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Growing concerns about the environmental impact of ionic liquids (ILs) have spurred research into their (eco)toxic effects, but studies on their mode of toxic action (MOA) still remain limited. However, understanding the MOA and identifying structural features responsible for enhanced toxicity is crucial for characterising the hazard and designing safer alternatives. Therefore, 45 ILs, with systematically varied chemical structures, were tested for cytotoxicity and two specific endpoints in reporter gene assays targeting the Nrf2-ARE mediated oxidative stress response (AREc32) and aryl hydrocarbon receptor activation (AhR-CALUX). While none of the ILs activated the reporter genes, cytotoxicity was high and markedly different between cell lines. Seven and 25 ILs proved more cytotoxic than predicted by baseline toxicity model in the AREc32 and the AhR-CALUX assays, respectively. The length of the side chain and headgroup structures of ILs altered the MOA of ILs. Cellular metabolism of the ILs, investigated by LC-MS/MS, showed side-chain oxidation of the long-chain quaternary ammonium compounds in AhR-CALUX cells and, to a lower extent, in AREc32 cells, however, this transformation could not explain the high cytotoxicity. Effect data for 72 ILs for ten endpoints retrieved from the Tox21 database identified the inhibition of aromatase activity and of mitochondrial membrane potential as potential MOAs. However, in vitro fluorimetric assays for these endpoints demonstrated that effects were activated in a non-specific manner, probably through cytotoxicity. Although many of the ILs tested induced cytotoxicity at concentrations lower than baseline toxicity, the specific MOAs responsible could not be identified. Alternatively, we suggest that the descriptors currently used may fail to define the affinity of ILs for cells. Testing of the affinity of ILs for a diverse range of biomolecules is needed to accurately describe their interactions with cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Von Neumann architecture requires information to be encoded as numerical values. For that reason, artificial neural networks running on computers require the data coming from sensors to be discretized. Other network architectures that more closely mimic biological neural networks (e.g., spiking neural networks) can be simulated on von Neumann architecture, but more important, they can also be executed on dedicated electrical circuits having orders of magnitude less power consumption. Unfortunately, input signal conditioning and encoding are usually not supported by such circuits, so a separate module consisting of an analog-to-digital converter, encoder, and transmitter is required. The aim of this article is to propose a sensor architecture, the output signal of which can be directly connected to the input of a spiking neural network. We demonstrate that the output signal is a valid spike source for the Izhikevich model neurons, ensuring the proper operation of a number of neurocomputational features. The advantages are clear: much lower power consumption, smaller area, and a less complex electronic circuit. The main disadvantage is that sensor characteristics somehow limit the parameters of applicable spiking neurons. The proposed architecture is illustrated by a case study involving a capacitive pressure sensor circuit, which is compatible with most of the neurocomputational properties of the Izhikevich neuron model. The sensor itself is characterized by very low power consumption: it draws only 3.49 μA at 3.3 V., (© 2024 Massachusetts Institute of Technology.)

The Liquid Organic Hydrogen Carrier (LOHC) technology offers a technically attractive way for hydrogen storage. If LOHC systems were to fully replace liquid fossil fuels, they would need to be handled at the multi-million tonne scale. To date, LOHC systems on the market based on toluene or benzyltoluene still offer potential for improvements. Thus, it is of great interest to investigate potential LOHCs that promise better performance and environmental/human hazard profiles. In this context, we investigated the acute aquatic toxicity of oxygen-containing LOHC (oxo-LOHC) systems. Toxic Ratio (TR) values of oxo-LOHC compounds classify them baseline toxicants (0.1 < TR < 10). Additionally, the mixture toxicity test conducted with D. magna suggests that the overall toxicity of a benzophenone-based system can be accurately predicted using a concentration addition model. The estimation of bioconcentration factors (BCF) through the use of the membrane-water partition coefficient indicates that oxo-LOHCs are unlikely to be bioaccumulative (BCF < 2000). None of the oxo-LOHC compounds exhibited hormonal disrupting activities at the tested concentration of 2 mg/L in yeast-based reporter gene assays. Therefore, the oxo-LOHC systems seem to pose a low level of hazard and deserve more attention in ongoing studies searching for the best hydrogen storage technologies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter Wasserscheid reports a relationship with Hydrogenious LOHC Technologies GmbH that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. (ES) has gained popularity for its adaptogenic, immunostimulant, and anti-inflammatory properties. Because of overexploitation of the roots, the species is considered to be endangered and has been put on the Red List in some countries (e.g., the Republic of Korea). Therefore, the fruits of E. senticosus might be explored as a new sustainable source of compounds with adaptogenic activity. This study aimed to assess the chemical composition and the safety profile (hepatotoxicity, blood morphology, biochemical parameters of blood plasma) of E. senticosus fruit intractum in Balb/c mice after oral administration of 750 and 1500 mg/kg b.w. UHPLC analysis coupled with DAD and MS detectors was used to quantify the metabolites. For the first time, oleanolic and ursolic acids were quantified in the intractum (16.01 ± 1.3 and 2.21 ± 0.17 µg/g of oleanolic and ursolic acids, respectively). Regarding polyphenols, chlorogenic acid (0.92 mg/g of dried extract), caffeic acid (0.43 mg/g), dicaffeoylquinic acids (in total: 1.27 mg/g), and an unidentified caffeic acid ester (0.81 mg/g) were identified. The results in Balb/c mice revealed that the intractum does not cause significant variations in red blood cells parameters. In turn, a significant decrease in the total number of leukocytes was observed (5.8 × 10 3 µL), with a percentage increase in lymphocytes among the groups (80.2, 81.8, and 82.6). The ability of the intractum to decrease alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels may indicate its anti-inflammatory activity. Our observations justify that the fruits of E. senticosus are safe in the doses used and do not cause significant changes in the activity of the liver enzymes or in blood parameters.

