bluuebunny/crossref_metadata_2025 huggingface dataset:
RVE1, DBB1b, and COL2 Transcription Factors Are Responsive to Combined Stress by UV-B Radiation and Cold in Bell Pepper (Capsicum annuum)
Authors: Morales-Merida Brandon Estefano , Grimaldi-Olivas Jesús Christian , Cruz-Mendívil Abraham , Villicaña Claudia , Valdez-Torres José Benigno , Heredia José Basilio , León-Chan Rubén , Lightbourn-Rojas Luis Alberto , León-Félix Josefina
Published: June 2023

Ultraviolet-B radiation (UV-B) and cold limit the growth and development of plants, which generates changes in gene expression. This allows plants to respond to stress through regulatory proteins, such as transcription factors, that activate or repress the expression of stress-response genes. RNA-Seq data and WGCNA analyses were utilized to identify the hub genes. Our study found a total of 25, 24, and 29 transcription factors at different time points T1, T2, and T3, respectively, under combined stress (ultraviolet-B radiation and cold). RVE1 (MYB-related), COL2 (CO-like), and DBB1b (DBB) were identified as candidate hub genes. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment showed that RVE1, DBB1b, and COL2 were mostly involved in energy production, the antioxidant system (enzymatic and non-enzymatic), signaling through abscisic acid and CA2+, response to light stimulus, and cellular homeostasis. These findings provide the basis for further investigation related to UV-B radiation and cold stress response mechanisms in plants.
Advanced Sentiment Analysis for Managing and Improving Patient Experience: Application for General Practitioner (GP) Classification in Northamptonshire
Authors: Pandey Aavash Raj , Seify Mahdi , Okonta Udoka , Hosseinian-Far Amin
Published: June 2023

This paper presents a novel analytical approach for improving patients’ experience in healthcare settings. The analytical tool uses a classifier and a recommend management approach to facilitate decision making in a timely manner. The designed methodology comprises of 4 key stages, which include developing a bot to scrap web data while performing sentiment analysis and extracting keywords from National Health Service (NHS) rate and review webpages, building a classifier with Waikato Environment for Knowledge Analysis (WEKA), analyzing speech with Python, and using Microsoft Excel for analysis. In the selected context, a total of 178 reviews were extracted from General Practitioners (GP) websites within Northamptonshire County, UK. Accordingly, 4764 keywords such as “kind”, “exactly”, “discharged”, “long waits”, “impolite staff”, “worse”, “problem”, “happy”, “late” and “excellent” were selected. In addition, 178 reviews were analyzed to highlight trends and patterns. The classifier model grouped GPs into gold, silver, and bronze categories. The outlined analytical approach complements the current patient feedback analysis approaches by GPs. This paper solely relied upon the feedback available on the NHS’ rate and review webpages. The contribution of the paper is to highlight the integration of easily available tools to perform higher level of analysis that provides understanding about patients’ experience. The context and tools used in this study for ranking services within the healthcare domain is novel in nature, since it involves extracting useful insights from the provided feedback.
Molecular Research in Rice
Authors: Subudhi Prasanta K.
Published: June 2023

Rice is the most important source of nutrition for approximately half of the human population [...]
Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation
Authors: Grajek Julia , Poleszczuk Jan
Published: June 2023

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid malignancies, including non-small-cell lung cancer. However, immunotherapy resistance constitutes a significant challenge. To investigate carbonic anhydrase IX (CAIX) as a driver of resistance, we built a differential equation model of tumor–immune interactions. The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs. Numerical simulations showed that, given an efficient immune response, CAIX KO tumors tended toward tumor elimination in contrast to their CAIX-expressing counterparts, which stabilized close to the positive equilibrium. Importantly, we demonstrated that short-term combination therapy with a CAIX inhibitor and immunotherapy could shift the asymptotic behavior of the original model from stable disease to tumor eradication. Finally, we calibrated the model with data from murine experiments on CAIX suppression and combination therapy with anti-PD-1 and anti-CTLA-4. Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs.
Nutrition and Gut Health: Recent Advances and Implications for Development of Functional Foods
Authors: Wu Guoyao
Published: June 2023

The small intestine is a highly differentiated and complex organ with many nutritional, physiological, and immunological functions [...]
Optimization of Mass Spectrometry Imaging for Drug Metabolism and Distribution Studies in the Zebrafish Larvae Model: A Case Study with the Opioid Antagonist Naloxone
Authors: Park Yu Mi , Meyer Markus R. , Müller Rolf , Herrmann Jennifer
Published: June 2023

Zebrafish (ZF; Danio rerio) larvae have emerged as a promising in vivo model in drug metabolism studies. Here, we set out to ready this model for integrated mass spectrometry imaging (MSI) to comprehensively study the spatial distribution of drugs and their metabolites inside ZF larvae. In our pilot study with the overall goal to improve MSI protocols for ZF larvae, we investigated the metabolism of the opioid antagonist naloxone. We confirmed that the metabolic modification of naloxone is in high accordance with metabolites detected in HepaRG cells, human biosamples, and other in vivo models. In particular, all three major human metabolites were detected at high abundance in the ZF larvae model. Next, the in vivo distribution of naloxone was investigated in three body sections of ZF larvae using LC-HRMS/MS showing that the opioid antagonist is mainly present in the head and body sections, as suspected from published human pharmacological data. Having optimized sample preparation procedures for MSI (i.e., embedding layer composition, cryosectioning, and matrix composition and spraying), we were able to record MS images of naloxone and its metabolites in ZF larvae, providing highly informative distributional images. In conclusion, we demonstrate that all major ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters, as part of in vivo pharmacokinetic studies, can be assessed in a simple and cost-effective ZF larvae model. Our established protocols for ZF larvae using naloxone are broadly applicable, particularly for MSI sample preparation, to various types of compounds, and they will help to predict and understand human metabolism and pharmacokinetics.
The Role of EMT-Related lncRNAs in Ovarian Cancer
Authors: Lampropoulou Dimitra Ioanna , Papadimitriou Marios , Papadimitriou Christos , Filippou Dimitrios , Kourlaba Georgia , Aravantinos Gerasimos , Gazouli Maria
Published: June 2023

