bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating Asymptotic Stability for Hybrid Cubic Integral Inclusion with Fractal Feedback Control on the Real Half-Axis
Authors: Hashem Hind H. G. , El-Sayed Ahmed M. A. , Al-Issa Shorouk M.
Published: June 2023

In this paper, we discuss the existence of solutions for a hybrid cubic delayed integral inclusion with fractal feedback control. We are seeking solutions for these hybrid cubic delayed integral inclusions that are defined, continuous, and bounded on the semi-infinite interval. Our proof is based on the technique associated with measures of noncompactness by a given modulus of continuity in the space in BC(R+). In addition, some sufficient conditions are investigated to demonstrate the asymptotic stability of the solutions of that integral inclusion. Finally, some cases analyzed are in the presence and absence of the control variable, and two examples are provided in order to indicate the validity of the assumptions.
Hawking Radiation and Lifetime of Primordial Black Holes in Braneworld
Authors: Turimov Bobur , Mamadjanov Akhror , Rahimov Ozodbek
Published: June 2023

The paper explores the thermodynamic properties of primordial black holes (PBHs) in the braneworld. Specifically, the researchers examined Hawking radiation and the lifetime of PBHs. Through their analysis, an exact analytical expression for the Bekenstein–Hawking entropy, temperature, and heat capacity was derived. Their findings suggest that the lifetime of PBHs in the early universe is reduced by at least one order of magnitude, ultimately leading to their evaporation. This could explain why we have not observed the final rapid evaporation of PBHs in the recent epoch of the universe.
Associations between Lipid Profiles and Graves’ Orbitopathy can Be HLA-Dependent
Authors: Stasiak Magdalena , Zawadzka-Starczewska Katarzyna , Tymoniuk Bogusław , Stasiak Bartłomiej , Lewiński Andrzej
Published: June 2023

The risk of Graves’ orbitopathy (GO) is related to the human leukocyte antigen (HLA) profile and was demonstrated to be increased in patients with elevated total cholesterol (TC) and/or low-density lipoprotein (LDL) cholesterol. We hypothesized that there were some HLA alleles that were related to both GO and TC and/or LDL levels. Therefore, the aim of the study was to compare the TC/LDL results in patients in whom GO-related HLA alleles were present to those in whom they did not occur. HLA classes were genotyped using a next-generation sequencing method in 118 patients with Graves’ disease (GD), including 63 and 55 patients with and without GO, respectively. Lipid profiles were assessed at the time of the GD diagnosis. A significant correlation between the presence of GO high-risk alleles (HLA-B*37:01 and C*03:02) and higher TC/LDL levels was found. Additionally, the presence of alleles associated with non-GO GD (HLA-C*17:01 and B*08:01), as well as alleles in linkage disequilibrium with B*08:01 (i.e., HLA-DRB1*03:01 and DQB1*02:01), was correlated with lower TC levels. These results further confirm the significance of TC/LDL in the risk of GO development and provide evidence that associations between TC/LDL and GO can be HLA-dependent.
Genome-Wide Assessment of Runs of Homozygosity by Whole-Genome Sequencing in Diverse Horse Breeds Worldwide
Authors: Chen Chujie , Zhu Bo , Tang Xiangwei , Chen Bin , Liu Mei , Gao Ning , Li Sheng , Gu Jingjing
Published: June 2023

In the genomes of diploid organisms, runs of homozygosity (ROH), consecutive segments of homozygosity, are extended. ROH can be applied to evaluate the inbreeding situation of individuals without pedigree data and to detect selective signatures via ROH islands. We sequenced and analyzed data derived from the whole-genome sequencing of 97 horses, investigated the distribution of genome-wide ROH patterns, and calculated ROH-based inbreeding coefficients for 16 representative horse varieties from around the world. Our findings indicated that both ancient and recent inbreeding occurrences had varying degrees of impact on various horse breeds. However, recent inbreeding events were uncommon, particularly among indigenous horse breeds. Consequently, the ROH-based genomic inbreeding coefficient could aid in monitoring the level of inbreeding. Using the Thoroughbred population as a case study, we discovered 24 ROH islands containing 72 candidate genes associated with artificial selection traits. We found that the candidate genes in Thoroughbreds were involved in neurotransmission (CHRNA6, PRKN, and GRM1), muscle development (ADAMTS15 and QKI), positive regulation of heart rate and heart contraction (HEY2 and TRDN), regulation of insulin secretion (CACNA1S, KCNMB2, and KCNMB3), and spermatogenesis (JAM3, PACRG, and SPATA6L). Our findings provide insight into horse breed characteristics and future breeding strategies.
Profiling of Antimicrobial Resistance Genes and Integron from Escherichia coli Isolates Using Whole Genome Sequencing
Authors: Joddha Harshrajsinh B. , Mathakiya Rafiyuddin A. , Joshi Kuldip V. , Khant Ravindra B. , Golaviya Akash V. , Hinsu Ankit T. , Desai Mansi R. , Jakhesara Subhash J. , Koringa Prakash G.
Published: June 2023

