bluuebunny/crossref_metadata_2025 huggingface dataset:
Searching for Biomarkers in the Blood of Patients at Risk of Developing Parkinson’s Disease at the Prodromal Stage
Authors: Katunina Elena A. , Blokhin Victor , Nodel Marina R. , Pavlova Ekaterina N. , Kalinkin Alexander L. , Kucheryanu Valerian G. , Alekperova Leyla , Selikhova Marianna V. , Martynov Mikhail Yu. , Ugrumov Michael V.
Published: January 2023

Parkinson’s disease (PD) is diagnosed many years after its onset, under a significant degradation of the nigrostriatal dopaminergic system, responsible for the regulation of motor function. This explains the low effectiveness of the treatment of patients. Therefore, one of the highest priorities in neurology is the development of the early (preclinical) diagnosis of PD. The aim of this study was to search for changes in the blood of patients at risk of developing PD, which are considered potential diagnostic biomarkers. Out of 1835 patients, 26 patients were included in the risk group and 20 patients in the control group. The primary criteria for inclusion in a risk group were the impairment of sleep behavior disorder and sense of smell, and the secondary criteria were neurological and mental disorders. In patients at risk and in controls, the composition of plasma and the expression of genes of interest in lymphocytes were assessed by 27 indicators. The main changes that we found in plasma include a decrease in the concentrations of l-3,4-dihydroxyphenylalanine (L-DOPA) and urates, as well as the expressions of some types of microRNA, and an increase in the total oxidative status. In turn, in the lymphocytes of patients at risk, an increase in the expression of the DA D3 receptor gene and the lymphocyte activation gene 3 (LAG3), as well as a decrease in the expression of the Protein deglycase DJ-1 gene (PARK7), were observed. The blood changes we found in patients at risk are considered candidates for diagnostic biomarkers at the prodromal stage of PD.
Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (Drosophila melanogaster) to Ether and Non-Ether Volatile Anesthetics
Authors: Borchardt Luke A. , Scharenbrock Amanda R. , Olufs Zachariah P. G. , Wassarman David A. , Perouansky Misha
Published: January 2023

The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The ND-2360114 and mt:ND2del1 lines of fruit flies (Drosophila melanogaster) that carry mutations in core subunits of Complex I of the mETC replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS. ND-2360114 flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II–V of the mETC cause AiN. We found that (i) ND-2360114 and mt:ND2del1 were susceptible to toxicity from halothane; (ii) in wild-type flies, halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II–V did not result in an AiN phenotype. We conclude that AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.
Molecular and Metabolic Insights into Anthocyanin Biosynthesis for Spot Formation on Lilium leichtlinii var. maximowiczii Flower Petals
Authors: Wang Zhen , Li Xin , Chen Minmin , Yang Liuyan , Zhang Yongchun
Published: January 2023

Plants exhibit remarkable diversity in their petal colors through biosynthesis and the accumulation of various pigments. Lilium, an important cut and potted flower, has many coloring pattern variations, including bicolors and spots. To elucidate the mechanisms regulating spot formation in Lilium leichtlinii var. maximowiczii petals, we used multiple approaches to investigate the changes in petal carotenoids, spot anthocyanins, and gene expression dynamics. This included green petals without spots (D1-Pe and D1-Sp), yellow–green petals with purple spots (D2-Pe and D2-Sp), light-orange petals with dark-purple spots (D3-Pe and D3-Sp), and orange petals with dark-purple spots (D4-Pe and D4-Sp). D3-Pe and D4-Pe contained large amounts of capsanthin and capsorubin and small amounts of zeaxanthin and violaxanthin, which contributed to the orange color. In addition to cyanidin-3-O-glucoside, pelargonidin-3-O-rutinoside, cyanidin-3-O-rutinoside, and peonidin-3-O-rutinoside may also contribute to L. leichtlinii var. maximowiczii‘s petal spot colors. KEGs involved in flavonoid biosyntheses, such as CHS, DFR, and MYB12, were significantly upregulated in D2-Sp and D3-Sp, compared with D1-Sp, as well as in spots, compared with petals. Upregulated anthocyanin concentrations and biosynthesis-related genes promoted spot formation and color transition. Our results provide global insight into pigment accumulation and the regulatory mechanisms underlying spot formation during flower development in L. leichtlinii var. maximowiczii.
Transplacental Therapeutic Drug Monitoring in Pregnant Women with Fetal Tachyarrhythmia Using HPLC-MS/MS
Authors: Starodubtseva Natalia , Kindysheva Svetlana , Potapova Alyona , Kukaev Evgenii , Khodzhaeva Zulfiya , Bockeria Ekaterina , Chagovets Vitaliy , Frankevich Vladimir , Sukhikh Gennady
Published: January 2023

