Relevance: Amino acids are one of the important group of myocardial metabolites. Today metabolomic analysis has become an essential tool for understanding the pathophysiology of cardiovascular disorders [1, 3]. Coagulation factors interact with platelets by binding to platelet receptors directly or indirectly or by cleaving of the platelet receptors. Arterial thrombosis as a most life threating atherosclerosis (AS) complication is characterized by significant interplay between platelets and coagulation [2]. Therefore, it is important to find pathogenic links between changes in platelet structure and coagulation data.

Materials and methods

78 patients were investigated. All patients were divided into two groups – 20 patients without AS (control group) and 58 patients with AS (mean group). Diagnosis was verified by carotid and peripheral arteries ultrasound. Statistically all groups were compatible by the main clinical features (age, gender, concominant disorders, etc.). For amino acid platelet determination, platelet-rich plasma was obtained after blood centrifugation at 3000 g 15 min of 10 ml of the remaining plasma. One milliliter of platelet-rich plasma was centrifuged at 2,500 g for 15 min to obtain a platelet pellet that was frozen at –20°C until assayed. All the samples were stored for a maximum of 3 mounth.  Platelets amino acid spectrum was checked by ion exchange liquid column gas chromatography.

Results

Patients of the mean group has significantly differences compared with control group: decreasing of taurine (6.54±9.49 vs 5.94±4.36 mkmol/107), threonine (0.48±1.69 vs 0.22±1.24 mkmol/107), glycine (2.10±3.79 vs 1.02±2.11 mkmol/107) and glutamine (2.54±5.70 vs 1.88±2.76 mkmol/107) levels; increasing alanine (1.99±4.03 vs 2.81±3.06 mkmol/107), valine (0.96±1.98 vs 1.63±1.26 mkmol/107) and isoleucine (0.53±1.84 vs 2.91±1.61 mkmol/107) levels. Also in mean group acquired leucine (2.51±0.93 mkmol/107) that was not present in control group. Total amount of branch-chained amino acids (BCAA) in platelets is also increased significantly. Therefore, in mean group patients were significant higher-level activated partial thromboplastin time (APTT) (34.3±2.87 vs 28.8±3.29 s) and lower fibrinogen (205±17 vs 213±2 mg/dl). Direct significant correlation was checked between glycine (r=0,634; p<0,05), alanine (r=0,587; p<0,05) and fibrinogen, also between APTT and platelets BCAA (r=0,724; p<0,01).

Conclusion

We obtained reliable changes in platelets amino acid spectrum and coagulation tests in patients with atherosclerosis. In addition, significant correlations between themes can be related with pathogenic platelets changes. In any case more deeper studies are desirable.
Sex-related proteomic differences of the athlete's heart
Authors: Barta BA , Olah A , Bottlik O , Ruppert M , Sayour AA , Merkely B , Schilling O , Radovits T
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bolyai János Research Scholarship - BO/00837/21 to O.A., National Research, Development and Innovation Office (NKFIH) of Hungary - K135076 to B.M.

Introduction

Regular physical activity results in characteristic structural and functional changes in the heart, which are collectively referred to as the athlete’s heart. However, the extent of exercise-induced left ventricular (LV) hypertrophy and functional changes show significant differences between men and women, the molecular background of which is not fully elucidated.

Purpose

The aim of this study was to provide a proteomic characterization of long-term, intense exercise-induced LV myocardial hypertrophy in a rat model, with a focus on sex-related differences.

Methods

Our rats were divided into trained (FEx) and control female (FCo) as well as trained (MEx) and control male (MCo) groups. In the trained groups, athlete’s heart was induced by a 12-week swimming protocol. Myocardial hypertrophy was confirmed by echocardiography and functional adaptation by pressure-volume analysis. Proteomic measurements based on liquid chromatograph-coupled mass spectrometry were performed on proteins isolated from our LV myocardial samples.

