bluuebunny/crossref_metadata_2025 huggingface dataset:
A Multi-Branch Training and Parameter-Reconstructed Neural Network for Assessment of Signal-to-Noise Ratio of Optical Remote Sensor on Orbit
Authors: Zhu Bo , Lv Xiaoning , Tan Congao , Xia Yuli , Zhao Junsuo
Published: February 2023

Signal-to-Noise Ratio (SNR) is the benchmark to evaluate the quality of optical remote sensors. For SNR estimation, most of the traditional methods have complicated processes, low efficiency, and general accuracy. In particular, they are not suitable for the distributed computation on intelligent satellites. Therefore, an intelligent SNR estimation algorithm with strong computing power and more accuracy is urgently needed. Considering the simplicity of distributed deployment and the lightweight goal, our first proposition is to design a convolutional neural network (CNN) similar to VGG (proposed by Visual Geometry Group) to estimate SNR for optical remote sensors. In addition, considering the advantages of multi-branch structures, the second proposition is to train the CNN in a novel method of multi-branch training and parameter-reconstructed inference. In this study, simulated and real remote sensing images with different ground features are utilized to validate the effectiveness of our model and the novel training method. The experimental results show that the novel training method enhances the fitting ability of the network, and the proposed CNN trained in this method has high accuracy and reliable SNR estimation, which achieves a 3.9% RMSE for noise-level-known simulated images. When compared to the accuracy of the reference methods, such as the traditional and typical SNR methods and the denoising convolutional neural network (DnCNN), the performance of the proposed CNN trained in a novel method is the best, which achieves a relative error of 5.5% for hyperspectral images. The study is fit for optical remote sensing images with complicated ground surfaces and different noise levels captured by different optical remote sensors.
Current Development of Chemical Penetration Enhancers for Transdermal Insulin Delivery
Authors: Sugumar Vaisnevee , Hayyan Maan , Madhavan Priya , Wong Won Fen , Looi Chung Yeng
Published: February 2023

The use of the transdermal delivery system has recently gained ample recognition due to the ability to deliver drug molecules across the skin membrane, serving as an alternative to conventional oral or injectable routes. Subcutaneous insulin injection is the mainstay treatment for diabetes mellitus which often leads to non-compliance among patients, especially in younger patients. Apart from its invasiveness, the long-term consequences of insulin injection cause the development of physical trauma, which includes lipohypertrophy at the site of administration, scarring, infection, and sometimes nerve damage. Hence, there is a quest for a better alternative to drug delivery that is non-invasive and easily adaptable. One of the potential solutions is the transdermal delivery method. However, the stratum corneum (the top layer of skin) is the greatest barrier in transporting large molecules like insulin. Therefore, various chemical enhancers have been proposed to promote stratum corneum permeability, or they are designed to increase the permeability of the full epidermis, such as the use of ionic liquid, peptides, chemical pre-treatment as well as packaging insulin with carriers or nanoparticles. In this review, the recent progress in the development of chemical enhancers for transdermal insulin delivery is discussed along with the possible mechanistic of action and the potential outlook on the proposed permeation approaches in comparison to other therapeutical drugs
Survival in Patients with Primary Parotid Gland Carcinoma after Surgery—Results of a Single-Centre Study
Authors: Carta Filippo , Bontempi Mauro , De Seta Daniele , Corrias Simone , Tatti Melania , Marrosu Valeria , Mariani Cinzia , Gerosa Clara , Shetty Sanjana Ashik , Atzeni Matteo , Buckley Christina , Figus Andrea , Puxeddu Roberto
Published: February 2023

This study aims to analyse a single-centre cohort series of patients who underwent parotidectomy for primary malignant parotid tumours. A retrospective chart review of 64 consecutive patients treated from November 2010 to March 2022 was performed. Outcomes were analysed by Kaplan-Meier curves. Sixty-four patients with a primary parotid malignancy were included in the study, with one bilateral case in this cohort. Patients were classified as stage I–II in 39 cases and stage III–IV in 26 cases. The five-year overall survival (OS), disease-specific survival (DSS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 78.4%, 89%, 92.5%, and 87.1%, respectively. Univariate analysis showed that high-risk histology, stage IV disease, lymphovascular invasion, perineural invasion, node metastasis, skin involvement, facial nerve involvement, and positive or close margins were risk factors associated with poorer outcomes. At present, the best evidence suggests that radical surgery should be the standard approach, and adjuvant therapy, in terms of radiotherapy/chemoradiotherapy, is recommended in patients with risk factors.
Sleep Apnea Detection Using Wavelet Scattering Transformation and Random Forest Classifier
Authors: Sharaf Ahmed I.
Published: February 2023

Obstructive Sleep Apnea (OSA) is a common sleep-breathing disorder that highly reduces the quality of human life. The most powerful method for the detection and classification of sleep apnea is the Polysomnogram. However, this method is time-consuming and cost-inefficient. Therefore, several methods focus on using electrocardiogram (ECG) signals to detect sleep apnea. This paper proposed a novel automated approach to detect and classify apneic events from single-lead ECG signals. Wavelet Scattering Transformation (WST) was applied to the ECG signals to decompose the signal into smaller segments. Then, a set of features, including higher-order statistics and entropy-based features, was extracted from the WST coefficients to formulate a search space. The obtained features were fed to a random forest classifier to classify the ECG segments. The experiment was validated using the 10-fold and hold-out cross-validation methods, which resulted in an accuracy of 91.65% and 90.35%, respectively. The findings were compared with different classifiers to show the significance of the proposed approach. The proposed approach achieved better performance measures than most of the existing methodologies.
Detecting Information Relays in Deep Neural Networks
Authors: Hintze Arend , Adami Christoph
Published: February 2023

