bluuebunny/crossref_metadata_2025 huggingface dataset:
A measurement method of blast wave parameters based on deformation of cantilever beam
Authors: Wu Ke , Chen Bo , Sui Yaguang , Zhang Yunfeng , Fang Long , Zhang Dezhi
Published: July 2023

In large equivalent explosion tests, the method of calculating blast wave parameters by the plastic deformation angle of a cantilever beam can effectively avoid the problem of power supply, storage, communication, and low survival rate of conventional blast wave sensors. In this paper, by means of theoretical analysis and numerical simulation, the deformation response of a pure aluminum cantilever beam with different scaled distances is calculated, and the relationship between the plastic bending angle and blast wave parameters is obtained, which provides a novel and effective method for the measurement of blast wave parameters. The experimental results show that the deformation of the cantilever beam is mainly dominated by the impulse load and the error of this measurement method is within 15%. This method can provide a complementary approach to more precise but complex sensor measurement and can effectively evaluate the impulse in the explosion accident outside.
Excitation wavelength dependent triple-mode photoluminescence of copper-based halides for advanced anti-counterfeiting
Authors: Liu Chengjun , Zhang Yuyi , Luo Manman , Wang Lixi , Liu Xingyu , Pan Jiangyong , Zhao Zihan , Fang Fan , Mao Lei , Huang Yuling , Wang Bingqi , Lin Congyuan , Lei Wei , Li Qing , Zhao Zhiwei , Wu Jun , Zhu Zhuoya , Ertugrul Mehmet , Zhang Xiaobing , Chen Jing , Zhao Dewei
Published: July 2023

New fluorescent materials with a low cost, hypotoxicity, and concealment are desired for the application of anti-counterfeiting. Herein, we report a CsCu2I3@Cs3Cu2I5 composite with a triple-mode photoluminescence (PL) feature by simply adjusting the excitation wavelengths, which are ascribed to the multiple excited states of different phases in the CsCu2I3@Cs3Cu2I5 composite. The broadband emission and high quantum yield (∼51%) of the composite originate from the structure-oriented self-trapped excitons effect of Cs3Cu2I5 and CsCu2I3 phases. Moreover, the incorporation of polyethylene oxide (PEO) into this composite improves the stability of CsCu2I3@Cs3Cu2I5@PEO against harsh environments. The CsCu2I3@Cs3Cu2I5@PEO composite has a slight decay of ∼5% of its initial PL intensity and only a 3.5% shift of the corresponding color coordinate after 30 days of storage. More importantly, its initial PL intensity shows only 10.3% decay under ultraviolet exposure for 200 h. Our work provides a promising approach to design materials for advanced anti-counterfeiting applications.
Enhancing SRF cavity stability and minimizing detuning with data-driven resonance control based on dynamic mode decomposition
Authors: Wang Faya
Published: July 2023

Effective resonance control of superconducting radio frequency (SRF) cavities is critical for large machines like LCLS-II, as failure to achieve proper control can result in increased RF power consumption, higher cryogenic heat loads, and increased costs. To address this challenge, we have developed a machine learning (ML) model based on the dynamic mode decomposition method to represent the forced cavity dynamics. Using this model, we designed a model predictive controller (MPC) and demonstrated through simulation that the MPC can effectively stabilize the amplitude and phase of SRF cavities using only a frequency actuator, even in the presence of multiple mechanical modes. The lightweight and explicit ML model makes the controller suitable for direct implementation on field-programmable gate arrays, unlocking the full potential of SRF linacs like LCLS-II, enabling higher beam power and energy, and also serving as an advanced motion controller for various applications, such as photon beamlines and storage rings.
Overview of the synthetic approaches to lysergic acid as a precursor to the psychedelic LSD
Authors: Nutt Michael J. , Woolf Nick , Stewart Scott G.
Published: July 2023

In this short primer we will discuss the total synthesis of lysergic acid, an important precursor to both lysergic acid diethylamide (LSD) and its derivatives. Lysergic acid is also noted as a precursor for many drugs targeting the serotonin receptor family of GPCRs, including multiple known hallucinogens. More recently, reinvigorated interest in the therapeutic potential of psychedelics from academic and commercial sectors has placed a renewed importance on practical, scalable means of accessing this complex alkaloid scaffold.
Food security issues at the regional level
Authors: Popova I V , Konstantinova N A , Okladchik S A , Prigozhin V L , Melikhova T V
Published: July 2023

Food security is the primary task of state authorities at the present stage. It is an essential component of the representation of state independence from products import on the world stage, the safety of people, the increase in live standard and the health of population. The article has considered the analysis of food security level in the Irkutsk region including the analysis of the dynamics of food basic types production, the provision of the population of the Irkutsk region with foodstuffs, and the dependence of the Irkutsk region upon imported products has been also analyzed.
Improving the efficiency of grain exports by processing organisations
Authors: Sokolov Sergei L , Shelkovnikov Sergei A , Stadnik Anatoly T , Samokhvalova Anastasia A , Essaulenko Dmitrii V
Published: July 2023