This study is designed to investigate Escherichia coli for the antibiotic resistance genes (ARGs) and integrons from healthy as well as diarrhoeic/diseased animals/birds’ faecal samples. A total of eight samples were selected for the study; from each animal, two samples were taken, one from healthy animals/birds and one from diarrhoeic/diseased animals/birds. Antibiotic sensitivity testing (AST) and whole genome sequencing (WGS) was performed for selected isolates. The E. coli isolates showed resistance to moxifloxacin, followed by erythromycin, ciprofloxacin, pefloxacin, tetracycline, levofloxacin, ampicillin, amoxicillin, and sulfadiazine (4/8, 50.00% each). The E. coli isolates were 100% sensitive to amikacin, followed by chloramphenicol, cefixime, cefoperazone, and cephalothin. A total of 47 ARGs from 12 different antibiotic classes were detected among the eight isolates by WGS. The different classes of antibiotics included aminoglycoside, sulphonamide, tetracycline, trimethoprim, quinolone, fosfomycin, phenicol, macrolide, colistin, fosmidomycin, and multidrug efflux. The class 1 integrons were detected in 6/8 (75.00%) isolates with 14 different gene cassettes.
Self-Reported Medication Adherence Measured with Morisky Scales in Rare Disease Patients: A Systematic Review and Meta-Analysis
Authors: García-Muñoz Ana María , Victoria-Montesinos Desirée , Cerdá Begoña , Ballester Pura , de Velasco Eloisa María , Zafrilla Pilar
Published: June 2023

Background: The visibility of Rare Diseases is a new challenge for society. These diseases are numerous, heterogeneous in nature and distribution, characterized by a high mortality rate but low prevalence, and usually presenting a severe evolution. Adherence to medication studies in rare diseases are uncommon, due to treatment scarcity. Objectives: The main purpose of this study is to do a meta-analysis, evaluating the level of adherence to medication in the most prevalent rare diseases. Methods: This work is a systematic review, and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (Registration number: CRD42022372843) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Adherence to treatment in this systematic review and meta-analysis was collected from all studies included, based on the crude numerators and denominators reported, using either the Morisky Medication Adherence Scale 4 or -8. Results: A total of 54 records were identified through database searches, or after screening relevant manuscripts’ references. Finally, 18 studies were included in this systematic review and meta-analysis. A total of 1559 participants (54.18% women) aged less than 84 years old were included. Twelve studies used the MMAS-8. In 8 of them, they established the level of adherence to treatment in three categories (low, medium, and high), with the mean prevalence in each of them being 41.4%, 30.4%, and 28.2%, respectively. Conclusions: The results observed in adherence to treatment in patients with rare diseases show great variability, due to the different aspects involved in the greater or lesser applicability of the medication.
Applying Floodplain Inundation Modeling to Estimate Suitable Spawning Habitat and Recruitment Success for Alligator Gar in the Guadalupe River, Texas
Authors: Meitzen Kimberly M. , Robertson Clinton R. , Jensen Jennifer L. , Daugherty Daniel J. , Hardy Thomas B. , Mayes Kevin B.
Published: May 2023

We developed a floodplain inundation model to extract specific flood extent and depth parameters and combined these with vegetation land cover and historic flow data to quantify spatial habitat suitability and temporal hydrologic metrics that support Alligator Gar Atractosteus spatula spawning within a 257 km segment of the lower Guadalupe River, Texas, USA. We modeled nine flows across a range of flood frequency recurrence intervals from 257 m3s−1 to ~4997 m3s−1 and estimated the availability of suitable spawning water depths (0.2 to 2 m) and lateral connectedness between the river and suitable floodplain landcover types. We estimated the ages via otoliths of 95 Alligator Gar collected in the reach to determine the year that they were recruited into the system. We analyzed a total of 30 Indicators of Hydrologic Alteration flow metrics to examine how the spatially derived suitable habitats related to the temporal aspects of flow occurrence during the spawning season for the period of flow record April–July (1935–2020) and to the years spanning the recruitment data of the Alligator Gar (1981–2010). A non-linear relationship existed between suitable spawning habitat area and the flow regime, with the most habitat availability corresponding to the 10–20-year flood recurrence interval frequency with peak flows of 2057–3108 m3s−1, respectively. The Alligator Gar recruitment data indicated that six years provided high recruitment, which correlated with peak flows of ~5-year frequency with an available spawning area of ~9000 Ha, moderate recruitment years related to peak flows with ~3-year frequency with an available spawning area of 6000 Ha, and low recruitment years where spawning was likely to occur at least every other year with at least 2500 Ha of available spawning area. The results of this model support the development of legislatively mandated environmental flow standards for the Guadalupe River Basin, inform field-based efforts for collecting empirical and observational data on the species’ reproduction, and provide spatial and temporal information for designing conservation strategies for Alligator Gar.
The Impact of Generativity on Maintaining Higher-Level Functional Capacity of Older Adults: A Longitudinal Study in Japan
Authors: Nonaka Kumiko , Murayama Hiroshi , Murayama Yoh , Murayama Sachiko , Kuraoka Masataka , Nemoto Yuta , Kobayashi Erika , Fujiwara Yoshinori
Published: June 2023

