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Epigenetic mechanisms are implicated in transcriptional programs driving chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain and extraterminal (BET) proteins, which are epigenetic readers that modulate gene expression. In the phase 3 BETonMACE trial, apabetalone reduced risk of major adverse cardiac events (MACE) by 50% in the CKD subpopulation, indicating favorable effects along the kidney-heart axis. Activation of human renal mesangial cells (HRMCs) to a contractile phenotype that overproduces extracellular matrix (ECM) and inflammatory cytokines, and promotes calcification, frequently accompanies CKD to drive pathology. Here, we show apabetalone downregulated HRMC activation with TGF-β1 stimulation by suppressing TGF-β1-induced α-smooth muscle actin (α-SMA) expression, α-SMA assembly into stress fibers, enhanced contraction, collagen overproduction, and expression of key drivers of fibrosis, inflammation, or calcification including thrombospondin, fibronectin, periostin, SPARC, interleukin 6, and alkaline phosphatase. Lipopolysaccharide-stimulated expression of inflammatory genes IL6, IL1B, and PTGS2 was also suppressed. Transcriptomics confirmed apabetalone affected gene sets of ECM remodeling and integrins. Clinical translation of in vitro results was indicated in CKD patients where a single dose of apabetalone reduced plasma levels of key pro-fibrotic and inflammatory markers, and indicated inhibition of TGF-β1 signaling. While plasma proteins cannot be traced to the kidney alone, anti-fibrotic and anti-inflammatory effects of apabetalone identified in this study are consistent with the observed decrease in cardiovascular risk in CKD patients.

Exosomes are nanosized lipid bilayer membranous microvesicles, extracellularly released from a variety of mammalian cells. They mediate intercellular signalling by transporting several types of RNA, lipids and proteins and participate in the intercellular exchange of DNA, RNA, micro RNA, proteins and other components. These microvesicles are present in all body fluids in physiological and pathological conditions and reflect the state of the host organism. The aim of the study was the isolation and molecular determination of exosomes in blood and supernatant fluids of bovine dendritic cell cultures infected with bovine leukaemia virus (BLV).

Abstract Carbon‐based nanomaterials have catalyzed breakthroughs across various scientific and engineering disciplines. The key to unlocking a new generation of tailor‐made nanomaterials based on single‐walled carbon nanotubes (SWCNTs) lies in the precise sorting of raw material into individual chiralities, each possessing unique properties. This can be achieved using conjugated polymer extraction (CPE), but to a very limited extent since the process generates only a few chirality‐enriched suspensions. Therefore, it is imperative to comprehend the mechanism of the wrapping of SWCNTs by polymers to unleash CPE's full potential. However, the lack of a diverse palette of chirality‐selective polymers with varying macromolecular parameters has hindered a comprehensive understanding of how the nature of the polymer affects the performance and selectivity of SWCNT isolation. To address this gap, multiple batches of such polymers are synthesized to elucidate the impact of molecular weight and dispersity on the purity and concentrations of the generated SWCNT suspensions. The obtained results explain the inconsistent outcomes reported in the literature, greatly improving the application potential of this promising SWCNT sorting approach. Concomitantly, the discovered significant influence of the macromolecular characteristics of conjugated polymers on the SWCNT isolation efficacy sheds considerable insight into the unresolved mechanism of this sorting technique.

Abstract Conjugated polymers are promising tools to differentiate various types of semiconducting single-walled carbon nanotubes (s-SWCNTs). However, their synthesis is challenging. Insufficient control over molecular weights, and unpredictive/unrepeatable batches hinder possible applications and scale-up. Furthermore, commercial homogeneous catalysts often require inert conditions and are almost impossible to recycle. To overcome these problems, we present a nanocatalyst consisting of magnetic nickel nanowires decorated with highly active palladium nanoparticles. A two-step wet chemical reduction protocol with the assistance of sonochemistry was employed to obtain a heterogeneous catalyst capable of conducting step-growth Suzuki polycondensation of a fluorene-based monomer. Additionally, we enhanced the performance of our catalytic system via controlled microwave irradiation, which significantly shortened the reaction time from 3 d to only 1 h. We studied the influence of the main process parameters on the yield and polymer chain length to gain insight into phenomena occurring in the presence of metallic species under microwave irradiation. Finally, the produced polymers were used to extract specific s-SWCNTs by conjugated polymer extraction to validate their utility.