Increasing the efficiency of agricultural production and its processing is a priority since the farming industry provides the population with the necessary food. The provision of the domestic market with processing products of the crop industry and its high competition is forcing domestic flour milling organisations to pay more and more attention to foreign markets, but this requires solving the problem of the relatively high cost of Russian flour, the main component of which is grain, the price of which is constantly growing. The increase in world trade in flour also contributes to expanding export deliveries. At the same time, the fact that each country seeks to establish its flour production becomes a deterrent. Russian flour is more expensive than Turkish, Kazakh, and Ukrainian, but in terms of quality, it has the advantage of not using toxic substances (which many foreign manufacturers “sin” with). The task of ensuring and maximising the efficiency of production and processing of grain requires a successful solution to take into account a large number of factors - labour, investment, economics, and others, which are comprehensively taken into account in the process of analysing the efficiency of production, processing, and export of grain about value added to material costs.
Biological nitrogen contribution to the increased forage value of soybean grains in the Non-Chernozem zone of Russia
Authors: Belyshkina M E , Kobozeva T P , Ananyeva T V , Popova N P , Yu Romanovskaya A
Published: July 2023

The article presents the results of the studied effect of biological nitrogen fixation on the yield, forage value, protein and oil productivity of soybean varieties belonging to the northern ecotype (Mageva, Okskaya and Svetlaya), depending on the water supply. Under the conditions of the Central Non-Chernozem Region, soybean varieties of the northern ecotype have been proved to provide the maximum yield of 3.05 t/ha; the protein content – of 43.51%; the fat content – of 20.67%; the protein yield – 1322 kg/ha; the yield of essential amino acids – 833 kg/ha; the fat yield – 531 kg/ha; the yield in forage units – 4118 kg/ha. In years with excessive and optimal water supply, pre-sowing seed inoculation with an active strain 605b of Rhizobium japonicum (Kirchner) significantly increases soybean productivity: the yield increases by 0.21-0.25 t/ha, the protein content in seeds – by 2.11-3.35%, the fat yield – by 0.33-0.57%, the protein yield – by 125-176 kg/ha, the fat yield – by 43-72 kg/ha, the yield of essential amino acids – by 84-111 kg/ha, the lysine yield – by 7-8 kg, the yield of unsaturated fatty acids – by 29-37 kg/ha, the yield in forage units – by 305-348 kg/ha.
The application of information technologies to control environmental safety in agricultural production
Authors: Udartseva O.V.
Published: July 2023

The article considers a new approach to the study of environmental safety of chemical spraying technologies for the purpose of crop protection based on the use of an information and software complex. The possibility of implementing the developed software product into agricultural production to control environment safety is substantiated. Developed and approved by a Certificate of computer program registration, the information and software complex equipped with piezo sensors includes three modules: a collection module, a processing module, and an information analysis module. As a result of the measurements carried out, it is possible to assess the environment safety and the effectiveness of technical machines and spraying means, to form and visualize data based on the study results. This software complex contains modules not only for recording and processing data obtained from fields, but also allows to form a database by year, site, substances used, as well as visualize and transmit information in the form of tables, diagrams, and graphs.
Prospects for digitalization of monitoring of Lepidoptera phytophages of grapes
Authors: Radionovskaya Yana , Galkina Evgenia , Andreev Vladimir , Belash Sergey , Didenko Pavel
Published: July 2023

The effectiveness of phytophagous insect control systems depends on the accuracy of the chosen method of monitoring their numbers and the available information on the dynamics of the population number. As part of the automation of the processes of collecting and analyzing data on the biological activity of pheromone preparations of the phytophage of grapes Lobesia botrana Den. et Schiff., the method of counting the number of pest butterflies on the glue inserts of pheromone traps has been improved by the use of digital cameras and MCView software. According to the validation results, it was found that, relative to the actual data, the improved method ensured the accuracy of counting butterflies at a density of 45-321 imago/insert at an average of 99.1%, which exceeded the results of counting by the traditional visual method by an average of 5%. It is shown that partial method automation made it possible to reduce the influence of a particular researcher, as a subjective factor, on the experiment results. An increase in the time required for counting butterflies by the improved method relative to the visual method by an average of 30% was noted. The presented method of quantitative evaluation of the results of pheromone monitoring in vineyards is a transitional stage to the full automation of this information collection and analysis. For this purpose, to date, photosets have been collected containing more than 1000 photos of glue inserts of pheromone traps with captured butterflies and training of a convolutional neural network has begun designed to detect and quantify such grape lepidopteran phytophages as Lobesia botrana, Helicoverpa armigera Hbn., Theresimima ampelophaga Bayl. (Insecta: Lepidoptera).
Legume plant yields using biopreparation and plant growth regulators
Authors: Volobueva O G
Published: July 2023