Generativity is defined as an individual’s concern for and actions dedicated toward the well-being of others, especially youth and subsequent generations. It is a key stage of psychological development from midlife to older age and can be a guiding concept for promoting engagement of older adults in productive and contributive activities, which benefit their well-being. This study examined the longitudinal association between generativity and higher-level functional capacity (HLFC) decline in older Japanese adults. The two-year longitudinal data of 879 older adults aged 65–84 years were analyzed. Participants’ HLFC and generativity were assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence and the Revised Japanese version of the Generativity Scale, respectively. The binary logistic regression analysis results showed that a higher generativity score was negatively associated with HLFC decline, indicating that generativity effectively prevents HLFC decline over 2 years. On adding the interaction term between generativity and sex to examine whether the protective effect of generativity differed by sex, we found that generativity was especially effective in protecting the HLFC decline in men with higher generativity. The study results highlight the importance of promoting engagement of older adults in generative activities to maintain their HLFC.
Preemption in State Tobacco Minimum Legal Sales Age Laws in the US, 2022: A Policy Analysis of State Statutes and Case Laws
Authors: Dobbs Page D. , Chadwick Ginny , Crosbie Eric , Breslin Jessica , Henriksen Lisa
Published: June 2023

Preemptive statutory language within tobacco minimum legal sales age (MLSA) laws has prohibited localities from enacting stricter laws than state statutes. With the recent uptake of state Tobacco 21 laws in the US, the current landscape of preempted MLSA laws is unknown. This study sought to update the status of preemption in MLSA laws enacted in US states between 2015–2022. A public health attorney reviewed state tobacco MLSA laws (n = 50) and state tobacco control codes, searching for language regarding preemption. When statutes were unclear, case law was reviewed by examining local ordinances that were invalidated by state court decisions. Overall, 40 states enacted Tobacco 21 laws, seven of which expanded or introduced preemption when they increased the MLSA; a total of 26 states (52%) included preemption. Six states (12%) retained ‘savings clauses’ included in the MLSA prior to Tobacco 21, and 18 states (36%) did not mention preemption. Based on the precedent set by state courts, eight of these 18 states may preempt localities from raising their MLSA. Historically, preemption has slowed the diffusion of best practices in tobacco control, and once implemented, the laws are difficult to repeal. The recent expansion of preemption could inhibit the evolution, development, and implementation of effective tobacco control policies.
From the Perspectives of Pollution Governance and Public Health: A Research of China’s Fiscal Expenditure on Energy Conservation and Environmental Protection
Authors: Zhang Di , Dong Xiao
Published: June 2023

Improving the scale and effectiveness of China’s energy conservation and environmental protection fiscal expenditure is crucial to enhancing the capacity of ecological and environmental governance of China, considering the dual perspectives of pollution governance and public health. This article first explains the mechanism by which national energy conservation and environmental protection fiscal expenditure can improve pollution control and promote public health. Secondly, this article scrutinizes the current status and limitations of China’s fiscal expenditure, highlighting the contribution of fiscal expenditure in the construction of ecological civilization from the standpoints of environmental governance and public health. Additionally, this study empirically uses DEA to measure the efficiency of the government’s fiscal expenditure. Conclusions found that: First, environmental protection fiscal expenditure is mainly focused on technological transformation and pollution control, while relatively little is spent on public health protection. Second, the efficiency of environmental protection fiscal funds is relatively low. These suggestions aim to optimize the positive impact of energy conservation and environmental protection fiscal expenditure for improving pollution governance and promoting public health.
Knowledge in Motion: A Comprehensive Review of Evidence-Based Human Kinetics
Authors: Ramalho André , Petrica João
Published: June 2023

This comprehensive review examines critical aspects of evidence-based human kinetics, focusing on bridging the gap between scientific evidence and practical implementation. To bridge this gap, the development of tailored education and training programs is essential, providing practitioners with the expertise and skills to effectively apply evidence-based programs and interventions. The effectiveness of these programs in improving physical fitness across all age groups has been widely demonstrated. In addition, integrating artificial intelligence and the principles of slow science into evidence-based practice promises to identify gaps in knowledge and stimulate further research in human kinetics. The purpose of this review is to provide researchers and practitioners with comprehensive information on the application of scientific principles in human kinetics. By highlighting the importance of evidence-based practice, this review is intended to promote the adoption of effective interventions to optimize physical health and enhance performance.
Latinx and Indigenous Mexican Caregivers’ Perspectives of the Salton Sea Environment on Children’s Asthma, Respiratory Health, and Co-Presenting Health Conditions
Authors: Cheney Ann Marie , Ortiz Gabriela , Trinidad Ashley , Rodriguez Sophia , Moran Ashley , Gonzalez Andrea , Chavez Jaír , Pozar María
Published: June 2023

This research investigated Latinx and Indigenous Mexican caregivers’ perspectives of the Salton Sea’s environment (e.g., dust concentrations and other toxins) on child health conditions. The Salton Sea is a highly saline drying lakebed located in the Inland Southern California desert borderland region and is surrounded by agricultural fields. Children of Latinx and Indigenous Mexican immigrant families are especially vulnerable to the Salton Sea’s environmental impact on chronic health conditions due to their proximity to the Salton Sea and structural vulnerability. From September 2020 to February 2021, we conducted semi-structured interviews and focus groups with a total of 36 Latinx and Indigenous Mexican caregivers of children with asthma or respiratory distress living along the Salton Sea. A community investigator trained in qualitative research conducted interviews in Spanish or Purépecha, an indigenous language spoken by immigrants from Michoacán, Mexico. Template and matrix analysis was used to identify themes and patterns across interviews and focus groups. Participants characterized the Salton Sea’s environment as toxic, marked by exposure to sulfuric smells, dust storms, chemicals, and fires, all of which contribute to children’s chronic health conditions (e.g., respiratory illnesses such as asthma, bronchitis, and pneumonia, co-presenting with allergies and nosebleeds). The findings have important environmental public health significance for structurally vulnerable child populations in the United States and globally.
Control of Tongue Position in Patients with Obstructive Sleep Apnea: Concept and Protocol for a Randomized Controlled Crossover Trial
Authors: Fukuda Tatsuya , Kohzuka Yuuya , Almeida Fernanda R. , Iijima Takehiko , Masuda Rikuo , Tsuiki Satoru
Published: June 2023