Deep learning of artificial neural networks (ANNs) is creating highly functional processes that are, unfortunately, nearly as hard to interpret as their biological counterparts. Identification of functional modules in natural brains plays an important role in cognitive and neuroscience alike, and can be carried out using a wide range of technologies such as fMRI, EEG/ERP, MEG, or calcium imaging. However, we do not have such robust methods at our disposal when it comes to understanding functional modules in artificial neural networks. Ideally, understanding which parts of an artificial neural network perform what function might help us to address a number of vexing problems in ANN research, such as catastrophic forgetting and overfitting. Furthermore, revealing a network’s modularity could improve our trust in them by making these black boxes more transparent. Here, we introduce a new information-theoretic concept that proves useful in understanding and analyzing a network’s functional modularity: the relay information IR. The relay information measures how much information groups of neurons that participate in a particular function (modules) relay from inputs to outputs. Combined with a greedy search algorithm, relay information can be used to identify computational modules in neural networks. We also show that the functionality of modules correlates with the amount of relay information they carry.
Evidence of an Absence of Inbreeding Depression in a Wild Population of Weddell Seals (Leptonychotes weddellii)
Authors: Powell John H. , Kalinowski Steven T. , Taper Mark L. , Rotella Jay J. , Davis Corey S. , Garrott Robert A.
Published: February 2023

Inbreeding depression can reduce the viability of wild populations. Detecting inbreeding depression in the wild is difficult; developing accurate estimates of inbreeding can be time and labor intensive. In this study, we used a two-step modeling procedure to incorporate uncertainty inherent in estimating individual inbreeding coefficients from multilocus genotypes into estimates of inbreeding depression in a population of Weddell seals (Leptonychotes weddellii). The two-step modeling procedure presented in this paper provides a method for estimating the magnitude of a known source of error, which is assumed absent in classic regression models, and incorporating this error into inferences about inbreeding depression. The method is essentially an errors-in-variables regression with non-normal errors in both the dependent and independent variables. These models, therefore, allow for a better evaluation of the uncertainty surrounding the biological importance of inbreeding depression in non-pedigreed wild populations. For this study we genotyped 154 adult female seals from the population in Erebus Bay, Antarctica, at 29 microsatellite loci, 12 of which are novel. We used a statistical evidence approach to inference rather than hypothesis testing because the discovery of both low and high levels of inbreeding are of scientific interest. We found evidence for an absence of inbreeding depression in lifetime reproductive success, adult survival, age at maturity, and the reproductive interval of female seals in this population.
Valorization of Spent Brewer’s Yeast for the Production of High-Value Products, Materials, and Biofuels and Environmental Application
Authors: Zeko-Pivač Anđela , Habschied Kristina , Kulisic Biljana , Barkow Ingo , Tišma Marina
Published: February 2023

Spent brewer’s yeast (SBY) is a byproduct of the brewing industry traditionally used as a feed additive, although it could have much broader applications. In this paper, a comprehensive review of valorization of SBY for the production of high-value products, new materials, and biofuels, as well as environmental application, is presented. An economic perspective is given by mirroring marketing of conventional SBY with innovative high-value products. Cascading utilization of fine chemicals, biofuels, and nutrients such as proteins, carbohydrates, and lipids released by various SBY treatments has been proposed as a means to maximize the sustainable and circular economy.
The Effect of Business Intelligence on Bank Operational Efficiency and Perceptions of Profitability
Authors: Rahman Md. Mominur
Published: February 2023

The purpose of the study is to examine the effects of business intelligence on the bank’s operational efficiency and perceptions of profitability. The study is based on 259 responses from 27 branches of a commercial bank, employing a simple random sampling technique. This research uses the partial least square- structural equation method (PLS-SEM) method to test the hypotheses. The study verifies construct’s reliability and construct’s validity of the measurement model, and tests the fitness of the structural model. The study finds that business intelligence is positively associated with operational efficiency and profitability. Further, the study reveals that operational efficiency through business intelligence positively affects bank’s profitability. Based on competitive theory, this research states that business intelligence allows the productive entity to generate superior margins compared to its market rivals. Thus, banks can offer better options more cheaply than their rivals and thereby ensure competitive advantage. Further, based on resource-based view theory, the study argues that business intelligence as a strategic resource can provide the foundation to develop bank capabilities that can lead to superior performance over time. Therefore, the study implies business intelligence application in the banking companies and helps decision-making effectiveness for the management body of banks, academics, and policymakers.
Time-Dependent Numerical Modelling of Acoustic Cavitation in Liquid Metal Driven by Electromagnetic Induction
Authors: Djambazov Georgi
Published: February 2023