Ovarian cancer (OC) is one of the deadliest cancers worldwide; late diagnosis and drug resistance are two major factors often responsible for high morbidity and treatment failure. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that has been closely linked with cancer. Long non-coding RNAs (lncRNAs) have been also associated with several cancer-related mechanisms, including EMT. We conducted a literature search in the PubMed database in order to sum up and discuss the role of lncRNAs in regulating OC-related EMT and their underlying mechanisms. Seventy (70) original research articles were identified, as of 23 April 2023. Our review concluded that the dysregulation of lncRNAs is highly associated with EMT-mediated OC progression. A comprehensive understanding of lncRNAs’ mechanisms in OC will help in identifying novel and sensitive biomarkers and therapeutic targets for this malignancy.
In Vitro Study of Zirconia Surface Modification for Dental Implants by Atomic Layer Deposition
Authors: Hayashi Tatsuhide , Asakura Masaki , Koie Shin , Hasegawa Shogo , Mieki Akimichi , Aimu Koki , Kawai Tatsushi
Published: June 2023

Zirconia is a promising material for dental implants; however, an appropriate surface modification procedure has not yet been identified. Atomic layer deposition (ALD) is a nanotechnology that deposits thin films of metal oxides or metals on materials. The aim of this study was to deposit thin films of titanium dioxide (TiO2), aluminum oxide (Al2O3), silicon dioxide (SiO2), and zinc oxide (ZnO) on zirconia disks (ZR-Ti, ZR-Al, ZR-Si, and ZR-Zn, respectively) using ALD and evaluate the cell proliferation abilities of mouse fibroblasts (L929) and mouse osteoblastic cells (MC3T3-E1) on each sample. Zirconia disks (ZR; diameter 10 mm) were fabricated using a computer-aided design/computer-aided manufacturing system. Following the ALD of TiO2, Al2O3, SiO2, or ZnO thin film, the thin-film thickness, elemental distribution, contact angle, adhesion strength, and elemental elution were determined. The L929 and MC3T3-E1 cell proliferation and morphologies on each sample were observed on days 1, 3, and 5 (L929) and days 1, 4, and 7 (MC3T3-E1). The ZR-Ti, ZR-Al, ZR-Si, and ZR-Zn thin-film thicknesses were 41.97, 42.36, 62.50, and 61.11 nm, respectively, and their average adhesion strengths were 163.5, 140.9, 157.3, and 161.6 mN, respectively. The contact angle on ZR-Si was significantly lower than that on all the other specimens. The eluted Zr, Ti, and Al amounts were below the detection limits, whereas the total Si and Zn elution amounts over two weeks were 0.019 and 0.695 ppm, respectively. For both L929 and MC3T3-E1, the cell numbers increased over time on ZR, ZR-Ti, ZR-Al, and ZR-Si. Particularly, cell proliferation in ZR-Ti exceeded that in the other samples. These results suggest that ALD application to zirconia, particularly for TiO2 deposition, could be a new surface modification procedure for zirconia dental implants.
Changes in the Subchondral Bone, Visfatin, and Cartilage Biomarkers after Pharmacological Treatment of Experimental Osteoarthritis with Metformin and Alendronate
Authors: Lambova Sevdalina Nikolova , Ivanovska Nina , Stoyanova Stela , Belenska-Todorova Lyudmila , Georgieva Elenka , Batsalova Tsvetelina , Moten Dzhemal , Apostolova Desislava , Dzhambazov Balik
Published: June 2023

Subchondral bone that has intense communication with the articular cartilage might be a potential target for pharmacological treatment in the early stages of osteoarthritis (OA). Considering the emerging data about the role of adipokines in the pathogenesis of OA, the administration of drugs that influence their level is also intriguing. Metformin and alendronate were administered in mice with collagenase-induced OA (CIOA) as a monotherapy and in combination. Safranin O staining was used for the assessment of changes in subchondral bone and articular cartilage. Before and after treatment, serum levels of visfatin and biomarkers of cartilage turnover (CTX-II, MMP-13, and COMP) were assessed. In the current study, the combined administration of alendronate and metformin in mice with CIOA led to the protection against cartilage and subchondral bone damage. In mice with CIOA, metformin led to a decrease in visfatin level. In addition, treatment with metformin, alendronate, or their combination lowered the level of cartilage biomarkers (CTX-II and COMP), while the level of MMP-13 was not influenced. In conclusion, personalized combination treatment in OA according to clinical phenotype, especially in the early stages of the disease, might lead to the identification of a successful disease-modifying therapeutic protocol in OA.
An In Vitro Alveolar Model Allows for the Rapid Assessment of Particles for Respiratory Sensitization Potential
Authors: Gibb Matthew , Sayes Christie M.
Published: June 2023