In contrast to plants, humans are unable to synthesise carotenoids and have to obtain them from diet. Carotenoids fulfil several crucial biological functions in the organism; however, due to poor solubility in water, their bioavailability from plant-based food is low. The processes of carotenoid absorption and availability in the human body have been intensively studied. The recent experimental findings concerning these processes are briefly presented in the introductory part of this review, together with a summary of such topics as carotenoid carriers, body transport and tissue delivery, to finally report on molecular-level studies of carotenoid binding by membrane receptors. The main message of the review is contained in the section describing computational investigations of carotenoid intercalation and dynamic behaviour in lipid bilayers. The relevance of these computational studies lies in showing the direct link between the microscopic behaviour of molecules and the characteristics of their macroscopic ensembles. Furthermore, studying the interactions between carotenoids and lipid bilayers, and certainly proteins, on the molecular- and atomic-level using computational methods facilitates the interpretation and explanation of their macroscopic properties and, hopefully, helps to better understand the biological functions of carotenoids.

Zinc is required for virtually all biological processes. In plasma, Zn 2+ is predominantly transported by human serum albumin (HSA), which possesses two Zn 2+ -binding sites of differing affinities (sites A and B). Fatty acids (FAs) are also transported by HSA, with seven structurally characterized FA-binding sites (named FA1-FA7) known. FA binding inhibits Zn 2+ -HSA interactions, in a manner that can impact upon hemostasis and cellular zinc uptake, but the degree to which binding at specific FA sites contributes to this inhibition is unclear. Wild-type HSA and H9A, H67A, H247A, and Y150F/R257A/S287A (FA2-KO) mutant albumins were expressed in Pichia pastoris. Isothermal titration calorimetry studies revealed that the Zn 2+ -binding capacity at the high-affinity Zn 2+ site (site A) was reduced in H67A and H247A mutants, with site B less affected. The H9A mutation decreased Zn 2+ binding at the lower-affinity site, establishing His9 as a site B ligand. Zn 2+ binding to HSA and H9A was compromised by palmitate, consistent with FA binding affecting site A. 13 C-NMR experiments confirmed that the FA2-KO mutations prohibited FA binding at site FA2. Zn 2+ binding to the FA2-KO mutant was unaffected by myristate, suggesting binding at FA2 is solely responsible for inhibition. Molecular dynamics studies identified the steric obstruction exerted by bound FA in site FA2, which impedes the conformational change from open (FA-loaded) to closed (FA-free) states, required for Zn 2+ to bind at site A. The successful targeting of the FA2 site will aid functional studies exploring the interplay between circulating FA levels and plasma Zn 2+ speciation in health and disease., Competing Interests: Conflict of interest J. S. is a co-founder and CEO at AFFINImeter. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients., (© 2024. The Author(s).)

The purpose of this article is to report the author's technique for using patient-specific distractors for customized distraction osteogenesis of the mandible in patients with Pierre Robin sequence and upper airway obstruction. The advantages of virtual planning and patient-specific plates in other aspects of craniomaxillofacial surgery, such as orthognathic and reconstructive surgery, have been reported previously. Similar to patient-specific plates, the theorized advantages of patient-specific distractors in infants with Robin sequence and upper airway obstruction include increased accuracy, decreased operating time, and less morbidity to vital anatomic structures such as the inferior alveolar nerve and developing tooth buds. This technique is novel in using patient-specific distractors in the craniomaxillofacial skeleton., Competing Interests: Competing interests None., (Copyright © 2023 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background/aims: Microglial cells play a crucial role in the development of neuroinflammation in response to harmful stimuli, such as infection, ischemia or injury. Their chronic activation, however, is associated with a progression of neurodegenerative diseases. Therefore, looking for potential factors limiting microglial activation, the effect of docosahexaenoic acid (DHA) on the inflammatory response and TREM2-dependent phagocytic activity in microglia was investigated., Methods: In LPS-induced primary microglia preincubated with DHA, or without preincubation the expression of ATF3 and TREM2 genes and TREM2, Syk, Akt proteins were determined by RT-PCR and WB, respectively. Cell viability was assayed by MTT and cytokine and chemokine expression was determined by the Proteome Profiler assay. Moreover, the phagocytic activity of microglia was assayed using immunofluorescence., Results: We found that DHA significantly increased the expression of ATF3 , and decreased the levels of CINC-1, CINC-2αβ, CINC-3 chemokines, IL-1α and IL-1β cytokines, and ICAM-1 adhesion protein. Additionally, preincubation of microglia with DHA resulted in increased Src/Syk kinases activation associated with increased phagocytic microglia activity., Conclusion: These findings indicate that DHA efficiently inhibits ATF3-dependent release of proinflammatory mediators and enhances phagocytic activity of microglia. The study provides a new mechanism of DHA action in reactive microglia, which may help limit neuronal damage caused by the pro-inflammatory milieu in the brain., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