The effect of the biopreparation Rizotorfin and growth regulators Albit, Kornevin, Epin-Extra on symbiotic activity and yield of the bean plant varieties Geliada and Shokoladnitsa was studied under field conditions. The nitrogenase activity was increased in Heliada bean plants after treatment of seeds with Epin-Extra against the increase of bacteroides area, amount and area of volutin and decrease of area and amount of poly-ß-oxybutyric acid (POM). The protective effect of Rizotorfin was evident in the variety Shokoladnitsa. The relationship between symbiotic nitrogen fixation and yield of bean plants of varieties Heliada and Shokoladnitsa was detected. The varietal responses of these plants to the use of Risotorfin and growth regulators have been identified. To increase the efficiency of legume-rhizobium symbiosis and plant productivity, the pre-sowing treatment of seeds with a biopreparation based on nodule bacteria and growth regulators is recommended.
Genetic productivity potential in soft spring wheat varieties of the collection of the All-Russian Institute of Genetic Plant Resources (VIR) in the Trans-Urals
Authors: Novokhatin V V , Shelomentseva T V , Aitbayeva R N , Zuev E V
Published: July 2023

Out of 277 varieties, according to the complex of economically valuable characteristics, 72 were distinguished in 2017-2020, 2022, of which 20 varieties were intensive. Their average yield in the dry years of 2017 and 2020 is 305-354 g/m2 (st. 260-283 g/m2), while the best of the collection were: Grenada, AC Pollet, Jin Mai 71, Greina, Toronit (380-442-502 g/m2). High potential yields are characterized by: Alabuga, Grenada, Kommissar, India 288, Remus (550-592-633 g/m2). In dry years, the environment index Ii is negative (-77; -48), in other years it is positive (10; 7) and quite pronounced in 2022 (106). Plasticity (lower ranks and their sums) is expressed in Grenada, Kommissar, Alabuga, Greina, AC Pollet. Positive effects on the reaction of the medium - Er, are well manifested in: India 288, Margarita, SSL 46-50, Grenada, Omskaya 41, Kedem, Tyumenskaya 25, Tyumenskaya 29; negative - in 3-4 media in Line (k-65021), UI Alta Blanca, Omskaya 36, Toronit, India 288, Jin Mai 71, reduce their value. The following varieties are distinguished with the complex of yield indices (5 pcs.): Grenada, AC Pollet, Omskaya 41, Greina, Toronit, Uralosibirskaya 2. The selected varieties are recommended for breeding for productivity.
Laminin binding surface protein as an epitope vaccine against Streptococcus suis by oral vector
Authors: Fudi Yang , Afonyushkin Vasiliy
Published: July 2023

We plan to clone the active epitope sequence of the laminin binding surface protein of Streptococcus suis into B. subtilis, and then administer it orally to observe whether there is immune activity and other adverse reactions. In this way, it may be possible to create a new low-cost and convenient operation vaccine of S. suis to help agricultural production.
From machines in clusters in the agricultural sector system effective use
Authors: Karimov M S , Yuldashev Sh U , Sh Sharipov Z , Norov B
Published: July 2023

The article discusses the issues and a number of technical recommendations for the effective use of existing agricultural and reclamation equipment available in the clusters of the republic, as well as the prospects for their development for large-scale use in the implementation of technological processes and those technical problems that may arise during operation and ways to eliminate them in production conditions. A number of irreplaceable technical recommendations are given for the modernization of machine and mechanism designs, improvement of reliability indicators, i.e. work without breakdowns, the strength of parts during manufacture, their resistance to friction, wear resistance, maintainability, storage, diagnostics, maintenance and repair, adaptation to storage and increase of technical resources, further increase of their resource conservation.
Calculation of water flow discharge using the truncated triangular prisms method
Authors: Shcherbakov A , Baramykov M
Published: July 2023

The article describes the calculating method for the water flow discharge. This method is based on the “velocity-area” proportion. In the proposed method, the flow of water passing through the cross section of the channel is represented as a body, the volume of which consists of a set of elements in the form of truncated triangular prisms. The side edges of the prism are the velocity vectors measured at the corresponding points. The bases of these prisms are the areas of triangles, the vertices of which are the points of measurement of the corresponding velocities. The volume of every element is determined by the formula for calculating the volume of a truncated prism. As a reference body, as a model of the diagram of flow velocities, one fourth of a sphere with a unit radius is taken, the volume of which can be calculated with the high accuracy. There are 15 speed verticals (they are also taken as measurement verticals) with five speed measurement points on every vertical: “surface”, 0.2h, 0.6h, 0.8h, “bottom”. The velocity value is represented by the length of the vector directed perpendicularly from the velocity vertical, from the point of velocity measurement to the surface of the sphere. Three adjacent velocity vectors are the side edges of the prism. The method of calculating the flow rate according to the approved measurement procedure is chosen for comparison. The results obtained by both methods are compared. As a result, the volume of the model, as one fourth of a sphere with the unit radius, was 1.0472; the volume calculated by the standard method was 1.0279; and by the method of prisms - 1.0124. Despite the absence of correction factors, the volume obtained by the prism method is only 1.55% less than one with the standard method. To smooth the results obtained by the method of truncated triangular prisms, the range of correction factors of 1.03…1.07 was determined, depending on the number of velocity verticals.
Turkey meat semi-finished products enriched with flax and flaxseed oil for the prevention of cardiovascular diseases of the population of the Smolensk region
Authors: Borisova V L , Stefanova I L , Sazonova E A , Kurskaya Yu A , Nikonorova A A
Published: July 2023

