bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing Reliability of Chinese Geotagged Social Media Data for Spatiotemporal Representation of Human Mobility
Authors: Liu Lingbo , Wang Ru , Guan Weihe Wendy , Bao Shuming , Yu Hanchen , Fu Xiaokang , Liu Hongqiang
Published: February 2022

Understanding the space-time dynamics of human activities is essential in studying human security issues such as climate change impacts, pandemic spreading, or urban sustainability. Geotagged social media posts provide an open and space-time continuous data source with user locations which is convenient for studying human movement. However, the reliability of Chinese geotagged social media data for representing human mobility remains unclear. This study compares human movement data derived from the posts of Sina Weibo, one of the largest social media software in China, and that of Baidu Qianxi, a high-resolution human movement dataset from ‘Baidu Map’, a popular location-based service in China with 1.3 billion users. Correlation analysis was conducted from multiple dimensions of time periods (weekly and monthly), geographic scales (cities and provinces), and flow directions (inflow and outflow), and a case study on COVID-19 transmission was further explored with such data. The result shows that Sina Weibo data can reveal similar patterns as that of Baidu Qianxi, and that the correlation is higher at the provincial level than at the city level and higher at the monthly scale than at the weekly scale. The study also revealed spatial variations in the degree of similarity between the two sources. Findings from this study reveal the values and properties and spatiotemporal heterogeneity of human mobility data extracted from Weibo tweets, providing a reference for the proper use of social media posts as the data sources for human mobility studies.
Genome-Wide Comparative Analysis of the R2R3-MYB Gene Family in Five Solanaceae Species and Identification of Members Regulating Carotenoid Biosynthesis in Wolfberry
Authors: Yin Yue , Guo Cong , Shi Hongyan , Zhao Jianhua , Ma Fang , An Wei , He Xinru , Luo Qing , Cao Youlong , Zhan Xiangqiang
Published: February 2022

The R2R3-MYB is a large gene family involved in various plant functions, including carotenoid biosynthesis. However, this gene family lacks a comprehensive analysis in wolfberry (Lycium barbarum L.) and other Solanaceae species. The recent sequencing of the wolfberry genome provides an opportunity for investigating the organization and evolutionary characteristics of R2R3-MYB genes in wolfberry and other Solanaceae species. A total of 610 R2R3-MYB genes were identified in five Solanaceae species, including 137 in wolfberry. The LbaR2R3-MYB genes were grouped into 31 subgroups based on phylogenetic analysis, conserved gene structures, and motif composition. Five groups only of Solanaceae R2R3-MYB genes were functionally divergent during evolution. Dispersed and whole duplication events are critical for expanding the R2R3-MYB gene family. There were 287 orthologous gene pairs between wolfberry and the other four selected Solanaceae species. RNA-seq analysis identified the expression level of LbaR2R3-MYB differential gene expression (DEGs) and carotenoid biosynthesis genes (CBGs) in fruit development stages. The highly expressed LbaR2R3-MYB genes are co-expressed with CBGs during fruit development. A quantitative Real-Time (qRT)-PCR verified seven selected candidate genes. Thus, Lba11g0183 and Lba02g01219 are candidate genes regulating carotenoid biosynthesis in wolfberry. This study elucidates the evolution and function of R2R3-MYB genes in wolfberry and the four Solanaceae species.
Unilateral Acute Renal Ischemia-Reperfusion Injury Induces Cardiac Dysfunction through Intracellular Calcium Mishandling
Authors: Junho Carolina Victoria Cruz , González-Lafuente Laura , Navarro-García José Alberto , Rodríguez-Sánchez Elena , Carneiro-Ramos Marcela Sorelli , Ruiz-Hurtado Gema
Published: February 2022