Recently, more consumers have reached for plant-based milk substitutes, mainly for health, dietary, and flavour reasons. This study aimed to evaluate the physicochemical and bioactive properties and sensory profile of 10 selected rice drinks available on the EU market. Assessment of the physicochemical characteristics included measurement of soluble solids, pH, osmolality, foaming properties and colour parameters. Analysis of bioactive compounds involved the determination of polyphenolic compounds and antioxidant activity. Based on the manufacturer’s data, the composition and nutritional value of the above-mentioned beverages were also analysed in this study. The tested beverages were characterised by a low fat content of 0.6–1.3 g/100 mL, derived mainly from added sunflower oil, but are a good source of energy (energy value of 37–55 kcal/100 mL), derived mainly from naturally occurring carbohydrates whose content ranged from 8.0–11.0 g/100 mL. The protein content of all rice drinks was shallow, not exceeding 0.5 g/100 mL. Of the ten rice drinks analysed, in only two were vitamins B12 and D added (0.38 μg/100 mL and 0.75 μg/100 mL, respectively) and in only three was calcium (120 mg/100 mL) added. In evaluating the physicochemical characteristics, the drinks showed a pH close to neutral (mean 6.85 ± 0.01). The average soluble solids content was about 11%, which was determined by the carbohydrate content. The osmolality of the beverages averaged 324.73 ± 70.17 mOsm/kg H2O, with four beverages classifiable as hypertonic ones (osmolality > 330 mOsm/kg H2O), three as isotonic ones (with osmolality between 270–330 mOsm/kg H2O), and three as hypotonic beverages (osmolality < 270 mOsm/kg H2O). Only two rice drinks evaluated in this study showed foaming properties. The high whiteness index (81.79 ± 2.55) indicated high white colour saturation of the tested beverages. The rice drinks were characterised by a relatively diverse sensory quality regarding aroma and flavour notes. The overall sensory quality was rated highest for the beverages with the highest sugar content. The tested beverages were characterised by a low content of total polyphenols (average 1.40 ± 0.62 mg GAE/100 mL) and relatively high antioxidant activity (average 418.33 ± 59.65 µM TEAC/100 mL). Based on the research conducted and the analysis of the manufacturer’s data, it can be concluded that the rice drinks studied in this paper can be included in the daily diet, providing a rehydrating beverage that shows free radical-neutralizing properties and provides carbohydrates. At the same time, it should be highlighted that the studied drinks have a low nutritional value and cannot be recommended as milk substitutes due to low protein levels and lack of milk-specific vitamins and minerals.

Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood – brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of in vitro endothelial activation, including monocyte chemoattractant protein-1 (MCP-1) and RANTES chemokine secretion, cell surface expression of endothelial cell adhesion molecule VCAM-1, as well as endothelial capture of THP-1 monocytes in static and shear stress conditions. Apabetalone pretreatment of THP-1 downregulates cell surface expression of chemokine receptors CCR1, CCR2, and CCR5, and of the VCAM-1 cognate receptor, integrin α4. Consequently, apabetalone reduces THP-1 chemoattraction towards soluble CCR ligands MCP-1 and RANTES, and THP-1 adhesion to activated BMVECs. In a mouse model of brain inflammation, apabetalone counters lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, consistent with decreased neuroendothelial inflammation. In conclusion, apabetalone decreases proinflammatory activation of brain endothelial cells and monocytes in vitro and in the mouse brain during systemic inflammation.

Experimental methods are presented for determining the thermal resistance of vertical-cavity surfaceemitting lasers (VCSELs) and the lateral electrical conductivity of their p-type semiconductor layers. A VCSEL structure was manufactured from III-As compounds on a gallium arsenide substrate. Conductivity was determined using transmission line measurement (TLM). Electrical and thermal parameters were determined for various ambient temperatures. The results could be used for computer analysis of VCSELs. Keywords: TLM, thermal resistance, VCSEL, AlGaAs.

Calypogeia is a genus of liverworts in the family Calypogeiaceae. The subject of this study was Calypogeia suecica. Samples of the liverwort Calypogeia suecica were collected from various places in southern Poland. A total of 25 samples were collected in 2021, and 25 samples were collected in 2022. Volatile organic compounds (VOCs) from liverworts were analyzed by gas chromatography–mass spectrometry (GC–MS). A total of 107 compounds were detected, of which 38 compounds were identified. The identified compounds were dominated by compounds from the sesquiterpene group (up to 34.77%) and sesquiterpenoids (up to 48.24%). The tested samples of Calypogeia suecica also contained compounds belonging the aromatic classification (up to 5.46%), aliphatic hydrocarbons (up to 1.66%), and small amounts of monoterpenes (up to 0.17%) and monoterpenoids (up to 0.30%). Due to the observed differences in the composition of VOCs, the tested plant material was divided into two groups, in accordance with genetic diversity.