The article provides information about the impact of nutrition on human health and the formation of nutritional diseases. Irrational nutrition is typical for the population of Russia, in particular of the Smolensk region. The article provides an overview of the functional properties of flax seeds and linseed oil in terms of fatty acid composition and functional properties. The data of studies on the determination of fatty acid composition in samples enriched with flax seeds, flaxseed oil compared to the control sample (initial minced turkey breast meat) are presented. The introduction of functional ingredients improved the fatty acid composition and increased the efficiency of enriched semi-finished products. The positive effect of oilseed flax and flaxseed oil on the organoleptic characteristics of the developed chopped semi-finished products was noted. Improving the Omega-3: Omega-6 ratio in the developed semi-finished products allows to consider enriched semi-finished products as a functional food product.
Ways to increase the efficiency of industrial production of combined feed
Authors: Pavlidis Victoria , Chkalova Marina
Published: July 2023

This paper aims at finding a solution to the main problem of feed production: increasing the efficiency of the production process while improving the quality of products. The article aims to develop an adequate mathematical model of the technological process of combined feed industrial production. The authors have developed the theoretical background for describing this process on the basis of flow models within the framework of the original “three effects” concept, a stochastic model has been created taking into account the preservation of the exergy balance of the technological system. The main research tool is the apparatus of system analysis and the theory of random processes. An engineering-mathematical calculation of the parameters of the constructed model was performed, verification of the stochastic model of the technological process of preparing compound feeds in laboratory conditions was carried out. As a result of the research, the authors established the possibility of controlling the stochastic feed flow in all subsystems of the production technological system, outlined ways to solve the problem of increasing the efficiency of feed production by reducing energy costs and improving the output product granulometric composition.
New approaches to increasing the nutritional value of bread products based on the use of non-traditional cereals and biologically active substances with detoxifying properties
Authors: Altynbayeva G K , Azimova S T , Konarbayeva Z K , Tautaeva A T , Aidarkhanov A M
Published: July 2023

A practical solution to the problem of increasing the nutritional value of bread is the use of high-protein soy seeds and pumpkin processing product - pectin, the potential of which is to improve the quality of bread, intensify the technological process, enhance the detoxification properties of finished products, including easily fermentable sugars, nitrogenous and mineral substances, vitamins, dietary fiber. The possibility of using whole-ground soy flour in the production of poly-strain starter culture is shown, which contributes to the improvement of the vital activity of lactic acid bacteria. The introduction of poly-strain soy sourdough and 0.5% by weight of dry pumpkin pectin flour into the bread intensifies the dough making process due to easily fermentable sugars, improves the quality of the finished bread, provides it with an increased content of protein, dietary fiber, nitrogenous and mineral substances, vitamins, giving bread detoxifying properties and increasing its freshness.
CFD and experimental investigation of AM surfaces with different build orientations
Authors: Mandloi Kuldeep , Allen Angela , Cherukuri Harish , Miller Jimmie , Duttrer Brian , Raquet Jeff
Published: July 2023

Additive manufacturing (AM) surfaces offer the possibility of novel cooling channel geometries for high temperature applications. AM processes can optimize the internal geometry of cooling channels, which is generally constrained by limitations of conventional machining processes. The AM process gives rise to surface textures that depend on the build and scan orientations that also potentially contribute to heat-transfer characteristics and provide additional considerations for optimization. The motivation behind this research work is to explore the correlation between AM roughness characteristics (build-orientations, density of spatter deposits and their sizes, amplitudes/wavelengths, etc) and the resulting effect on heat transfer and pressure drop across cooling channels. In this study, the actual AM surfaces with different build angles were fabricated using Laser powder bed fusion (LPBF) and the roughness data of these surfaces were acquired. These measured surface topographies were used for developing simplified surfaces for the purposes of CFD simulations. Modeled AM surfaces with different build orientations were used to analyze the effect of built orientation and spatter deposits in terms of heat transfer for different flow conditions. The CFD simulations also informed the design of the experimental set-up for the validation of computational results. For the comparison, a reference smooth surface is machined from forged Inconel-625 for experiments and CFD simulations were also carried out for the validation. Results from CFD simulations show that the surface features (such as build angles and spatter deposits) significantly affect the heat transfer and fluid flow in terms of Nusselt number and pressure drop and the surface area impact on heat transfer is minimal in all the cases for both laminar and turbulent flow conditions. Under turbulent flow conditions, transverse track alignment shows the highest efficiency in terms of the Nusselt number and adding particles improves heat transfer efficiency for smooth and parallel-tracked surfaces. However, when the flow becomes laminar, reversed behavior is observed and surfaces show downside effects in terms of Nu. Also we define a performance factor that assesses the combined effects of both the thermal and the fluid flow characteristics to differentiate the performance of the AM channels.
Flexible resistive memory device based on agar
Authors: Chang Yu-Chi , Liu Hao-Jung , Chen Bo-Jhang
Published: July 2023