Results

Echocardiography and post-mortem myocardial mass showed significant LV hypertrophy in both sexes, which was more pronounced in female animals (tibial length normalized LV muscle mass: + 17.4% MEx vs. MCo, + 31.0% FEx vs. FCo). LV contractility increased to the same extent in both sexes. Relative expression of 3074 proteins were determined by proteomics. There was a significant change in expression of 229 proteins in males and 599 in females compared to the level of same-sex controls. Based on our gene ontological analysis, physiological LV remodeling in females is characterized by increased expression of proteins in cellular respiration and fatty acid oxidation, whereas in males, proteins that bind to the actin cytoskeleton is primarily increased.

Conclusions

Our data suggests that physiological LV hypertrophy resulting from regular, balanced exercise is associated with sex-specific changes in the myocardial proteome. Our results contribute to the understanding of the development of physiological myocardial hypertrophy.
Evidence of Sialylation pathways alteration in peripheral blood of Brugada Syndrome patients
Authors: Tarantino A , Ghiroldi A , Creo P , D'imperio S , Giuseppe C , Micaglio E , Monasky M , Vicedomini G , Pappone C , Anastasia L
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): RICERCA CORRENTE, Italian Ministry of Health

Background

Brugada syndrome (BrS) is a cardiac arrhythmia associated with an increased risk of sudden cardiac death (SCD). BrS is considered a genetic disorder, and the most commonly mutated gene is SCN5A, which encodes the alpha subunit of the voltage-gated cardiac sodium channel (NaV1.5). Mutations of SCN5A generally cause impairment of NaV1.5 function, resulting in alteration of the action potential. However, mutations of SCN5A are responsible for only 30% of BrS cases. Therefore, it is conceivable that other mechanisms such as post-translational modifications (PTMs) could affect NaV1.5 activity. Among others, sialylation may alter ion channel activity by carrying a sugar with a negative charge. Alterations in sialylation have previously been described in several cardiovascular diseases, including myocardial infarction, Chagas disease, and congenital disorders of glycosylation, a family of diseases affecting the heart. For these reasons, the aim was to study alterations in sialylation in BrS patients to get new information about the pathogenesis of BrS.

Materials and Methods

Peripheral blood mononuclear cells (PBMCs) were collected from BrS patients and healthy controls. To characterize the protein sialylation status of PBMCs, SNA lectin, which is sialic acid-binding proteins, was used by Western blot and flow cytometry. Gene expression of enzymes involved in the biosynthesis, activation, transfer, degradation, and recycling of sialic acid was examined in PBMCs by real-time PCR.

Results

The extracellular and intracellular sialylation levels of PBMCs differed between BrS patients and controls. In particular, CD3+/CD4+ T cells exhibited a lower significant amount of sialic acid. Moreover, gene expression of enzymes involved in the biosynthesis and activation of sialic acid was downregulated in patients compared to controls. In contrast, the sialyltransferases St3Gal1, St3Gal4, and St6Gal2, enzymes responsible for binding sialic acid to the protein surface, showed significant enzyme-specific differences between BrS patients and controls. Moreover, the levels of sialyltransferases and sialylated proteins are inversely correlated with the epicardial area of the cardiac pathological substrate and with potential duration, two clinical indicators of BrS severity.

Discussion

These preliminary results demonstrate the involvement of sialylation in BrS syndrome and suggest that impairment of the sialylation process may be associated with the onset and/or manifestation of BrS. In addition, biochemical alteration of cells of the BrS immune system was reported for the first time, supporting the hypothesis that BrS is a systemic disease whose final manifestation is an increased risk of SCD.
Silent myocardial infarction in non-insulin dependent type 2 diabetes mellitus patients with low adherence to blood glucose monitoring
Authors: Viligorska K
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Decompensated diabetic patients frequently suffer from ischemic complications including silent ST-elevation myocardial infarction (STEMI).

Purpose

Aim of this study was to define prognostic value of low adherence to self-monitoring of blood glucose (SMBG) in type 2 diabetes mellitus (T2DM)  patients  as risk factor that leads to silent STEMI.

