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There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated 172, demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro. In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

Abstract Background Organellar genomes have become increasingly essential for studying genetic diversity, phylogenetics, and evolutionary histories of seaweeds. The order Dictyotales (Dictyotophycidae), a highly diverse lineage within the Phaeophyceae, is long-term characterized by a scarcity of organellar genome datasets compared to orders of the brown algal crown radiation (Fucophycidae). Results We sequenced the organellar genomes of Padina usoehtunii, a representative of the order Dictyotales, to investigate the structural and evolutionary differences by comparing to five other major brown algal orders. Our results confirmed previously reported findings that the rate of structural rearrangements in chloroplast genomes is higher than that in mitochondria, whereas mitochondrial sequences exhibited a higher substitution rate compared to chloroplasts. Such evolutionary patterns contrast with land plants and green algae. The expansion and contraction of the inverted repeat (IR) region in the chloroplast correlated with the changes in the number of boundary genes. Specifically, the size of the IR region influenced the position of the boundary gene rpl21, with complete rpl21 genes found within the IR region in Dictyotales, Sphacelariales and Ectocarpales, while the rpl21 genes in Desmarestiales, Fucales, and Laminariales span both the IR and short single copy (SSC) regions. The absence of the rbcR gene in the Dictyotales may indicate an endosymbiotic transfer from the chloroplast to the nuclear genome. Inversion of the SSC region occurred at least twice in brown algae. Once in a lineage only represented by the Ectocarpales in the present study and once in a lineage only represented by the Fucales. Photosystem genes in the chloroplasts experienced the strongest signature of purifying selection, while ribosomal protein genes in both chloroplasts and mitochondria underwent a potential weak purifying selection. Conclusions Variations in chloroplast genome structure among different brown algal orders are evolutionarily linked to their phylogenetic positions in the Phaeophyceae tree. Chloroplast genomes harbor more structural rearrangements than the mitochondria, despite mitochondrial genes exhibiting faster mutation rates. The position and the change in the number of boundary genes likely shaped the IR regions in the chloroplast, and the produced structural variability is important mechanistically to create gene diversity in brown algal chloroplast.

Abstract Plastic crystals as barocaloric materials exhibit the large entropy change rivalling freon, however, the limited pressure-sensitivity and large hysteresis of phase transition hinder the colossal barocaloric effect accomplished reversibly at low pressure. Here we report reversible colossal barocaloric effect at low pressure in two-dimensional van-der-Waals alkylammonium halides. Via introducing long carbon chains in ammonium halide plastic crystals, two-dimensional structure forms in (CH3–(CH2)n-1)2NH2X (X: halogen element) with weak interlayer van-der-Waals force, which dictates interlayer expansion as large as 13% and consequently volume change as much as 12% during phase transition. Such anisotropic expansion provides sufficient space for carbon chains to undergo dramatic conformation disordering, which induces colossal entropy change with large pressure-sensitivity and small hysteresis. The record reversible colossal barocaloric effect with entropy change ΔSr ~ 400 J kg−1 K−1 at 0.08 GPa and adiabatic temperature change ΔTr ~ 11 K at 0.1 GPa highlights the design of novel barocaloric materials by engineering the dimensionality of plastic crystals.

Achieving carbon neutrality is an important initiative to cope with global warming. Most studies on the role of tourism towards carbon neutrality were based on the carbon emission reduction (CER) perspective while the carbon sink (CS) perspective was lacking. Based on the quasi-natural experiment of high-standard scenic spots, this paper aimed to examine the effect of tourism resources development on regional CS with high-precision multi-source datasets of 2601 Chinese county units. According to the results of the time-varying difference-in-difference (DID) model regression, CNSA significantly deteriorated CS, but the findings of the rolling regression test confirmed that the adverse effect diminished over time. [ABSTRACT FROM AUTHOR]