Fetal arrhythmia develops in 0.1–5% of pregnancies and may cause fetal heart failure and fetal hydrops, thus increasing fetal, neonatal, and infant mortality. The timely initiation of transplacental antiarrhythmic therapy (ART) promotes the conversion of fetal tachycardia to sinus rhythm and the regression of the concomitant non-immune fetal hydrops. The optimal treatment regimen search for the fetus with tachyarrhythmia is still of high value. Polymorphisms of these genes determines the individual features of the drug pharmacokinetics. The aim of this study was to study the pharmacokinetics of transplacental anti-arrhythmic drugs in the fetal therapy of arrhythmias using HPLC-MS/MS, as well as to assess the effect of the multidrug-resistance gene ABCB1 3435C > T polymorphism on the efficacy and maternal/fetal complications of digoxin treatment. The predisposition to a decrease in the bioavailability of the digoxin in patients with a homozygous variant of the CC polymorphism showed a probable association with the development of ART side effects. A pronounced decrease in heart rate in women with the 3435TT allele of the ABCB1 gene was found. The homozygous TT variant in the fetus showed a probable association with an earlier response to ART and rhythm disruptions on the digoxin dosage reduction. high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) methods for digoxin and sotalol therapeutic drug monitoring in blood plasma, amniotic fluid, and urine were developed. The digoxin and sotalol concentrations were determined in the plasma blood, urine, and amniotic fluid of 30 pregnant women at four time points (from the beginning of the transplacental antiarrhythmic therapy to delivery) and the plasma cord blood of 30 newborns. A high degree of correlation between the level of digoxin and sotalol in maternal and cord blood was found. The ratio of digoxin and sotalol in cord blood to maternal blood was 0.35 (0.27 and 0.46) and 1.0 (0.97 and 1.07), accordingly. The digoxin concentration in the blood of the fetus at the moment of the first rhythm recovery episode, 0.58 (0.46, 0.8) ng/mL, was below the therapeutic interval. This confirms the almost complete transplacental transfer of sotalol and the significant limitation in the case of digoxin. Previously, ABCB1/P-glycoprotein had been shown to limit fetal exposure to drugs. Further studies (including multicenter ones) to clarify the genetic features of the transplacental pharmacokinetics of antiarrhythmic drugs are needed.
Targeting Gut Microbiota in Cancer Cachexia: Towards New Treatment Options
Authors: Panebianco Concetta , Villani Annacandida , Potenza Adele , Favaro Enrica , Finocchiaro Concetta , Perri Francesco , Pazienza Valerio
Published: January 2023

Cancer cachexia is a complex multifactorial syndrome whose hallmarks are weight loss due to the wasting of muscle tissue with or without the loss of adipose tissue, anorexia, systemic inflammation, and multi-organ metabolic alterations, which negatively impact patients’ response to anticancer treatments, quality of life, and overall survival. Despite its clinical relevance, cancer cachexia often remains an underestimated complication due to the lack of rigorous diagnostic and therapeutic pathways. A number of studies have shown alterations in gut microbiota diversity and composition in association with cancer cachexia markers and symptoms, thus supporting a central role for dysbiosis in the pathogenesis of this syndrome. Different tools of microbiota manipulation, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, have been investigated, demonstrating encouraging improvements in cachexia outcomes. Albeit pioneering, these studies pave the way for future research with the aim of exploring the role of gut microbiota in cancer cachexia more deeply and setting up effective microbiota-targeting interventions to be translated into clinical practice.
Roles of Estrogen, Estrogen Receptors, and Estrogen-Related Receptors in Skeletal Muscle: Regulation of Mitochondrial Function
Authors: Yoh Kenta , Ikeda Kazuhiro , Horie Kuniko , Inoue Satoshi
Published: January 2023

Estrogen is an essential sex steroid hormone that functions primarily in female reproductive system, as well as in a variety of tissues and organs with pleiotropic effects, such as in cardiovascular, nervous, immune, and musculoskeletal systems. Women with low estrogen, as exemplified by those in postmenopause, are therefore prone to suffer from various disorders, i.e., cardiovascular disease, dementia, metabolic syndrome, osteoporosis, sarcopenia, frailty, and so on. Estrogen regulates the expression of its target genes by binding to its cognate receptors, estrogen receptors (ERs) α and β. Notably, the estrogen-related receptors (ERRs) α, β, and γ are originally identified as orphan receptors that share substantial structural homology and common transcriptional targets with ERs. Accumulating evidence suggests that ERs and ERRs play crucial roles in skeletal muscles, such as muscle mass maintenance, muscle exercise physiology, and muscle regeneration. In this article, we review potential regulatory roles of ERs and ERRs in muscle physiology, particularly with regard to mitochondrial function and metabolism.
Prevention of Chemotherapy-Induced Peripheral Neuropathy by Inhibiting C-X-C Motif Chemokine Receptor 2
Authors: Cho Hee Seong , Choi Young In , Park Seon Uk , Han Yi Seul , Kwon Jean , Jung Sung Jun
Published: January 2023

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drawback in the use of chemotherapeutic agents for patients with cancer. Although studies have investigated a broad number of molecules that might be related to CIPN, the differences in the chemokine pathways between various chemotherapeutic agents, such as vincristine and oxaliplatin, which are some of the most widely used treatments, have not been fully elucidated. We confirmed that the administration (intraperitoneal injections for seven days) of vincristine (0.1 mg/kg) and oxaliplatin (3 mg/kg) induced pain by using the von Frey behavioral test. Subsequent applications with vincristine and oxaliplatin led to mechanical allodynia that lasted more than one week from the fifth day. After the induction of mechanical allodynia, the mRNA expression of CXCR2, CXCL1, CXCL3, and CXCL5 was examined in the dorsal root ganglia (DRG) and spinal cord of the CIPN models. As a result, the mRNA expression of CXCR2 robustly increased in the lumbar spinal cord in the oxaliplatin-treated mice. Next, to evaluate the involvement of CXCR2 in CIPN, reparixin, a CXCR1/2 inhibitor, was administered intrathecally or intraperitoneally with vincristine or oxaliplatin and was further verified by treatment with ruxolitinib, which inhibits Janus kinase 2 downstream of the CXCR1/2 pathway. Reparixin and ruxolitinib blocked oxaliplatin-induced allodynia but not vincristine-induced allodynia, which suggests that CXCR2-related pathways are associated with the development of oxaliplatin-induced neuropathy. Together with the above results, this suggests that the prevention of oxaliplatin-induced neuropathy by CXCR2 inhibition can lead to successful chemotherapy, and it is important to provide appropriate countermeasures against CIPN development for each specific chemotherapeutic agent.
Preventive and Therapeutic Effects of Punica granatum L. Polyphenols in Neurological Conditions
Authors: Aleksandrova Simona , Alexova Ralitza , Dragomanova Stela , Kalfin Reni , Nicoletti Ferdinando , Fagone Paolo , Petralia Maria Cristina , Mangano Katia , Tancheva Lyubka
Published: January 2023