Methods

The electronic search in Cochrane Library, Scopus, PubMed and Web of Science for the period of 2016-2018 systematic literature review concentrated on types of educational interventions administered before SMBG in type 2 diabetes mellitus patients who are not using insulin was conducted. 18 studies were eligible for inclusion. We included all randomized controlled trials on SMBG education in T2DM patients compared with standard care in adult patients. As a proof of self-efficacy after SMBG glycated hemoglobin (HbA1c) was chosen as primary endpoint. Study group: 12 (7 females, 5 male, age 56-85 years) T2DM patients with non-insulin dependent diabetes for >5 years, low skills of SMBG that were admitted to surgery department with diabetic foot ulcers for the period of August 2019-September 2019 developed silent STEMI. Control group 10 (5 females, 5 males) T2DM patients that corresponded by age and study parameters, but did SMBG once a week via individual glucometers. Blood glucose, troponin I (cTnI) levels were registered. Statistical analysis:IBM SPSS Statistics v.23, RevMan5.

Results

During systematic review evidence indicated that a SMBG education was associated with more stress and lower rate in well-being and treatment satisfaction in comparison to a standard care (random-effects SMD: 0.45; 95% CI: 0.25-0.65; P < 0.0001). Depending on type of SMBG record subgroup analysis indicated that SMBG skills depend on SMBG education delivery. Patients that did feet checking, SMBG at least once a week had lower risk of complications development (P<0.05). STEMI development was associated with low SMBG in a form of checking only at visits to general practitioner (HR 1.15, 95% CI:1.04-1.13). Mean level of cTnI for study group patients was 0.045 ng/ml with no specific cardiac complaints.

Conclusions

There is a higher risk of silent ST-elevation myocardial infarction development in diabetic patients that have low SMBG skills) due to lacking information about importance of self-monitoring of blood glucose level as a predictor of cardiovascular complications.
Rictor is a central target of the molecular network of cardiac ProtectomiRs
Authors: Makkos A , Agg B , Varga ZV , Giricz Z , Gyongyosi M , Lukovic D , Schulz R , Bartekova M , Gorbe A , Ferdinandy P
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751); MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary

We have previously identified several cardiac microRNAs that are involved in cardioprotection and termed them as ProtectomiRs. mRNA targets of these ProtectomiRs may reveal new drug targets for cardioprotection.

Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction.

Network theoretical approach was utilized to identify 882 potential target genes of 18 previously described protectomiRs. Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, expression of Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of acute myocardial infarction and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning.

This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.
Responsiveness of the widely used cardiomyocyte cell platforms to simulated ischemia/reperfusion
Authors: Kiss B , Onodi ZS , Makkos A , Pelyhe CS , Apati A , Varga N , Ree D , Ferdinandy P , Gorbe A , Varga Z
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751)

MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary

Ischemic heart disease is the leading cause of death worldwide; therefore, the development of cardioprotective therapies is currently a main focus of research. Cultured cell lines and primary cell cultures play an integral role in cardiovascular research. However, there are many limitations when using these models, including variations in proliferation capacity, uncontrolled stress during cell isolation, poor reproducibility and low translational value. The aim of our study was to test the responsiveness of the most widely used cardiomyocyte platforms to simulated ischemia/reperfusion injury (SI/R) considering the effect of differentiation protocols.

Human, rat and mouse cell lines as well as primary cell cultures were used for in vitro viability assay with or without widely used differentiation protocols. The cells were exposed to normoxic or simulated ischemia/reperfusion protocols: a simulated ischemic period of 6 hours was used for the primary and the differentiated cell cultures, while for the non-differentiated cells 16 hours of simulated ischemia followed by 2 hours of reperfusion was applied. The duration of simulated ischemia was determined from preliminary experiments. Viability of the cells was measured by calcein assay.