Background: Identifying predictive biomarkers for allergen immunotherapy response is crucial for enhancing clinical efficacy. This study aims to identify such biomarkers in patients with allergic rhinitis (AR) undergoing subcutaneous immunotherapy (SCIT) for house dust mite allergy. Methods: The Tongji (discovery) cohort comprised 72 AR patients who completed 1‐year SCIT follow‐up. Circulating T and B cell subsets were characterized using multiplexed flow cytometry before SCIT. Serum immunoglobulin levels and combined symptom and medication score (CSMS) were assessed before and after 12‐month SCIT. Responders, exhibiting ≥30% CSMS improvement, were identified. The random forest algorithm and logistic regression analysis were used to select biomarkers and establish predictive models for SCIT efficacy in the Tongji cohort, which was validated in another Wisco cohort with 43 AR patients. Results: Positive SCIT response correlated with higher baseline CSMS, allergen‐specific IgE (sIgE)/total IgE (tIgE) ratio, and frequencies of Type 2 helper T cells, Type 2 follicular helper T (TFH2) cells, and CD23+ nonswitched memory B (BNSM) and switched memory B (BSM) cells, as well as lower follicular regulatory T (TFR) cell frequency and TFR/TFH2 cell ratio. The random forest algorithm identified sIgE/tIgE ratio, TFR/TFH2 cell ratio, and BNSM frequency as the key biomarkers discriminating responders from nonresponders in the Tongji cohort. Logistic regression analysis confirmed the predictive value of a combination model, including sIgE/tIgE ratio, TFR/TFH2 cell ratio, and CD23+ BSM frequency (AUC = 0.899 in Tongji; validated AUC = 0.893 in Wisco). Conclusions: A T‐ and B‐cell signature combination efficiently identified SCIT responders before treatment, enabling personalized approaches for AR patients. [ABSTRACT FROM AUTHOR]

Regulating the electronic structure of Bi-based materials by alloying engineering is promising to promote the electrocatalytic activity, but it remains some challenges to be solved. In this study, a facile electrochemical co-deposition strategy is developed to synthesize the bimetallic Bi9Cu1 alloy nanosheet on carbon cloth (Bi9Cu1/CC), which represents a novel self-supporting electrode for the electrocatalytic carbon dioxide (CO2) reduction reaction (CO2RR). The Bi9Cu1/CC catalyst has achieved a remarkable catalytic performance with high Faradaic efficiencies (FE) of over 90% for formate at wide potentials from −0.7 to −1.2 V vs. reversible hydrogen electrode (RHE). Moreover, the reversible Zn-CO2 battery can be driven by Bi9Cu1/CC cathode with a largest power density of 1.4 mW·cm−2, and superior operating stability. The systematic characterizations and electrochemical results confirm that the improved catalytic active sites, the enhanced mass/charge transport and the optimal reaction kinetics of Bi nanosheet are realized for CO2RR by Cu alloying. In situ attenuated total reflection infrared (ATR-IR) result confirms the bimetallic Bi-Cu active sites prefer to follow the ⋆OCHO conversion pathway. The density functional theory (DFT) calculations suggest that the Cu alloying contributes to the increased density of states near the Fermi surface of Bi and the optimized adsorption of ⋆OCHO intermediates on the Bi sites, resulting in the excellent catalytic performance. [ABSTRACT FROM AUTHOR]

Tuning coordination environment of single‐atom catalysts (SACs) is widely applied for the electrochemical CO2 reduction reaction (CO2RR). However, the influence of the interaction between SACs and support on the catalytic performance are not comprehensive. Herein, taking cobalt phthalocyanine (CoPc) as a conceptual example, a hetero S‐atom doping strategy of hollow carbon sphere (S‐NHC) is put forward as a carrier, revealing the intrinsic relationship between microenvironment regulation and catalytic activity of single Co‐atom. The additional S doping may induce more carbon defect and increases the content of pyrrolic N in the S‐NHC sample, leading to stronger electronic interaction of heterogeneous CoPc/S‐NHC for boosting CO2RR performance. Remarkably, the catalyst achieves a highest CO selectivity of nearly 100% at −0.6 V, and the FECO are over 90% in a wide potential range from −0.4 to −0.8 V in a flow cell. The maximum power density is high as 2.68 mW cm−2 at 4.7 mA cm−2 for the Zn–CO2 battery with CoPc/S‐NHC cathode. In situ attenuated total reflection infrared (ATR‐IR) spectroscopy reveals the formation of key *COOH and *CO intermediates, while the calculation result confirm the optimized Gibbs free energy of these intermediates on CoPc/S‐NHC, suggesting the feasibility of the regulation strategy. [ABSTRACT FROM AUTHOR]

Destination residents' environmental concern (REC) is a pivotal force in promoting sustainable destination development. However, empirical evidence on how ecotourism development affects REC is scarce within the framework of tourism economics. Based on a quasi-natural experiment of China's National Ecotourism Demonstration Area (CNEDA) designation, we fill this gap using multi-source data of 282 Chinese prefecture-level cities from 2011 to 2019. The evidence indicates that CNEDA designation significantly promotes destination REC and passes the robustness tests, but this effect is short-term. The positive impact is amplified in tourism-dependent cities. The impact of ecotourism development on REC is structurally different, favouring promote residents' ecological values and environmental cognitions over environmental behavioural intention. Relevant policy implications are also provided. [ABSTRACT FROM AUTHOR]