Background: Acute renal failure (ARF) following renal ischemia-reperfusion (I/R) injury is considered a relevant risk factor for cardiac damage, but the underlying mechanisms, particularly those triggered at cardiomyocyte level, are unknown. Methods: We examined intracellular Ca2+ dynamics in adult ventricular cardiomyocytes isolated from C57BL/6 mice 7 or 15 days following unilateral renal I/R. Results: After 7 days of I/R, the cell contraction was significantly lower in cardiomyocytes compared to sham-treated mice. It was accompanied by a significant decrease in both systolic Ca2+ transients and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity measured as Ca2+ transients decay. Moreover, the incidence of pro-arrhythmic events, measured as the number of Ca2+ sparks, waves or automatic Ca2+ transients, was greater in cardiomyocytes from mice 7 days after I/R than from sham-treated mice. Ca2+ mishandling related to systolic Ca2+ transients and contraction were recovered to sham values 15 days after I/R, but Ca2+ sparks frequency and arrhythmic events remained elevated. Conclusions: Renal I/R injury causes a cardiomyocyte Ca2+ cycle dysfunction at medium (contraction-relaxation dysfunction) and long term (Ca2+ leak), after 7 and 15 days of renal reperfusion, respectively.
VPA and TSA Interrupt the Interplay between mutp53 and HSP70, Leading to CHK1 and RAD51 Down-Regulation and Sensitizing Pancreatic Cancer Cells to AZD2461 PARP Inhibitor
Authors: Romeo Maria Anele , Gilardini Montani Maria Saveria , Benedetti Rossella , Arena Andrea , D’Orazi Gabriella , Cirone Mara
Published: February 2022

HDAC inhibitors (HDACi) represent promising anti-cancer treatments, as the acetylation of histone and non-histone proteins is often dysregulated in cancer and contributes to cancer onset and progression. HDACi have been also reported to increase the cytotoxicity of DNA-damaging agents, such as radiation or cisplatin. In this study, we found that TSA and, even more effectively, VPA synergized with AZD2461, PARP1, 2 and 3 inhibitor (PARPi) to induce DNA damage and reduce pancreatic cancer cell survival. At a molecular level, VPA and TSA down-regulated CHK1 and RAD51, which is correlated with the interruption of the cross-talk between mutp53 and HSP70. Moreover, VPA and to a lesser extent TSA reactivated wtp53 in these cells, which contributed to CHK1 and RAD51 reduction. These findings suggest that the combination of HDACi and PARPi might improve the treatment of pancreatic cancer, which remains one of the most aggressive and therapy-resistant cancers.
Transcriptome and Coexpression Network Analyses Provide In-Sights into the Molecular Mechanisms of Hydrogen Cyanide Synthesis during Seed Development in Common Vetch (Vicia sativa L.)
Authors: Li Mingyu , Zhao Lu , Zhou Qiang , Fang Longfa , Luo Dong , Liu Wenxian , Searle Iain Robert , Liu Zhipeng
Published: February 2022

The common vetch (Vicia sativa L.) seed is an ideal plant-based protein food for humans, but its edible value is mainly limited by the presence of cyanogenic glycosides that hydrolyze to produce toxic hydrogen cyanide (HCN), and the genes that regulate HCN synthesis in common vetch are unknown. In this study, seeds from common vetch at 5, 10, 15, 20, 25, 30, and 35 days after anthesis were sampled, and the seven stages were further divided into five developmental stages, S1, S2, S3, S4, and S5, based on morphological and transcriptome analyses. A total of 16,403 differentially expressed genes were identified in the five developmental stages. The HCN contents of seeds in these five stages were determined by alkaline titration, and weighted gene coexpression network analysis was used to explain the molecular regulatory mechanism of HCN synthesis in common vetch seeds. Eighteen key regulatory genes for HCN synthesis were identified, including the VsGT2, VsGT17 and CYP71A genes, as well as the VsGT1 gene family. VsGT1, VsGT2, VsGT17 and CYP71A jointly promoted HCN synthesis, from 5 to 25 days after anthesis, with VsGT1-1, VsGT1-4, VsGT1-11 and VsGT1-14 playing major roles. The HCN synthesis was mainly regulated by VsGT1, from 25 to 35 days after anthesis. As the expression level of VsGT1 decreased, the HCN content no longer increased. In-depth elucidation of seed HCN synthesis lays the foundations for breeding common vetch with low HCN content.
Expanding Gene-Editing Potential in Crop Improvement with Pangenomes
Authors: Tay Fernandez Cassandria G. , Nestor Benjamin J. , Danilevicz Monica F. , Marsh Jacob I. , Petereit Jakob , Bayer Philipp E. , Batley Jacqueline , Edwards David
Published: February 2022