The co-occurrence of COVID-19 conspiracy theories (CCT) and fear of the coronavirus (FCV) can be linked to how safe people feel and how much they endorse vaccinations. School teachers were one of the vaccination priority groups in Poland. We conducted three cross-sectional studies ( N1  = 1006; N2  = 1689; N3  = 627) to find out the potential interaction effects of CCT belief and FCV in predicting sense of safety (SoS; Studies 1-3), opinions about vaccinations efficacy (Studies 2-3) and endorsement of vaccinations of children (Study 3) among school teachers. In all three studies, the belief in CCT was related to lower SoS only when FCV was low. For low CCT belief, although the belief in vaccination efficacy was higher than for CCT endorsers, it was unrelated to FCV. However, for high and average CCT belief, FCV was linked to belief in vaccination efficacy. FCV was positively related to acceptance of vaccinating children on all levels of CCT endorsement. The results are discussed in light of the available literature and their potential use in public health.

Due to the ongoing climate changes, temperate forests are increasingly exposed to fires. However, until now the functioning of post-fire temperate forest ecosystems with regard to used forest management method has been weakly recognized. Here, we examined three variants of forest restoration after fire (two variants of natural regeneration with no soil preparation-NR, and artificial restoration by planting following soil preparation-AR) regarding their environmental consequences in development of post-fire Scots pine (Pinus sylvestris) ecosystem. The study was conducted using a 15-year timespan in a long-term research site located in the Cierpiszewo area (N Poland) being one of the biggest post-fire grounds in European temperate forests in last decades. We focused on soil and microclimatic variables as well as on growth dynamics of post-fire pines generation. We found that the restoration rates of soil organic matter, carbon and most studied nutritional elements stocks were higher in NR plots than in AR. This could be primarily linked to the higher (p < 0.05) density of pines in naturally regenerated plots, and the subsequent faster organic horizon reconstruction after fire. The difference in tree density also involved regular differences in air and soil temperature among plots: consistently higher in AR than in both NR plots. In turn, lower water uptake by trees in AR implied that soil moisture was constantly the highest in this plot. Our study delivers strong arguments to pay more attention to restore post-fire forest areas with the use of natural regeneration with no soil preparation., (© 2023. The Author(s).)

Heterocyclic polyaromatic hydrocarbons (heterocyclic PAHs) are of increasing concern and their environmental and human health impacts should be assessed due to their widespread presence and potential persistence in the environment. This study investigated the ultimate and primary biodegradability of ten heterocyclic PAHs, nine of which were found to be non-readily biodegradable. To generate a microbial community capable of degrading such compounds, a bacterial inoculum isolated from the effluent of a wastewater treatment plant (WWTP) was adapted to a mixture of heterocyclic PAHs for one year. Throughout the adaptation process, bacterial samples were collected at different stages to conduct primary biodegradation, ultimate biodegradation, and inoculum toxicity tests. Interestingly, after one year of adaptation, the community developed the ability to mineralize carbazole, but in the same time showed an increasing sensitivity to the toxic effects of benzo[c]carbazole. In two consecutive primary biodegradation experiments, degradation of four heterocycles was observed, while no biodegradation was detected for five compounds in any of the tests. Furthermore, the findings of this work were compared with predictions from in silico models regarding biodegradation timeframe and sorption, and it was found that the models were partially successful in describing these processes. The results of study provide valuable insights into the persistence of a representative group of heterocyclic PAHs in aquatic environments, which contributes to the hazard assessment of this particular class of substances., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Environmental occurrence and hazardous nature of heterocyclic polyaromatic hydrocarbons (heterocyclic PAHs) has the potential to threaten the health of aquatic ecosystems. Here, we investigate the acute toxicity of heterocyclic PAHs (log K OW 3.7-6.9) to aquatic organisms: marine bacteria (Aliivibrio fischeri), freshwater green algae (Raphidocelis subcapitata), and water fleas (Daphnia magna) using passive dosing to maintain stable exposure. The membrane-water partition coefficient (K MW ) of the heterocycles was measured to elucidate its relationship with toxicity. Our findings show that the tested heterocycles had little inhibitory effect on A. fischeri, while most compounds were highly toxic to R. subcapitata and D. magna. Toxicity generally increased with increasing K MW values, and nonpolar narcosis was identified as the most likely mode of toxic action of the heterocycles. Comparison of standard protocols with passive dosing emphasizes the importance of maintaining a constant concentration during toxicity testing, as very high losses occurred in standard tests and passive dosing experiments revealed higher toxicities. These results indicate a potentially high risk to aquatic life and call for more in-depth investigation of the (eco)toxic effects of NSO-PAHs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The lipid matrix of thylakoid membranes is a lamellar bilayer, but under a certain condition it can convert locally into a nonlamellar structure. This is possible because one of the main membrane lipids, MGDG, promotes the formation of an inverse hexagonal phase. Here, the spontaneous transformation of aligned hydrated MGDG bilayers into nonlamellar structures is investigated using all-atom molecular dynamics simulation. Previous studies have demonstrated that MGDG polar head groups connect vertically across the interface. In this study, the evolution of the system's initial structure into a lattice of water channels and contacted surfaces created by numerous vertical MGDG connections depended on the width of the hydrating water layers. These widths controlled the bilayers' ability to bend, which was a prerequisite for channel formation. Locally, an intensive exchange of MGDG molecules between apposing bilayer leaflets occurred, although a stable semi-toroidal stalk did not develop., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