Abstract Background and Aims Major adverse cardiac events (MACE) remain a leading cause of mortality in chronic kidney disease (CKD). Apabetalone is an orally available inhibitor of bromodomain & extraterminal (BET) proteins – epigenetic readers that modulate gene expression involved in fibrosis, inflammation and calcification. In the phase 3 BETonMACE trial, apabetalone treatment was associated with reduction in MACE in the subpopulation with CKD (eGFR < 60 mL/min/1.73m2; HR 0.50 95% CI 0.26,0.96 p=0.04]) implying favorable effects of apabetalone on cellular responses along the kidney-heart axis. This study examines effects of apabetalone on primary human renal mesangial cells (HRMCs) in culture on fibrosis, inflammation, reactive oxygen species (ROS) and calcification pathways that contribute to renal pathology. Method HRMCs from donors without kidney dysfunction were stimulated with TGF-β1 or lipopolysaccharide (LPS) ± 1-25µM apabetalone, 0.15-0.5µM JQ1 or 0.1µM MZ1 (BET inhibitors [BETi] with chemical scaffolds different than apabetalone). Gene expression was measured by real-time PCR and RNA-seq. Smooth muscle actin (α-SMA) was examined by immunofluorescence microscopy, and alkaline phosphatase enzyme activity in a biochemical assay. RNA-seq from TGF-β1 treated HRMC ± BETi was evaluated by Gene Ontology (GO) Enrichment and Ingenuity Pathway Analysis (IPA). Results TGF-β1 is a pro-fibrotic cytokine that activates HRMC to a fibroblast-like state which over-produces extracellular matrix (ECM). Apabetalone dose dependently suppressed TGF-β1 induced gene expression of (a) α-SMA, a marker of fibrotic activation, up to 90% p0.05 at 5µM) and NRF2-Mediated Oxidative Stress Response (z score 2.3, p

Steroid resistance is a common condition occurring in children with nephrotic syndrome. Until now, over 50 genes involved in steroid-resistant nephrotic syndrome (SRNS) pathogenesis have been identified, among which the most prevalent are NPHS1, NPHS2, CD2AP, and PTPRO. The patterns of inheritance of SRNS are autosomal recessive, autosomal dominant, or mitochondrial, and tissues of those patients show focal segmental glomerulosclerosis (FSGS) signs in histopathological image analysis. We present a case of a 6-year-old girl who was admitted to the pediatric nephrology department due to nephrotic range proteinuria and edema of the lower leg. We started therapy with prednisone at a dose of 45 mg (60 mg/m 2 ), enalapril as a nephroprotection, and antihistamines as an additional treatment. During in-patient treatment, we detected increased blood pressure. Due to persistent proteinuria in spite of 6-week treatment with steroids at the maximal dose, we confirmed disease resistance to steroids. Additionally, FSGS signs were confirmed in kidney biopsy samples. After genetic screening for SRNS and detection of the rare gene mutation NUP93 we reduced prednisone but maintained nephroprotective treatment and administered cyclosporin A. The girl remains currently under the care of nephrologists with normal arterial blood pressure, trace proteinuria in follow-up examination, and normal kidney function. NUP93 mutation is extremely rare; therefore few cases have been described to date. The onset of the symptoms in all pediatric patients appeared before the age of 8 and they developed end stage kidney disease (ESKD). They might manifest symptoms from the other systems.

The development of wind energy has been observed for many years. Both construction firms and the scientific world are analyzing new design solutions, atmospheric conditions and the technical performance achieved. The main goal of this research is to evaluate the requirements that have to be met to design wind power stations that would be an optimal fit for the climatic conditions in Poland. This study combines the results of empirical studies on wind velocity distributions with the physical fundamentals of wind power station design. This paper presents modelling of the relationships between wind velocity distributions observed in Poland and technical requirements for wind power stations design. The wind velocities distributions for various locations in Poland are determined and expressed in Weibull distribution parameters. Theoretical computations concerning the dependence of wind power stations as function of wind speed and air’s physical properties are presented. Conclusions important for the design of power stations fitted to the atmospheric conditions in Poland are given. LabVIEW 2021 was used for computer modeling.

Breast cancer is associated with high mortality and morbidity rates. As about 20–30% of patients exhibiting ER-positive phenotype are resistant to hormonal treatment with the standard drug tamoxifen, finding new therapies is a necessity. Postbiotics, metabolites, and macromolecules isolated from probiotic bacteria cultures have been proven to have sufficient bioactivity to exert prohealth and anticancer effects, making them viable adjunctive agents for the treatment of various neoplasms, including breast cancer. In the current study, postbiotics derived from L. plantarum and L. rhamnosus cultures were assessed on an in vitro breast cancer model as potential adjunctive agents to therapy utilizing tamoxifen and a candidate aziridine–hydrazide hydrazone derivative drug. Cell viability and cell death processes, including apoptosis, were analyzed for neoplastic MCF-7 cells treated with postbiotics and synthetic compounds. Cell cycle progression and proliferation were analyzed by PI-based flow cytometry and Ki-67 immunostaining. Postbiotics decreased viability and triggered apoptosis in MCF-7, modestly affecting the cell cycle and showing a lack of negative impact on normal cell viability. Moreover, they enhanced the cytotoxic effect of tamoxifen and the new candidate drug toward MCF-7, accelerating apoptosis and the inhibition of proliferation. This illustrates postbiotics’ potential as natural adjunctive agents supporting anticancer therapy based on synthetic drugs.