Pomegranate (Punica granatum L.) is a polyphenol-rich food and medicinal plant containing flavonols, anthocyanins, and tannins. Ellagitannins (ETs) are the most abundant polyphenols in pomegranate. A growing body of research shows that polyphenol-rich pomegranate extracts and their metabolites target multiple types of brain cell and support their redox balance, proliferation and survival, as well as cell signaling. Independent studies have demonstrated that the significant neuroprotective effects of ETs are mediated by their antioxidant and anti-inflammatory effects, their chelating properties, by their ability to activate various signaling pathways, as well as the ability to influence mitochondrial damage, thus regulating autophagy, apoptosis and neurotransmitter signaling. The multitude of in vitro and in vivo studies summarized in the present review suggest that pomegranate polyphenols act on both neuronal and glial cells directly, and also affect blood–brain barrier function, restoring redox balance in the blood and brain and increasing blood flow to the brain.
Role of Microglial Cells in the Pathophysiology of MS: Synergistic or Antagonistic?
Authors: Mado Hubert , Adamczyk-Sowa Monika , Sowa Paweł
Published: January 2023

Many studies indicate an important role of microglia and their cytokines in the pathophysiology of multiple sclerosis (MS). Microglia are the macrophages of the central nervous system (CNS). They have many functions, such as being “controllers” of the CNS homeostasis in pathological and healthy conditions, playing a key role in the active immune defense of the CNS. Macroglia exhibit a dual role, depending on the phenotype they adopt. First, they can exhibit neurotoxic effects, which are harmful in the case of MS. However, they also show neuroprotective and regenerative effects in this disease. Many of the effects of microglia are mediated through the cytokines they secrete, which have either positive or negative properties. Neurotoxic and pro-inflammatory effects can be mediated by microglia via lipopolysaccharide and gamma interferon. On the other hand, the mediators of anti-inflammatory and protective effects secreted by microglia can be, for example, interleukin-4 and -13. Further investigation into the role of microglia in MS pathophysiology may perhaps lead to the discovery of new therapies for MS, as recent research in this area has been very promising.
Unravelling Differential DNA Methylation Patterns in Genotype Dependent Manner under Salinity Stress Response in Chickpea
Authors: Gupta Khushboo , Garg Rohini
Published: January 2023

DNA methylation is one of the epigenetic mechanisms that govern gene regulation in response to abiotic stress in plants. Here, we analyzed the role of epigenetic variations by exploring global DNA methylation and integrating it with differential gene expression in response to salinity stress in tolerant and sensitive chickpea genotypes. Genome-wide DNA methylation profiles showed higher CG methylation in the gene body regions and higher CHH methylation in the TE body regions. The analysis of differentially methylated regions (DMRs) suggested more hyper-methylation in response to stress in the tolerant genotype compared to the sensitive genotype. We observed higher enrichment of CG DMRs in genes and CHH DMRs in transposable elements (TEs). A positive correlation of gene expression with CG gene body methylation was observed. The enrichment analysis of DMR-associated differentially expressed genes revealed they are involved in biological processes, such as lateral root development, transmembrane transporter activity, GTPase activity, and regulation of gene expression. Further, a high correlation of CG methylation with CHG and CHH methylation under salinity stress was revealed, suggesting crosstalk among the methylation contexts. Further, we observed small RNA-mediated CHH hypermethylation in TEs. Overall, the interplay between DNA methylation, small RNAs, and gene expression provides new insights into the regulatory mechanism underlying salinity stress response in chickpeas.
Design, Characterization, and Biological Activities of Erythromycin-Loaded Nanodroplets to Counteract Infected Chronic Wounds Due to Streptococcus pyogenes
Authors: Mandras Narcisa , Luganini Anna , Argenziano Monica , Roana Janira , Giribaldi Giuliana , Tullio Vivian , Cavallo Lorenza , Prato Mauro , Cavalli Roberta , Cuffini Anna Maria , Allizond Valeria , Banche Giuliana
Published: January 2023