The numerically simulated method of using electromagnetic field from an alternating current is a patented method to create in liquid metal, under the conditions of resonance, acoustic waves of sufficient strength to cause cavitation and implosion of gas bubbles, leading to beneficial degassing and grain refinement. The modelling stages of electromagnetics are described below along with acoustics in liquids, bubble dynamics, and their interactions. Sample results are presented for a cylindrical container with liquid aluminium surrounded by an induction coil. The possibility of establishing acoustic resonance and sustaining the bubble oscillation at a useful level is demonstrated. Limitations of the time-dependent approach to this multi-physics modelling problem are also discussed.
A City in Dérive: Bucharest in Mihail Sebastian’s Journal 1935–1944: The Fascist Years
Authors: Levick Carmen
Published: February 2023

Mihail Sebastian’s Journal 1935–1944 accurately reflects the changing historical realities in Romania in general and in the capital city of Bucharest in particular, before and during the Second World War. As a Jewish Romanian writer, Sebastian records a landscape of ideological change that has a clear impact on him as a lawyer, an intellectual and a member of the city’s literary high society. This article proposes a new reading and analysis of Sebastian’s work, by focusing on the close relationship between the writer and the city as a vibrant, organic space. My work introduces a new critical vocabulary to the literary analysis of Sebastian’s Journal, through the use of terminology commonly employed by performance studies. The Situationist practices of walking and drifting, further conceptualised by performance studies scholar Carl Lavery, will be utilised as methods of exploring the visual and emotional richness of Sebastian’s work. The intimate relationship between the writer and the city will be constantly framed by the historical and political realities of the time, ensuring a balanced discussion of both literary achievement and historical witnessing.
Evaluation, Description and Magnitude of Readmission Phenomenon in Azienda Ospedaliero Universitaria Pisana (AOUP) for Chronic-Degenerative Diseases in the Period 2018–2021
Authors: Filippi Matteo , Del Prete Erika , Aquilini Ferruccio , Totaro Michele , Di Serafino Francesca , Civitelli Sara , Geminale Giulia , Rocchi David , Zotti Nunzio , Baggiani Angelo
Published: February 2023

Background: Readmissions are hospitalizations following a previous hospitalization (called index hospitalization) of the same patient that occurred in the same facility or nursing home. They may be a consequence of the progression of the natural history of a disease, but they may also reveal a previous suboptimal stay, or ineffective management of the underlying clinical condition. Preventing avoidable readmissions has the potential to improve both a patient’s quality of life, by avoiding exposure to the risks of re-hospitalization, and the financial well-being of health care systems. Methods: We investigated the magnitude of 30 day repeat hospitalizations for the same Major Diagnostic Category (MDC) in the Azienda Ospedaliero Universitaria Pisana (AOUP) over the period from 2018 to 2021. Records were divided into only admissions, index admissions and repeated admission. The length of the stay of all groups was compared using analysis of variance and subsequent multi-comparison tests. Results: Results showed a reduction in readmissions over the period examined (from 5.36% in 2018 to 4.46% in 2021), likely due to reduced access to care during the COVID-19 pandemic. We also observed that readmissions predominantly affect the male sex, older age groups, and patients with medical Diagnosis Related Groups (DRGs). The length of stay of readmissions was longer than that of index hospitalization (difference of 1.57 days, 95% CI 1.36–1.78 days, p < 0.001). The length of stay of index hospitalization is longer than that of single hospitalization (difference of 0.62 days, 95% CI 0.52–0.72 days, p < 0.001). Conclusions: A patient who goes for readmission thus has an overall hospitalization duration of almost two and a half times the length of the stay of a patient with single hospitalization, considering both index hospitalization and readmission. This represents a heavy use of hospital resources, about 10,200 more inpatient days than single hospitalizations, corresponding to a 30-bed ward working with an occupancy rate of 95%. Knowledge of readmissions is an important piece of information in health planning and a useful tool for monitoring the quality of models of patient care.
Climate Change and UNESCO World Heritage-Listed Cultural Properties: A Systematic Review, 2008–2021
Authors: Nguyen Ky Nam , Baker Sarah
Published: February 2023

Underpinned by the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) 2020 Statement, this systematic review analyses 58 peer-reviewed articles published during 2008–2021 and retrieved from Scopus and Google Scholar that address the relationship between climate change and UNESCO World Heritage-listed cultural properties. The review reveals a suite of observations that will be important to consider for future research, including: the significant increase in publications since 2008; the prevalence of scholarship focused on the region of Europe and North America; the diversity of research methods and approaches; the instances of climate change hazards; the numerous adaptation measures and barriers. The study also showcases a much greater scholarly concentration on natural sites compared to cultural sites, observing that a reliance on a nature/culture binary does not bode well for the effective safeguarding of cultural World Heritage sites. This article also highlights the need for greater representation from the Global South in terms of both geographic focus and authorship, the lack of collaboration between Science, Technology, Engineering and Mathematics (STEM) and Humanities, Arts and Social Science (HASS) disciplines, the capacity for collective action from different stakeholders, the importance of intangible elements, and the effects of both international and national legal frameworks and regulations.
Multiobjective Gate Assignment Model Considering Carbon Emissions
Authors: Shan Yixuan , Shao Yuwei , Yuan Qi , Jiang Yu
Published: February 2023