In non-differentiated human AC16 and rat H9C2 cardiac cell lines, cell viability was significantly reduced (50%) by 16h SI / 2h R in contrast, the viability of the mouse HL-1 cell line was not reduced by 16 h SI. In primary rat neonatal cardiac myocytes 6h SI / 2h R caused significant cell death (25%). In primary human iPSC-derived cardiac myocytes 6h SI / 2h R did not result significant injury (10%) whereas 16h did (37%). Responsiveness of different cell types to SI/R ranged between 40-100%.

We have shown that the responsiveness of primary cardiac cells and non-differentiated cardiac cell lines is significantly different to simulated ischemia / reperfusion. Differentiation protocols in cell lines markedly affects their response to simulated ischemia / reperfusion. Comparative analyses of different types of cardiomyocytes can provide a good basis for accurate design of in vitro cardioprotective test systems.
Left ventricular SGLT1 expression is upregulated in heart failure in humans and rat model
Authors: Sayour AA , Ruppert M , Olah A , Barta BA , Zsary E , Benke K , Horvath EM , Hartyanszky I , Merkely B , Radovits T
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary;

Ministry of Human Capacities of Hungary

Introduction

Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to contribute to cardiac pathological processes, whereas humans with functionally limited SGLT1 are at lower risk of developing heart failure (HF). The novel HF medications, SGLT2 inhibitors, non-selectively inhibit SGLT1 to different extent, therefore, characterization of its expression in disease conditions is relevant.

Purpose

To investigate left ventricular (LV) SGLT1 expression in humans with end-stage HF, and in a rat model of HF.

Methods

Myocardial LV samples were harvested from control subjects (Controls, n=9) undergoing valve surgery, and from patients with end-stage dilated cardiomyopathy (DCM, n=12) undergoing heart transplantation. The rat model of aorto-caval fistula (ACF, n=12) was used to induce HF with predominant LV dilation in rats during a course of 24 weeks; sham-operated animals served as controls (Sham-A, n=12). Echocardiography was used to assess LV structure and function prior to surgery in humans, as well as in rats at the end of the follow-up period. Western blotting was performed to characterize LV SGLT1 protein expression and to investigate the activity of the master regulators AMPK and ERK1/2. The extent of LV nitro-oxidative stress was quantified by immunohistochemistry (3-nitrotyrosine) in rats with HF.

Results

Both humans with DCM and rats with ACF-induced HF presented with severely dilated LVs compared to respective controls, whereas LV SGLT1 protein expression was significantly upregulated similarly by ~1.7-fold in both cases (both P<0.01). These increases in SGLT1 expressions were accompanied by significant reductions in ERK1/2 activating phosphorylation (both P<0.05), whereas AMPK activity was unaffected. In rats with HF, LV SGLT1 expression correlated significantly with the extent of myocardial nitro-oxidative stress (r=0.762, P=0.037).

Conclusions

LV SGLT1 expression is upregulated in HF in both humans and small animals, and ERK1/2 shows a concomitantly reduced activity. LV SGLT1 expression correlates with the extent of nitro-oxidative stress, suggesting a possible pathological role in HF. Whether SGLT2 inhibitors exert direct cardiac actions via inhibition of myocardial SGLT1 needs to be elucidated.
A novel translational stratification system for electrophysiological characterization: evaluating arrhythmia complexity from the lab to the clinic
Authors: Sanchez De La Nava AM , Gomez-Cid L , Fernandez-Santos ME , Arenal A , Atienza F , Fernandez-Aviles F
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III

CIBERCV

Introduction

Cardiac arrhythmias can originate as a consequence of the proarrhythmic effects of some therapeutical regenerative products. In vitro studies have demonstrated different levels of electrophysiological complexity but these models usually lack of direct translation into the clinical practice.

Objective

To develop an arrhythmia complexity evaluation method that enables to characterize electrophysiological complexity in translational scenarios.

Methodology: To build a new evaluation method, frequency and rotor biomarkers from in vitro cell cultures presenting fibrillatory activity (N=15) were evaluated using optical mapping recordings (Rhod-2AM Ca2+ transient dye, 30-minute incubation, excited with green light). The patterns observed at in vitro level were analyzed and characterized by means of frequency and rotor biomarkers.