Dust, both industrial and household, contains particulates that can reach the most distal aspects of the lung. Silica and nickel compounds are two such particulates and have known profiles of poor health outcomes. While silica is well-characterized, nickel compounds still need to be fully understood for their potential to cause long-term immune responses in the lungs. To assess these hazards and decrease animal numbers used in testing, investigations that lead to verifiable in vitro methods are needed. To understand the implications of these two compounds reaching the distal aspect of the lungs, the alveoli, an architecturally relevant alveolar model consisting of epithelial cells, macrophages, and dendritic cells in a maintained submerged system, was utilized for high throughput testing. Exposures include crystalline silica (SiO2) and nickel oxide (NiO). The endpoints measured included mitochondrial reactive oxygen species and cytostructural changes assessed via confocal laser scanning microscopy; cell morphology evaluated via scanning electron microscopy; biochemical reactions assessed via protein arrays; transcriptome assessed via gene arrays, and cell surface activation markers evaluated via flow cytometry. The results showed that, compared to untreated cultures, NiO increased markers for dendritic cell activation, trafficking, and antigen presentation; oxidative stress and cytoskeletal changes, and gene and cytokine expression of neutrophil and other leukocyte chemoattractants. The chemokines and cytokines CCL3, CCL7, CXCL5, IL-6, and IL-8 were identified as potential biomarkers of respiratory sensitization.
The Role of Diabetic Choroidopathy in the Pathogenesis and Progression of Diabetic Retinopathy
Authors: Scuderi Luca , Fragiotta Serena , Di Pippo Mariachiara , Abdolrahimzadeh Solmaz
Published: June 2023

Diabetic choroidopathy was first described on histopathological specimens of diabetic eyes. This alteration was characterized by the accumulation of PAS-positive material within the intracapillary stroma. Inflammation and polymorphonuclear neutrophils (PMNs) activation are crucial elements in choriocapillaris impairment. The evidence of diabetic choroidopathy in vivo was confirmed with multimodal imaging, which provides key quantitative and qualitative features to characterize the choroidal involvement. The choroid can be virtually affected in each vascular layer, from Haller’s layer to the choriocapillaris. However, the damage on the outer retina and photoreceptor cells is essentially driven by a choriocapillaris deficiency, which can be assessed through optical coherence tomography angiography (OCTA). The identification of characteristic features of diabetic choroidopathy can be significant for understanding the potential pathogenic and prognostic implications in diabetic retinopathy.
Neutralizing Antibodies in COVID-19 Serum from Tatarstan, Russia
Authors: Hamza Shaimaa , Martynova Ekaterina , Garanina Ekaterina , Shakirova Venera , Bilalova Alisa , Moiseeva Svetlana , Khaertynova Ilsiyar , Ohlopkova Olesia , Blatt Nataliya , Markelova Maria , Khaiboullina Svetlana
Published: June 2023

The severity of COVID-19 is a result of the complex interplay between various branches of the immune system. However, our understanding of the role of neutralizing antibodies and the activation of cellular immune response in COVID-19 pathogenesis remains limited. In this study, we investigated neutralizing antibodies in patients with mild, moderate, and severe COVID-19, analyzing their cross-reactivity with the Wuhan and Omicron variants. We also assessed the activation of the immune response by measuring serum cytokines in patients with mild, moderate, and severe COVID-19. Our findings suggest the early activation of neutralizing antibodies in moderate COVID-19 compared to mild cases. We also observed a strong correlation between the cross-reactivity of neutralizing antibodies to the Omicron and Wuhan variants and the severity of the disease. In addition, we found that Th1 lymphocyte activation was present in mild and moderate cases, while inflammasomes and Th17 lymphocytes were activated in severe COVID-19. In conclusion, our data indicate that the early activation of neutralizing antibodies is evident in moderate COVID-19, and there is a strong correlation between the cross-reactivity of neutralizing antibodies and the severity of the disease. Our findings suggest that the Th1 immune response may play a protective role, while inflammasome and Th17 activation may be involved in severe COVID-19.
Molecular and Functional Relevance of NaV1.8-Induced Atrial Arrhythmogenic Triggers in a Human SCN10A Knock-Out Stem Cell Model
Authors: Hartmann Nico , Knierim Maria , Maurer Wiebke , Dybkova Nataliya , Hasenfuß Gerd , Sossalla Samuel , Streckfuss-Bömeke Katrin
Published: June 2023

In heart failure and atrial fibrillation, a persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV1.8 contributes to arrhythmogenesis by inducing a INaL. Genome-wide association studies indicate that mutations in the SCN10A gene (NaV1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the INaL and action potential duration. Ca2+ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca2+ leak. The INaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of NaV1.8. No effects on atrial APD90 were detected in any groups. Both SCN10A KO and specific blockers of NaV1.8 led to decreased Ca2+ spark frequency and a significant reduction of arrhythmogenic Ca2+ waves. Our experiments demonstrate that NaV1.8 contributes to INaL formation in human atrial CMs and that NaV1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore NaV1.8 could be a new target for antiarrhythmic strategies.
Plasma Pattern of Extracellular Vesicles Isolated from Hepatitis C Virus Patients and Their Effects on Human Vascular Endothelial Cells
Authors: Grossini Elena , Smirne Carlo , Venkatesan Sakthipriyan , Tonello Stelvio , D’Onghia Davide , Minisini Rosalba , Cantaluppi Vincenzo , Sainaghi Pier Paolo , Comi Cristoforo , Tanzi Adele , Bussolati Benedetta , Pirisi Mario
Published: June 2023