It has been a main concern for governments to reduce the carbon emission of the aviation industry. The paper proposes a multiobjective gate assignment model that considers the carbon emission at the airport surface to facilitate environmental-friendly airport construction. Three objectives are considered in the model to reduce carbon emissions, including the proportion of flights assigned to the contact gate, aircraft taxiing fuel consumption, and gate assignment robustness. In order to achieve better performance on all objectives, a Non-dominated Sorting Genetic Algorithm-II (NSGA-II) is used to obtain the optimal results. The operation data from a domestic airport is deployed to validate the model. The optimal results of the gate assignment model are compared with the original scheme. It indicates that the proposed model can effectively reduce carbon emissions. The study can provide a strategy for gate assignment to reduce carbon emissions and improve the management of the airport.
Molecular Mechanisms of the Protective Effects of Olive Leaf Polyphenols against Alzheimer’s Disease
Authors: Romero-Márquez Jose M. , Forbes-Hernández Tamara Y. , Navarro-Hortal María D. , Quirantes-Piné Rosa , Grosso Giuseppe , Giampieri Francesca , Lipari Vivian , Sánchez-González Cristina , Battino Maurizio , Quiles José L.
Published: February 2023

Alzheimer’s Disease (AD) is the cause of around 60–70% of global cases of dementia and approximately 50 million people have been reported to suffer this disease worldwide. The leaves of olive trees (Olea europaea) are the most abundant by-products of the olive grove industry. These by-products have been highlighted due to the wide variety of bioactive compounds such as oleuropein (OLE) and hydroxytyrosol (HT) with demonstrated medicinal properties to fight AD. In particular, the olive leaf (OL), OLE, and HT reduced not only amyloid-β formation but also neurofibrillary tangles formation through amyloid protein precursor processing modulation. Although the isolated olive phytochemicals exerted lower cholinesterase inhibitory activity, OL demonstrated high inhibitory activity in the cholinergic tests evaluated. The mechanisms underlying these protective effects may be associated with decreased neuroinflammation and oxidative stress via NF-κB and Nrf2 modulation, respectively. Despite the limited research, evidence indicates that OL consumption promotes autophagy and restores loss of proteostasis, which was reflected in lower toxic protein aggregation in AD models. Therefore, olive phytochemicals may be a promising tool as an adjuvant in the treatment of AD.
Metabolic Syndrome as a Risk Factor for Alzheimer’s Disease: A Focus on Insulin Resistance
Authors: Ezkurdia Amaia , Ramírez María J. , Solas Maite
Published: February 2023

Alzheimer’s disease (AD) is the main type of dementia and is a disease with a profound socioeconomic burden due to the lack of effective treatment. In addition to genetics and environmental factors, AD is highly associated with metabolic syndrome, defined as the combination of hypertension, hyperlipidemia, obesity and type 2 diabetes mellitus (T2DM). Among these risk factors, the connection between AD and T2DM has been deeply studied. It has been suggested that the mechanism linking both conditions is insulin resistance. Insulin is an important hormone that regulates not only peripheral energy homeostasis but also brain functions, such as cognition. Insulin desensitization, therefore, could impact normal brain function increasing the risk of developing neurodegenerative disorders in later life. Paradoxically, it has been demonstrated that decreased neuronal insulin signalling can also have a protective role in aging and protein-aggregation-associated diseases, as is the case in AD. This controversy is fed by studies focused on neuronal insulin signalling. However, the role of insulin action on other brain cell types, such as astrocytes, is still unexplored. Therefore, it is worthwhile exploring the involvement of the astrocytic insulin receptor in cognition, as well as in the onset and/or development of AD.
Molecular Mechanisms of Hyperoxia-Induced Neonatal Intestinal Injury
Authors: Wang Hsiao-Chin , Chou Hsiu-Chu , Chen Chung-Ming
Published: February 2023

Oxygen therapy is important for newborns. However, hyperoxia can cause intestinal inflammation and injury. Hyperoxia-induced oxidative stress is mediated by multiple molecular factors and leads to intestinal damage. Histological changes include ileal mucosal thickness, intestinal barrier damage, and fewer Paneth cells, goblet cells, and villi, effects which decrease the protection from pathogens and increase the risk of necrotizing enterocolitis (NEC). It also causes vascular changes with microbiota influence. Hyperoxia-induced intestinal injuries are influenced by several molecular factors, including excessive nitric oxide, the nuclear factor-κB (NF-κB) pathway, reactive oxygen species, toll-like receptor-4, CXC motif ligand-1, and interleukin-6. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathways and some antioxidant cytokines or molecules including interleukin-17D, n-acetylcysteine, arginyl-glutamine, deoxyribonucleic acid, cathelicidin, and health microbiota play a role in preventing cell apoptosis and tissue inflammation from oxidative stress. NF-κB and Nrf2 pathways are essential to maintain the balance of oxidative stress and antioxidants and prevent cell apoptosis and tissue inflammation. Intestinal inflammation can lead to intestinal damage and death of the intestinal tissue, such as in NEC. This review focuses on histologic changes and molecular pathways of hyperoxia-induced intestinal injuries to establish a framework for potential interventions.
mtR_find: A Parallel Processing Tool to Identify and Annotate RNAs Derived from the Mitochondrial Genome
Authors: Mohideen Asan M. S. H. , Johansen Steinar D. , Babiak Igor
Published: February 2023