Streptococcus pyogenes causes a wide spectrum of diseases varying from mild to life threatening, despite antibiotic treatment. Nanoparticle application could facilitate the foreign pathogen fight by increasing the antimicrobial effectiveness and reducing their adverse effects. Here, we designed and produced erythromycin-loaded chitosan nanodroplets (Ery-NDs), both oxygen-free and oxygen-loaded. All ND formulations were characterized for physico-chemical parameters, drug release kinetics, and tested for biocompatibility with human keratinocytes and for their antibacterial properties or interactions with S. pyogenes. All tested NDs possessed spherical shape, small average diameter, and positive Z potential. A prolonged Ery release kinetic from Ery-NDs was demonstrated, as well as a favorable biocompatibility on human keratinocytes. Confocal microscopy images showed ND uptake and internalization by S. pyogenes starting from 3 h of incubation up to 24 h. According to cell counts, NDs displayed long-term antimicrobial efficacy against streptococci significantly counteracting their proliferation up to 24 h, thanks to the known chitosan antimicrobial properties. Intriguingly, Ery-NDs were generally more effective (104–103 log10 CFU/mL), than free-erythromycin (105 log10 CFU/mL), in the direct killing of streptococci, probably due to Ery-NDs adsorption by bacteria and prolonged release kinetics of erythromycin inside S. pyogenes cells. Based on these findings, NDs and proper Ery-NDs appear to be the most promising and skin-friendly approaches for the topical treatment of streptococcal skin infections allowing wound healing during hypoxia.
Important Role of Endogenous Nerve Growth Factor Receptor in the Pathogenesis of Hypoxia-Induced Pulmonary Hypertension in Mice
Authors: Goten Chiaki , Usui Soichiro , Takashima Shin-ichiro , Inoue Oto , Yamaguchi Kosei , Hashimuko Daiki , Takeda Yusuke , Nomura Ayano , Sakata Kenji , Kaneko Shuichi , Takamura Masayuki
Published: January 2023

Pulmonary arterial hypertension (PAH) remains a disease with poor prognosis; thus, a new mechanism for PAH treatment is necessary. Circulating nerve growth factor receptor (Ngfr)-positive cells in peripheral blood mononuclear cells are associated with disease severity and the prognosis of PAH patients; however, the role of Ngfr in PAH is unknown. In this study, we evaluated the function of Ngfr using Ngfr gene-deletion (Ngfr−/−) mice. To elucidate the role of Ngfr in pulmonary hypertension (PH), we used Ngfr−/− mice that were exposed to chronic hypoxic conditions (10% O2) for 3 weeks. The development of hypoxia-induced PH was accelerated in Ngfr−/− mice compared to littermate controls. In contrast, the reconstitution of bone marrow (BM) in Ngfr−/− mice transplanted with wild-type BM cells improved PH. Notably, the exacerbation of PH in Ngfr−/− mice was accompanied by the upregulation of pulmonary vascular remodeling-related genes in lung tissue. In a hypoxia-induced PH model, Ngfr gene deletion resulted in PH exacerbation. This suggests that Ngfr may be a key molecule involved in the pathogenesis of PAH.
Combined Metabolome and Transcriptome Analyses Unveil the Molecular Mechanisms of Fruit Acidity Variation in Litchi (Litchi chinensis Sonn.)
Authors: Jiang Yonghua , Qi Yingwei , Chen Xilong , Yan Qian , Chen Jiezhen , Liu Hailun , Shi Fachao , Wen Yingjie , Cai Changhe , Ou Liangxi
Published: January 2023

Fruit acidity determines the organoleptic quality and nutritive value of most fruits. In litchi, although the organic acid composition of pulps is known, the molecular mechanisms and genes underlying variation in fruit acidity remain elusive. Herein, developing pulps of two contrasting litchi varieties, Huaizhi (HZ, low-acidity) and Boye_No.8 (B8, high-acidity), were subjected to metabolomics and transcriptomics, and the dynamic metabolome and transcriptional changes were determined. Measurements revealed that the dominant acidity-related organic acid in litchi pulps is malate, followed in low levels by citrate and tartrate. Variation in litchi pulps’ acidity is mainly associated with significant differences in malate and citrate metabolisms during fruit development. Malic acid content decreased by 91.43% and 72.28% during fruit ripening in HZ and B8, respectively. The content of citric acid increased significantly in B8, while in HZ it was reduced considerably. Differentially accumulated metabolites and differentially expressed genes analyses unveiled fumarate, succinate, 2-oxoglutarate, GABA (γ-aminobutyric acid), phosphoenolpyruvate, and citrate metabolisms as the key driving pathways of litchi fruits’ acidity variation. The drastic malate and citrate degradation in HZ was linked to higher induction of fumarate and GABA biosynthesis, respectively. Thirty candidate genes, including three key genes (LITCHI026501.m2, fumarase; LITCHI020148.m5, glutamate decarboxylase; and LITCHI003343.m3, glutamate dehydrogenase), were identified for functional studies toward genetic modulation of litchi fruit acidity. Our findings provide insights into the molecular basis of acidity variation in litchi and provide valuable resources for fruit quality improvement.
Germline Mutations in Steroid Metabolizing Enzymes: A Focus on Steroid Transforming Aldo-Keto Reductases
Authors: Detlefsen Andrea J. , Paulukinas Ryan D. , Penning Trevor M.
Published: January 2023

Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in SRD5A2, HSD17B3, and HSD3B2 genes that lead to disordered sexual development, salt wasting, and other severe disorders provide a glimpse of the impacts of mutations in steroid hormone transforming enzymes. In a departure from these established examples, this review examines disease-associated germline coding mutations in steroid-transforming members of the human aldo-keto reductase (AKR) superfamily. We consider two main categories of missense mutations: those resulting from nonsynonymous single nucleotide polymorphisms (nsSNPs) and cases resulting from familial inherited base pair substitutions. We found mutations in human AKR1C genes that disrupt androgen metabolism, which can affect male sexual development and exacerbate prostate cancer and polycystic ovary syndrome (PCOS). Others may be disease causal in the AKR1D1 gene that is responsible for bile acid deficiency. However, given the extensive roles of AKRs in steroid metabolism, we predict that with expanding publicly available data and analysis tools, there is still much to be uncovered regarding germline AKR mutations in disease.
Traditional vs. Microfluidic Synthesis of ZnO Nanoparticles
Authors: Popa Maria Leila , Preda Manuela Daniela , Neacșu Ionela Andreea , Grumezescu Alexandru Mihai , Ginghină Octav
Published: January 2023

Microfluidics provides a precise synthesis of micro-/nanostructures for various applications, including bioengineering and medicine. In this review article, traditional and microfluidic synthesis methods of zinc oxide (ZnO) are compared concerning particle size distribution, morphology, applications, reaction parameters, used reagents, and microfluidic device materials. Challenges of traditional synthesis methods are reviewed in a manner where microfluidic approaches may overcome difficulties related to synthesis precision, bulk materials, and reproducibility.
Analysis of Single Biomacromolecules and Viruses: Is It a Myth or Reality?
Authors: Pleshakova Tatyana O. , Ivanov Yuri D. , Valueva Anastasia A. , Shumyantseva Victoria V. , Ilgisonis Ekaterina V. , Ponomarenko Elena A. , Lisitsa Andrey V. , Chekhonin Vladimir P. , Archakov Alexander I.
Published: January 2023

The beginning of the twenty-first century witnessed novel breakthrough research directions in the life sciences, such as genomics, transcriptomics, translatomics, proteomics, metabolomics, and bioinformatics. A newly developed single-molecule approach addresses the physical and chemical properties and the functional activity of single (individual) biomacromolecules and viral particles. Within the alternative approach, the combination of “single-molecule approaches” is opposed to “omics approaches”. This new approach is fundamentally unique in terms of its research object (a single biomacromolecule). Most studies are currently performed using postgenomic technologies that allow the properties of several hundreds of millions or even billions of biomacromolecules to be analyzed. This paper discusses the relevance and theoretical, methodological, and practical issues related to the development potential of a single-molecule approach using methods based on molecular detectors.
Pro- vs. Anti-Inflammatory Features of Monocyte Subsets in Glioma Patients
Authors: Lehman Natalia , Kowalska Wioleta , Zarobkiewicz Michał , Mazurek Marek , Mrozowska Karolina , Bojarska-Junak Agnieszka , Rola Radosław
Published: January 2023

Monocytes constitute a heterogenous group of antigen-presenting cells that can be subdivided based on CD14, CD16 and SLAN expression. This division reflects the functional diversity of cells that may play different roles in a variety of pathologies including gliomas. In the current study, the three monocyte subpopulations: classical (CD14+ CD16+ SLAN−), intermediate (CD14dim CD16+ SLAN−) and non-classical (CD14low/− CD16+ SLAN+) in glioma patients’ peripheral blood were analysed with flow cytometry. The immune checkpoint molecule (PD-1, PD-L1, SIRPalpha, TIM-3) expression along with pro- and anti-inflammatory cytokines (TNF, IL-12, TGF-beta, IL-10) were assessed. The significant overproduction of anti-inflammatory cytokines by intermediate monocytes was observed. Additionally, SLAN-positive cells overexpressed IL-12 and TNF when compared to the other two groups of monocytes. In conclusion, these results show the presence of different profiles of glioma patient monocytes depending on CD14, CD16 and SLAN expression. The bifold function of monocyte subpopulations might be an additional obstacle to the effectiveness of possible immunotherapies.
Plk4 Is a Novel Substrate of Protein Phosphatase 5
Authors: Ábrahám Edit , Réthi-Nagy Zsuzsánna , Vilmos Péter , Sinka Rita , Lipinszki Zoltán
Published: January 2023

The conserved Ser/Thr protein phosphatase 5 (PP5) is involved in the regulation of key cellular processes, including DNA damage repair and cell division in eukaryotes. As a co-chaperone of Hsp90, PP5 has been shown to modulate the maturation and activity of numerous oncogenic kinases. Here, we identify a novel substrate of PP5, the Polo-like kinase 4 (Plk4), which is the master regulator of centriole duplication in animal cells. We show that PP5 specifically interacts with Plk4, and is able to dephosphorylate the kinase in vitro and in vivo, which affects the interaction of Plk4 with its partner proteins. In addition, we provide evidence that PP5 and Plk4 co-localize to the centrosomes in Drosophila embryos and cultured cells. We demonstrate that PP5 is not essential; the null mutant flies are viable without a severe mitotic phenotype; however, its loss significantly reduces the fertility of the animals. Our results suggest that PP5 is a novel regulator of the Plk4 kinase in Drosophila.
Comparison of Rheological Properties of Healthy versus Dupuytren Fibroblasts When Treated with a Cell Contraction Inhibitor by Atomic Force Microscope
Authors: Pérez-Domínguez Sandra , López-Alonso Javier , Lafont Frank , Radmacher Manfred
Published: January 2023