Pangenomes aim to represent the complete repertoire of the genome diversity present within a species or cohort of species, capturing the genomic structural variance between individuals. This genomic information coupled with phenotypic data can be applied to identify genes and alleles involved with abiotic stress tolerance, disease resistance, and other desirable traits. The characterisation of novel structural variants from pangenomes can support genome editing approaches such as Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR associated protein Cas (CRISPR-Cas), providing functional information on gene sequences and new target sites in variant-specific genes with increased efficiency. This review discusses the application of pangenomes in genome editing and crop improvement, focusing on the potential of pangenomes to accurately identify target genes for CRISPR-Cas editing of plant genomes while avoiding adverse off-target effects. We consider the limitations of applying CRISPR-Cas editing with pangenome references and potential solutions to overcome these limitations.
Interplay between ceRNA and Epigenetic Control of microRNA: Modelling Approaches with Application to the Role of Estrogen in Ovarian Cancer
Authors: Huang Tzy-Wei , Cheng Frank H. C. , Yan Ching-Cher Sanders , Chuang Yu-Ming , Cho Chien-Hong , Lai Hung-Cheng , Shieh Shih-Feng , Chan Michael W. Y. , Tsai Je-Chiang
Published: February 2022

MicroRNAs (miRNAs) play an important role in gene regulation by degradation or translational inhibition of the targeted mRNAs. It has been experimentally shown that the way miRNAs interact with their targets can be used to explain the indirect interactions among their targets, i.e., competing endogenous RNA (ceRNA). However, whether the protein translated from the targeted mRNAs can play any role in this ceRNA network has not been explored. Here we propose a deterministic model to demonstrate that in a network of one miRNA interacting with multiple-targeted mRNAs, the competition between miRNA-targeted mRNAs is not sufficient for the significant change of those targeted mRNA levels, while dramatic changes of these miRNA-targeted mRNAs require transcriptional inhibition of miRNA by its target proteins. When applied to estrogen receptor signaling pathways, the miR-193a targets E2F6 (a target of estrogen receptor), c-KIT (a marker for cancer stemness), and PBX1 (a transcriptional activator for immunosuppressive cytokine, IL-10) in ovarian cancer, such that epigenetic silencing of miR-193a by E2F6 protein is required for the significant change of c-KIT and PBX1 mRNA level for cancer stemness and immunoevasion, respectively, in ovarian cancer carcinogenesis
Nuclear and Membrane Receptors for Sex Steroids Are Involved in the Regulation of Delta/Serrate/LAG-2 Proteins in Rodent Sertoli Cells
Authors: Lustofin Sylwia , Kamińska Alicja , Brzoskwinia Małgorzata , Cyran Joanna , Kotula-Balak Małgorzata , Bilińska Barbara , Hejmej Anna
Published: February 2022

Delta/Serrate/LAG-2 (DSL) proteins, which serve as ligands for Notch receptors, mediate direct cell–cell interactions involved in the determination of cell fate and functioning. The present study aimed to explore the role of androgens and estrogens, and their receptors in the regulation of DSL proteins in Sertoli cells. To this end, primary rat Sertoli cells and TM4 Sertoli cell line were treated with either testosterone or 17β-estradiol and antagonists of their receptors. To confirm the role of particular receptors, knockdown experiments were performed. mRNA and protein expressions of Jagged1 (JAG1), Delta-like1 (DLL1), and Delta-like4 (DLL4) were analyzed using RT-qPCR, Western blot, and immunofluorescence. Testosterone caused downregulation of JAG1 and DLL1 expression, acting through membrane androgen receptor ZRT- and Irt-like protein 9 (ZIP9) or nuclear androgen receptor (AR), respectively. DLL4 was stimulated by testosterone in the manner independent of AR and ZIP9 in Sertoli cells. The expression of all studied DSL proteins was upregulated by 17β-estradiol. Estrogen action on JAG1 and DLL1 was mediated chiefly via estrogen receptor α (ERα), while DLL4 was controlled via estrogen receptor β (ERβ) and membrane G-protein-coupled estrogen receptor (GPER). To summarize, the co-operation of nuclear and membrane receptors for sex steroids controls DSL proteins in Sertoli cells, contributing to balanced Notch signaling activity in seminiferous epithelium.
An Engineered Nanocomplex with Photodynamic and Photothermal Synergistic Properties for Cancer Treatment
Authors: Varon Eli , Blumrosen Gaddi , Sinvani Moshe , Haimov Elina , Polani Shlomi , Natan Michal , Shoval Irit , Jacob Avi , Atkins Ayelet , Zitoun David , Shefi Orit
Published: February 2022

Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising therapeutic methods for cancer treatment; however, as single modality therapies, either PDT or PTT is still limited in its success rate. A dual application of both PDT and PTT, in a combined protocol, has gained immense interest. In this study, gold nanoparticles (AuNPs) were conjugated with a PDT agent, meso-tetrahydroxyphenylchlorin (mTHPC) photosensitizer, designed as nanotherapeutic agents that can activate a dual photodynamic/photothermal therapy in SH-SY5Y human neuroblastoma cells. The AuNP-mTHPC complex is biocompatible, soluble, and photostable. PDT efficiency is high because of immediate reactive oxygen species (ROS) production upon mTHPC activation by the 650-nm laser, which decreased mitochondrial membrane potential (∆ψm). Likewise, the AuNP-mTHPC complex is used as a photoabsorbing (PTA) agent for PTT, due to efficient plasmon absorption and excellent photothermal conversion characteristics of AuNPs under laser irradiation at 532 nm. Under the laser irradiation of a PDT/PTT combination, a twofold phototoxicity outcome follows, compared to PDT-only or PTT-only treatment. This indicates that PDT and PTT have synergistic effects together as a combined therapeutic method. Our study aimed at applying the AuNP-mTHPC approach as a potential treatment of cancer in the biomedical field.
GnRH Analogues as a Co-Treatment to Therapy in Women of Reproductive Age with Cancer and Fertility Preservation
Authors: Valsamakis Georgios , Valtetsiotis Konstantinos , Charmandari Evangelia , Lambrinoudaki Irene , Vlahos Nikolaos F.
Published: February 2022

In this review, we analyzed existing literature regarding the use of Gonadotropin-releasing Hormone (GnRH) analogues (agonists, antagonists) as a co-treatment to chemotherapy and radiotherapy. There is a growing interest in their application as a prophylaxis to gonadotoxicity caused by chemotherapy and/or radiotherapy due to their ovarian suppressive effects, making them a potential option to treat infertility caused by such chemotherapy and/or radiotherapy. They could be used in conjunction with other fertility preservation options to synergistically maximize their effects. GnRH analogues may be a valuable prophylactic agent against chemotherapeutic infertility by inhibiting rapid cellular turnover on growing follicles that contain types of cells unintentionally targeted during anti-cancer treatments. These could create a prepubertal-like effect in adult women, limiting the gonadotoxicity to the lower levels that young girls have. The use of GnRH agonists was found to be effective in hematological and breast cancer treatment whereas for ovarian endometrial and cervical cancers the evidence is still limited. Studies on GnRH antagonists, as well as the combination of both agonists and antagonists, were limited. GnRH antagonists have a similar protective effect to that of agonists as they preserve or at least alleviate the follicle degradation during chemo-radiation treatment. Their use may be preferred in cases where treatment is imminent (as their effects are almost immediate) and whenever the GnRH agonist-induced flare-up effect may be contra-indicated. The combination treatment of agonists and antagonists has primarily been studied in animal models so far, especially rats. Factors that may play a role in determining their efficacy as a chemoprotective agent that limits gonadal damage, include the type and stage of cancer, the use of alkylating agents, age of patient and prior ovarian reserve. The data for the use of GnRH antagonist alone or in combination with GnRH agonist is still very limited. Moreover, studies evaluating the impact of this treatment on the ovarian reserve as measured by Anti-Müllerian Hormone (AMH) levels are still sparse. Further studies with strict criteria regarding ovarian reserve and fertility outcomes are needed to confirm or reject their role as a gonadal protecting agent during chemo-radiation treatments.
Secretome of Adipose Tissue as the Key to Understanding the Endocrine Function of Adipose Tissue
Authors: Pogodziński Damian , Ostrowska Lucyna , Smarkusz-Zarzecka Joanna , Zyśk Beata
Published: February 2022

The prevalence of obesity has reached pandemic levels and is becoming a serious health problem in developed and developing countries. Obesity is associated with an increased prevalence of comorbidities that include type II diabetes, cardiovascular diseases and some cancers. The recognition of adipose tissue as an endocrine organ capable of secreting adipokines that influence whole-body energy homeostasis was a breakthrough leading to a better molecular understanding of obesity. Of the adipokines known to be involved in the regulation of energy metabolism, very few are considered central regulators of insulin sensitivity, metabolism and energy homeostasis, and the discovery and characterization of new adipocyte-derived factors are still ongoing. Proteomics techniques, such as liquid chromatography-mass spectrometry or gas chromatography-mass spectrometry, have proven to be useful tools for analyzing the secretory function of adipose tissue (the secretome), providing insights into molecular events that influence body weight. Apart from the identification of novel proteins, the considerable advantage of this approach is the ability to detect post-translational modifications that cannot be predicted in genomic studies. In this review, we summarize recent efforts to identify novel bioactive secretory factors through proteomics.
Using Graphene-Based Materials for Stiff and Strong Poly(ethylene glycol) Hydrogels
Authors: Ferreira Helena P. , Moura Duarte , Pereira Andreia T. , Henriques Patrícia C. , Barrias Cristina C. , Magalhães Fernão D. , Gonçalves Inês C.
Published: February 2022