RNAs originating from mitochondrial genomes are abundant in transcriptomic datasets produced by high-throughput sequencing technologies, primarily in short-read outputs. Specific features of mitochondrial small RNAs (mt-sRNAs), such as non-templated additions, presence of length variants, sequence variants, and other modifications, necessitate the need for the development of an appropriate tool for their effective identification and annotation. We have developed mtR_find, a tool to detect and annotate mitochondrial RNAs, including mt-sRNAs and mitochondria-derived long non-coding RNAs (mt-lncRNA). mtR_find uses a novel method to compute the count of RNA sequences from adapter-trimmed reads. When analyzing the published datasets with mtR_find, we identified mt-sRNAs significantly associated with the health conditions, such as hepatocellular carcinoma and obesity, and we discovered novel mt-sRNAs. Furthermore, we identified mt-lncRNAs in early development in mice. These examples show the immediate impact of miR_find in extracting a novel biological information from the existing sequencing datasets. For benchmarking, the tool has been tested on a simulated dataset and the results were concordant. For accurate annotation of mitochondria-derived RNA, particularly mt-sRNA, we developed an appropriate nomenclature. mtR_find encompasses the mt-ncRNA transcriptomes in unpreceded resolution and simplicity, allowing re-analysis of the existing transcriptomic databases and the use of mt-ncRNAs as diagnostic or prognostic markers in the field of medicine.
Irreversible Electroporation in Pancreatic Cancer—An Evolving Experimental and Clinical Method
Authors: Gajewska-Naryniecka Agnieszka , Szwedowicz Urszula , Łapińska Zofia , Rudno-Rudzińska Julia , Kielan Wojciech , Kulbacka Julita
Published: February 2023

Pancreatic cancer has no symptoms until the disease has advanced and is aggressive cancer with early metastasis. Up to now, the only curative treatment is surgical resection, which is possible in the early stages of the disease. Irreversible electroporation treatment offers new hope for patients with unresectable tumors. Irreversible electroporation (IRE) is a type of ablation therapy that has been explored as a potential treatment for pancreatic cancer. Ablation therapies involve the use of energy to destroy or damage cancer cells. IRE involves using high-voltage, low-energy electrical pulses to create resealing in the cell membrane, causing the cell to die. This review summarizes experiential and clinical findings in terms of the IRE applications. As was described, IRE can be a non-pharmacological approach (electroporation) or combined with anticancer drugs or standard treatment methods. The efficacy of irreversible electroporation (IRE) in eliminating pancreatic cancer cells has been demonstrated through both in vitro and in vivo studies, and it has been shown to induce an immune response. Nevertheless, further investigation is required to assess its effectiveness in human subjects and to comprehensively understand IRE’s potential as a treatment option for pancreatic cancer.
PD-L1, a Master Regulator of Immunity 2.0
Authors: Kochan Grazyna
Published: February 2023

Since the introduction of the first anticancer treatments at the beginning of the 20th century, many different chemotherapeutics have been developed [...]
The Effect of the Stress Induced by Hydrogen Peroxide and Corticosterone on Tryptophan Metabolism, Using Human Neuroblastoma Cell Line (SH-SY5Y)
Authors: Correia Ana Salomé , Silva Isabel , Reguengo Henrique , Oliveira José Carlos , Vasques-Nóvoa Francisco , Cardoso Armando , Vale Nuno
Published: February 2023

L-tryptophan (L-Trp) is an important amino acid in several physiological mechanisms, being metabolized into two important pathways: the kynurenine and the serotonin (5-HT) pathways. It is important in processes such as mood and stress response, the 5-HT pathway begins with the conversion of L-Trp to 5-hydroxytryptophan (5-HTP), that is metabolized into 5-HT, converted to melatonin or to 5-hydroxyindoleacetic acid (5-HIAA). Disturbances in this pathway are reported to be connected with oxidative stress and glucocorticoid-induced stress, are important to explore. Thus, our study aimed to understand the role of hydrogen peroxide (H2O2) and corticosterone (CORT)-induced stress on the serotonergic pathway of L-Trp metabolism, and on SH-SY5Y cells, focusing on the study of L-Trp, 5-HTP, 5-HT, and 5-HIAA in combination with H2O2 or CORT. We evaluated the effect of these combinations on cellular viability, morphology, and on the extracellular levels of the metabolites. The data obtained highlighted the different ways that stress induction led to different extracellular medium concentration of the studied metabolites. These distinct chemical transformations did not lead to differences in cell morphology/viability. Additionally, serotonin may be the most sensitive metabolite to the exposure to the different stress inducers, being more promissory to study conditions associated with cellular stress.
Impact of Acute High Glucose on Mitochondrial Function in a Model of Endothelial Cells: Role of PDGF-C
Authors: Rodríguez Adriana Grismaldo , Rodríguez Jairo Zamudio , Barreto Alfonso , Sanabria-Barrera Sandra , Iglesias José , Morales Ludis
Published: February 2023