We report the  long-term upper limb disability, health-related quality of life (HRQoL), functional impairment, self-perception of appearance and prevalence of neuropathic pain in patients with upper limb thalidomide embryopathy in the United Kingdom. One-hundred and twenty-seven patients responded to our electronic questionnaire. Mean Quick Version of the Disabilities of Arm, Shoulder, and Hand score was 54.3 (SD 22.6). Median EuroQoL 5-Dimension 5-Likert index, Work and Social Adjustment Scale, Derriford Appearance Scale 24 and Neuropathic Pain Scale were 0.6 (IQR 0.4 to 0.7), 15.5 (IQR 8.0 to 23.5), 35.5 (IQR 28.0 to 50.5), and -0.8 (IQR -1.4 to 0.8), respectively. Thirty-three patients (26%) reported neuropathic pain. Finger changes associated with radial longitudinal deficiency were an independent predictor of more severe upper limb disability. Eighty-nine patients (70%) reported deteriorating HRQoL with increasing age. Patients with upper limb thalidomide embryopathy experience age-related worsening of symptoms and function, highlighting the need for ongoing specialist care and support. Level of evidence: IV.

Photoreceptor membranes have a unique lipid composition. They contain a high level of polyunsaturated fatty acids including the most unsaturated fatty acid in nature, docosahexaenoic acid (22:6), and are enriched in phosphatidylethanolamines. The phospholipid composition and cholesterol content of the subcellular components of photoreceptor outer segments enables to divide photoreceptor membranes into three types: plasma membranes, young disc membranes, and old disc membranes. A high degree of lipid unsaturation, extended exposure to intensive irradiation, and high respiratory demands make these membranes sensitive to oxidative stress and lipid peroxidation. Moreover, all-trans retinal (AtRAL), which is a photoreactive product of visual pigment bleaching, accumulates transiently inside these membranes, where its concentration may reach a phototoxic level. An elevated concentration of AtRAL leads to accelerated formation and accumulation of bisretinoid condensation products such as A2E or AtRAL dimers. However, a possible structural impact of these retinoids on the photoreceptor-membrane properties has not yet been studied. In this work we focused just on this aspect. The changes induced by retinoids, although noticeable, seem not to be significant enough to be physiologically relevant. This is, however, an positive conclusion because it can be assumed that accumulation of AtRAL in photoreceptor membranes will not affect the transduction of visual signals and will not disturb the interaction of proteins engaged in this process.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10 -9 ) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46 , IKBKE , PARK2 , ULK4 , ATG5 , and CDKN2A associated with MM risk ( p = 4.47 × 10 -4 -5.79 × 10 -14 ). Mechanistically, we found that the ULK4 rs6599175 SNP correlated with circulating concentrations of vitamin D3 ( p = 4.0 × 10 -4 ), whereas the IKBKE rs17433804 SNP correlated with the number of transitional CD24 + CD38 + B cells ( p = 4.8 × 10 -4 ) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 ( p = 3.6 × 10 -4 ). We also found that the CD46 rs1142469 SNP correlated with numbers of CD19 + B cells, CD19 + CD3 - B cells, CD5 + IgD - cells, IgM - cells, IgD - IgM - cells, and CD4 - CD8 - PBMCs ( p = 4.9 × 10 -4 -8.6 × 10 -4 ) and circulating concentrations of interleukin (IL)-20 ( p = 0.00082). Finally, we observed that the CDKN2A rs2811710 SNP correlated with levels of CD4 + EMCD45RO + CD27 - cells ( p = 9.3 × 10 -4 ). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3 - , MCP-2 - , and IL20-dependent pathways.