We hypothesize that the control of tongue position using a newly developed tongue position retainer, where the tongue is held in a protruded position (i.e., intervention A) or in its resting position (i.e., intervention B), is effective for maintaining upper airway patency in obstructive sleep apnea (OSA) compared with no control of tongue position. This is a randomized, controlled, non-blinded, crossover, and two-armed trial (i.e., sequence AB/BA) in 26 male participants (i.e., sample size) who are scheduled to undergo a dental operation under intravenous sedation with OSA (10 ≤ respiratory event index < 30/h). Participants will be randomly allocated into either sequence by a permuted block method, stratified by body mass index. Under intravenous sedation, participants will undergo two interventions, separated by a washout period after receiving intervention A or intervention B using a tongue position retainer after baseline evaluation, before each intervention is provided. The primary outcome is the abnormal breathing index of apnea as determined by the frequency of apnea per hour. We expect that, compared with no control of tongue position, both intervention A and intervention B will improve the abnormal breathing events with superior effects achieved by the former, offering a therapeutic option for OSA.
What Other Than Acridinium Esters? Computational Search for New Acridinium-Based Chemiluminogens
Authors: Pieńkos Milena , Zadykowicz Beata
Published: May 2023

The rapid increase in disease prevalence in the world makes it extremely important to search for new or develop existing diagnostic methods, for example, chemiluminescent labeling used in immunodiagnostics. At present, acridinium esters are willingly used as chemiluminogenic fragments of labels. However, the search for new chemiluminogens that are particularly efficient is the main task of our studies. The density functional theory (DFT) and time-dependent (TD) DFT methods were used to obtain thermodynamic and kinetic results concerning the chemiluminescence and competitive dark reactions, which indicated whether some of the scrutinized derivatives have better characteristics than the chemiluminogens used so far. Synthesis of these candidates for efficient chemiluminogens, followed by studies of their chemiluminescent properties, and ultimately in chemiluminescent labeling, are further steps to confirm their potential applicability in immunodiagnostics.
Overexpressing Ribosomal Protein L16D Affects Leaf Development but Confers Pathogen Resistance in Arabidopsis
Authors: Li Ke , Yan Zhenwei , Mu Qian , Zhang Qingtian , Liu Huiping , Wang Fengxia , Li Ao , Ding Tingting , Zhao Hongjun , Wang Pengfei
Published: May 2023

In plant cells, multiple paralogs from ribosomal protein (RP) families are always synchronously expressed, which is likely contributing to ribosome heterogeneity or functional specialization. However, previous studies have shown that most RP mutants share common phenotypes. Consequently, it is difficult to distinguish whether the phenotypes of the mutants have resulted from the loss of specific genes or a global ribosome deficiency. Here, to investigate the role of a specific RP gene, we employed a gene overexpression strategy. We found that Arabidopsis lines overexpressing RPL16D (L16D-OEs) display short and curled rosette leaves. Microscopic observations reveal that both the cell size and cell arrangement are affected in L16D-OEs. The severity of the defect is positively correlated with RPL16D dosage. By combining transcriptomic and proteomic profiling, we found that overexpressing RPL16D decreases the expression of genes involved in plant growth, but increases the expression of genes involved in immune response. Overall, our results suggest that RPL16D is involved in the balance between plant growth and immune response.
Supramolecular Dimer as High-Performance pH Probe: Study on the Fluorescence Properties of Halogenated Ligands in Rigid Schiff Base Complex
Authors: Xu Jiajun , Huang Meifen , Jiao Liang , Pang Haijun , Wang Xia , Duan Rui , Wu Qiong
Published: May 2023

The development of high-performance fluorescence probes has been an active area of research. In the present work, two new pH sensors Zn-3,5-Cl-saldmpn and Zn-3,5-Br-saldmpn based on a halogenated Schiff ligand (3,5-Cl-saldmpn = N, N′-(3,3′-dipropyhnethylamine) bis (3,5-chlorosalicylidene)) with linearity and a high signal-to-noise ratio were developed. Analyses revealed an exponential intensification in their fluorescence emission and a discernible chromatic shift upon pH increase from 5.0 to 7.0. The sensors could retain over 95% of their initial signal amplitude after 20 operational cycles, demonstrating excellent stability and reversibility. To elucidate their unique fluorescence response, a non-halogenated analog was introduced for comparison. The structural and optical characterization suggested that the introduction of halogen atoms can create additional interaction pathways between adjacent molecules and enhance the strength of the interaction, which not only improves the signal-to-noise ratio but also forms a long-range interaction process in the formation of the aggregation state, thus enhancing the response range. Meanwhile, the above proposed mechanism was also verified by theoretical calculations.
Advances in Bcl-xL Research 2.0
Authors: Kervadec Joann , Priault Muriel
Published: May 2023