An increase in plasma high glucose promotes endothelial dysfunction mainly through increasing mitochondrial ROS production. High glucose ROS—induced has been implicated in the fragmentation of the mitochondrial network, mainly by an unbalance expression of mitochondrial fusion and fission proteins. Mitochondrial dynamics alterations affect cellular bioenergetics. Here, we assessed the effect of PDGF-C on mitochondrial dynamics and glycolytic and mitochondrial metabolism in a model of endothelial dysfunction induced by high glucose. High glucose induced a fragmented mitochondrial phenotype associated with the reduced expression of OPA1 protein, high DRP1pSer616 levels and reduced basal respiration, maximal respiration, spare respiratory capacity, non-mitochondrial oxygen consumption and ATP production, regarding normal glucose. In these conditions, PDGF-C significantly increased the expression of OPA1 fusion protein, diminished DRP1pSer616 levels and restored the mitochondrial network. On mitochondrial function, PDGF-C increased the non-mitochondrial oxygen consumption diminished by high glucose conditions. These results suggest that PDGF-C modulates the damage induced by HG on the mitochondrial network and morphology of human aortic endothelial cells; additionally, it compensates for the alteration in the energetic phenotype induced by HG.
Cobalamin (Vitamin B12) in Anticancer Photodynamic Therapy with Zn(II) Phthalocyanines
Authors: Mantareva Vanya , Iliev Ivan , Sulikovska Inna , Durmuş Mahmut , Angelov Ivan
Published: February 2023

Photodynamic therapy (PDT) is a curative method, firstly developed for cancer therapy with fast response after treatment and minimum side effects. Two zinc(II) phthalocyanines (3ZnPc and 4ZnPc) and a hydroxycobalamin (Cbl) were investigated on two breast cancer cell lines (MDA-MB-231 and MCF-7) in comparison to normal cell lines (MCF-10 and BALB 3T3). The novelty of this study is a complex of non-peripherally methylpyridiloxy substituted Zn(II) phthalocyanine (3ZnPc) and the evaluation of the effects on different cell lines due to the addition of second porphyrinoid such as Cbl. The results showed the complete photocytotoxicity of both ZnPc-complexes at lower concentrations (<0.1 μM) for 3ZnPc. The addition of Cbl caused a higher phototoxicity of 3ZnPc at one order lower concentrations (<0.01 μM) with a diminishment of the dark toxicity. Moreover, it was determined that an increase of the selectivity index of 3ZnPc, from 0.66 (MCF-7) and 0.89 (MDA-MB-231) to 1.56 and 2.31, occurred by the addition of Cbl upon exposure with a LED 660 nm (50 J/cm2). The study suggested that the addition of Cbl can minimize the dark toxicity and improve the efficiency of the phthalocyanines for anticancer PDT applications.
Clinical Study of Metabolic Parameters, Leptin and the SGLT2 Inhibitor Empagliflozin among Patients with Obesity and Type 2 Diabetes
Authors: Szekeres Zsolt , Sandor Barbara , Bognar Zita , Ramadan Fadi H. J. , Palfi Anita , Bodis Beata , Toth Kalman , Szabados Eszter
Published: February 2023

Obesity is a major public health problem worldwide, and it is associated with many diseases and abnormalities, most importantly, type 2 diabetes. The visceral adipose tissue produces an immense variety of adipokines. Leptin is the first identified adipokine which plays a crucial role in the regulation of food intake and metabolism. Sodium glucose co-transport 2 inhibitors are potent antihyperglycemic drugs with various beneficial systemic effects. We aimed to investigate the metabolic state and leptin level among patients with obesity and type 2 diabetes mellitus, and the effect of empagliflozin upon these parameters. We recruited 102 patients into our clinical study, then we performed anthropometric, laboratory, and immunoassay tests. Body mass index, body fat, visceral fat, urea nitrogen, creatinine, and leptin levels were significantly lower in the empagliflozin treated group when compared to obese and diabetic patients receiving conventional antidiabetic treatments. Interestingly, leptin was increased not only among obese patients but in type 2 diabetic patients as well. Body mass index, body fat, and visceral fat percentages were lower, and renal function was preserved in patients receiving empagliflozin treatment. In addition to the known beneficial effects of empagliflozin regarding the cardio-metabolic and renal systems, it may also influence leptin resistance.
Navigating Like a Fly: Drosophila melanogaster as a Model to Explore the Contribution of Serotonergic Neurotransmission to Spatial Navigation
Authors: Gajardo Ivana , Guerra Simón , Campusano Jorge M.
Published: February 2023

Serotonin is a monoamine that acts in vertebrates and invertebrates as a modulator promoting changes in the structure and activity of brain areas relevant to animal behavior, ranging from sensory perception to learning and memory. Whether serotonin contributes in Drosophila to human-like cognitive abilities, including spatial navigation, is an issue little studied. Like in vertebrates, the serotonergic system in Drosophila is heterogeneous, meaning that distinct serotonergic neurons/circuits innervate specific fly brain regions to modulate precise behaviors. Here we review the literature that supports that serotonergic pathways modify different aspects underlying the formation of navigational memories in Drosophila.
Towards a New Biomarker for Diabetic Retinopathy: Exploring RBP3 Structure and Retinoids Binding for Functional Imaging of Eyes In Vivo
Authors: Kaushik Vineeta , Gessa Luca , Kumar Nelam , Fernandes Humberto
Published: February 2023