Blood-contacting devices are increasingly important for the management of cardiovascular diseases. Poly(ethylene glycol) (PEG) hydrogels represent one of the most explored hydrogels to date. However, they are mechanically weak, which prevents their use in load-bearing biomedical applications (e.g., vascular grafts, cardiac valves). Graphene and its derivatives, which have outstanding mechanical properties, a very high specific surface area, and good compatibility with many polymer matrices, are promising candidates to solve this challenge. In this work, we propose the use of graphene-based materials as nanofillers for mechanical reinforcement of PEG hydrogels, and we obtain composites that are stiffer and stronger than, and as anti-adhesive as, neat PEG hydrogels. Results show that single-layer and few-layer graphene oxide can strengthen PEG hydrogels, increasing their stiffness up to 6-fold and their strength 14-fold upon incorporation of 4% w/v (40 mg/mL) graphene oxide. The composites are cytocompatible and remain anti-adhesive towards endothelial cells, human platelets and Staphylococcus aureus, similar to neat hydrogels. To the best of our knowledge, this is the first work to report such an increase of the tensile properties of PEG hydrogels using graphene-based materials as fillers. This work paves the way for the exploitation of PEG hydrogels as a backbone material for load-bearing applications.
A Mixture of Endocrine Disrupting Chemicals Associated with Lower Birth Weight in Children Induces Adipogenesis and DNA Methylation Changes in Human Mesenchymal Stem Cells
Authors: Lizunkova Polina , Engdahl Elin , Borbély Gábor , Gennings Chris , Lindh Christian , Bornehag Carl-Gustaf , Rüegg Joëlle
Published: February 2022

Endocrine Disrupting Chemicals (EDCs) are man-made compounds that alter functions of the endocrine system. Environmental mixtures of EDCs might have adverse effects on human health, even though their individual concentrations are below regulatory levels of concerns. However, studies identifying and experimentally testing adverse effects of real-life mixtures are scarce. In this study, we aimed at evaluating an epidemiologically identified EDC mixture in an experimental setting to delineate its cellular and epigenetic effects. The mixture was established using data from the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) study where it was associated with lower birth weight, an early marker for prenatal metabolic programming. This mixture was then tested for its ability to change metabolic programming of human mesenchymal stem cells. In these cells, we assessed if the mixture induced adipogenesis and genome-wide DNA methylation changes. The mixture increased lipid droplet accumulation already at concentrations corresponding to levels measured in the pregnant women of the SELMA study. Furthermore, we identified differentially methylated regions in genes important for adipogenesis and thermogenesis. This study shows that a mixture reflecting human real-life exposure can induce molecular and cellular changes during development that could underlie adverse outcomes.
Platelet-Released Factors: Their Role in Viral Disease and Applications for Extracellular Vesicle (EV) Therapy
Authors: Ostermeier Brita , Soriano-Sarabia Natalia , Maggirwar Sanjay B.
Published: February 2022

Platelets, which are small anuclear cell fragments, play important roles in thrombosis and hemostasis, but also actively release factors that can both suppress and induce viral infections. Platelet-released factors include sCD40L, microvesicles (MVs), and alpha granules that have the capacity to exert either pro-inflammatory or anti-inflammatory effects depending on the virus. These factors are prime targets for use in extracellular vesicle (EV)-based therapy due to their ability to reduce viral infections and exert anti-inflammatory effects. While there are some studies regarding platelet microvesicle-based (PMV-based) therapy, there is still much to learn about PMVs before such therapy can be used. This review provides the background necessary to understand the roles of platelet-released factors, how these factors might be useful in PMV-based therapy, and a critical discussion of current knowledge of platelets and their role in viral diseases.
β-Catenin-Specific Inhibitor, iCRT14, Promotes BoHV-1 Infection-Induced DNA Damage in Human A549 Lung Adenocarcinoma Cells by Enhancing Viral Protein Expression
Authors: Ding Xiuyan , Yuan Weifeng , Yang Hao , Liu Chang , Li Shitao , Zhu Liqian
Published: February 2022