Apoptosis is a form of programmed cell death that is highly conserved in metazoan organisms, where it ensures the proper development and homeostasis of tissues [...]
Design, Synthesis and Biological Activities of (Thio)Urea Benzothiazole Derivatives
Authors: Mendieta-Wejebe Jessica E. , Rosales-Hernández Martha C. , Padilla-Martínez Itzia I. , García-Báez Efrén V. , Cruz Alejandro
Published: May 2023

(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the 2-(thio)ureabenzothizoles [(T)UBTs] are formed, improving the physicochemical as well as the biological properties, making these compounds very interesting in medicinal chemistry. Frentizole, bentaluron and methabenzthiazuron are examples of UBTs used for treatment of rheumatoid arthritis and as wood preservatives and herbicides in winter corn crops, respectively. With this antecedent, we recently reported a bibliographic review about the synthesis of this class of compounds, from the reaction of substituted 2-aminobenzothiazoles (ABTs) with iso(thio)cyanates, (thio)phosgenes, (thio)carbamoyl chlorides, 1,1’-(thio)carbonyldiimidazoles, and carbon disulfide. Herein, we prepared a bibliographic review about those features of design, chemical synthesis, and biological activities relating to (T)UBTs as potential therapeutic agents. This review is about synthetic methodologies generated from 1968 to the present day, highlighting the focus to transform (T)UBTs to compounds containing a range substituents, as illustrated with 37 schemes and 11 figures and concluded with 148 references. In this topic, the scientists dedicated to medicinal chemistry and pharmaceutical industry will find useful information for the design and synthesis of this interesting group of compounds with the aim of repurposing these compounds.
The Muscle-Conditioned Medium Containing Protocatechuic Acid Improves Insulin Resistance by Modulating Muscle Communication with Liver and Adipose Tissue
Authors: Shakoor Hira , Hussein Haneen , Al-Hassan Nour , Alketbi Mouza , Kizhakkayil Jaleel , Platat Carine
Published: May 2023

Diabetes mellitus is a public health concern, affecting 10.5% of the population. Protocatechuic acid (PCA), a polyphenol, exerts beneficial effects on insulin resistance and diabetes. This study investigated the role of PCA in improving insulin resistance and the crosstalk between muscle with liver and adipose tissue. C2C12 myotubes received four treatments: Control, PCA, insulin resistance (IR), and IR-PCA. Conditioned media from C2C12 was used to incubate HepG2 and 3T3-L1 adipocytes. The impact of PCA was analyzed on glucose uptake and signaling pathways. PCA (80 µM) significantly enhanced glucose uptake in C2C12, HepG2, and 3T3-L1 adipocytes (p < 0.05). In C2C12, PCA significantly elevated GLUT-4, IRS-1, IRS-2, PPAR-γ, P-AMPK, and P-Akt vs. Control (p ≤ 0.05), and modulated pathways in IR-PCA. In HepG2, PPAR-γ and P-Akt increased significantly in Control (CM) vs. No CM, and PCA dose upregulated PPAR-γ, P-AMPK, and P-AKT (p < 0.05). In the 3T3-L1 adipocytes, PI3K and GLUT-4 expression was elevated in PCA (CM) vs. No CM. A significant elevation of IRS-1, GLUT-4, and P-AMPK was observed in IR-PCA vs. IR (p ≤ 0.001). Herein, PCA strengthens insulin signaling by activating key proteins of that pathway and regulating glucose uptake. Further, conditioned media modulated crosstalk between muscle with liver and adipose tissue, thus regulating glucose metabolism.
Galectin-3 Mediates NETosis and Acts as an Autoantigen in Systemic Lupus Erythematosus-Associated Diffuse Alveolar Haemorrhage
Authors: Chen Shih-Yao , Wang Chung-Teng , Chen Ching-Yi , Kuo Pin-Yu , Wang Chrong-Reen , Shiau Ai-Li , Chang Cheng-Hsi , Wu Chao-Liang
Published: May 2023

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with enhanced NETosis and impaired degradation of neutrophil extracellular traps (NETs). Galectin-3 is a β-galactoside binding protein and is associated with neutrophil functions as well as involved in mediating autoimmune disorders. In this study, we plan to examine the associations of galectin-3 with the pathogenesis of SLE and NETosis. Galectin-3 expression levels were determined in peripheral blood mononuclear cells (PBMCs) of SLE patients for the association with lupus nephritis (LN) or correlation of SLE disease activity index 2000 (SLEDAI-2K). NETosis was observed in human normal and SLE and murine galectin-3 knockout (Gal-3 KO) neutrophils. Gal-3 KO and wild-type (WT) mice induced by pristane were used to evaluate disease signs, including diffuse alveolar haemorrhage (DAH), LN, proteinuria, anti-ribonucleoprotein (RNP) antibody, citrullinated histone 3 (CitH3) levels, and NETosis. Galectin-3 levels are higher in PBMCs of SLE patients compared with normal donors and positively correlated with LN or SLEDAI-2K. Gal-3 KO mice have higher percent survival and lower DAH, LN proteinuria, and anti-RNP antibody levels than WT mice induced by pristane. NETosis and citH3 levels are reduced in Gal-3 KO neutrophils. Furthermore, galectin-3 resides in NETs while human neutrophils undergo NETosis. Galectin-3-associated immune complex deposition can be observed in NETs from spontaneously NETotic cells of SLE patients. In this study, we provide clinical relevance of galectin-3 to the lupus phenotypes and the underlying mechanisms of galectin-3-mediated NETosis for developing novel therapeutic strategies targeting galectin-3 for SLE.
Genome-Wide Identification of the MYB and bHLH Families in Carnations and Expression Analysis at Different Floral Development Stages
Authors: Leng Luhong , Zhang Xiaoni , Liu Weichao , Wu Zhiqiang
Published: May 2023