Mechanical properties of healthy and Dupuytren fibroblasts were investigated by atomic force microscopy (AFM). In addition to standard force curves, rheological properties were assessed using an oscillatory testing methodology, in which the frequency was swept from 1 Hz to 1 kHz, and data were analyzed using the structural damping model. Dupuytren fibroblasts showed larger apparent Young’s modulus values than healthy ones, which is in agreement with previous results. Moreover, cell mechanics were compared before and after ML-7 treatment, which is a myosin light chain kinase inhibitor (MLCK) that reduces myosin activity and hence cell contraction. We employed two different concentrations of ML-7 inhibitor and could observe distinct cell reactions. At 1 µM, healthy and scar fibroblasts did not show measurable changes in stiffness, but Dupuytren fibroblasts displayed a softening and recovery after some time. When increasing ML-7 concentration (3 µM), the majority of cells reacted, Dupuytren fibroblasts were the most susceptible, not being able to recover from the drug and dying. These results suggested that ML-7 is a potent inhibitor for MLCK and that myosin II is essential for cytoskeleton stabilization and cell survival.
AR and PI3K/AKT in Prostate Cancer: A Tale of Two Interconnected Pathways
Authors: Tortorella Elisabetta , Giantulli Sabrina , Sciarra Alessandro , Silvestri Ida
Published: January 2023

Prostate cancer (PCa) is the most common cancer in men. The androgen receptor (AR) has a pivotal role in the pathogenesis and progression of PCa. Many therapies targeting AR signaling have been developed over the years. AR signaling inhibitors (ARSIs), including androgen synthesis inhibitors and AR antagonists, have proven to be effective in castration-sensitive PCa (CSPC) and improve survival, but men with castration-resistant PCa (CRPC) continue to have a poor prognosis. Despite a good initial response, drug resistance develops in almost all patients with metastatic CRPC, and ARSIs are no longer effective. Several mechanisms confer resistance to ARSI and include AR mutations but also hyperactivation of other pathways, such as PI3K/AKT/mTOR. This pathway controls key cellular processes, including proliferation and tumor progression, and it is the most frequently deregulated pathway in human cancers. A significant interaction between AR and the PI3K/AKT/mTOR signaling pathway has been shown in PCa. This review centers on the current scene of different AR and PI3K signaling pathway inhibitors, either as monotherapy or in combination treatments in PCa, and the treatment outcomes involved in both preclinical and clinical trials. A PubMed-based literature search was conducted up to November 2022. The most relevant and recent articles were selected to provide essential information and current evidence on the crosstalk between AR and the PI3K signaling pathways. The ClinicalTrials.gov registry was used to report information about clinical studies and their results using the Advanced research tool, filtering for disease and target.
Commonalities and Disparities between Endometriosis and Chronic Endometritis: Therapeutic Potential of Novel Antibiotic Treatment Strategy against Ectopic Endometrium
Authors: Kitaya Kotaro , Yasuo Tadahiro
Published: January 2023

Chronic endometritis (CE) is a local mucosal inflammatory disorder of the uterine lining, which is histopathologically recognized as the unusual infiltration of CD138(+) plasmacytes into the endometrial stromal compartment. Accumulating body of research documented that CE is associated with female infertility and several obstetric/neonatal complications. The major cause of CE is thought to be intrauterine infection represented by common bacteria (Escherichia coli, Enterococcus faecalis, Streptococcus, and Staphylococcus), Mycoplasma/Ureaplasma, and Mycobacterium. Additionally, local dysbiosis in the female reproductive tract may be involved in the onset and development of CE. Antibiotic treatments against these microorganisms are effective in the elimination of endometrial stromal plasmacytes in the affected patients. Meanwhile, endometriosis is a common female reproductive tract disease characterized by endometriotic tissues (ectopic endometrium) growing outside the uterus and potentially causes chronic pelvic symptoms (dysmenorrhea, dyspareunia, dyschezia, and dysuria), infertility, and ovarian cancers. Endometriosis involves endocrinological, genetic, and epigenetic factors in its etiology and pathogenesis. Recent studies focus on immunological, inflammatory, and infectious aspects of endometriosis and demonstrate several common characteristics between endometriosis and CE. This review aimed to better understand the immunological and microbial backgrounds underlying endometriosis and CE and look into the therapeutic potential of the novel antibiotic treatment strategy against endometriosis in light of endometrial infectious disease.
Trimethylamine N-Oxide Response to a Mixed Macronutrient Tolerance Test in a Cohort of Healthy United States Adults
Authors: James Kristen L. , Gertz Erik R. , Kirschke Catherine P. , Allayee Hooman , Huang Liping , Kable Mary E. , Newman John W. , Stephensen Charles B. , Bennett Brian J.
Published: January 2023

Plasma trimethylamine n-oxide (TMAO) concentration increases in responses to feeding TMAO, choline, phosphatidylcholine, L-carnitine, and betaine but it is unknown whether concentrations change following a mixed macronutrient tolerance test (MMTT) with limited amounts of TMAO precursors. In this proof-of-concept study, we provided healthy female and male adults (n = 97) ranging in age (18–65 years) and BMI (18–44 kg/m2) a MMTT (60% fat, 25% sucrose; 42% of a standard 2000 kilo calorie diet) and recorded their metabolic response at fasting and at 30 min, 3 h, and 6 h postprandially. We quantified total exposure to TMAO (AUC-TMAO) and classified individuals by the blood draw at which they experienced their maximal TMAO concentration (TMAO-response groups). We related AUC-TMAO to the 16S rRNA microbiome, to two SNPs in the exons of the FMO3 gene (rs2266782, G>A, p.Glu158Lys; and rs2266780, A>G, p.Glu308Gly), and to a priori plasma metabolites. We observed varying TMAO responses (timing and magnitude) and identified a sex by age interaction such that AUC-TMAO increased with age in females but not in males (p-value = 0.0112). Few relationships between AUC-TMAO and the fecal microbiome and FMO3 genotype were identified. We observed a strong correlation between AUC-TMAO and TNF-α that depended on TMAO-response group. These findings promote precision nutrition and have important ramifications for the eating behavior of adults who could benefit from reducing TMAO exposure, and for understanding factors that generate plasma TMAO.
Machine Learning-Based Blood RNA Signature for Diagnosis of Autism Spectrum Disorder
Authors: Voinsky Irena , Fridland Oleg Y. , Aran Adi , Frye Richard E. , Gurwitz David
Published: January 2023