Next, we performed a forward translational study to evaluate these electrophysiological biomarkers at a clinical level. In 206 patients with atrial fibrillation (AF) with non-invasive body surface recordings using the Acorys system from Corify (67 electrodes, 4 second segments) (STRATIFY-AF study) were evaluated to analyze the same frequency and rotor biomarkers previously explored in vitro. Moreover, we build a complexity score that described from 0 to 1 the complexity at electrophysiological level, where 0 corresponded to simple scenarios and 1 to complex arrhythmic patterns. Patients were followed for 12 months to evaluate long term evolution.

Results

Complexity evaluation method identified the highest dominant frequency, median frequency and rotor time as the most important predictors for arrhythmia complexity definition. In vitro cultures results showed that samples presenting higher dominant frequency were also associated with small dominant frequency area extension and lower rotor time maintenance, i.e., with a high value of the complexity biomarker (Figure 1B). At clinical level, patients with high values of the complexity score were identified with Persistent AF patients showing complex patterns in whom AF recurred after ablation at 12 months (Figure 1D).

Conclusions

We developed a translational approach that enables to characterize arrhythmia complexity in different frameworks, which is crucial to evaluate potential undesirable effects of therapeutical regenerative products during the complete development and validation of the product.
Investigation of cardiotoxicity by dipeptidyl-peptidase-4 inhibitors in a human cardiomyocyte cell line as well as in samples from chronic heart failure patients
Authors: Voros I , Onodi ZS , Toth VE , Gergely T , Saghy E , Gorbe A , Kemeny A , Leszek P , Helyes ZS , Ferdinandy P , Varga ZV
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 research and innovation programme, Ministry for Innovation and Technology

Background

Dipeptidyl-peptidase-4 (DPP4) inhibitors are relatively new therapeutic tools for type 2 diabetes. The SAVOR-TIMI-53 clinical trial has revealed an increased heart failure (HF)-associated hospitalization rate in saxagliptin treated patients. Although this critical side effect could limit the therapeutic use considerably, the mechanism by which DPP4 inhibitors damage the heart is still unclear.

Aims

We aimed to set up a relevant cellular platform to investigate mechanistically DPP4 inhibition, and the role of its potentially important neuropeptide substrates (e.g. Substance P and Neuropeptide Y). Moreover, we aim to determine the expression of DDP4 and its neuropeptide substrates in human and cellular samples.

Methods

Western blot, ELISA, and radioimmunoassay experiments were performed to investigate the expression of DPP4 and its neuropeptide substrates in human hearts and in AC16 cells. Viability measurements with calcein staining and scratch assay experiments were used to test the potentially toxic effect of DPP4 inhibitors. The localization of DPP4 mRNA was determined with RNA Scope in situ hybridization.

Results

Expression of DPP4 and NPY proteins decreased in interventricular septum samples of patients with HF compared to healthy controls. In human hearts DPP4 mRNA is detectable in cardiomyocytes, while other cell types (endothelial cells, fibroblasts, and macrophages) show negligible expression. AC16 human cardiomyocyte cell line expresses DPP4 enzyme.  Treatment with various DPP4 inhibitors administered alone or in combination with neuropeptides don’t affect cellular survival; although, in scratch assay experiments treatments with neuropeptides decreased cell migration speed in the isolated neonatal rat cardiomyocyte-fibroblast co-culture. The migration speed reducing effect of NPY was revered by the administration of saxagliptin at the highest concentration of NPY.

Conclusions

Decreased activity of DPP4 may play a role in the pathomechanism of end-stage congestive heart failure. The DPP4 enzyme could be important as a compensating mechanism against the elevated sympathetic activity in HF and for the altered neuropeptide tone. Inhibition of DPP4 could decrease this adaptive mechanism thereby exacerbating myocardial damage.
Correlating electrical dysfunctions and structural remodeling in Arrhythmogenic Mouse Hearts by advanced optical methods
Authors: Giardini F , Olianti C , Biasci V , Arecchi G , Zaglia T , Mongillo M , Cerbai E , Zgierski-Johnston C , Kohl P , Sacconi L
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme - No 952166 (REPAIR)

Regione Toscana - Bando Ricerca Salute 2018 - PERCARE project.