Background: Macintosh laryngoscope is the most widely used laryngoscope for intubation. In some patients, e.g. with flaccid, drooping, aplastic epiglottis, usage of this laryngoscope, or even videolaryngoscopes, may not provide visualization of a glottis. Elevation of the laryngopharynx, like in intubation with Miller laryngoscope, may significantly improve intubating conditions. Methods: An anaesthesiologist with over 20 years of experience will perform direct laryngoscopy with randomly chosen Miller or Macintosh blade, evaluating the visibility of rima glottidis with Cormack-Lehane classification and POGO score with and without external laryngeal pressure. Then the second evaluation of glottis with other blade type will be obtained and the patient will be intubated. Comparison of the rima glottidis visibility when using both blades will be the primary endpoint of the study. The secondary endpoints consist of: demonstrating whether there is a group of adult patients in whom the use of the Miller blade associated with better vocal cord visibility may be predicted based on an anesthesiological examination, and whether external laryngeal pressure improves vocal cord visualization more when using the Miller blade compared with the Macintosh blade. Sample size: We performed minimal sample size calculations based on the data derived from the first 60 patients. We assessed the minimal sample size to obtain the alpha of 5 % and power of 90 %. We decide to enroll at least 286 patients. Discussion: this will be the first trial assessing Miller and Macintosh blades in the same population of adult patients. It will determine group of patients in whom Miller laryngoscope will provide better visualization of rima glottidis than Macintosh blade and associated technique, diminishing rate of prolonging intubations and reducing possible aftermaths of hypoxia.

Abstract Background and Aims Elevated serum alkaline phosphatase (ALP) independently predicts major adverse cardiac events (MACE) by contributing to vascular calcification and endothelial dysfunction arising in chronic kidney disease (CKD) and cardiovascular disease (CVD). Apabetalone is an orally active inhibitor of bromodomain and extraterminal (BET) proteins – epigenetic readers that modulate gene expression involved in vascular inflammation and calcification. Here we examined apabetalone’s effects on ALP post-hoc in recent clinical trials, then performed mechanistic studies into apabetalone’s impact on tissue non-specific ALP (TNALP) expression in mice and cell culture. Method Serum ALP was determined in CVD patients in phase 2 trials (3 month ASSERT and 6 month SUSTAIN & ASSURE) and in the phase 3 BETonMACE CVD outcomes trial, including subpopulations with CKD (eGFR55%, p 40%; p

This article presents the issue of using decision support tools to select the variant of organization of urban transport system. Two scenarios for the use of electric vehicles were compared, considering not only their emissions and fuel consumption but also the limited accessibility of conventional vehicles to the city. The authors assume that the development of urban traffic organization must go hand in hand with the challenges of planning sustainable urban mobility and reducing harmful exhaust fumes. Furthermore, decision-makers should be equipped with simple decision support tools to generate the best option considering the expectations of transport users. The PTV VISUM tool was used to analyse and visualize two different organization scenarios for a selected city in Poland.

As the Reformation progressed in the 16th century, Poland became increasingly populated by representatives of Protestant denominations. Because political elites and nobility disagreed on religious matters, the issue of religious tolerance required appropriate formal and legal solutions. That was particularly important during the first interregnum following the death of King Sigismund Augustus, when the spectre of anarchy loomed over the state. The Warsaw Confederation Act was introduced during the Convocation Sejm to preserve order in the country during the interregnum. This document also included provisions on religious tolerance, which remained a source of dispute for both supporters and opponents of religious peace for many years. This article addresses the first stage of the struggle for formal recognition of religious tolerance, which occurred between the death of the last monarch of the Jagiellonian dynasty (7 July 1572) and the end of the session of the Convocation Sejm during the first interregnum (28 January 1573). The study was built on 16th-century historiography - the works of Marcin Bielski, Świętosław Orzelski and Reinhold Heidenstein. The paper aims to reconstruct the events that led to the creation of the Warsaw Confederation Act. Moreover, the sources reflect the atmosphere prevailing in the country at that time, which is undoubtedly significant in capturing the topic under consideration. The paper is a three-part inquiry that, aside from research methodologies, displays the historical context in the introduction while the remainder of the text is a comparative analysis of the source material, from which relevant conclusions were drawn.