Potential applications of natural materials in environmentally friendly electronics include for information storage. In this work, natural material–agar was used to fabricate a flexible resistive memory device. Agar is one of the most widely used biomaterials for tissue engineering, medicine and other biotechnological applications. Agar is a suitable material for flexible electronics due to its good film formation, biocompatibility, low-temperature solution processability, transparency and flexibility. The flexible agar memory device described in this article exhibits an ON/OFF ratio of 103 under a bending radius of 5 mm, good bending endurance and a stable data retention time of over 104 s. Moreover, the agar could easily use a leaf as a substrate to make a fully biodegradable device. Agar, due to its exceptional flexibility, is emerging as a promising candidate for wearable and skin-compatible electronics, particularly in memory devices.
Microstructural characterization and mechanical properties of Inconel 625 wall fabricated by GTAW-based WAAM using stringer bead and circular weave pattern
Authors: Akash P , Puviyarasan M , Senthil T S , Rathinasuriyan C , Sindhiya S
Published: July 2023

In this work, Inconel 625 alloy was used to manufacture walls using the Wire Arc Additive Manufacturing (WAAM) technology, which is based on Gas Tungsten Arc Welding (GTAW). The wall was fabricated using a circular weave and stringer bead pattern. Microstructural analysis and tensile characteristics were evaluated for both walls. Using scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and elemental mapping, the fracture zones of the tensile specimens were examined. The microstructure is mostly made up of equiaxed dendrites, with the rare presence of continuous and discontinuous cellular dendrites along the cross-section. In tensile tests, circular weaved walls performed better than stringer bead walls. The circular weave specimen had an ultimate tensile strength (UTS) of 762 MPa in the horizontal and 722 MPa in the vertical orientations. Also, the Inconel 625 wall showed anisotropic behavior (5.3%) during tensile testing. The fracture morphology analysis revealed that all the specimens were fractured as a result of large plastic deformation, corresponding to ductile failure. Based on the EDS results, the fracture zone mainly consists of Ni and Cr with a small percentage of Nb and Mo. The absence of laves phases makes the fracture mode ductile. The elemental mapping shows uniform dispersion of Ni and Cr within the fracture region, further supporting the ductile failure mode.
Semi-equivariant conditional normalizing flows, with applications to target-aware molecule generation
Authors: Rozenberg Eyal , Freedman Daniel
Published: July 2023

Learning over the domain of 3D graphs has applications in a number of scientific and engineering disciplines, including molecular chemistry, high energy physics, and computer vision. We consider a specific problem in this domain, namely: given one such 3D graph, dubbed the base graph, our goal is to learn a conditional distribution over another such graph, dubbed the complement graph. Due to the three-dimensional nature of the graphs in question, there are certain natural invariances such a distribution should satisfy: it should be invariant to rigid body transformations that act jointly on the base graph and the complement graph, and it should also be invariant to permutations of the vertices of either graph. We propose a general method for learning the conditional probabilistic model, the central part of which is a continuous normalizing flow. We establish semi-equivariance conditions on the flow which guarantee the aforementioned invariance conditions on the conditional distribution. Additionally, we propose a graph neural network architecture which implements this flow, and which is designed to learn effectively despite the typical differences in size between the base graph and the complement graph. We demonstrate the utility of our technique in the molecular setting by training a conditional generative model which, given a receptor, can generate ligands which may successfully bind to that receptor. The resulting model, which has potential applications in drug design, displays high quality performance in the key ΔBinding metric.
O09 Dynamic impact of chronic inflammation on epidermal autophagy pathway
Authors: Uddin Nazia , Ostano Paola , Chiorino Giovanna , di Domizio Jeremy , Gilliet Michel , Philpott Mike , Hannen Rosalind , Bergamaschi Daniele
Published: July 2023

Chronic inflammatory signalling significantly affects epidermal homeostasis leading to different types of skin conditions characterized by a deregulated stratification of epidermal keratinocytes. Our project aims to investigate how chronic inflammation mechanistically influences autophagy signalling in the epidermis. We have previously reported impairment of the autophagic flux in an established psoriatic keratinocyte model (PSA cells) when compared to corresponding controls from healthy skin (KT2 and NTERT cells). To understand the dynamic impact of chronic inflammation on the epidermal autophagy pathway we have custom made a cytokine cocktail which induces interleukin-1β release at different times in keratinocyte cultures and stimulates keratinocyte proliferation. Stimulation of healthy keratinocytes with chronic inflammatory cocktail-induced activation of initial steps of the autophagy process. This is confirmed by the protein expression of key components of ULK1 and VPS34 complexes. Analysis of the elongation-stage markers confirmed the activation and correct proceeding of the pathway, until we observed LC3-I accumulation. In autophagy, the phospholipid phosphatidylethanolamine (PE) is crucial for LC3-I conversion to LC3-II. Changes in phospholipid metabolism have been reported in inflammatory skin conditions, including PE downregulation in psoriatic keratinocytes. By increasing PE expression in inflamed keratinocytes, we show increased LC3-II lipidation and restoration of the autophagy pathway functionality. Moreover, inflammation-induced p62 upregulation (a cargo degraded by the lysosomal autophagy compartment) and deregulated the lysosomal membrane permeability integrity, as confirmed by the expression of glycosylated and deglycosylated lysosomal protein (LAMP1, LAMP2 and LAMP3) expression. Our data are supported by independent transcriptomic data analysis from the GEO database, comparing autophagy gene expression in psoriatic and healthy matched or nonmatched controls. Spatial transcriptomic mapping of autophagic genes in lesional psoriatic skin provided further insight into the epidermal autophagy pathway regulation in inflammatory skin conditions. Immunofluorescence staining of both healthy and psoriatic human skin samples finally translate the differences in key autophagy marker expression observed in our two- and three-dimensional cell models, including deregulation of LC3, p62 and lysosomal membrane protein expression. Overall, our results exhibit a comprehensive and mechanistical analysis of how chronic inflammation could affect the integrity of this metabolic pathway, which significantly regulates epidermal homeostasis. Our data provide novel targets for therapeutic strategies and supports autophagy stimulation as viable modes of treatment to counteract chronic inflammatory skin conditions.
P03 Hydroxypyridone antifungals induce myofibroblast apoptosis in an in vitro model of hypertrophic scars
Authors: Lapthorn Alice , Ilg Marcus , Sullivan Justine , Dziewulski Peter , Cellek Selim
Published: July 2023