Hepatitis C virus (HCV) patients are at increased risk of cardiovascular disease (CVD). In this study, we aimed to evaluate the role of extracellular vesicles (EVs) as pathogenic factors for the onset of HCV-related endothelial dysfunction. Sixty-five patients with various stages of HCV-related chronic liver disease were enrolled in this case series. Plasma EVs were characterized and used to stimulate human vascular endothelial cells (HUVEC), which were examined for cell viability, mitochondrial membrane potential, and reactive oxygen species (ROS) release. The results showed that EVs from HCV patients were mainly of endothelial and lymphocyte origin. Moreover, EVs were able to reduce cell viability and mitochondrial membrane potential of HUVEC, while increasing ROS release. Those harmful effects were reduced by the pretreatment of HUVEC with the NLR family pyrin domain containing 3 (NLRP3)/AMP-activated protein kinase and protein kinase B blockers. In conclusion, in HCV patients, we could highlight a circulating pattern of EVs capable of inducing damage to the endothelium. These data represent a novel possible pathogenic mechanism underlying the reported increase of CVD occurrence in HCV infection and could be of clinical relevance also in relation to the widespread use of antiviral drugs.
Abnormal Spontaneous Discharges of Primary Sensory Neurons and Pain Behavior in a Rat Model of Vascular Dementia
Authors: Song Xiaodan , Wang Yuchen , Yang Wei , Wang Yingji , Yang Chunjuan , Chen Zhiyong
Published: June 2023

Patients with vascular dementia experience more pain than healthy elders, potentially due to the presence of central neuropathic pain. However, the mechanisms underlying neuropathic pain in vascular dementia remain poorly understood, and there is currently a lack of effective treatment available. In this study, a rat model of vascular dementia was induced by permanently occluding the common carotid arteries bilaterally (2-VO). The cognitive impairments in the 2-VO rats were evaluated using the Morris Water Maze test, while HE and LBF staining were employed to assess brain tissue lesions in the hippocampal, cerebral cortex, and white matter regions known to be associated with severe memory and learning deficits. Furthermore, pain-related behavioral tests, including mechanical and thermal stimuli assessments, were conducted, and in vivo electrophysiological recordings of primary sensory neurons were performed. Compared to sham-operated and pre-operative rats, rats with vascular dementia exhibited mechanical allodynia and thermal hyperalgesia 30 days after surgery. Furthermore, in vivo electrophysiology revealed a significant increase in the occurrence of spontaneous activity of Aβ- and C-fiber sensory neurons in the rat model of vascular dementia. These results indicate that neuropathic pain behaviors developed in the rat model of vascular dementia, and abnormal spontaneous discharges of primary sensory neurons may play a crucial role in the development of pain after vascular dementia.
Circadian Rhythm Does Not Affect the miRNA Cargo of Bovine Raw Milk Extracellular Vesicles
Authors: Saenz-de-Juano Mara D. , Silvestrelli Giulia , Ulbrich Susanne E.
Published: June 2023

Extracellular vesicles (EVs) and their microRNA (miRNA) cargo have been proposed as possible mammary gland health biomarkers in cattle. However, throughout the day, the biologically active milk components, such as miRNAs, may change due to the dynamic nature of milk. The current study aimed to evaluate the circadian fluctuation of milk EVs miRNA cargo to assess the feasibility of milk EVs as future biomarkers for mammary gland health management. Milk from four healthy dairy cows was collected for four consecutive days in the two daily milking sessions in the morning and the evening. The isolated EVs were heterogeneous, intact, and carried the EV protein markers CD9, CD81, and TSG101, as shown by transmission electron microscopy and western blot. The miRNA sequencing results demonstrate that the abundance of miRNA cargo in milk EVs remained stable, unlike other milk components, such as somatic cells, that changed during milking sessions. These findings indicated that the miRNA cargo within milk EVs remains stable irrespective of the time of day, suggesting their potential utility as diagnostic markers for mammary gland health.
Light-Dependent Expression and Promoter Methylation of the Genes Encoding Succinate Dehydrogenase, Fumarase, and NAD-Malate Dehydrogenase in Maize (Zea mays L.) Leaves
Authors: Eprintsev Alexander T. , Fedorin Dmitry N. , Igamberdiev Abir U.
Published: June 2023

The expression and methylation of promoters of the genes encoding succinate dehydrogenase, fumarase, and NAD-malate dehydrogenase in maize (Zea mays L.) leaves depending on the light regime were studied. The genes encoding the catalytic subunits of succinate dehydrogenase showed suppression of expression upon irradiation by red light, which was abolished by far-red light. This was accompanied by an increase in promoter methylation of the gene Sdh1-2 encoding the flavoprotein subunit A, while methylation was low for Sdh2-3 encoding the iron-sulfur subunit B under all conditions. The expression of Sdh3-1 and Sdh4 encoding the anchoring subunits C and D was not affected by red light. The expression of Fum1 encoding the mitochondrial form of fumarase was regulated by red and far-red light via methylation of its promoter. Only one gene encoding the mitochondrial NAD-malate dehydrogenase gene (mMdh1) was regulated by red and far-red light, while the second gene (mMdh2) did not respond to irradiation, and neither gene was controlled by promoter methylation. It is concluded that the dicarboxylic branch of the tricarboxylic acid cycle is regulated by light via the phytochrome mechanism, and promoter methylation is involved with the flavoprotein subunit of succinate dehydrogenase and the mitochondrial fumarase.
SDS-PAGE-Based Quantitative Assay of Hemolymph Proteins in Honeybees: Progress and Prospects for Field Application
Authors: Isani Gloria , Bellei Elisa , Rudelli Cecilia , Cabbri Riccardo , Ferlizza Enea , Andreani Giulia
Published: June 2023