This article proposes a modular system for prosumer installations composed of photovoltaic (PV) panels and energy storage (ES) integrated with the low voltage (LV) network through a common 4-wire AC/DC inverter. The novel idea is a control strategy for the inverter in which additional functionalities are incorporated. Apart from transmitting an active power generated by the PV source, the same inverter is used to manage energy generated by the PV and to compensate for the current unbalance, harmonics (including subharmonics and interharmonics) and reactive power of the prosumer loads. As a result of the algorithm operation, the currents flowing to the prosumer installation are sinusoidal, symmetrical and purely active, which results in voltage balancing and improving voltage waveforms at the point of common coupling (PCC). In this way, with the widespread use of this solution among prosumers, the impact of the prosumer installation on the distribution network is minimized, and power quality (PQ) disturbances such as unacceptable voltage rises, voltage unbalance and harmonics are avoided. The presented approach may be a solution to the problems network operators face nowadays due to the uncontrolled connection of PV sources. The proposed modular system is also beneficial for the prosumer as the instances of unacceptable overvoltage and, consequently, shutdowns of prosumer installations are reduced. The features of the proposed method are shown in relation to other means applied for PQ improvement in the networks with distributed generation. A principle of the control and the involving algorithm for the inverter is presented. The efficiency of the control strategy was tested in a simulation developed in the PSCAD/EMTDC program. The results of simulations are presented, and the proposed solution is concluded.

Every year, ulcerative dermal necrosis (UDN) affects salmonids that spend most of their lives in the sea during their migration to the rivers of northern Poland to spawn. The clinical form of the disease manifests itself in ulcerative skin lesions, which lead to significant weakening of the fish and, in most cases, result in their death. This study was carried out on samples taken from sea trout in the Słupia River in northern Poland. In order to identify the pathogen, experiments on the transmission of the disease were carried out, and additional histopathological, microbiological and electron microscopic examinations were performed. As a result of these studies, it was possible to experimentally transfer the disease from sick to healthy fish. The results indicate a complex etiology of the disease (lack of a clearly defined pathogen), in which the change in the environment from salty to freshwater triggers the related changes in skin physiology, which are the main causes of increased susceptibility to the development of the disease.

Regaining greater independence in performing daily activities constitutes a priority for people with tetraplegia following spinal cord injury (SCI). The highest expectations are connected with the improvement of hand function. Therefore, it is so important for the clinician to identify reliable and commonly applicable prognostic factors for functional improvement. The aim of this study was to conduct an analysis to assess the impact of initial functional factors on the clinical improvement in patients during early neurological rehabilitation (ENR). This study assessed 38 patients with complete SCI aged 17–78 who underwent ENR in 2012–2022. The analysis included the motor score from the AIS (MS), the Barthel Index (BI) and the SCIM scale values at the beginning of the ENR program and after its completion. During ENR, patients achieved a statistically significant improvement in MS, BI and SCIM. The initial MS and the level of neurological injury constituted the predictors of functional improvement during ENR. Significant statistical relationships were observed primarily in the correlations between the initial MS and BI, and the increase in the analyzed functional scales of SCI patients. Higher initial MS may increase the chances of a greater and faster functional improvement during ENR.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

Chronic neuropathic pain may be caused, in part, by loss of inhibition in spinal pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABAAR-mediated currents by agonist ligands for δ subunit-containing GABAARs. However, typical ligands that target δ subunit-containing GABAARs are limited due to sedative effects at higher doses. We used the spinal nerve ligation (SNL) and gp120 models of experimental neuropathic pain to evaluate compound 2-261, a nonbenzodiazepine site positive allosteric modulator of α4β3δ GABAARs optimized to be nonsedative by selective activation of β2/3-subunit-containing GABAARs over receptor subtypes incorporating β1 subunits. Similar levels of 2-261 were detected in the brain and plasma after intraperitoneal administration. Although systemic 2-261 did not alter sensory thresholds in sham-operated animals, it significantly reversed SNL-induced thermal and tactile hypersensitivity in a GABAAR-dependent fashion. Intrathecal 2-261 produced conditioned place preference and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated, rats. In addition, systemic pretreatment with 2-261 blocked conditioned place preference from spinal clonidine in SNL rats. Moreover, 2-261 reversed thermal hyperalgesia and partially reversed tactile allodynia in the gp120 model of HIV-related neuropathic pain. The effects of 2-261 likely required interaction with the α4β3δ GABAAR because 2-301, a close structural analog of 2-261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2-261 may produce pain relief with diminished side effects through selective modulation of β2/3-subunit-containing extrasynaptic GABAARs.

Background and aimsApabetalone is an inhibitor of bromodomain and extraterminal (BET) proteins. In clinical trials, apabetalone reduced the incidence of major adverse cardiac events (MACE) in patients with cardiovascular disease and reduced circulating factors that promote vascular calcification (VC). Because VC contributes to MACE, effects of apabetalone on pro-calcific processes were examined.Methods and resultsApabetalone inhibited extracellular calcium deposition and opposed induction of transdifferentiation markers in human coronary artery vascular smooth muscle cells (VSMCs) under osteogenic culture conditions. Tissue-nonspecific alkaline phosphatase (TNAP) is a key contributor to VC, and apabetalone suppressed osteogenic induction of the mRNA, protein and enzyme activity. The liver is a major source of circulating TNAP, and apabetalone also downregulated TNAP expression in primary human hepatocytes. BRD4, a transcriptional regulator and target of apabetalone, has been linked to calcification. Osteogenic transdifferentiation of VSMCs resulted in disassembly of 100 BRD4-rich enhancers, with concomitant enlargement of remaining enhancers. Apabetalone reduced the size of BRD4-rich enhancers, consistent with disrupting BRD4 association with chromatin. 38 genes were uniquely associated with BRD4-rich enhancers in osteogenic conditions; 11 were previously associated with calcification. Apabetalone reduced levels of BRD4 on many of these enhancers, which correlated with decreased expression of the associated gene. Bioinformatics revealed BRD4 may cooperate with 7 specific transcription factors to promote transdifferentiation and calcification.ConclusionsApabetalone counters transdifferentiation and calcification of VSMCs via an epigenetic mechanism involving specific transcription factors. The mechanistic findings, combined with evidence from clinical trials, support further development of apabetalone as a therapeutic for VC.