Purpose: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. Recurrence makes the prognosis for some patients with PTC worse. Increasing evidence have suggested that N6-methyladenosine (m6A) RNA methylation plays an important role in tumorigenesis. However, the significance of m6A-related lncRNAs in the malignant progression of PTC remains unknown. In this study, we explored the significance of M6A-related lncrnas in the malignant progression of PTC. Patients and Methods: Transcriptome and clinical data of PTC were achieved and integrated from The Cancer Genome Atlas (TCGA). Firstly, a Spearman correlation analysis was performed to obtain m6A RNA methylation-associated lncRNAs. Next, We constructed a prognostic signature and assessed the accuracy of the signature by receiver operating characteristic (ROC) curve and Kaplan Meier survival analyses. Furthermore, functional enrichment analysis was performed on the high- and low-risk groups. Finally, we determined prognostic gene expression in clinical samples using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results: We identified 56 differentially expressed lncRNAs associated with m6A RNA methylation. Univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses showed that the survival-related lncRNAs associated with m6A RNA methylation were detected, which showed superior calibration and discrimination. Moreover, the biological processes related to energy metabolism were significantly activated in the high-risk group. Finally, the co-expressed genes of lncRNAs in the risk model were significantly enriched in biological processes related to copper ion response. Finally, we validated the expression levels of three prognostic genes in clinical samples using RT-qPCR. Conclusion: Our study revealed m6A RNA methylation-associated lncRNAs were significantly associated with disease-free survival in patients with papillary thyroid cancer, which would improve our understanding of the relationship between m6A RNA methylation-associated lncRNAs and PTC. [ABSTRACT FROM AUTHOR]

In order to produce art textiles with visual, embossed and wrinkled effects, as well as tassel decoration, based on limited 16 pages heald of regular dobby loom, the warp and weft patterning weave, wrinkling and pad weaving technology, and cutting process were multiple composited. The warp patterning weave and symmetrical threading method were used to configure the weave points, weft cycle was extended to increase the number of patterns, large jacquard loom was replaced to produce visual fabrics. Bubble warp was connected through the linkage cable at the lower end of the 16th heald, relaxation or tension of the bubble warp was controlled through the lifting and lowering of the heald, the change of bubble warp tension and weaving wrinkled effect were achieved. Wrinkle amplitude was controlled by controlling the number of warp and weft weave points of the pattern of the heald, wave bubble wrinkle effect was formed. Pad weaving multiple weft yarns into the same shed, embossed effect was created. Cuting after weaving with weft fabric, tassel decorative effect was formed and finally multiple composite art textiles was produced. [ABSTRACT FROM AUTHOR]

Objective To investigate whether shikonin can regulate autophagy and promote wound healing in diabetic rats by upregulating C-X-C chemokine receptor type 4 (CXCR4). Methods A total of 24 Sprague-Dawley (SD) rats were assigned to control, diabetic, diabetic+ Shikonin, and diabetic+Shikonin+sh-CXCR4 groups (6 rats in each group) using random number table method. A diabetic rat model was established by intraperitoneal injection of streptozotocin, and a 1 cm-diameter skin punch was used to create an ulcer model on the back of the rat. Wound healing rates were calculated on days 0, 7, 14, and 21 after wounding. On day 21 after wounding, skin tissues were collected for hematoxylin & eosin and Masson trichrome staining to analyze the pathological changes of the wound. CD31 immunohistochemistry was performed to analyze the microvascular density of the wound and Western blotting was used to detect the expression of CXCR4 and cell autophagy-related proteins microtubule-related proteins light chain 3 (LC3) II/ LC3 I, Beclin1, and soluble p62 in the wound tissue. Autophagosomes were observed by transmission electron microscopy. One-way analysis of variance was used for comparison between groups. Results Compared with the control group, the diabetic group had reduced wound healing rate (on day 21: 72.44%±6.21% vs. 93.71%±6.76%), neovascularization, collagen deposition, microvascular density, levels of CXCR4, LC3 II /LC3 I, and Beclin, and increased p62 levels in the wound tissue, as well as decreased autophagosomes (P<0.05). Compared with the diabetic group, wound healing rate (on day 21: 86.74%±4.86% vs. 72.44%±6.21%), neovascularization, collagen deposition, microvascular density, levels of CXCR4, LC3 II/LC3 I, and Beclin, and autophagosomes were increased, but p62 levels were decreased in the diabetic+Shikonin group (P<0.05). Compared with the diabetic+Shikonin group, the diabetic+Shikonin group had decreased wound healing rate (on day 21: 76.15%±3.85% vs. 86.74%±4.86%), neovascularization, collagen deposition, microvascular density, levels of CXCR4, LC3 II/LC3 I, and Beclin, and autophagosomes in the wound tissue, as well as increased p62 levels (P<0.05). Conclusion Shikonin promotes the healing of diabetic ulcer wounds by upregulating CXCR4 expression and activating cell autophagy. [ABSTRACT FROM AUTHOR]