Evidence has grown recently on the correlation between lifestyle and physical activity, and their impact on the functioning of the entire organism. In addition, a decrease in physical efficiency may be an indicator of the early diagnosis of systemic diseases. The aim of this study was to determine whether there is a relationship between exercise tolerance and possible erectile dysfunction or mental disorders. A cross-sectional study was conducted among 254 men in 4 cardiac rehabilitation centers in Poland using the standardized International Index of Erectile Function 5 (IIEF-5) and Beck Depression Inventory (BDI) questionnaires. Erectile dysfunction was directly proportional to the metabolic equivalent of the task (MET) variable. An increase in exercise tolerance by 1 point was associated with an increase in the IIEF-5 score by 1.62 points, indicating a reduction in the severity of erectile dysfunction. The 1-point increase in MET was associated with a 1.8-point decrease in BDI, indicating that an increase in exercise tolerance is associated with a decrease in the severity of depressive disorders. Increasing the tolerance of physical effort has a beneficial effect not only on the general well-being, but also on the sexual and mental health of men. An increase in exercise tolerance is associated with a reduction in the incidence of erectile dysfunction. On the other hand, in patients with depressive disorders, the improvement of exercise tolerance reduces the intensity of depression symptoms. Exercise tolerance can be an early and simple marker at the onset of erectile dysfunction or mood disorders.

Introduction: The skin is the largest organ in the human body and it is also a complex organ. Its protective function is properly maintained due to its continuous renewal. Malignancies develop when the balance between proliferation and cell death is dysregulated in skin cells. Skin epithelial cancers are the most common neoplasms in humans. Although caspases are proteins which regulate the cell cycle and cell death, caspase 14 is a unique representative of the caspase family which does not participate in apoptosis. The detailed role of caspase 14 in skin epithelial malignancies has not been elucidated., Material and Methods: We performed a prospective study aimed at the analysis of the mRNA expression of caspase 14 in groups of skin epithelial malignancies. We enrolled 56 patients (control group n = 21, study group n = 35). The mRNA expression of caspase 14 was lower in the non-lesional skin of patients with basal cell cancer or squamous cell cancer compared to a combined group of non-lesional samples from actinic keratosis patients and the control group., Results: The prognostic potential of caspase 14 mRNA is suggested when trying to identify patients predisposed to skin cancer. Moreover, the expression level was lower in combined groups of non-lesional skin obtained from patients with basal cell cancer (BCC)/squamous cell cancer (SCC) in comparison with lesional samples obtained from patients with BCC/SCC., Conclusions: We present primary results of a pilot study and define further goals for research continuation., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 Termedia Sp. z o. o.)

Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1)-a suppressor of the BRAF/MEK/ERK pathway-via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors.

Heterocyclic polyaromatic hydrocarbons (heterocyclic PAHs) are frequently found in the environment yet, compared to homocyclic PAHs, little attention has been paid to their environmental behavior and a comprehensive hazard assessment has not been undertaken. Surprisingly, the physicochemical data necessary to perform at least a screening-level assessment are also limited. To address this, we began by experimentally determining the physicochemical properties of heterocyclic PAHs, namely, water solubility ( S w ), n -octanol-water partition coefficients ( K ow ), and organic carbon-water partition coefficients ( K oc ). The physicochemical data obtained in this study allowed for the development of clear structure-property relationships and evaluation of the predictive power of in silico models including conductor-like screening model for realistic solvation, the poly-parameter linear solvation energy relationship, and the quantitative structure-property relationship. Finally, heterocyclic and homocyclic PAHs were evaluated in terms of persistence, bioaccumulation, mobility, and toxicity to perform a screening-level comparative hazard assessment by integrating the data and evidence from multiple sources.

Dormancy development in micropropagated plantlets at the acclimatization stage and early growth ex vitro is undesirable as it lowers their survival rate and restricts the efficient year-round production of planting material. Thus far, little is known about the factors and mechanisms involved in the dormancy development of micropropagated herbaceous perennials, including rhubarb. This study determined physiological and molecular changes in the Rheum rhaponticum (culinary rhubarb) 'Raspberry' planting material in response to photoperiod and temperature. We found that the rhubarb plantlets that were grown under a 16-h photoperiod (LD) and a temperature within the normal growth range (17-23 °C) showed active growth of leaves and rhizomes and did not develop dormancy. Rapid growth cessation and dormancy development were observed in response to a 10-h photoperiod (SD) or elevated temperature under LD. These morphological changes were accompanied by enhanced abscisic acid (ABA) and starch levels and also the upregulation of various genes involved in carbohydrate synthesis and transport ( SUS3, AMY3 , BMY3, BGLU17 ) and ABA synthesis and signaling ( ZEP and ABF2 ). We also found enhanced expression levels of heat shock transcription factors ( HSFA2 and HSFA6B ), heat shock proteins ( HSP22 , HSP70.1 , HSP90.2 and HSP101 ) and antioxidant enzymes ( PRX12 , APX2 and GPX ). This may suggest that dormancy induction in micropropagated rhubarb plantlets is a stress response to light deficiency and high temperatures and is endogenously coordinated by the ABA, carbohydrate and ROS pathways.