Pyoderma gangrenosum (PG) is a rare condition characterized by the development of aseptic, non-healing skin ulcers. Any skin trauma, such as a surgical incision, can trigger an outbreak of lesions. Our case and literature review show that a physician should consider PG in every event of a non-healing, aseptic wound after surgery. The treatment of PG requires collaboration within a multidisciplinary team and immunosuppressive therapy is the first line of treatment, while surgical interventions should be avoided in the active stage of PG.

The article is an attempt to draw attention to the intention of the Ministry of Family and Social Policy to shape its own legal policy with regard to the ability of the officials of the Social Insurance Institution (ZUS) to obtain information about individuals subject to official control. Within the proposed changes to Art. 61a of the Act of 25 June 1999 on cash benefits from social insurance in the event of sickness and maternity (Journal of Laws 1999, 60.636, as amended), the Ministry, not taking into account the requirement to ensure the existence of constitutionally guaranteed rights and freedoms, consciously shapes the law positive for full-range surveillance of every person covered by the interest of ZUS. In such circumstances, after adopting the amendments by the Polish Parliament (Sejm), ZUS will be included in the group of law enforcement authorities, as the scope of powers and possibilities its officials in the field have of obtaining information will be unlimited.

Introduction Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is a major treatment for many haematological malignancies. The procedure has a good success rate but high transplant-related toxicity (TRM). TRM is mostly related to graft-versus-host disease (GvHD) and infectious complications. Alterations of the intestinal microbiota plays a major role in the development of allo-HSCT complications. The gut microbiota could be restored by faecal microbiota transplantation (FMT). However, there are no published randomised studies assessing the efficacy of FMT for GvHD prophylaxis.Methods and analysis This prospective, open-label, multi-centre, parallel-group, randomised phase-II clinical trial has been designed to assess the effect of FMT on toxicity in patients treated with myeloablative allo-HSCT for haematological malignancy. Based on Fleming’s single-stage sample size estimation procedure, the design plans to include 60 male and female patients aged 18 or over per arm, to be randomly assigned to two groups, one with and one without (control group) FMT. The primary endpoint is GvHD-free relapse-free survival rate at 1 year after allo-HSCT. Secondary endpoints are outcome measures of the impact of FMT on allo-HSCT-related morbidity and mortality (overall survival and progression-free survival at 1 and 2 years, haematological parameters, infectious complications, tolerance and safety of FMT). The primary endpoint will be evaluated according to assumptions of the single-stage Fleming design, compared between groups by a log-rank test and further investigated in a multivariate marginal structural Cox model taking into account centre effect. The proportional-hazard hypothesis will be verified using Schoenfeld’s test and by plotting residuals.Ethics and dissemination The local institutional review board (CPP Sud-Est II, France) issued approval on 27 January 2021. The French national authorities issued approval on 15 April 2021. The outcome of the study will be disseminated via peer-reviewed publications and at congresses.Trial registration number NCT04935684.

Abstract Etiopathogenesis of fluoroquinolone-associated disability (FQAD) syndrome is not fully understood, yet research could progress by utilizing induced pluripotent stem cells (iPSc) from people with this syndrome. Similarly, iPSc, or rather their derivatives, could be used in their therapy, not only for FQAD but also for other disorders in which generated autologous iPSc and their derivatives might be helpful. Urine was collected from ten donors with FQAD, and reprogramming of these cells was conducted with the use of Epi5TM Episomal iPSC Reprogramming Kit. IPSc were generated in one out of ten person’s urine cells. While urinary cells are considered the easiest mature cells to be reprogrammed into iPSc, the urinary cells from six consecutive donors quickly became senescent. Stable urine primary cell cultures could not be obtained from the three remaining donors. Repeated attempts to reprogram epithelial cells were not successful. During parallel studies conducted for healthy donors, reprogramming success was achieved in six out of ten cases. These data may suggest serious limitations in the regeneration system of individuals with FQAD. Consequently, it indicates that therapy with autologous iPSc derivatives may face serious difficulties in their case, still, the first iPSc cell line from a person with FQAD was established.