Diabetic retinopathy (DR) is a severe disease with a growing number of afflicted patients, which places a heavy burden on society, both socially and financially. While there are treatments available, they are not always effective and are usually administered when the disease is already at a developed stage with visible clinical manifestation. However, homeostasis at a molecular level is disrupted before visible signs of the disease are evident. Thus, there has been a constant search for effective biomarkers that could signal the onset of DR. There is evidence that early detection and prompt disease control are effective in preventing or slowing DR progression. Here, we review some of the molecular changes that occur before clinical manifestations are observable. As a possible new biomarker, we focus on retinol binding protein 3 (RBP3). We argue that it displays unique features that make it a very good biomarker for non-invasive, early-stage DR detection. Linking chemistry to biological function and focusing on new developments in eye imaging and two-photon technology, we describe a new potential diagnostic tool that would allow rapid and effective quantification of RBP3 in the retina. Moreover, this tool would also be useful in the future to monitor therapeutic effectiveness if levels of RBP3 are elevated by DR treatments.
Metabolic Reprogramming of Macrophages upon In Vitro Incubation with Aluminum-Based Adjuvant
Authors: Danielsson Ravi , Ferey Nathan , Mile Irene , Eriksson Håkan
Published: February 2023

Aluminum-based adjuvants have been extensively used in vaccines. Despite their widespread use, the mechanism behind the immune stimulation properties of these adjuvants is not fully understood. Needless to say, extending the knowledge of the immune-stimulating properties of aluminum-based adjuvants is of utmost importance in the development of new, safer, and efficient vaccines. To further our knowledge of the mode of action of aluminum-based adjuvants, the prospect of metabolic reprogramming of macrophages upon phagocytosis of aluminum-based adjuvants was investigated. Macrophages were differentiated and polarized in vitro from human peripheral monocytes and incubated with the aluminum-based adjuvant Alhydrogel®. Polarization was verified by the expression of CD markers and cytokine production. In order to recognize adjuvant-derived reprogramming, macrophages were incubated with Alhydrogel® or particles of polystyrene as control, and the cellular lactate content was analyzed using a bioluminescent assay. Quiescent M0 macrophages, as well as alternatively activated M2 macrophages, exhibited increased glycolytic metabolism upon exposure to aluminum-based adjuvants, indicating a metabolic reprogramming of the cells. Phagocytosis of aluminous adjuvants could result in an intracellular depot of aluminum ions, which may induce or support a metabolic reprogramming of the macrophages. The resulting increase in inflammatory macrophages could thus prove to be an important factor in the immune-stimulating properties of aluminum-based adjuvants.
Proteomic Fingerprint of Lung Fibrosis Progression and Response to Therapy in Bleomycin-Induced Mouse Model
Authors: Principi Lucrezia , Ferrini Erica , Ciccimarra Roberta , Pagani Lisa , Chinello Clizia , Previtali Paolo , Smith Andrew , Villetti Gino , Zoboli Matteo , Ravanetti Francesca , Stellari Franco Fabio , Magni Fulvio , Piga Isabella
Published: February 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the two FDA-approved drugs for IPF treatment; however, the exact pathophysiological mechanisms of fibrosis progression and response to therapy are still poorly understood. In this work, the molecular fingerprint of fibrosis progression and response to nintedanib treatment have been investigated by mass spectrometry-based bottom-up proteomics in paraffin-embedded lung tissues from bleomycin-induced (BLM) pulmonary fibrosis mice. Our proteomics results unveiled that (i) samples clustered depending on the tissue fibrotic grade (mild, moderate, and severe) and not on the time course after BLM treatment; (ii) the dysregulation of different pathways involved in fibrosis progression such as the complement coagulation cascades, advanced glycation end products (AGEs) and their receptors (RAGEs) signaling, the extracellular matrix-receptor interaction, the regulation of actin cytoskeleton, and ribosomes; (iii) Coronin 1A (Coro1a) as the protein with the highest correlation when evaluating the progression of fibrosis, with an increased expression from mild to severe fibrosis; and (iv) a total of 10 differentially expressed proteins (padj-value ≤ 0.05 and Fold change ≤−1.5 or ≥1.5), whose abundance varied in the base of the severity of fibrosis (mild and moderate), were modulated by the antifibrotic treatment with nintedanib, reverting their trend. Notably, nintedanib significantly restored lactate dehydrogenase B (Ldhb) expression but not lactate dehydrogenase A (Ldha). Notwithstanding the need for further investigations to validate the roles of both Coro1a and Ldhb, our findings provide an extensive proteomic characterization with a strong relationship with histomorphometric measurements. These results unveil some biological processes in pulmonary fibrosis and drug-mediated fibrosis therapy.
Modeling of Respiratory Diseases Evolving with Fibrosis from Organoids Derived from Human Pluripotent Stem Cells
Authors: Chamorro-Herrero Irene , Zambrano Alberto
Published: February 2023

Respiratory disease is one of the leading causes of morbidity and mortality worldwide. There is no cure for most diseases, which are treated symptomatically. Hence, new strategies are required to deepen the understanding of the disease and development of therapeutic strategies. The advent of stem cell and organoid technology has enabled the development of human pluripotent stem cell lines and adequate differentiation protocols for developing both airways and lung organoids in different formats. These novel human-pluripotent-stem-cell-derived organoids have enabled relatively accurate disease modeling. Idiopathic pulmonary fibrosis is a fatal and debilitating disease that exhibits prototypical fibrotic features that may be, to some extent, extrapolated to other conditions. Thus, respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or the one caused by SARS-CoV-2 may reflect some fibrotic aspects reminiscent of those present in idiopathic pulmonary fibrosis. Modeling of fibrosis of the airways and the lung is a real challenge due to the large number of epithelial cells involved and interaction with other cell types of mesenchymal origin. This review will focus on the status of respiratory disease modeling from human-pluripotent-stem-cell-derived organoids, which are being used to model several representative respiratory diseases, such as idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, and COVID-19.
Malonyl-CoA Accumulation as a Compensatory Cytoprotective Mechanism in Cardiac Cells in Response to 7-Ketocholesterol-Induced Growth Retardation
Authors: Cheng Mei-Ling , Yang Cheng-Hung , Wu Pei-Ting , Li Yi-Chin , Sun Hao-Wei , Lin Gigin , Ho Hung-Yao
Published: February 2023