Oncolytic bovine herpesvirus type 1 (BoHV-1) infection induces DNA damage in human lung adenocarcinoma cell line A549. However, the underlying mechanisms are not fully understood. We found that BoHV-1 infection decreased the steady-state protein levels of p53-binding protein 1 (53BP1), which plays a central role in dictating DNA damage repair and maintaining genomic stability. Furthermore, BoHV-1 impaired the formation of 53BP1 foci, suggesting that BoHV-1 inhibits 53BP1-mediated DNA damage repair. Interestingly, BoHV-1 infection redistributed intracellular β-catenin, and iCRT14 (5-[[2,5-Dimethyl-1-(3-pyridinyl)-1H-pyrrol-3-yl]methylene]-3-phenyl-2,4-thiazolidinedione), a β-catenin-specific inhibitor, enhanced certain viral protein expression, such as the envelope glycoproteins gC and gD, and enhanced virus infection-induced DNA damage. Therefore, for the first time, we provide evidence showing that BoHV-1 infection disrupts 53BP1-mediated DNA damage repair and suggest β-catenin as a potential host factor restricting both virus replication and DNA damage in A549 cells.
In-Vitro Catalytic and Antibacterial Potential of Green Synthesized CuO Nanoparticles against Prevalent Multiple Drug Resistant Bovine Mastitogen Staphylococcus aureus
Authors: Ul-Hamid Anwar , Dafalla Hatim , Hakeem Abbas Saeed , Haider Ali , Ikram Muhammad
Published: February 2022

Nanoparticles prepared from bio-reduction agents are of keen interest to researchers around the globe due to their ability to mitigate the harmful effects of chemicals. In this regard, the present study aims to synthesize copper oxide nanoparticles (CuO NPs) by utilizing root extracts of ginger and garlic as reducing agents, followed by the characterization and evaluation of their antimicrobial properties against multiple drug resistant (MDR) S. aureus. In this study, UV-vis spectroscopy revealed a reduced degree of absorption with an increase in the extract amount present in CuO. The maximum absorbance for doped NPs was recorded around 250 nm accompanying redshift. X-ray diffraction analysis revealed the monoclinic crystal phase of the particles. The fabricated NPs exhibited spherical shapes with dense agglomeration when examined with FE-SEM and TEM. The crystallite size measured by using XRD was found to be within a range of 23.38–46.64 nm for ginger-doped CuO and 26–56 nm for garlic-doped CuO. Green synthesized NPs of ginger demonstrated higher bactericidal tendencies against MDR S. aureus. At minimum and maximum concentrations of ginger-doped CuO NPs, substantial inhibition areas for MDR S. aureus were (2.05–3.80 mm) and (3.15–5.65 mm), and they were measured as (1.1–3.55 mm) and (1.25–4.45 mm) for garlic-doped NPs. Conventionally available CuO and crude aqueous extract (CAE) of ginger and garlic roots reduced MB in 12, 21, and 38 min, respectively, in comparison with an efficient (100%) reduction of dye in 1 min and 15 s for ginger and garlic doped CuO NPs.
Old and Novel Therapeutic Approaches in the Management of Hyperglycemia, an Important Risk Factor for Atherosclerosis
Authors: Janjusevic Milijana , Fluca Alessandra Lucia , Gagno Giulia , Pierri Alessandro , Padoan Laura , Sorrentino Annamaria , Beltrami Antonio Paolo , Sinagra Gianfranco , Aleksova Aneta
Published: February 2022

Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), could be considered a powerful tool for to reduce glucose concentration and cardiovascular risk. Interestingly, many patients with type 2 diabetes mellitus (T2DM) and insulin resistance have been found to be deficient in vitamin D. Recent studies pointed out the unfavorable prognostic values of T2DM and vitamin D deficiency in patients with cardiac dysfunction, either when considered individually or together, which shed light on the role of vitamin D in general health status. New evidence suggests that SGLT2i could adversely affect the production of vitamin D, thereby increasing the risk of fractures, which are common in patients with T2DM. Therefore, given the biological effects of vitamin D as an anti-inflammatory mediator and a regulator of endothelial function and calcium equilibrium, these new findings should be taken into consideration as well. The aim of this review is to gather the latest advancements regarding the use of antidiabetic and antiplatelet drugs coupled with vitamin D supplementation to control glucose levels, therefore reducing the risk of coronary artery disease (CAD).
Metrics, Explainability and the European AI Act Proposal
Authors: Sovrano Francesco , Sapienza Salvatore , Palmirani Monica , Vitali Fabio
Published: February 2022