New quality that has been delivered by the provisions of General Data Protection Regulation (GDPR) (EU) 2016/679 is intended to secure a higher level of safety for personal data processing operations. The following elaboration was produced as an attempt to address the questions regarding practical methods of implementation for the indispensable mechanism of GDPR compliance. The guidelines contained in the article are supposed to be helpful in enhancing the safety level for processed personal data. Theoretical and legal studies over the status and functioning of the valid legislation with reference to the practical application of personal data processing procedures have been applied in the article. The main sources of knowledge included valid legal acts, opinions from Article 29 Working Party, technical norms as well as available general knowledge. The outcomes of the said studies indicated the complexity of the issue and established the necessity to continue further studies in practical implementation methods, such as the national and European mechanism of certification or sector codes of good practices.

Background: Gliomas are the most malignant tumors of the central nervous system. One of the factors in their high drug resistance is avoiding programmed death (PCD) induction. This is related to the overexpression of intracellular survival pathways: PI3K-Akt/PKB-mTOR and Ras-Raf-MEK-ERK. Apoptosis and autophagy are co-existing processes due to the interactions between Bcl-2 and beclin-1 proteins. Their complex may be a molecular “toggle-switch” between PCD types. The aim of this research was to investigate the role of Bcl-2:beclin-1 complex in glioma cell elimination through the combined action of LY294002 and sorafenib. Methods: Drug cytotoxicity was estimated with an MTT test. The type of cell death was evaluated using variant microscopy techniques (fluorochrome staining, immunocytochemistry, and transmission electron microscopy), as well as the Bcl-2:beclin-1 complex formation and protein localization. Molecular analysis of PCD indicators was conducted through immunoblotting, immunoprecipitation, and ELISA testing. SiRNA was used to block Bcl-2 and beclin-1 expression. Results: The results showed the inhibitors used in simultaneous application resulted in Bcl-2:beclin-1 complex formation and apoptosis becoming dominant. This was accompanied by changes in the location of the tested proteins. Conclusions: “Switching” between apoptosis and autophagy using PI3K and Raf inhibitors with Bcl-2:beclin-1 complex formation opens new therapeutic perspectives against gliomas.

Liverworts contain a large number of biologically active compounds that are synthesised and stored in their oil bodies. However, knowledge about the chemical composition of individual species is still incomplete. The subject of the study was Calypogeia integristipula, a species representing leafy liverworts. Plant material for chemotaxonomic studies was collected from various locations in Poland. The chemical composition was determined in 74 samples collected from the natural environment in 2021 and 2022 in three growing seasons: spring, summer and autumn, and for comparison with samples originating from in vitro culture. The plants were classified as Calypogeia integristipula on the basis of morphological characteristics, oil bodies, and DNA markers. The volatile organic compounds (VOCs) from the biological material were extracted by headspace solid phase microextraction (HS-SPME). The samples were then analysed by gas chromatography–mass spectrometry (GC-MS). A total of 79 compounds were detected, of which 44 compounds were identified. The remaining compounds were described using the MS fragmentation spectrum. Cyclical changes in the composition of compounds associated with the growing season of Calypogeia integristipula were observed. Moreover, samples from in vitro culture and samples taken from the natural environment were shown to differ in the composition of chemical compounds. In terms of quantity, among the volatile compounds, compounds belonging to the sesquiterpene group (46.54–71.19%) and sesqiuterpenoid (8.12–22.11%) dominate. A smaller number of compounds belong to aromatic compounds (2.30–10.96%), monoterpenes (0.01–0.07%), monoterpenoids (0.02–0.33%), and aliphatic hydrocarbons (1.11–6.12%). The dominant compounds in the analysed liverworts were: anastreptene (15.27–31.14%); bicyclogermacrene (6.99–18.09%), 4,5,9,10-dehydro-isolongifolene (2.00–8.72%), palustrol (4.95–9.94%), spathulenol (0.44–5.11%).

Abstract In recent years, we have seen the integration of magnetic resonance imaging (MRI) simulators into radiotherapy centres and the emergence MR linear accelerators (MR‐linac). Currently, there are limited studies to demonstrate the clinical effectiveness of MRI guided radiotherapy (MRIgRT) treatment for breast cancer patients. The objective of this scoping review was to identify and map the existing evidence surrounding the clinical implementation of MRIgRT for breast cancer patients. We also identified the challenges and knowledge gaps in the literature. The scoping review was reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta‐Analysis (PRISMA) extension for Scoping Reviews reporting guidelines. Titles and abstracts were screened by two independent reviewers. Quantitative and qualitative data were extracted and summarised using thematically organised tables. Results identify that accelerated partial breast irradiation (APBI) is the most common form of treatment for MRIgRT. The presence of the magnet does not affect target coverage or violate organ at risk (OAR) constraints compared to standard radiotherapy methods. Consideration is advised for skin and chest wall (CW) due to the electron return effect (ERE) and areas such as armpit and chin due to the electron stream effect (ESE). Clinically, bolus has been used to protect and prevent unwanted dose in these areas. Overall treatment for APBI on the MR‐linac is feasible.