In human and veterinary medicine, serum proteins are considered to be useful biomarkers for assessing the health and nutritional status of the organism. Honeybee hemolymph has a unique proteome that could represent a source of valuable biomarkers. Therefore, the aims of this study were to separate and identify the most abundant proteins in the hemolymph of worker honeybees to suggest a panel of these proteins that could represent useful biomarkers for assessing the nutritional and health status of the colonies and, finally, to analyze them in different periods of the year. Four apiaries were selected in the province of Bologna, and the bees were analyzed in April, May, July, and November. Thirty specimens from three hives of each apiary were sampled and their hemolymph was collected. The most represented bands obtained after 1D sodium-dodecyl-sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) were cut from the gel, and the proteins were identified using an LC-ESI-Q-MS/MS System. A total of twelve proteins were unmistakably identified; the two most abundant proteins were apolipophorin and vitellogenin, which are known biomarkers of bee trophic and health status. The two other proteins identified were transferrin and hexamerin 70a, the first being involved in iron homeostasis and the second being a storage protein. Most of these proteins showed an increase from April to November, mirroring the physiological changes of honeybees during the productive season. The current study suggests a panel of biomarkers from honeybee hemolymph worth testing under different physiological and pathological field conditions.
Oxidative Stress and Skeletal Muscle Function
Authors: Duranti Guglielmo
Published: June 2023

Skeletal muscle is continuously exposed during its activities to mechanical/oxidative damage [...]
Posttranslational Modification of Human Cytochrome CYP4F11 by 4-Hydroxynonenal Impairs ω-Hydroxylation in Malaria Pigment Hemozoin-Fed Monocytes: The Role in Malaria Immunosuppression
Authors: Skorokhod Oleksii , Triglione Vincenzo , Barrera Valentina , Di Nardo Giovanna , Valente Elena , Ulliers Daniela , Schwarzer Evelin , Gilardi Gianfranco
Published: June 2023

Malaria is a frequent parasitic infection becomes life threatening due to the disequilibrated immune responses of the host. Avid phagocytosis of malarial pigment hemozoin (HZ) and HZ-containing Plasmodium parasites incapacitates monocyte functions by bioactive lipoperoxidation products 4-hydroxynonenal (4-HNE) and hydroxyeicosatetraenoic acids (HETEs). CYP4F conjugation with 4-HNE is hypothesised to inhibit ω-hydroxylation of 15-HETE, leading to sustained monocyte dysfunction caused by 15-HETE accumulation. A combined immunochemical and mass-spectrometric approach identified 4-HNE-conjugated CYP4F11 in primary human HZ-laden and 4-HNE-treated monocytes. Six distinct 4-HNE-modified amino acid residues were revealed, of which C260 and H261 are localized in the substrate recognition site of CYP4F11. Functional consequences of enzyme modification were investigated on purified human CYP4F11. Palmitic acid, arachidonic acid, 12-HETE, and 15-HETE bound to unconjugated CYP4F11 with apparent dissociation constants of 52, 98, 38, and 73 µM, respectively, while in vitro conjugation with 4-HNE completely blocked substrate binding and enzymatic activity of CYP4F11. Gas chromatographic product profiles confirmed that unmodified CYP4F11 catalysed the ω-hydroxylation while 4-HNE-conjugated CYP4F11 did not. The 15-HETE dose dependently recapitulated the inhibition of the oxidative burst and dendritic cell differentiation by HZ. The inhibition of CYP4F11 by 4-HNE with consequent accumulation of 15-HETE is supposed to be a crucial step in immune suppression in monocytes and immune imbalance in malaria.
Transcription Factor TaMYB30 Activates Wheat Wax Biosynthesis
Authors: Liu Lang , Li Haoyu , Wang Xiaoyu , Chang Cheng
Published: June 2023

The waxy cuticle covers a plant’s aerial surface and contributes to environmental adaptation in land plants. Although past decades have seen great advances in understanding wax biosynthesis in model plants, the mechanisms underlying wax biosynthesis in crop plants such as bread wheat remain to be elucidated. In this study, wheat MYB transcription factor TaMYB30 was identified as a transcriptional activator positively regulating wheat wax biosynthesis. The knockdown of TaMYB30 expression using virus-induced gene silencing led to attenuated wax accumulation, increased water loss rates, and enhanced chlorophyll leaching. Furthermore, TaKCS1 and TaECR were isolated as essential components of wax biosynthetic machinery in bread wheat. In addition, silencing TaKCS1 and TaECR resulted in compromised wax biosynthesis and potentiated cuticle permeability. Importantly, we showed that TaMYB30 could directly bind to the promoter regions of TaKCS1 and TaECR genes by recognizing the MBS and Motif 1 cis-elements, and activate their expressions. These results collectively demonstrated that TaMYB30 positively regulates wheat wax biosynthesis presumably via the transcriptional activation of TaKCS1 and TaECR.
Delayed Biotin Therapy in a Child with Atypical Profound Biotinidase Deficiency: Late Arrival of the Truth and a Lesson Worth Thinking
Authors: Liu Shu , Zhang Ye , Deng Zhi , He Hui , Zheng Xianhua , Hong Qingshan , Luo Xianqiong
Published: June 2023