On 21 April 2021, the European Commission proposed the first legal framework on Artificial Intelligence (AI) to address the risks posed by this emerging method of computation. The Commission proposed a Regulation known as the AI Act. The proposed AI Act considers not only machine learning, but expert systems and statistical models long in place. Under the proposed AI Act, new obligations are set to ensure transparency, lawfulness, and fairness. Their goal is to establish mechanisms to ensure quality at launch and throughout the whole life cycle of AI-based systems, thus ensuring legal certainty that encourages innovation and investments on AI systems while preserving fundamental rights and values. A standardisation process is ongoing: several entities (e.g., ISO) and scholars are discussing how to design systems that are compliant with the forthcoming Act, and explainability metrics play a significant role. Specifically, the AI Act sets some new minimum requirements of explicability (transparency and explainability) for a list of AI systems labelled as “high-risk” listed in Annex III. These requirements include a plethora of technical explanations capable of covering the right amount of information, in a meaningful way. This paper aims to investigate how such technical explanations can be deemed to meet the minimum requirements set by the law and expected by society. To answer this question, with this paper we propose an analysis of the AI Act, aiming to understand (1) what specific explicability obligations are set and who shall comply with them and (2) whether any metric for measuring the degree of compliance of such explanatory documentation could be designed. Moreover, by envisaging the legal (or ethical) requirements that such a metric should possess, we discuss how to implement them in a practical way. More precisely, drawing inspiration from recent advancements in the theory of explanations, our analysis proposes that metrics to measure the kind of explainability endorsed by the proposed AI Act shall be risk-focused, model-agnostic, goal-aware, intelligible, and accessible. Therefore, we discuss the extent to which these requirements are met by the metrics currently under discussion.
The Good, the Bad, and the Invisible with Its Opportunity Costs: Introduction to the ‘J’ Special Issue on “the Impact of Artificial Intelligence on Law”
Authors: Pagallo Ugo , Durante Massimo
Published: February 2022

Scholars and institutions have been increasingly debating the moral and legal challenges of AI, together with the models of governance that should strike the balance between the opportunities and threats brought forth by AI, its ‘good’ and ‘bad’ facets. There are more than a hundred declarations on the ethics of AI and recent proposals for AI regulation, such as the European Commission’s AI Act, have further multiplied the debate. Still, a normative challenge of AI is mostly overlooked, and regards the underuse, rather than the misuse or overuse, of AI from a legal viewpoint. From health care to environmental protection, from agriculture to transportation, there are many instances of how the whole set of benefits and promises of AI can be missed or exploited far below its full potential, and for the wrong reasons: business disincentives and greed among data keepers, bureaucracy and professional reluctance, or public distrust in the era of no-vax conspiracies theories. The opportunity costs that follow this technological underuse is almost terra incognita due to the ‘invisibility’ of the phenomenon, which includes the ‘shadow prices’ of economy. This introduction provides metrics for such assessment and relates this work to the development of new standards for the field. We must quantify how much it costs not to use AI systems for the wrong reasons.
The Utility of Genomic Testing for Hyperphenylalaninemia
Authors: Tendi Elisabetta Anna , Guarnaccia Maria , Morello Giovanna , Cavallaro Sebastiano
Published: February 2022

Hyperphenylalaninemia (HPA), the most common amino acid metabolism disorder, is caused by defects in enzymes involved in phenylalanine metabolism, with the consequent accumulation of phenylalanine and its secondary metabolites in body fluids and tissues. Clinical manifestations of HPA include mental retardation, and its early diagnosis with timely treatment can improve the prognosis of affected patients. Due to the genetic complexity and heterogeneity of HPA, high-throughput molecular technologies, such as next-generation sequencing (NGS), are becoming indispensable tools to fully characterize the etiology, helping clinicians to promptly identify the exact patients’ genotype and determine the appropriate treatment. In this review, after a brief overview of the key enzymes involved in phenylalanine metabolism, we represent the wide spectrum of genes and their variants associated with HPA and discuss the utility of genomic testing for improved diagnosis and clinical management of HPA.
IDELVION: A Comprehensive Review of Clinical Trial and Real-World Data
Authors: Escobar Miguel , Mancuso Maria Elisa , Hermans Cedric , Leissinger Cindy , Seifert Wilfried , Li Yanyan , McKeand William , Oldenburg Johannes
Published: February 2022