Despite being the most common complication following burn injury, there are no medications to prevent the formation of hypertrophic scars. Myofibroblasts are key cells involved in scar formation, responsible for producing excessive amounts of extracellular matrix and have been shown to be resistant to apoptosis. We have previously shown that hydroxypyridone antifungals can inhibit the transformation of fibroblasts to myofibroblasts, and exhibit other antifibrotic effects. This study aimed to investigate the effect of these drugs on established myofibroblasts. Primary human dermal fibroblasts, derived from scars of patients with burns, were exposed to 10 ng mL–1 transforming growth factor (TGF)-β1 to induce myofibroblast transformation. The In-Cell enzyme-linked immunosorbent assay method was used to measure α-smooth muscle actin (α-SMA), with DRAQ5 staining used to measure cell viability. Concentration–response curves for the three hydroxypyridone antifungals (ciclopirox, ciclopirox ethanolamine and piroctone olamine) were constructed (0.03–300 µmol L–1) to see if the drugs could reverse myofibroblast transformation. TUNEL staining was used to investigate if the drugs (at 10 µmol L–1) induced apoptosis in the myofibroblasts. When applied to established myofibroblasts, the hydroxypyridone antifungals did not reverse myofibroblast transformation. Instead, the drugs exhibited a concentration-dependent decrease in myofibroblast cell viability. A 22% reduction in myofibroblast cell viability was observed at 10 µmol L–1, compared to fibroblasts treated in coincubation with TGF-β1 and the hydroxypyridones. To see if this reduction in cell viability was due to the induction of apoptosis in the myofibroblasts, TUNEL staining was used. TUNEL staining confirmed that the hydroxypyridone antifungals induced apoptosis in myofibroblasts after 72 h of treatment. This affect was not seen in the fibroblasts treated in coincubation with TGF-β1 and the hydroxypyridone antifungals. This is the first study to show that hydroxypyridone antifungals can induce apoptosis in established myofibroblasts, derived from burn scar tissue. Together with our previous results, this suggests that hydroxypyridone antifungals can prevent scar formation by tackling continuous myofibroblast transformation and myofibroblast persistence.
P05 Inducible MDM2 ablation increases p53 expression to block papillomatogenesis in HK1.ras transgenic mice
Authors: Crispini Ana Gutierrez , Slosarska Aleksandra , Greenhalgh David
Published: July 2023