Early diagnosis of autism spectrum disorder (ASD) is crucial for providing appropriate treatments and parental guidance from an early age. Yet, ASD diagnosis is a lengthy process, in part due to the lack of reliable biomarkers. We recently applied RNA-sequencing of peripheral blood samples from 73 American and Israeli children with ASD and 26 neurotypically developing (NT) children to identify 10 genes with dysregulated blood expression levels in children with ASD. Machine learning (ML) analyzes data by computerized analytical model building and may be applied to building diagnostic tools based on the optimization of large datasets. Here, we present several ML-generated models, based on RNA expression datasets collected during our recently published RNA-seq study, as tentative tools for ASD diagnosis. Using the random forest classifier, two of our proposed models yield an accuracy of 82% in distinguishing children with ASD and NT children. Our proof-of-concept study requires refinement and independent validation by studies with far larger cohorts of children with ASD and NT children and should thus be perceived as starting point for building more accurate ML-based tools. Eventually, such tools may potentially provide an unbiased means to support the early diagnosis of ASD.
Identification and Analysis of the CBF Gene Family in Three Species of Acer under Cold Stress
Authors: Zhao Qiushuang , Han Rui , Cai Kewei , Yan Huiling , Li Yan , Qu Guanzheng , Liu Lin , Zhao Xiyang
Published: January 2023

The C-Repeat Binding Factor (CBF) gene family has been identified and characterized in multiple plant species, and it plays a crucial role in responding to low temperatures. Presently, only a few studies on tree species demonstrate the mechanisms and potential functions of CBFs associated with cold resistance, while our study is a novel report on the multi-aspect differences of CBFs among three tree species, compared to previous studies. In this study, genome-wide identification and analysis of the CBF gene family in Acer truncatum, Acer pseudosieboldianum, and Acer yangbiense were performed. The results revealed that 16 CBF genes (five ApseCBFs, four AcyanCBFs, and seven AtruCBFs) were unevenly distributed across the chromosomes, and most CBF genes were mapped on chromosome 2 (Chr2) and chromosome 11 (Chr11). The analysis of phylogenetic relationships, gene structure, and conserved motif showed that 16 CBF genes could be clustered into three subgroups; they all contained Motif 1 and Motif 5, and most of them only spanned one exon. The cis-acting elements analysis showed that some CBF genes might be involved in hormone and abiotic stress responsiveness. In addition, CBF genes exhibited tissue expression specificity. High expressions of ApseCBF1, ApseCBF3, AtruCBF1, AtruCBF4, AtruCBF6, AtruCBF7, and ApseCBF3, ApseCBF4, ApseCBF5 were detected on exposure to low temperature for 3 h and 24 h. Low expressions of AtruCBF2, AtruCBF6, AtruCBF7 were detected under cold stress for 24 h, and AtruCBF3 and AtruCBF5 were always down-regulated under cold conditions. Taken together, comprehensive analysis will enhance our understanding of the potential functions of the CBF genes on cold resistance, thereby providing a reference for the introduction of Acer species in our country.
Critical Link between Calcium Regional Heterogeneity and Atrial Fibrillation Susceptibility in Sheep Left Atria
Authors: Niort Barbara , Recalde Alice , Cros Caroline , Brette Fabien
Published: January 2023

Background: Atrial fibrillation is the most sustained form of arrhythmia in the human population that leads to important electrophysiological and structural cardiac remodeling as it progresses into a chronic form. Calcium is an established key player of cellular electrophysiology in the heart, yet to date, there is no information that maps calcium signaling across the left atrium. Objective: The aim of this study is to determine whether calcium signaling is homogenous throughout the different regions of the left atrium. This work tests the hypothesis that differences across the healthy left atrium contribute to a unique, region-dependent calcium cycling and participates in the pro-arrhythmic activity during atrial fibrillation. Methods: An animal model relevant to human cardiac function (the sheep) was used to characterize both the electrical activity and the calcium signaling of three distinct left atrium regions (appendage, free wall and pulmonary veins) in control conditions and after acetylcholine perfusion (5 μM) to induce acute atrial fibrillation. High-resolution dual calcium-voltage optical mapping on the left atria of sheep was performed to explore the spatiotemporal dynamics of calcium signaling in relation to electrophysiological properties. Results: Action potential duration (at 80% repolarization) was not significantly different in the three regions of interest for the three pacing sites. In contrast, the time to 50% calcium transient decay was significantly different depending on the region paced and recorded. Acetylcholine perfusion and burst pacing-induced atrial fibrillation when pulmonary veins and appendage regions were paced but not when the free wall region was. Dantrolene (a ryanodine receptor blocker) did not reduce atrial fibrillation susceptibility. Conclusion: These data provide the first evidence of heterogenous calcium signaling across the healthy left atrium. Such basal regional differences may be exacerbated during the progression of atrial fibrillation and thus play a crucial role in focal arrhythmia initiation without ryanodine receptor gating modification.
Heart Rate Variability Impairment Is Associated with Right Ventricular Overload and Early Mortality Risk in Patients with Acute Pulmonary Embolism
Authors: Lisicka Monika , Skowrońska Marta , Karolak Bartosz , Wójcik Jan , Pruszczyk Piotr , Bienias Piotr
Published: January 2023