We present a linear-optical scheme for generating an arbitrary state of three qubits. It requires only three independent particles in the input and post-selection of the coincidence type at the output. The success probability of the protocol is equal for any desired state. Furthermore, the optical design remains insensitive to particle statistics (bosons, fermions or anyons). This approach builds upon the no-touching paradigm, which demonstrates the utility of particle indistinguishability as a resource of entanglement for practical applications., (© 2022. The Author(s).)

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be related to the occurrence of complications, including graft-versus-host disease (GvHD) and infections. The pathogenesis of acute GvHD is connected with T lymphocytes, which identify alloantigens on host's antigen-presenting cells, activate production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), and act on the immune effector cells and damage tissues and organs., Aim: The aim of the study was to investigate and distinguish serum concentration profiles of IFN-gamma and IL-2 within a 30-d period after allo-HSCT., Methods: We enrolled 62 patients, i.e. , 30 (48%) male and 32 (52%) female subjects [median age 49.5 (19-68) years], after allo-HSCT from siblings ( n = 12) or unrelated donors ( n = 50) due to acute myeloid leukemia with myeloablative conditioning ( n = 26; 42%) and with non-myeloablative conditioning ( n = 36; 58%). All patients were given standard immunosuppressive therapy with cyclosporin-A and methotrexate and pre-transplant antithymocyte globulin in the unrelated setting. Blood samples were collected pre-transplant before and after (on day -1) the conditioning therapy and on days +2,+4, +6, +10, +20, and +30 after allo-HSCT. Serum levels of IL-2 and IFN-gamma were determined using ELISA., Results: Patients were divided into four groups depending on the presence of acute GvHD and clinical manifestations of infection. Group I included patients with neither acute GvHD nor infections [ n = 15 (24%)], group II consisted of patients with infections without acute GvHD [ n = 17 (27%)], group III was comprised of patients with acute GvHD without infections [ n = 9 (15%)], and group IV included patients with both acute GvHD and infections [ n = 21 (34%)]. IFN-gamma concentrations were higher in Group II than in other groups on days +20 ( P = 0.014) and +30 ( P = 0.008). Post-hoc tests showed lower concentrations of IFN-gamma on day +30 in groups I ( P = 0.039) and IV ( P = 0.017) compared to group II. The levels of IL-2 were mostly undetectable., Conclusion: Serum levels of IFN-gamma following allo-HSCT progressively escalate. High serum levels of IFN-gamma are related to infectious complications rather than acute GvHD. Serum concentrations of IL-2 in most patients are undetectable., Competing Interests: Conflict-of-interest statement: All the authors declare no conflict of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

The amount of industrial pollution entering the environment and its impact on living organisms is an ongoing concern. At the same time, due to an increasing awareness, new methods of wastewater treatment are being explored that are not only effective but also environmentally acceptable. Meeting environmental standards for permitted concentrations is a necessity, but investigating the effects of wastewater on living organisms is also an important issue. In this paper, the influence of metal ions (Fe(III), Cr(III), Ni(II), Cu(II)) in industrial wastewater from electropolishing of stainless steel on Daphnia magna has been investigated. Daphnids have been exposed to wastewater both before and after treatment (Ca(OH) 2 precipitation, sorption with peat). Immobilisation in a 48-h acute toxicity test and EC 50 has been determined. In the case of studied industrial wastewater, the organic content (expressed as total organic carbon) of the effluent has a positive impact in terms of the survival of D. magna and increases the range of heavy metal concentrations tolerated by them. The application of a two-stage process with Ca(OH) 2 neutralisation followed by sorption with peat allows for the removal of almost 100% of metal ions from the wastewater. The reduction obtained ensured a limited impact on D. magna and a decrease in immobilisation to less than 10%. Proper execution of the wastewater treatment process ensures a reduction of its negative impact on living organisms., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, carried out using computational methods, the organisation of the lipid/water interface of bilayers composed of galactolipids with both α-linolenoyl acyl chains is analysed and compared in three different lyotropic liquid-crystalline phases. These systems include the monogalactosyldiglyceride (MGDG) and digalactosyldiglyceride (DGDG) bilayers in the lamellar phase, the MGDG double bilayer during stalk phase formation and the inverse hexagonal MGDG phase. For each system, lipid-water and direct and water-mediated lipid-lipid interactions between the lipids of one bilayer leaflet and those of two apposing leaflets at the onset of new phase (stalk) formation, are identified. A network of interactions between DGDG molecules and its topological properties are derived and compared to those for the MGDG bilayer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hryc, Szczelina, Markiewicz and Pasenkiewicz-Gierula.)