Biotinidase (BTD) deficiency (OMIM 253260) is an autosomal recessively inherited metabolic disorder resulting from deficient activity of the BTD enzyme, which can cleave and release biotin from a variety of biotin-dependent carboxylases, and is therefore recognized as a tool to recycle biotin. Being a condition caused by variations on BTD gene with a consequence of free biotin shortage, BTD deficiency may impair the activity of biotin-dependent carboxylases, and thus bring about a buildup of potentially toxic compounds in the body, primarily 3-hydroxyisovaleryl-carnitine in plasma as well as 3-hydroxyisovaleric acid in urine. The phenotype of BTD deficiency may vary dramatically, from asymptomatic adults to severe neurological anomalies, even death in infancy. In the present study, we reported on a 5-month-old boy, whose parents sought for medical consultation in our clinic for their son due to his loss of consciousness, repeated tetany, and motor retardation. Detailed clinical features included severe psychomotor retardation, hypotonia, as well as failure to thrive. The brain MRI at 12 months showed cerebellar hypoplasia and multiple foci of leukodystrophy. The result of antiepileptic therapy was not satisfying. During hospitalization, BTD deficiency was suggested by elevated concentration of 3-hydroxyisovaleryl-carnitine in the blood spots and 3-hydroxyisovaleric acid in the urine. The child was then diagnosed with profound BTD deficiency based on the above findings and low BTD enzyme activity. Subsequent mutational analysis revealed a novel homozygous variant, c.637_637delC (p.H213Tfs*51) in exon 4 of BTD gene in the proband, which was recognized as a further support to the diagnosis. Therefore, biotin treatment was started immediately, eventually with satisfactory outcomes achieved in terms of prevention of epileptic seizure, performance in deep tendon reflexes, and improvement of muscular hypotonia, but unfortunately, the therapy failed to show any evident effects on poor feeding and intellectual disability. This painful lesson suggests that newborn screening for inherited metabolic diseases is essential for early identification and treatment, which should have been performed in this case to avoid this tragedy.
Proteolytic Resistance Determines Albumin Nanoparticle Drug Delivery Properties and Increases Cathepsin B, D, and G Expression
Authors: Kolesova Ekaterina P. , Egorova Vera S. , Syrocheva Anastasiia O. , Frolova Anastasiia S. , Kostyushev Dmitry , Kostyusheva Anastasiia , Brezgin Sergey , Trushina Daria B. , Fatkhutdinova Landysh , Zyuzin Mikhail , Demina Polina A. , Khaydukov Evgeny V. , Zamyatnin Andrey A. , Parodi Alessandro
Published: June 2023

Proteolytic activity is pivotal in maintaining cell homeostasis and function. In pathological conditions such as cancer, it covers a key role in tumor cell viability, spreading to distant organs, and response to the treatment. Endosomes represent one of the major sites of cellular proteolytic activity and very often represent the final destination of internalized nanoformulations. However, little information about nanoparticle impact on the biology of these organelles is available even though they represent the major location of drug release. In this work, we generated albumin nanoparticles with a different resistance to proteolysis by finely tuning the amount of cross-linker used to stabilize the carriers. After careful characterization of the particles and measurement of their degradation in proteolytic conditions, we determined a relationship between their sensitivity to proteases and their drug delivery properties. These phenomena were characterized by an overall increase in the expression of cathepsin proteases regardless of the different sensitivity of the particles to proteolytic degradation.
Histological Approach to the Study of Morphogenesis in Callus Cultures In Vitro: A Review
Authors: Kruglova Natalia , Zinatullina Anna , Yegorova Natalia
Published: June 2023

The use of in vitro callus cultures as experimental model systems allows us to get closer to understanding the patterns and features of morphogenesis in intact plants. In this regard, the problem of realizing the morphogenetic potential of callus cells due to their pluri- and totipotency properties is of great interest. To solve this problem, it is important to use the histological approach, which involves studying the structures of developing tissues, organs and organisms in their interactions and relationships. This review article analyzes data devoted to the study of the histological features of formed primary morphogenic calli (formation of morphogenetic centers and superficial meristematic zones), as well as the in vitro morphogenesis pathways in calli that lead to the formation of regenerants (de novo organogenesis and in vitro somatic embryogenesis). The terminology used is considered. Some questions for discussion are raised. The opinion is expressed that histological (structural) studies should be considered as a methodologic basis for further investigation of various morphogenetic scenarios in in vitro callus cultures, especially in economically valuable plants and for biotechnological purposes.
Revealing the Electrochemistry of All-Solid-State Li-SeS2 Battery via Transmission Electron Microscopy
Authors: Yan Rui , Liu Fangchao , Fu Zhengwen
Published: June 2023