IntroductionApabetalone, a small molecule inhibitor, targets epigenetic readers termed BET proteins that contribute to gene dysregulation in human disorders. Apabetalone has in vitro and in vivo anti-inflammatory and antiatherosclerotic properties. In phase 2 clinical trials, this drug reduced the incidence of major adverse cardiac events in patients with cardiovascular disease. Chronic kidney disease is associated with a progressive loss of renal function and a high risk of cardiovascular disease. We studied the impact of apabetalone on the plasma proteome in patients with impaired kidney function.MethodsSubjects with stage 4 or 5 chronic kidney disease and matched controls received a single dose of apabetalone. Plasma was collected for pharmacokinetic analysis and for proteomics profiling using the SOMAscan 1.3k platform. Proteomics data were analyzed with Ingenuity Pathway Analysis to identify dysregulated pathways in diseased patients, which were targeted by apabetalone.ResultsAt baseline, 169 plasma proteins (adjusted P value

The progressive degradation of the environment makes implementing pro-ecological solutions in various areas of our lives more meaningful. These measures also apply to transport, responsible for around 30% of total carbon dioxide emissions in the EU. Implementing ecological solutions in road transport encounters various barriers resulting mainly from the specificity of transport tasks. One of the most promising solutions in the high-tonnage road transport sector seems to be LNG-fueled engines, which allow for similar operating conditions to traditional combustion vehicles. The article aims to identify the environmental benefits of the use of high-tonnage LNG-fueled vehicles in freight transport and to conduct a comprehensive assessment of the economic efficiency of this solution. The article assesses the effectiveness of using an LNG-fueled vehicle and a diesel-fueled vehicle that meets the highest exhaust emission standard in high-tonnage transport, both in terms of economy and an impact of these solutions on the environment. The research was carried out on a given route, taking into account variants of vehicle manning and simulations of transport cycle time. In conclusion, a discussion of the obtained results was carried out, emphasizing the factors determining the profitability of using high-tonnage vehicles with LNG drive or its lack. Regardless of the indicated lack of clarity in the economic assessment of the effectiveness of LNG drives in high-tonnage vehicles, the identified environmental benefits from implementing these solutions seem to be quite unequivocal. Thus, it should be expected that in the event of loss of economic competitiveness of these solutions, appropriate fiscal instruments should be used - especially since LNG drives in the policies of individual countries are considered pro-ecological solutions.

The trend to replace traditional fossil fuel vehicles is becoming increasingly apparent. The replacement concerns the use of pure biofuels or in blends with traditional fuels, the use of hydrogen as an alternative fuel and, above all, the introduction of electric propulsion. The introduction of new types of vehicle propulsion affects the demand for specific fuels, the needs for new infrastructure, or the nature of the emissions to the environment generated by fuel production and vehicle operation. The article presents a mathematical model using the difference of two logistic functions, the first of which describes the development of the production of a specific type of vehicle, and the second, the withdrawal of this type of vehicle from traffic after its use. The model makes it possible to forecast both the number of vehicles of each generation as a function of time, as well as changes in energy demand from various sources and changes in exhaust emissions. The results of the numerical simulation show replacing classic vehicles with alternative vehicles increases the total energy demand if the generation of the next generation occurs earlier than the decay of the previous generation of vehicles and may decrease in the case of overlapping or delays in the creation of new vehicles compared to the course of the decay function of the previous generation. For electric vehicles, carbon dioxide emissions are largely dependent on the emissions from electricity generation. The proposed model can be used to forecast technology development variants, as well as analyze the current situation based on the approximation of real data from Vehicle Registration Offices.

Abstract The aim of the study was to investigate the relationship between the severity of typical clinical symptoms, severity of histopathological lesions in kidney biopsies in IgA vasculitis nephritis (IgAVN) and to propose indications for kidney biopsy in children. Material and methods This retrospective study enrolled 106 patients, included in the IgAVN registry of Polish children, diagnosed by kidney biopsy. Renal and extrarenal symptoms at onset of the disease were analyzed. Biopsy results were assessed using Oxford classifications (MEST-C). The patients were divided into 3 groups depending on the severity of proteinuria: A-nephrotic proteinuria with hematuria; B-non-nephrotic proteinuria with hematuria; C-isolated hematuria. Results The first symptoms of nephropathy were observed at the 0.7 (1–128.4) months from the onset of extrarenal symptoms. Kidney biopsy was performed on 39 (6–782) days after the onset of nephropathy symptoms. MEST-C score 4 or 5 was significantly more frequent in children from group A than in groups B and C. Significantly higher mean MEST-C score was found in patients with abdominal symptoms than without. In group A: S0 and T0 we found in significantly shorter time to kidney biopsy than in S1, T1–2 p