The major oxidized product of cholesterol, 7-Ketocholesterol (7KCh), causes cellular oxidative damage. In the present study, we investigated the physiological responses of cardiomyocytes to 7KCh. A 7KCh treatment inhibited the growth of cardiac cells and their mitochondrial oxygen consumption. It was accompanied by a compensatory increase in mitochondrial mass and adaptive metabolic remodeling. The application of [U-13C] glucose labeling revealed an increased production of malonyl-CoA but a decreased formation of hydroxymethylglutaryl-coenzyme A (HMG-CoA) in the 7KCh-treated cells. The flux of the tricarboxylic acid (TCA) cycle decreased, while that of anaplerotic reaction increased, suggesting a net conversion of pyruvate to malonyl-CoA. The accumulation of malonyl-CoA inhibited the carnitine palmitoyltransferase-1 (CPT-1) activity, probably accounting for the 7-KCh-induced suppression of β-oxidation. We further examined the physiological roles of malonyl-CoA accumulation. Treatment with the inhibitor of malonyl-CoA decarboxylase, which increased the intracellular malonyl-CoA level, mitigated the growth inhibitory effect of 7KCh, whereas the treatment with the inhibitor of acetyl-CoA carboxylase, which reduced malonyl-CoA content, aggravated such a growth inhibitory effect. Knockout of malonyl-CoA decarboxylase gene (Mlycd−/−) alleviated the growth inhibitory effect of 7KCh. It was accompanied by improvement of the mitochondrial functions. These findings suggest that the formation of malonyl-CoA may represent a compensatory cytoprotective mechanism to sustain the growth of 7KCh-treated cells.
PPP3R1 Promotes MSCs Senescence by Inducing Plasma Membrane Depolarization and Increasing Ca2+ Influx
Authors: Li Molin , Gong Weimin , Chen Jie , Zhang Yining , Ma Yufei , Tu Xiaolin
Published: February 2023

Aging of mesenchymal stem cells(MSCs) has been widely reported to be strongly associated with aging-related diseases, including osteoporosis (OP). In particular, the beneficial functions of mesenchymal stem cells decline with age, limiting their therapeutic efficacy in age-related bone loss diseases. Therefore, how to improve mesenchymal stem cell aging to treat age-related bone loss is the current research focus. However, the underlying mechanism remains unclear. In this study, protein phosphatase 3, regulatory subunit B, alpha isoform, calcineurin B, type I (PPP3R1) was found to accelerate the senescence of mesenchymal stem cells, resulting in reduced osteogenic differentiation and enhanced adipogenic differentiation in vitro. Mechanistically, PPP3R1 induces changes in membrane potential to promote cellular senescence by polarizing to depolarizing, increasing Ca2+ influx and activating downstream NFAT/ATF3/p53 signaling. In conclusion, the results identify a novel pathway of mesenchymal stem cell aging that may lead to novel therapeutic approaches for age-related bone loss.
The PPAR-γ Agonist Pioglitazone Modulates Proliferation and Migration in HUVEC, HAOSMC and Human Arteriovenous Fistula-Derived Cells
Authors: Ciavarella Carmen , Motta Ilenia , Vasuri Francesco , Palumbo Teresa , Lisi Anthony Paul , Costa Alice , Astolfi Annalisa , Valente Sabrina , Versura Piera , Fornasiero Eugenio F. , Mauro Raffaella , Gargiulo Mauro , Pasquinelli Gianandrea
Published: February 2023

The failure of arteriovenous fistulas (AVFs) following intimal hyperplasia (IH) increases morbidity and mortality rates in patients undergoing hemodialysis for chronic kidney disease. The peroxisome-proliferator associated receptor (PPAR-γ) may be a therapeutic target in IH regulation. In the present study, we investigated PPAR-γ expression and tested the effect of pioglitazone, a PPAR-γ agonist, in different cell types involved in IH. As cell models, we used Human Endothelial Umbilical Vein Cells (HUVEC), Human Aortic Smooth Muscle Cells (HAOSMC), and AVF cells (AVFCs) isolated from (i) normal veins collected at the first AVF establishment (T0), and (ii) failed AVF with IH (T1). PPAR-γ was downregulated in AVF T1 tissues and cells, in comparison to T0 group. HUVEC, HAOSMC, and AVFC (T0 and T1) proliferation and migration were analyzed after pioglitazone administration, alone or in combination with the PPAR-γ inhibitor, GW9662. Pioglitazone negatively regulated HUVEC and HAOSMC proliferation and migration. The effect was antagonized by GW9662. These data were confirmed in AVFCs T1, where pioglitazone induced PPAR-γ expression and downregulated the invasive genes SLUG, MMP-9, and VIMENTIN. In summary, PPAR-γ modulation may represent a promising strategy to reduce the AVF failure risk by modulating cell proliferation and migration.