Li-SeS2 batteries balance the opposing and complimentary qualities of Li-S and Li-Se batteries by having a high specific capacity and high electrical conductivity. However, there is still a lack of knowledge regarding the electrochemical characteristics of Li-SeS2 all-solid-state batteries (ASSB). Herein, transmission electron microscopy (TEM) is used to reveal the electrochemistry of a Li-SeS2 battery. It is discovered that, without the Polyethylene glycol (PEG), amorphous SeS2 in Li-SeS2 ASSB change into crystalline selenium and a small amount of sulfur. The continuous loss of sulfur from the active material may be related to the failure of the cell at 15 cycles and the severe instability of the Coulombic efficiency. It was found that the PEG coating selenium disulfide graphene composite (PEG@rGO-SeS2) cathode maintained a specific capacity of 258 mAh g−1 and a stable Coulombic efficiency of about 97% after 50 cycles. TEM analysis shows that the charging product remains as a granular amorphous selenium disulfide with a constant Se/S ratio during cycling. The PEG-protected selenium disulfide can effectively limit the loss of elemental sulfur and regulate the reaction mechanism of the Li-SeS2 batteries.
A Protein Asteroid with PIN Domain in Silkworm Bombyx mori Is Involved in Anti-BmNPV Infection
Authors: Xia Yuchen , Jiang Mouzhen , Hu Xiaoxuan , Wang Qing , Qian Cen , Zhu Baojian , Wei Guoqing , Wang Lei
Published: June 2023

Nuclease is a type of protein that degrades nucleic acids, which plays an important role in biological processes, including RNA interference efficiency and antiviral immunity. However, no evidence of a link between nuclease and Bombyx mori nucleopolyhedrovirus (BmNPV) infection in silkworm B. mori has been found. In this study, a protein asteroid (BmAst) containing the PIN domain and XPG domain was identified in silkworm B. mori. BmAst gene was highest expressed in hemocytes and fat body of the 5th instar larvae, and high expression in the pupa stage. The transcriptional levels of the BmAst gene in 5th instar larvae were significantly induced by BmNPV or dsRNA. After knocking down BmAst gene expression by specific dsRNA, the proliferation of BmNPV in B. mori was increased significantly, whereas the survival rate of larvae was significantly lower when compared with the control. Our findings indicate that BmAst is involved in silkworm resistance to BmNPV infection.
Relationship between Serum Cortisol, Dehydroepiandrosterone Sulfate (DHEAS) Levels, and Natural Killer Cell Activity: A Cross-Sectional Study
Authors: Suh Eunkyung , Cho A-Ra , Haam Ji-Hee , Gil Minchan , Lee Yun-Kyong , Kim Young-Sang
Published: June 2023

The adrenal steroid hormones, cortisol and dehydroepiandrosterone sulfate (DHEAS), are associated with the immune system in opposite actions. This study aimed to investigate the relationship between cortisol and DHEAS serum concentrations, their ratio (CDR), and natural killer cell activity (NKA). This cross-sectional study included 2275 subjects without current infection or inflammation in the final analyses. NKA was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells; low NKA was defined as IFN-γ level < 500 pg/mL. Cortisol, DHEAS levels, and CDRs were categorized by quartiles in men, premenopausal women, and postmenopausal women. Compared with the lowest quartile as reference, the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for low NKA of the highest cortisol and CDR group were 1.66 (1.09–2.51) and 1.68 (1.11–2.55) in men, 1.58 (1.07–2.33) and 2.33 (1.58–3.46) in premenopausal women, and 2.23 (1.28–3.87) and 1.85 (1.07–3.21) in postmenopausal women. Only in premenopausal women, the highest DHEAS group showed significantly lower risk of low NKA (OR: 0.51, 95% CI: 0.35–0.76). HPA axis activation indicated as high cortisol level, CDR was significantly associated with low NKA, while high DHEAS levels were inversely associated with low NKA in premenopausal women.
Factors Impacting the Use or Rejection of Hearing Aids—A Systematic Review and Meta-Analysis
Authors: Marcos-Alonso Susana , Almeida-Ayerve Cristina Nicole , Monopoli-Roca Chiara , Coronel-Touma Guillermo Salib , Pacheco-López Sofía , Peña-Navarro Paula , Serradilla-López José Manuel , Sánchez-Gómez Hortensia , Pardal-Refoyo José Luis , Batuecas-Caletrío Ángel
Published: June 2023

Purpose: To examine the prevalence of adherence to hearing aids and determine their rejection causes. Methods: This study was conducted according to the Preferred Reporting terms for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed an electronic search using PubMed, BVS, and Embase. Results: 21 studies that met the inclusion criteria were selected. They analyzed a total of 12,696 individuals. We observed that the most common causes for positive adherence to hearing aid use included having a higher degree of hearing loss, patients being aware of their condition, and requiring the device in their daily life. The most common causes for rejection were the lack of perceived benefits or discomfort with the use of the device. The results from the meta-analysis show a prevalence of patients who used their hearing aid of 0.623 (95% CI 0.531, 0.714). Both groups are highly heterogeneous (I2 = 99.31% in each group, p < 0.05). Conclusions: A significant proportion of patients (38%) do not use their hearing aid devices. Homogeneous multicenter studies using the same methodology are needed to analyze the causes of rejection of hearing aids.
Isolated Limb Infusion for Limb-Threatening, Unresectable Sarcoma: Past Progress, Current Applications, and Future Directions
Authors: DePalo Danielle K. , Zager Jonathan S.
Published: June 2023