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged ≥50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m 2 IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

In this study, we investigated the relationship between social media use and women's sexual functioning during the COVID-19 pandemic. Data were collected between April and November 2021. Online surveys including the Female Sexual Functioning Index (FSFI) and Bergen Social Media Addiction Scale (BSMAS) questionnaires were distributed to young, sexually active women. Information was collected on their demographics, sexual life, and use of social media. We enrolled 546 women (mean age 23.07 ± 4.69). In general, 5.68% of the women were at high risk of social media addiction. Social media addiction had a negative impact on FSFI scores, while pornography use had a positive effect on women's sexual functioning. Users of dating apps also obtained lower FSFI scores than non-users. No differences in FSFI scores were observed between gamers and non-gamers. The impact of time spent on social media on FSFI scores was not significant. We conclude that social media addiction negatively affected women's sexual functioning during the COVID-19 pandemic.

Lipids play a central role within the cell. They not only encompass it but are also engaged in many processes such as cellular transport and energy production. Despite ongoing advances in experimental studies, computer simulations are a viable method to trace their behavior at the atomic level and on an elusive time scale. In molecular modeling studies, the quality of the obtained results is associated with the considered force field and its parameters. In the present work, the authors have investigated the procedure of partial charges fitting on the example of a triacetin molecule, containing chemical moieties present in the glycerol backbone. The goal of the study was to validate assigned partial charges based on the quality of the torsion profiles using optimally assigned torsional coefficients and reproduction of the condensed phase properties of triacetin. We applied various approaches and noticed a significant improvement in the parameterization of triacetin compared to the original one. The results showed that it is important to take into account the intermolecular interactions in the partial charges fitting procedure to obtain good quality validation results., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Microplastic (MP) pollution has become a global concern in terms of its environmental abundance and potential detrimental effects. Fibrous microplastics (FMPs) released from synthetic textiles are believed to contribute significantly to environmental MP pollution. This review provides an overview of current knowledge relating to the environmental impact of FMPs through a summary and discussion of (1) the concentrations in different environmental compartments including water, soil and air, (2) emission from wastewater treatment plants: via effluent discharges to waters and via sludge to land, (3) environmental transport and fate, and (4) toxicity and associated effects. How the properties of FMPs influence these aspects is discussed and their behaviour is compared to MPs of other shapes. We have summarised the Environmental Concentrations and derived Predicted No-Effect Concentrations for a preliminary risk assessment of FMPs by extrapolating the risk quotient for each respective environmental compartment. The uncertainties surrounding current assessment methods are discussed. In particular we address the need to improve determination of exposure levels and to better characterise the effects of FMPs. We conclude by presenting topics for future studies to address, which will improve our still limited understanding of the interactions between FMPs and the environment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In cross-border areas of East Africa, sexual networks include partnerships across resident, migrant, and mobile populations, and risky behaviors can coincide with fragmented health services given the challenges of cross-border coordination. Among those most at risk are female sex workers (FSWs). We map HIV prevalence among FSWs in 14 cross-border areas, estimate associations between FSW characteristics and HIV and undiagnosed HIV, and estimate progress towards the UNAIDS 90-90-90 targets. The 2016-2017 East Africa Cross-Border Integrated Health Study recruited 4040 women; 786 were classified as FSWs. Overall HIV prevalence among FSWs was 10.8% (95% CI 8.2%, 13.3%), though area-specific estimates varied considerably. Among FSWs living with HIV, 46.1% (95% CI 33.2%, 59.0%) knew their status, 80.6% (95% CI 66.3%, 94.9%) of FSWs who knew their status were on ART, and 84.8% (95% CI 66.1%, 100.0%) of FSWs on ART were virally suppressed. Results indicate a need for expanded HIV testing., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Culinary rhubarb is a vegetable crop, valued for its stalks, very rich in different natural bioactive ingredients. In commercial rhubarb stalk production, the bud dormancy development and release are crucial processes that determine the yields and quality of stalks. To date, reports on rhubarb bud dormancy regulation, however, are lacking. It is known that dormancy status depends on cultivars. The study aimed to determine the dormancy regulation in a valuable selection of rhubarb 'Malinowy'. Changes in carbohydrate, total phenolic, endogenous hormone levels, and gene expression levels during dormancy development and release were studied in micropropagated rhubarb plantlets. Dormancy developed at high temperature (25.5 °C), and long day. Leaf senescence and dying were consistent with a significant increase in starch, total phenolics, ABA, IAA and SA levels. Five weeks of cooling at 4 °C were sufficient to break dormancy, but rhizomes stored for a longer duration showed faster and more uniformity leaf growing, and higher stalk length. No growth response was observed for non-cooled rhizomes. The low temperature activated carbohydrate and hormone metabolism and signalling in the buds. The increased expression of AMY3 , BMY3 , SUS3 , BGLU17 , GAMYB genes were consistent with a decrease in starch and increase in soluble sugars levels during dormancy release. Moreover, some genes ( ZEP , ABF2 , GASA4 , GA2OX8 ) related to ABA and GA metabolism and signal transduction were activated. The relationship between auxin (IAA, IBA, 5-Cl-IAA), and phenolic, including SA levels and dormancy status was also observed.