Previously, p53 loss was a consistent theme in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of phosphatase and tensin homolog (PTEN)-mediated Akt regulation (K14.creP/Δ5PTENflx), leading to well-differentiated squamous cell carcinoma. Given that MDM2 is a ubiquitin ligase that targets p53 for degradation, the potential efficacy of MDM2 functional knockout to protect p53 levels and thus inhibit tumour formation was investigated. Initial experiments investigated the inhibition of benign papilloma formation in HK1.ras mice as analysis of endogenous MDM2 status showed that activated p-MDM2166 activity was confined to suprabasal layers, resulting in strong nuclear p53 expression in basal layers that inhibited conversion. Yet, earlier hyperplasia expressed only sporadic p53/MDM2, suggesting that should MDM2 activity be inhibited, increased p53 in hyperplasia may inhibit papilloma formation. Therefore, loss of MDM2-mediated p53 degradation was investigated via inducible ablation of MDM2 exons 5 and 6, which bind p53 and chaperone for ubiquitination, employing K14-driven Cre/lox-P and treatment with topical RU486 (K14cre-Δ5/6MDM2flx/flx). In control, RU486-treated K14cre-Δ5/6MDM2flx/flx littermates, surprisingly few effects were observed, as normal epidermis expressed only sporadic p53/MDM2 as keratinocytes divided. Similarly, early HK1.ras hyperplasia displayed sporadic p53/MDM2 coexpression, suggesting an epidermis was relatively tolerant of Ras-mediated proliferation, where p53 overexpression risks problems of barrier maintenance due to excess apoptosis. With time, HK1.ras papillomas increased nuclear basal layer p53; p-MDM2166 also increased but remained suprabasal – alongside p-Akt1473 – possibly geared to maintain barrier functions from potential p53-mediated apoptosis. Conversely, in RU486-treated HK1.ras-Δ5/6MDM2flx/flx littermates, while hyperplasia histotype appeared unaffected, expression analysis found strong, elevated p53 expression in all compartments, consistent with loss of MDM2 inhibition. Moreover, this level of basal layer p53 in early hyperplasia apparently blocked papilloma formation and fed back to inhibit p-Akt1, whereas heterozygous MDM2 HK1.ras-Δ5/6MDM2flx/wt littermates exhibited a papillomatogenesis identical to wild-type HK1.ras littermates, with suprabasal p-MDM2166 and p-Akt1473. These findings suggest that MDM2 inhibition can inhibit benign tumour formation via maintaining p53 levels; however, with time (> 20 weeks), small papillomas did appear, showing that this inhibition can be circumvented.
P07 Optimizing DNA specificity and applicability of base and prime editors on COL7A1 variants causing recessive dystrophic epidermolysis bullosa
Authors: Brooks Imogen , Rudnytska Maria , Gebrezgabher Ruta  , Laczmanski Lukasz , Newby Gregory  , Liu David , McGrath John , Jackow Joanna
Published: July 2023

Base and prime editors are novel CRISPR variants that reduce the risk of off-target effects by avoiding double-stranded DNA cleavage, bypassing the need for homology-directed repair. These tools offer great therapeutic potential for inherited skin diseases such as recessive dystrophic epidermolysis bullosa (RDEB). Biallelic loss-of-function mutations in COL7A1 cause RDEB, resulting from loss of functional type VII collagen (C7) in the basement membrane zone. Current therapies for RDEB are limited, but ex vivo and in vivo COL7A1 base or prime editing therapies can potentially restore normal protein production with a single intervention treatment. This study compared DNA editing specificity, safety and efficiency on RDEB fibroblasts harbouring a homozygous c.4448 G>A (p.Gly1483Asp) mutation in COL7A1. Firstly, transfected adenine base editor (ABE8e) mRNA together with single guide RNA (sgRNA) were introduced into patient primary fibroblasts with Lipofectamine MessengerMax. By varying concentrations and ratios of guide RNA and ABE8e mRNA, we have achieved 100% biallelic correction without introducing any bystander mutations using 200 ng ABE8e and 28 ng sgRNA by transfecting 100 000 cells. Initial prime editing experiments are underway with PEmax plasmid and engineered prime editing guide RNAs (epegRNA) to optimize the guide design and to compare PE2max and PE4max editing systems. The functionality of the 100% biallelic correction using ABE8e is being evaluated with Western blot and in three-dimensional skin models. These early experiments demonstrate the potential value of base editing as a gene-editing tool in RDEB therapeutics; however, more functional work and off-target analyses are needed.
P18 KLICK syndrome is a hyperproliferative inflammatory skin disorder
Authors: Cherry Hannah , Parsons Maddy , Rastrick Joe , Hardman-Smart Jonathan , DiMeglio Paola , McGrath John
Published: July 2023

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultra-rare genodermatosis. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. To date, all affected individuals carry a homozygous pathogenic variant, c.-95delC in POMP, which encodes for proteasome maturation protein. Disease pathophysiology is not well understood, resulting in nonspecific and limited treatment options. However, clinically, the phenotype shows erythema and inflammation, indicating that there may be uncharacterized inflammatory pathways in KLICK syndrome, similar to some other ichthyoses. The aim of this work was to characterize KLICK syndrome at the cellular and molecular level. A lesional skin biopsy was obtained, following informed consent, from a 32-year-old woman with KLICK syndrome. Sanger sequencing confirmed the presence of the homozygous single nucleotide deletion in the 5′ untranslated region in POMP. Skin architecture was assessed using immunostaining, which revealed dynamic proliferative keratinocytes, precocious expression of involucrin and loricrin, and retention of loricrin in the stratum corneum. Lymphocytic infiltrates in the upper dermis were suggestive of inflammation and imaging mass cytometry was used to visualize and identify the immune subsets present. RNA sequencing revealed dysregulated pathways relating to keratinocyte differentiation, keratinization, cornification, and interferon signalling. Functional classification of differentially expressed genes using PANTHER additionally implicated WNT signalling, EGFR signalling and inflammatory signalling pathways as dysregulated in KLICK syndrome. KLICK syndrome can therefore be characterized as a hyperproliferative inflammatory skin disorder. Using a reverse transcriptomics approach, epidermal growth factor receptor (EGFR) inhibition and phosphoinositide 3-kinase (PI3K) inhibition were identified as potential treatment options that warrant further investigation. Understanding the pathobiology of KLICK syndrome may yield novel mechanisms driving inflammatory skin disease, which may be therapeutically targetable in patients with currently limited treatment options.
P22 Fibrosis in delayed wound healing in diabetes: the role of insulin-like growth factor binding proteins
Authors: Were Sharlene , Wilson Taryn , Martin Patricia , Wright Catherine
Published: July 2023