Carnations are one of the most popular ornamental flowers in the world with varied flower colors that have long attracted breeders and consumers alike. The differences in carnation flower color are mainly the result of the accumulation of flavonoid compounds in the petals. Anthocyanins are a type of flavonoid compound that produce richer colors. The expression of anthocyanin biosynthetic genes is mainly regulated by MYB and bHLH transcription factors. However, these TFs have not been comprehensively reported in popular carnation cultivars. Herein, 106 MYB and 125 bHLH genes were identified in the carnation genome. Gene structure and protein motif analyses show that members of the same subgroup have similar exon/intron and motif organization. Phylogenetic analysis combining the MYB and bHLH TFs from Arabidopsis thaliana separates the carnation DcaMYBs and DcabHLHs into 20 subgroups each. Gene expression (RNAseq) and phylogenetic analysis shows that DcaMYB13 in subgroup S4 and DcabHLH125 in subgroup IIIf have similar expression patterns to those of DFR, ANS, and GT/AT, which regulate anthocyanin accumulation, in the coloring of carnations, and in red-flowered and white-flowered carnations, DcaMYB13 and DcabHLH125 are likely the key genes responsible for the formation of red petals in carnations. These results lay a foundation for the study of MYB and bHLH TFs in carnations and provide valuable information for the functional verification of these genes in studies of tissue-specific regulation of anthocyanin biosynthesis.
Special Issue “Small Molecules, Influence of Molecular Pathways 2.0”
Authors: Ong Eng Shi
Published: May 2023

Small molecules play an important role in extracting energy from cells, synthesising new macromolecules, and indicating metabolic shift and other processes (Figure 1) [...]
Genome-Wide Identification and Comparative Transcriptome Methods Reveal FaMDHAR50 Regulating Ascorbic Acid Regeneration and Quality Formation of Strawberry Fruits
Authors: Hou Guoyan , Yang Min , He Caixia , Jiang Yuyan , Peng Yuting , She Musha , Li Xin , Chen Qing , Li Mengyao , Zhang Yong , Lin Yuanxiu , Zhang Yunting , Wang Yan , He Wen , Wang Xiaorong , Tang Haoru , Luo Ya
Published: May 2023

Ascorbic acid (AsA) is a crucial water-soluble antioxidant in strawberry fruit, but limited research is currently available on the identification and functional validation of key genes involved in AsA metabolism in strawberries. This study analyzed the FaMDHAR gene family identification, which includes 168 genes. Most of the products of these genes are predicted to exist in the chloroplast and cytoplasm. The promoter region is rich in cis-acting elements related to plant growth and development, stress and light response. Meanwhile, the key gene FaMDHAR50 that positively regulates AsA regeneration was identified through comparative transcriptome analysis of ‘Benihoppe’ strawberry (WT) and its natural mutant (MT) with high AsA content (83 mg/100 g FW). The transient overexpression experiment further showed that overexpression of FaMDHAR50 significantly enhanced the AsA content by 38% in strawberry fruit, with the upregulated expression of structural genes involved in AsA biosynthesis (FaGalUR and FaGalLDH) and recycling and degradation (FaAPX, FaAO and FaDHAR) compared with that of the control. Moreover, increased sugar (sucrose, glucose and fructose) contents and decreased firmness and citric acid contents were observed in the overexpressed fruit, which were accompanied by the upregulation of FaSNS, FaSPS, FaCEL1 and FaACL, as well as the downregulation of FaCS. Additionally, the content of pelargonidin 3-glucoside markedly decreased, while cyanidin chloride increased significantly. In summary, FaMDHAR50 is a key positive regulatory gene involved in AsA regeneration in strawberry fruit, which also plays an important role in the formation of fruit flavor, apperance and texture during strawberry fruit ripening.
An Overview of the Potential Medicinal and Pharmaceutical Properties of Ru(II)/(III) Complexes
Authors: Skoczynska Anna , Lewinski Andrzej , Pokora Mateusz , Paneth Piotr , Budzisz Elzbieta
Published: May 2023

This review examines the existing knowledge about Ru(II)/(III) ion complexes with a potential application in medicine or pharmacy, which may offer greater potential in cancer chemotherapy than Pt(II) complexes, which are known to cause many side effects. Hence, much attention has been paid to research on cancer cell lines and clinical trials have been undertaken on ruthenium complexes. In addition to their antitumor activity, ruthenium complexes are under evaluation for other diseases, such as type 2 diabetes, Alzheimer’s disease and HIV. Attempts are also being made to evaluate ruthenium complexes as potential photosensitizers with polypyridine ligands for use in cancer chemotherapy. The review also briefly examines theoretical approaches to studying the interactions of Ru(II)/Ru(III) complexes with biological receptors, which can facilitate the rational design of ruthenium-based drugs.
Genome-Wide Analysis of WRKY Transcription Factors Involved in Abiotic Stress and ABA Response in Caragana korshinskii
Authors: Liu Jinhua , Li Guojing , Wang Ruigang , Wang Guangxia , Wan Yongqing
Published: May 2023