Severe remodeling processes may occur in the heart due to both genetic and non-genetic diseases. Structural remodeling, such as collagen deposition (fibrosis) and cellular misalignment, can affect electrical conduction at different orders of magnitude and, eventually, lead to arrhythmias. In this scenario, arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease that involves ventricular dysfunction, arrhythmias, and localized replacement of contractile fibers with fibrofatty scar tissue. Unfortunately, nowadays, predicting the impact of fine structural alterations on the electrical dysfunction in entire organs is challenging, due to the inefficacy of standard imaging methods in performing high-resolution three-dimensional reconstructions in massive tissues.

In this work, we developed a new full-optical correlative approach to quantify and integrate the electrical dysfunctions with three-dimensional structural reconstructions of entire hearts, both in controls and in a mouse model of ACM. We combined optical mapping of the action potential propagation (APP) with advances in tissue clearing and light-sheet microscopy techniques. First, we employed an optical platform to map and analyze the APP in Langendorff-perfused hearts. Then, we optimized the SHIELD procedure for the clearing of cardiac tissue, thus converting the previously electrically characterized samples into well-preserved and fully-transparent specimens. A high-throughput light-sheet microscope has been developed following the mesoSPIM project: the conceived microscope allows the reconstruction of the whole mouse heart with a micrometric resolution allowing fine quantification of myocytes alignment and fibrosis deposition across the organ. Finally, we developed a software pipeline that employs high-resolution 3D images to analyze and co-register APP maps with the 3D anatomy, contractile fibers disarray, and fibrosis deposition on each heart.

We believe that this promising methodological framework will allow clarifying the involvement of fine structural alterations in the electrical dysfunctions, thus enabling a unified investigation of the structural causes that lead to electrical and mechanical alterations after the tissue remodeling.
Exploring the contribution of mechano-sensing to cardiomyopathy
Authors: Azad A , Jiang H , Hooper C , Davies B , Watkin H , Gehmlich K
Published: June 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Medical Research Council (MR/V009540/1),

Wellcome Trust (201543/B/16/Z)

British Heart Foundation (FS/12/40/29712).

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition associated with diastolic dysfunction and sudden cardiac death. Disease genes for HCM are traditionally coding for proteins involved in force generation. More recently, it has emerged that variants in genes coding for proteins involved in biomechanical stress-signalling can also cause HCM.

One such protein is filamin C, with proposed mechano-sensing functions in the heart. Within the protein, the immunoglobulin-like domain 20 (Ig20) may play a crucial role in mediating binding to muscle specific ligands. While the mechano-sensing functions of filamin C have been investigated well in skeletal muscle, the underlying cardiac disease mechanisms are not completely understood.

Aim

This work attempts to provide insights into the role of filamin C in cardiac mechano-sensing and dissect disease pathways leading to HCM in the presence of the FLNC variants in Ig20.

Methods

Using mass spectrometry, we aimed to provide a detailed analysis of the proteome of mice carrying the filamin C variant, using ventricular tissue samples from 14wk old homozygous mice. Samples were subject to molecular biology technical and underwent subcellular fractionation (n = 6 per genotype) and were investigated by label-free mass spectrometry.

Results

Utilising whole genome sequencing, a heterozygous FLNC missense variant in Ig20 was identified in a three-generation family affected by HCM. Mice carrying this variant recapitulate molecular features of HCM in the homozygous setting. Three proteins (FLNC, MYH7, MYOT) were found to be upregulated in the myofilament-enriched fraction. Up-regulations of key proteins were found to relocalise towards load-baring sites.

Conclusion

Our data indicate that changes in filamin C and its binding partners expression and localisation are involved in the pathogenesis of HCM in this mouse model.