Treatment of soft tissue sarcomas (STSs) is complicated by disease heterogeneity. Further, it has not benefitted much from the recent therapeutic advances in other soft tissue malignancies. Surgical resection remains the gold standard in resectable disease, but unresectable, locally advanced STS requires alternative and multimodal approaches. Isolated limb infusion (ILI) provides regional chemotherapy to extremity STS and offers the potential for limb salvage. Despite being in use for nearly 3 decades, there is limited literature on ILI in STS. This review provides an overview of patient eligibility, the procedure, significant publications in this field, and opportunities for further progress.
Endothelial and Hemodynamic Function in a Large Animal Model in Relation to Different Extracorporeal Membrane Oxygenation Cannulation Strategies and Intra-Aortic Balloon Pumping
Authors: Gerfer Stephen , Djordjevic Ilija , Maier Johanna , Movahed Ana , Elskamp Mara , Kuhn Elmar , Liakopoulos Oliver , Wahlers Thorsten , Deppe Antje C.
Published: June 2023

Background: The use of simultaneous veno-arterial extracorporeal membrane oxygenation (ECMO) with or without an Intra-Aortic Balloon Pump (IABP) is a widely used tool for mechanical hemodynamic support. Endothelial function, especially in relation to different cannulation techniques, is rarely investigated in the setting of extracorporeal life support (ECLS). In this study, we analyzed endothelial function in relation to hemodynamic and laboratory parameters for central and peripheral ECMO, with or without concomitant IABP support in a large animal model to gain a better understanding of the underlying basic mechanisms. Methods: In this large animal model, healthy female pigs with preserved ejection fraction were divided into the following groups related to cannulation strategy for ECMO and simultaneous IBAP support: control (no ECMO, no IABP), peripheral ECMO (pECMO), central ECMO (cECMO), pECMO and IABP or cECMO and IABP. During the experimental setting, the blood flow in the ascending aorta, left coronary artery and arteria carotis was measured. Afterwards, endothelial function was investigated after harvesting the right coronary artery, arteria carotis and renal artery. In addition, laboratory markers, such as creatine kinase (CK), creatine kinase muscle–brain (CK-MB), troponin, creatinine and endothelin were analyzed. Results: The blood flow in the ascending aorta and the left coronary artery was significantly lower in all discussed experimental settings compared to the control group. Of note, the cECMO cannulation strategy generated favorable hemodynamic circumstances with higher blood flow in the coronary arteries than pECMO regardless of flow circumstances in the ascending aorta. The concomitant usage of IABP did not result in an improvement of the coronary blood flow, but partially showed a negative impact on the endothelial function of coronary arteries in comparison to the control. These findings correlate to higher CK/CK-MB levels in the setting of cECMO + IABP and pECMO + IABP. Conclusions: The usage of mechanical circulatory support with concomitant ECMO and IABP in a large animal model might have an influence on the endothelial function of coronary arteries while not improving the coronary artery perfusion in healthy hearts with preserved ejection.
Timing of Lung Transplant Referral in Patients with Severe COVID-19 Lung Injury Supported by ECMO
Authors: Levy Liran , Deri Ofir , Huszti Ella , Nachum Eyal , Ledot Stephane , Shimoni Nir , Saute Milton , Sternik Leonid , Kremer Ran , Kassif Yigal , Zeitlin Nona , Frogel Jonathan , Lambrikov Ilya , Matskovski Ilia , Chatterji Sumit , Seluk Lior , Furie Nadav , Shafran Inbal , Mass Ronen , Onn Amir , Raanani Ehud , Grinberg Amir , Levy Yuval , Afek Arnon , Kreiss Yitshak , Kogan Alexander
Published: June 2023

Severe respiratory failure caused by COVID-19 often requires mechanical ventilation, including extracorporeal membrane oxygenation (ECMO). In rare cases, lung transplantation (LTx) may be considered as a last resort. However, uncertainties remain about patient selection and optimal timing for referral and listing. This retrospective study analyzed patients with severe COVID-19 who were supported by veno-venous ECMO and listed for LTx between July 2020 and June 2022. Out of the 20 patients in the study population, four who underwent LTx were excluded. The clinical characteristics of the remaining 16 patients were compared, including nine who recovered and seven who died while awaiting LTx. The median duration from hospitalization to listing was 85.5 days, and the median duration on the waitlist was 25.5 days. Younger age was significantly associated with a higher likelihood of recovery without LTx after a median of 59 days on ECMO, compared to those who died at a median of 99 days. In patients with severe COVID-19-induced lung damage supported by ECMO, referral to LTx should be delayed for 8–10 weeks after ECMO initiation, particularly for younger patients who have a higher probability of spontaneous recovery and may not require LTx.
Managing Early Onset Osteoporosis: The Impact of Premature Ovarian Insufficiency on Bone Health
Authors: Meczekalski Blazej , Niwczyk Olga , Bala Gregory , Szeliga Anna
Published: June 2023

Premature ovarian insufficiency is a reproductive endocrine disorder characterized by the cessation of ovarian function before the age of 40 years. Although the etiopathology of POI remains largely unknown, certain causative factors have been identified. Individuals affected by POI are at an increased risk of experiencing bone mineral density (BMD) loss. Hormonal replacement therapy (HRT) is recommended for patients with POI to mitigate the risk of decreased BMD, starting from the time of diagnosis until reaching the average age of natural menopause. Various studies have compared the dose-effect relationship of estradiol supplementation, as well as different HRT formulations on BMD. The impact of oral contraception on reduced BMD or the potential benefits of adding testosterone to estrogen replacement therapy are still subjects of ongoing discussion. This review provides an overview of the latest advancements in the diagnosis, evaluation, and treatment of POI as it relates to BMD loss.