The WRKY transcription factor family plays a vital role in plant development and environmental response. However, the information of WRKY genes at the genome-wide level is rarely reported in Caragana korshinskii. In this study, we identified and renamed 86 CkWRKY genes, which were further classified into three groups through phylogenetic analysis. Most of these WRKY genes were clustered and distributed on eight chromosomes. Multiple sequence alignment revealed that the conserved domain (WRKYGQK) of the CkWRKYs was basically consistent, but there were also six variation types (WRKYGKK, GRKYGQK, WRMYGQK, WRKYGHK, WKKYEEK and RRKYGQK) that appeared. The motif composition of the CkWRKYs was quite conservative in each group. In general, the number of WRKY genes gradually increased from lower to higher plant species in the evolutionary analysis of 28 species, with some exceptions. Transcriptomics data and RT-qPCR analysis showed that the CkWRKYs in different groups were involved in abiotic stresses and ABA response. Our results provided a basis for the functional characterization of the CkWRKYs involved in stress resistance in C. korshinskii.
Involvement of Nitric Oxide and Melatonin Enhances Cadmium Resistance of Tomato Seedlings through Regulation of the Ascorbate–Glutathione Cycle and ROS Metabolism
Authors: Xu Junrong , Wei Zhien , Lu Xuefang , Liu Yunzhi , Yu Wenjin , Li Changxia
Published: May 2023

Melatonin (MT) and nitric oxide (NO) act as signaling molecules that can enhance cadmium (Cd) stress resistance in plants. However, little information is available about the relationship between MT and NO during seedling growth under Cd stress. We hypothesize that NO may be involved in how MT responds to Cd stress during seedling growth. The aim of this study is to evaluate the relationship and mechanism of response. The results indicate that different concentrations of Cd inhibit the growth of tomato seedlings. Exogenous MT or NO promotes seedling growth under Cd stress, with a maximal biological response at 100 μM MT or NO. The promotive effects of MT-induced seedling growth under Cd stress are suppressed by NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (cPTIO), suggesting that NO may be involved in MT-induced seedling growth under Cd stress. MT or NO decreases the content of hydrogen peroxide (H2O2), malonaldehyde (MDA), dehydroascorbic acid (DHA), and oxidized glutathione (GSSG); improves the content of ascorbic acid (AsA) and glutathione (GSH) and the ratios of AsA/DHA and GSH/GSSG; and enhances the activities of glutathione reductase (GR), monodehydroascorbic acid reductase (MDHAR), dehydroascorbic acid reductase (DHAR), ascorbic acid oxidase (AAO), and ascorbate peroxidase (APX) to alleviate oxidative damage. Moreover, the expression of genes associated with the ascorbate–glutathione (AsA-GSH) cycle and reactive oxygen species (ROS) are up-regulated by MT or NO under Cd conditions, including AAO, AAOH, APX1, APX6, DHAR1, DHAR2, MDHAR, and GR. However, NO scavenger cPTIO reverses the positive effects regulated by MT. The results indicate that MT-mediated NO enhances Cd tolerance by regulating AsA-GSH cycle and ROS metabolism.
Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies
Authors: Paschoudi Kiriaki , Yannaki Evangelia , Psatha Nikoletta
Published: May 2023

Beta-hemoglobinopathies are the most common genetic disorders worldwide, caused by a wide spectrum of mutations in the β-globin locus, and associated with morbidity and early mortality in case of patient non-adherence to supportive treatment. Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) used to be the only curative option, although the indispensable need for an HLA-matched donor markedly restricted its universal application. The evolution of gene therapy approaches made possible the ex vivo delivery of a therapeutic β- or γ- globin gene into patient-derived hematopoietic stem cells followed by the transplantation of corrected cells into myeloablated patients, having led to high rates of transfusion independence (thalassemia) or complete resolution of painful crises (sickle cell disease-SCD). Hereditary persistence of fetal hemoglobin (HPFH), a syndrome characterized by increased γ-globin levels, when co-inherited with β-thalassemia or SCD, converts hemoglobinopathies to a benign condition with mild clinical phenotype. The rapid development of precise genome editing tools (ZFN, TALENs, CRISPR/Cas9) over the last decade has allowed the targeted introduction of mutations, resulting in disease-modifying outcomes. In this context, genome editing tools have successfully been used for the introduction of HPFH-like mutations both in HBG1/HBG2 promoters or/and in the erythroid enhancer of BCL11A to increase HbF expression as an alternative curative approach for β-hemoglobinopathies. The current investigation of new HbF modulators, such as ZBTB7A, KLF-1, SOX6, and ZNF410, further expands the range of possible genome editing targets. Importantly, genome editing approaches have recently reached clinical translation in trials investigating HbF reactivation in both SCD and thalassemic patients. Showing promising outcomes, these approaches are yet to be confirmed in long-term follow-up studies.
Free Light Chains κ and λ as New Biomarkers of Selected Diseases
Authors: Gudowska-Sawczuk Monika , Mroczko Barbara
Published: May 2023