The breast cancer resistance protein (BCRP or ABCG2) involved in cancer multidrug resistance (MDR), transports many hydrophobic compounds, including a number of anti-cancer drugs. Our comprehensive study using a mouse model reveals that a subcutaneously growing tumor strongly affects the expression of BCRP in the host's normal organs on both the transcriptional and translational level. Additionally, the efflux of BCRP substrates is markedly enhanced. The levels of BCRP and its transcript in normal tissues distant from the tumor site correlate with tumor growth and the levels of cytokines in the peripheral blood. Thus, oncogenic stress causes transient systemic upregulation of BCRP in the host's normal tissues and organs, which is possibly mediated via cytokines. Because BCRP upregulation takes place in many organs as early as the initial stages of tumor development, it reveals a most basic mechanism that may be responsible for the induction of primary MDR. We hypothesize that such effects are not tumor-specific responses, but rather constitute a more universal defense strategy. The xenobiotic transporters are systemically mobilized due to various stresses, seemingly in a pre-emptive manner so that the body can be quickly and efficiently detoxified. Our findings shed new light on the biology of cancer and on the complexity of cancer-host interactions and are highly relevant to cancer therapies as well as to the design of new generations of therapeutics and personalized medicine.

Foreign body aspiration in children is a common condition and can bring about serious undesired results. Fast and accurate diagnosis and foreign body extraction from airways are essential. We performed a retrospective study on rigid bronchoscopy outcomes due to suspected foreign body aspiration. A total of 66 children were admitted to the Chair and Department of Pediatric Otolaryngology, Phoniatrics and Audiology, Medical University of Lublin between 2015 and 2020 and underwent rigid bronchoscopy in general anesthesia due to suspected foreign body aspiration. We analyzed the data, including patients age and sex, reported complaints, and bronchoscopy findings. Analyzed children were aged from 8 months to 17 years old; 74.24% of them were under 3 years old during the procedure, and most of the operated patients were males. In 36.36% cases, no foreign body was identified, and 57.14% foreign bodies were located in right main bronchus. A total of 80.95% of foreign bodies extracted from airways were organic, mostly nuts. Diagnosis and treatment of suspected foreign body aspiration requires consistent cooperation between pediatricians, pulmonologists, anesthesiologists, and otolaryngologists.

Petri nets (PNs) have many advantages such as graphical representation, formal description, and the possibility of sequential and concurrent control. An important aspect of using PNs is hierarchical modeling, which may be provided in different ways. In this paper, a new concept and definition of the hierarchical structure for Fuzzy Interpreted Petri Net (FIPN) are proposed. The concept of macroplace with several input, output, and input-output places is introduced to the net. The functionality of the macroplace instances and the hierarchy graph are also proposed. They are implemented in a computer simulator called HFIPN-SML. In this study, FIPN is employed since it allows the use of analogue sensors directly for process control. Better visualization and more precise control are among advantages of the introduced approach.

The use of renewable resources for powering self-ignition engines in European Union countries involves a high demand for renewable energy which is not accompanied by the development of its production infrastructure. The application of biofuel in vehicle powering is supposed to provide reductions in greenhouse gas emissions and an increase in the share of renewable energy resources in the total energy consumption. The study includes the analyses of power unit exhaust components, such as oxygen, carbon monoxide, nitric oxides, carbonizers, carbon dioxide and a quantity of exhaust particles contained in exhaust gases. Tests using an exhaust gas analyzer and a vapor analyzer were conducted. Three high-pressure engines, characterized by direct fuel injection, were tested. The vehicle computer software adjustments included increasing the fuel dose and the air load. Mixtures of diesel oil and fatty acid methyl esters were used in the tests. Based on the results, a statistical analysis was performed and an assessment model was developed to understand the functioning of the research objects fueled with these mixtures, with simultaneous software changes in the vehicle computers. On the basis of the conducted analysis, it was found that only 30% of fatty acid methyl ester additives to diesel oil reduced the performance parameters of the drive units.

The tailorable and often unique properties of ionic liquids (ILs) drive their implementation into a broad variety of seminal technologies. The modular design of ILs allows in this context a proactive selection of structures that favor environmental sustainability─ideally without compromising their technological performance. To achieve this objective, the whole life cycle must be taken into account and various aspects considered simultaneously. In this review, we discuss how the structural design of ILs affects their environmental impacts throughout all stages of their life cycles and scrutinize the available data in order to point out knowledge gaps that need further research activities. The design of more sustainable ILs starts with the selection of the most beneficial precursors and synthesis routes, takes their technical properties and application specific performance into due account, and considers its environmental fate particularly in terms of their (eco)toxicity, biotic and abiotic degradability, mobility, and bioaccumulation potential. Special emphasis is placed on reported structure-activity relationships and suggested mechanisms on a molecular level that might rationalize the empirically found design criteria.