Skin fibrosis is thought to be a factor in delayed wound healing in people with diabetes. Insulin-like growth factor binding protein 5 (IGFBP-5), which is fibrotic in other organs, is augmented in the skin of people with diabetes. We examined the effects of IGFBP-5, connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β1 on skin fibrosis and wound-healing capacity in human primary dermal fibroblasts from people with and without diabetes. In vitro scrape wound closure in diabetic dermal fibroblasts was delayed in diabetic fibroblasts. IGFBP-5 treatment further retarded scrape-wound closure rates above that seen with diabetic fibroblasts. Diabetic fibroblasts were more adhesive to substrates than normal fibroblasts in adhesion assays, reducing their migratory capacity, and normal fibroblasts treated with IGFBP-5 and TGF-β1 showed increased adhesion over controls. Diabetic fibroblasts also had reduced cell viability. Fibronectin and collagen production by fibroblasts were increased with IGFBP-5 in cultures; thus upregulated IGFBP-5 in diabetic skin may increase extracellular matrix (ECM) deposition. IGFBP-5 and α-smooth muscle actin protein was overexpressed in diabetic fibroblasts by Western blotting, so IGFBP-5 induces fibroblast to myofibroblast transition. Gene expression of matrix metalloproteinase (MMP)-1, MMP-9, CTGF and tissue inhibitor of metalloproteinase 1 (TIMP-1) was raised in diabetic fibroblasts; MMP-9, MMP-1 and TIMP-1 expression levels were increased with IGFBP-5 treatment. Elevated levels of IGFBP-5 and CGTF in the dermis may contribute to retarded wound healing and ulceration in people with diabetes (despite increases in fibroblast MMPs), causing fibroblasts to lay down more ECM, contributing to fibrosis and compromising the wound bed. Diabetic dermal fibroblasts are compromised in viability and migratory capacity, and are more adhesive and stiffer, making it more difficult for them to populate granulation tissue. They are thus less able to close wounds and hyperproliferate around wound edges. IGFBP-5 and CTGF could be novel therapeutic targets to mitigate diabetic skin fibrosis and improve wound healing.
P25 Hsa-miR-6727-5p contributes to the impact of high-density lipoprotein on fibroblast wound healing in vitro
Authors: Bastaki Khaled , Tarlton Jamie , Lightbody Richard , Martin Patricia , Graham Annette
Published: July 2023

There is a clear unmet clinical need to develop effective strategies to improve chronic nonhealing wound closure rates, with distinct skin cell populations responding to potential therapies in different ways. Recent evidence suggests that high-density lipoproteins (HDL) can enhance wound closure rates, but, owing to the complexity, heterogeneity and relative instability of this lipoprotein fraction, developing a translational rationale to explore this observation is challenging. In the present work we explored the ability of primary human neonatal keratinocytes (HKn) and fibroblasts (HDFn), and adult dermal fibroblasts (HDFa), to respond to HDL by monitoring cholesterol efflux and scratch wound assays. Global changes in expression of small noncoding microRNA sequences (miRs), following the exposure of HDFn and HDFa to HDL, was determined by microchip array, validated by independent quantitative polymerase chain reaction, and the impact of a selected miRNA mimic on scrape wound closure assessed. All experiments were performed in triplicate. The data revealed that all cell types respond to HDL in terms of cholesterol efflux, confirming the functionality of this lipoprotein, but promotion of wound healing only occurs in HDFn and HDFa cells, with no response in HKn. Exposure of both HDFn and HDFa cells to HDL induces multiple changes in the expression of miR sequences, including hsa-miR-6727-5p. Levels of this miR increased in HDFn, but decreased in HDFa cells, following HDL exposure. Delivery of a hsa-miR6727-5p mimic repressed the expression of different target genes in HDFn (ZNF584) and HDFa (EDEM3, KRAS), while rates of wound closure were enhanced in the presence of a hsa-6727-5p mimic in HDFn cells and an inhibitor in HDFa cells. Intriguingly, analysis of the microarray data also revealed distinct expression landscapes in neonatal and adult fibroblasts, providing insight into the epigenetic evolution of these cells during the wound healing process. Thus, exposure to HDL has distinct impacts on the expression of the miR hsa-mir-6727-5p in neonatal and adult fibroblasts, which play differential roles in wound healing. We identify a range of pathways influenced by this miR but note that this miR alone cannot replicate the myriad effects of HDL. Future work will explore the impact of (dys)functional HDL and hsa-miR-6727-5p on wound closure rates in fibroblasts isolated from diabetic patients. Moreover, this study offers opportunities to expand knowledge of how profound changes in epigenetic profile can influence wound healing during ageing.

Funding sources: K.B. was supported by a PhD scholarship provided by the Kuwaiti government; human fibroblasts were provided by the GCU Research Tissue Bank (NHS REC Ref 16/E0069).