Background: Organellar genomes have become increasingly essential for studying genetic diversity, phylogenetics, and evolutionary histories of seaweeds. The order Dictyotales (Dictyotophycidae), a highly diverse lineage within the Phaeophyceae, is long-term characterized by a scarcity of organellar genome datasets compared to orders of the brown algal crown radiation (Fucophycidae)., Results: We sequenced the organellar genomes of Padina usoehtunii, a representative of the order Dictyotales, to investigate the structural and evolutionary differences by comparing to five other major brown algal orders. Our results confirmed previously reported findings that the rate of structural rearrangements in chloroplast genomes is higher than that in mitochondria, whereas mitochondrial sequences exhibited a higher substitution rate compared to chloroplasts. Such evolutionary patterns contrast with land plants and green algae. The expansion and contraction of the inverted repeat (IR) region in the chloroplast correlated with the changes in the number of boundary genes. Specifically, the size of the IR region influenced the position of the boundary gene rpl21, with complete rpl21 genes found within the IR region in Dictyotales, Sphacelariales and Ectocarpales, while the rpl21 genes in Desmarestiales, Fucales, and Laminariales span both the IR and short single copy (SSC) regions. The absence of the rbcR gene in the Dictyotales may indicate an endosymbiotic transfer from the chloroplast to the nuclear genome. Inversion of the SSC region occurred at least twice in brown algae. Once in a lineage only represented by the Ectocarpales in the present study and once in a lineage only represented by the Fucales. Photosystem genes in the chloroplasts experienced the strongest signature of purifying selection, while ribosomal protein genes in both chloroplasts and mitochondria underwent a potential weak purifying selection., Conclusions: Variations in chloroplast genome structure among different brown algal orders are evolutionarily linked to their phylogenetic positions in the Phaeophyceae tree. Chloroplast genomes harbor more structural rearrangements than the mitochondria, despite mitochondrial genes exhibiting faster mutation rates. The position and the change in the number of boundary genes likely shaped the IR regions in the chloroplast, and the produced structural variability is important mechanistically to create gene diversity in brown algal chloroplast., (© 2024. The Author(s).)