Diagnostic and prognostic markers are necessary to help in patient diagnosis and the prediction of future clinical events or disease progression. As promising biomarkers of selected diseases, the free light chains (FLCs) κ and λ were considered. Measurements of FLCs are currently used in routine diagnostics of, for example, multiple myeloma, and the usefulness of FLCs as biomarkers of monoclonal gammopathies is well understood. Therefore, this review focuses on the studies concerning FLCs as new potential biomarkers of other disorders in which an inflammatory background has been observed. We performed a bibliometric review of studies indexed in MEDLINE to assess the clinical significance of FLCs. Altered levels of FLCs were observed both in diseases strongly connected with inflammation such as viral infections, tick-borne diseases or rheumatic disorders, and disorders that are moderately associated with immune system reactions, e.g., multiple sclerosis, diabetes, cardiovascular disorders and cancers. Increased concentrations of FLCs appear to be a useful prognostic marker in patients with multiple sclerosis or tick-borne encephalitis. Intensive synthesis of FLCs may also reflect the production of specific antibodies against pathogens such as SARS-CoV-2. Moreover, abnormal FLC concentrations might predict the development of diabetic kidney disease in patients with type 2 diabetes. Markedly elevated levels are also associated with increased risk of hospitalization and death in patients with cardiovascular disorders. Additionally, FLCs have been found to be increased in rheumatic diseases and have been related to disease activity. Furthermore, it has been suggested that inhibition of FLCs would reduce the progression of tumorigenesis in breast cancer or colitis-associated colon carcinogenesis. In conclusion, abnormal levels of κ and λ FLCs, as well as the ratio of κ:λ, are usually the result of disturbances in the synthesis of immunoglobulins as an effect of overactive inflammatory reactions. Therefore, it seems that κ and λ FLCs may be significant diagnostic and prognostic biomarkers of selected diseases. Moreover, the inhibition of FLCs appears to be a promising therapeutical target for the treatment of various disorders where inflammation plays an important role in the development or progression of the disease.
Bioenergetic and Cytokine Profiling May Help to Rescue More DCD Livers for Transplantation
Authors: Hofmann Julia , Meszaros Andras T. , Buch Madita L. , Nardin Florian , Hackl Verena , Strolz Carola J. , Zelger Bettina , Fodor Margot , Cardini Benno , Oberhuber Rupert , Resch Thomas , Weissenbacher Annemarie , Troppmair Jakob , Schneeberger Stefan , Hautz Theresa
Published: May 2023

The majority of organs used for liver transplantation come from brain-dead donors (DBD). In order to overcome the organ shortage, increasingly donation after circulatory death (DCD) organs are also considered. Since normothermic machine perfusion (NMP) restores metabolic activity and allows for in-depth assessment of organ quality and function prior to transplantation, such organs may benefit from NMP. We herein compare the bioenergetic performance through a comprehensive evaluation of mitochondria by high-resolution respirometry in tissue biopsies and the inflammatory response in DBD and DCD livers during NMP. While livers were indistinguishable by perfusate biomarker assessment and histology, our findings revealed a greater impairment of mitochondrial function in DCD livers after static cold storage compared to DBD livers. During subsequent NMPs, DCD organs recovered and eventually showed a similar performance as DBD livers. Cytokine expression analysis showed no differences in the early phase of NMP, while towards the end of NMP, significantly elevated levels of IL-1β, IL-5 and IL-6 were found in the perfusate of DCD livers. Based on our results, we find it worthwhile to reconsider more DCD organs for transplantation to further extend the donor pool. Therefore, donor organ quality criteria must be developed, which may include an assessment of bioenergetic function and cytokine quantification.
Acceptors and Effectors Alter Substrate Inhibition Kinetics of a Plant Glucosyltransferase NbUGT72AY1 and Its Mutants
Authors: Liao Jieren , Lederer Veronika , Bardhi Alba , Zou Zhiwei , Hoffmann Timothy D. , Sun Guangxin , Song Chuankui , Hoffmann Thomas , Schwab Wilfried
Published: May 2023

One of the main obstacles in biocatalysis is the substrate inhibition (SI) of enzymes that play important roles in biosynthesis and metabolic regulation in organisms. The promiscuous glycosyltransferase UGT72AY1 from Nicotiana benthamiana is strongly substrate-inhibited by hydroxycoumarins (inhibitory constant Ki < 20 µM), but only weakly inhibited when monolignols are glucosylated (Ki > 1000 µM). Apocarotenoid effectors reduce the inherent UDP-glucose glucohydrolase activity of the enzyme and attenuate the SI by scopoletin derivatives, which could also be achieved by mutations. Here, we studied the kinetic profiles of different phenols and used the substrate analog vanillin, which has shown atypical Michaelis–Menten kinetics in previous studies, to examine the effects of different ligands and mutations on the SI of NbUGT72AY1. Coumarins had no effect on enzymatic activity, whereas apocarotenoids and fatty acids strongly affected SI kinetics by increasing the inhibition constant Ki. Only the F87I mutant and a chimeric version of the enzyme showed weak SI with the substrate vanillin, but all mutants exhibited mild SI when sinapaldehyde was used as an acceptor. In contrast, stearic acid reduced the transferase activity of the mutants to varying degrees. The results not only confirm the multi-substrate functionality of NbUGT72AY1, but also reveal that the enzymatic activity of this protein can be fine-tuned by external metabolites such as apocarotenoids and fatty acids that affect SI. Since these signals are generated during plant cell destruction, NbUGT72AY1 likely plays an important role in plant defense by participating in the production of lignin in the cell wall and providing direct protection through the formation of toxic phytoalexins.