The association between heart rate variability (HRV) and mortality risk of acute pulmonary embolism (APE), as well as its association with right ventricular (RV) overload is not well established. We performed an observational study on consecutive patients with confirmed APE. In the first 48 h after admission, 24 h Holter monitoring with assessment of time-domain HRV, echocardiography and NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurement were performed in all participants. We pre-examined 166 patients: 32 (20%) with low risk of early mortality, 65 (40%) with intermediate–low, 65 (40%) with intermediate–high, and 4 (0.02%) in the high risk category. The last group was excluded from further analysis due to sample size, and finally, 162 patients aged 56.3 ± 18.5 years were examined. We observed significant correlations between HRV parameters and echocardiographic signs of RV overload. SDNN (standard deviation of intervals of all normal beats) correlated with echocardiography-derived RVSP (right ventricular systolic pressure; r = −0.31, p = 0.001), TAPSE (tricuspid annulus plane systolic excursion; r = 0.21, p = 0.033), IVC (inferior vena cava diameter; r = −0.27, p = 0.002) and also with NT-proBNP concentration (r = −0.30, p = 0.004). HRV indices were also associated with APE risk stratification, especially in the low-risk category (r = 0.30, p = 0.004 for SDNN). Univariate and multivariate analyses confirmed that SDNN values were associated with signs of RV overload. In conclusion, we observed a significant association between time-domain HRV parameters and echocardiographic and biochemical signs of RV overload. Impaired HRV parameters were also associated with worse a clinical risk status of APE.
Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study
Authors: Li Qilan , Wang Jianqun , Cheng Yang , Hu Anpei , Li Dan , Wang Xiaojing , Guo Yanhua , Zhou Yi , Chen Guo , Bao Banghe , Gao Haiyang , Song Jiyu , Du Xinyi , Zheng Liduan , Tong Qiangsong
Published: January 2023

Neuroblastoma is the most common extracranial solid malignancy in children. This study was undertaken to determine the long-term survival of neuroblastoma patients receiving conventional therapeutics (surgery, chemotherapy, and radiotherapy). The neuroblastoma patients examined were registered in the Surveillance, Epidemiology and End Results (SEER) database (1975–2016). Using propensity score matching analysis, the patients were paired by record depending on whether they received surgery, chemotherapy, or radiotherapy. Univariate and multivariate analyses of the disease-specific survival of the paired patients were performed by the log-rank test and Cox regression assay. A total of 4568 neuroblastoma patients were included in this study. During 1975–2016, the proportion of histopathological grade III/IV cases receiving surgery gradually increased, while the number of patients with tumors of grade I to IV undergoing chemotherapy or radiotherapy was stable or even decreased. After propensity score analysis, for Grade I + II and Grade III tumors, surgery obviously improved the disease-specific survival of patients, while chemotherapy was unfavorable for patient prognosis, and radiotherapy exerted no obvious effect on the patients. However, no matter what treatment was chosen, the patients with advanced-histopathological-grade tumors had a poor prognosis. Meanwhile, for all histopathological grades, the patients receiving surgery and subsequent chemotherapy or radiotherapy suffered from worsen disease-specific survival than those simply undergoing surgery. Fortunately, the negative effects of surgery, chemotherapy, or radiotherapy improved gradually over time. Surgery improved the long-term survival of the neuroblastoma patients, while chemotherapy and radiotherapy exerted an unfavorable impact on patient outcome. These results provide an important reference for the clinical treatment of neuroblastoma.
Effects of Postoperative Atropine Eye Drops on Visual Quality in Patients Undergoing Trabeculectomy
Authors: Laspas Panagiotis , Maier Elisa , Schuster Alexander , McAlinden Colm , Pfeiffer Norbert , Hoffmann Esther
Published: January 2023

The aim of this study was to investigate the effects of atropine on patients’ perception of visual quality after trabeculectomy. Forty patients undergoing standard trabeculectomy with mitomycin C were enrolled in this prospective randomized study. All surgeries were conducted at the ophthalmology department of the University Medical Center of Mainz, Germany. All patients received the same postoperative treatment with ofloxacin and dexamethasone eye drops. Following randomization of patients into two groups of 20 patients, the intervention group also received atropine eye drops three times daily for the first 2 days after surgery to stabilize the anterior chamber. All patients completed a visual quality questionnaire before surgery and 2 and 6 weeks after surgery. Results were compared using the Wilcoxon test. After surgery, there was a reduction in visual quality in all patients. Patients who received atropine eye drops described a greater and longer-lasting reduction in visual quality than those who did not receive atropine eye drops. Trabeculectomy often leads to a transient reduction in visual quality. This reduction was greater in severity and duration in patients who received postoperative atropine eye drops. Thus, unless there is an underlying medical necessity, we would discourage the application of atropine as a standard therapy for trabeculectomy surgery.