High-entropy compounds have been emerging as promising candidates for electrolysis, yet their controllable electrosynthesis strategy remains a formidable challenge because of the ambiguous ionic interaction and codeposition mechanism. Herein, we report a oxygenates directionally induced electrodeposition strategy to construct high-entropy materials with amorphous features, on which the structural evolution from high-entropy phosphide to oxide is confirmed by introducing vanadate, thus realizing the simultaneous optimization of composition and structure. The representative P-CoNiMnWVO x shows excellent bifunctional catalytic performance toward alkaline hydrogen evolution reaction and ethanol oxidation reaction (EOR), with small potentials of -168 mV and 1.38 V at 100 mA cm -2 , respectively. In situ spectroscopy illustrates that the electrochemical reconstruction of P-CoNiMnWVO x induces abundant Co-O species as the main catalytic active species for EOR and follows the conversion pathway of the C 2 product. Theoretical calculations reveal the optimized electronic structure and adsorption free energy of reaction intermediates on P-CoNiMnWVO x , thereby resulting in a facilitated kinetic process. A membrane-free electrolyzer delivers both high Faradaic efficiencies of acetate and H 2 over 95% and superior stability at100 mA cm -2 during 120 h electrolysis. In addition, the unique composition and structural advantages endow P-CoNiMnWVO x with multifunctional catalytic activity and realize multipathway electrosynthesis of formate-coupled hydrogen production., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: Bushen Zhuyun Decoction (BSZY), a traditional Chinese herbal prescription has shown promising effects on gynecological infertility, but the mechanism for endometrial receptivity is still unclear. This study aimed to investigate the regulatory effects of BSZY on endometrial receptivity, which plays a key role in colonization of embryo, and its regulatory mechanisms associated with NF- κB/NLRP3 pathway., Methods: SD rats at reproductive age with affected endometrial receptivity was established using mifepristone (RU486), and the regulatory effects of BSZY on endometrial receptivity were evaluated by H&E staining, and changes in sex hormones by ELISA and Western blot. Moreover, human endometrial RL95-2 cells were treated with H2O2, and inflammatory cytokines in rats and RL95-2 cells were analyzed by ELISA. The activation of NF-κB/NLRP3 signaling pathway in RL95-2 cells were characterized using immunofluorescence and Western blot. Mitochondrial morphology and function in RL95-2 cells were observed by transmission electron microscope and cell mitochondrial stress test., Results: BSZY increased uterine endometrial thickness and attenuate histopathological changes induced by RU486. BSZY can regulate endometrial estrogen receptor and progesterone receptor, and the levels of sex hormones and inflammatory cytokines in pregnant rats. BSZY-containing serum also showed strong anti-inflammatory and cytoprotective effects in vitro. In addition, BSZY-containing serum inhibited the activation of NF-κB/NLRP3 signaling pathway, and improve mitochondrial morphology and function in RL95-2 cells., Conclusion: BSZY can improve endometrial receptivity, potentially by improving mitochondrial morphology and function to inhibit the activation of NF-κB/NLRP3 signaling pathway in endometrial cells, thus regulate inflammation to improve endometrial receptivity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. Recurrence makes the prognosis for some patients with PTC worse. Increasing evidence have suggested that N6-methyladenosine (m 6 A) RNA methylation plays an important role in tumorigenesis. However, the significance of m 6 A-related lncRNAs in the malignant progression of PTC remains unknown. In this study, we explored the significance of M 6 A-related lncrnas in the malignant progression of PTC., Patients and Methods: Transcriptome and clinical data of PTC were achieved and integrated from The Cancer Genome Atlas (TCGA). Firstly, a Spearman correlation analysis was performed to obtain m 6 A RNA methylation-associated lncRNAs. Next, We constructed a prognostic signature and assessed the accuracy of the signature by receiver operating characteristic (ROC) curve and Kaplan Meier survival analyses. Furthermore, functional enrichment analysis was performed on the high- and low-risk groups. Finally, we determined prognostic gene expression in clinical samples using quantitative reverse transcription polymerase chain reaction (RT-qPCR)., Results: We identified 56 differentially expressed lncRNAs associated with m 6 A RNA methylation. Univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses showed that the survival-related lncRNAs associated with m 6 A RNA methylation were detected, which showed superior calibration and discrimination. Moreover, the biological processes related to energy metabolism were significantly activated in the high-risk group. Finally, the co-expressed genes of lncRNAs in the risk model were significantly enriched in biological processes related to copper ion response. Finally, we validated the expression levels of three prognostic genes in clinical samples using RT-qPCR., Conclusion: Our study revealed m 6 A RNA methylation-associated lncRNAs were significantly associated with disease-free survival in patients with papillary thyroid cancer, which would improve our understanding of the relationship between m 6 A RNA methylation-associated lncRNAs and PTC., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Li et al.)

Electrochemical carbon dioxide reduction (CO 2 RR), as an emerging technology, can combine with sustainable energies to convert CO 2 into high value-added products, providing an effective pathway to realize carbon neutrality. However, the high activation energy of CO 2 , low mass transfer, and competitive hydrogen evolution reaction (HER) leads to the unsatisfied catalytic activity. Recently, Indium (In)-based materials have attracted significant attention in CO 2 RR and a series of regulation strategies of nanostructured engineering are exploited to rationally design various advanced In-based electrocatalysts, which forces the necessary of a comprehensive and fundamental summary, but there is still a scarcity. Herein, this review provides a systematic discussion of the nanostructure engineering of In-based materials for the efficient electrocatalytic conversion of CO 2 to fuels. These efficient regulation strategies including morphology, size, composition, defects, surface modification, interfacial structure, alloying, and single-atom structure, are summarized for exploring the internal relationship between the CO 2 RR performance and the physicochemical properties of In-based catalysts. The correlation of electronic structure and adsorption behavior of reaction intermediates are highlighted to gain in-depth understanding of catalytic reaction kinetics for CO 2 RR. Moreover, the challenges and opportunities of In-based materials are proposed, which is expected to inspire the development of other effective catalysts for CO 2 RR., (© 2023 Wiley-VCH GmbH.)

Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease., (Copyright © 2023. Published by Elsevier Inc.)