Hemophilia B is a bleeding disorder caused by a deficiency of coagulation factor IX (FIX). Treatment with FIX replacement products can increase FIX activity levels to minimize or prevent bleeding events. However, frequent dosing with standard-acting FIX products can create a high treatment burden. Long-acting products have been developed to maintain bleed protection with extended dosing intervals. Recombinant factor IX–albumin fusion protein (rIX-FP) is a long-acting product indicated for the treatment and prophylaxis of bleeding events and perioperative management in adult and pediatric patients. This review outlines data from all previously treated patients in the Prophylaxis and On-Demand Treatment using Longer Half-Life rIX-FP (PROLONG-9FP) clinical trial program and summarizes real-world data evaluating the use of rIX-FP in routine clinical practice. In the PROLONG-9FP program, rIX-FP demonstrated effective hemostasis in all patients at dose regimens of up to 21 days in patients aged ≥ 18 years and up to 14 days in patients aged < 12 years. rIX-FP has a favorable pharmacokinetic profile and an excellent safety and tolerability profile. Extended dosing intervals with rIX-FP led to high levels of adherence and reduced consumption compared with other FIX therapies. Data from real-world practice are encouraging and reflect the results of the clinical trials.
A Novel Doppler TRPG/AcT Index Improves Echocardiographic Diagnosis of Pulmonary Hypertension after Pulmonary Embolism
Authors: Dzikowska-Diduch Olga , Kurnicka Katarzyna , Lichodziejewska Barbara , Zdończyk Olga , Dąbrowska Dominika , Roik Marek , Pacho Szymon , Bielecki Maksymilian , Pruszczyk Piotr
Published: February 2022

Background: We hypothesized that a Doppler index, the ratio of tricuspid regurgitation peak gradient (TRPG) to pulmonary ejection acceleration time (AcT), improves the assessment of the echocardiographic probability of pulmonary hypertension in the identification of CTEPH and chronic thromboembolic pulmonary disease (CTED) in symptomatic patients after PE. Doppler echocardiography is recommended as the initial imaging tool for the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE). Methods: We analyzed the data from 845 consecutive PE (468 women; 61 ± 18 years) survivors who completed at least 6 months of anticoagulation therapy. Here, 555 patients (325 women; 66 ± 16 years) reporting functional impairment (FI) underwent transthoracic echocardiography. We included 506 patients (297 women; age 63.4 ± 16.6 years) in whom both AcT and TRPG were available into the current study. The presence of a minimum of intermediate echocardiographic probability of PH necessitated the diagnosis of CTEPH. Results: Echocardiography revealed a high echocardiographic probability of PH in 69 (13.6%) and intermediate echocardiographic probability in 109 (21.5%) patients. CTEPH was diagnosed in 35 (6.9%) patients and CTED in 22 (4.3%) patients. TRPG/AcT was significantly higher in the combined CTEPH + CTED group than in those with other causes of FI (0.412 (0.100–2.197) vs. 0.208 (0.026–0.115), p < 0.001), and the area under the receiver operating characteristic curve of the TRPG/AcT for CTEPH + CTED was 0.804 (95% confidence interval (CI): 0.731–0.876). Importantly, multiple logistic regression showed that TRPG/AcT is a significant predictor of CTEPH + CTED after considering echocardiographic probability (odds ratio = 1.51, 95% CI: 1.25–1.91, p < 0.001). Conditional inference trees analysis revealed that TRPG/AcT > 0.595 identified patients with CTEPH or CTED with a positive predictive value of 78.6% and negative predictive value of 92.7%. Conclusions: A Doppler index TRPG/AcT improves the assessment of symptomatic PE survivors. TRPG/AcT > 0.6 indicates a high probability of CTEPH or CTED, whereas TRPG/AcT < 0.6 allows for the safe exclusion of CTEPH + CTED in patients with a low echocardiographic probability of PH.
Feasibility of a Multimodal Telemedical Intervention for Patients with Parkinson’s Disease—A Pilot Study
Authors: Bendig Jonas , Wolf Anna-Sophie , Mark Tony , Frank Anika , Mathiebe Josephine , Scheibe Madlen , Müller Gabriele , Stahr Marcus , Schmitt Jochen , Reichmann Heinz , Loewenbrück Kai F. , Falkenburger Björn H.
Published: February 2022

Symptoms of Parkinson’s disease (PD) can be controlled well, but treatment often requires expert judgment. Telemedicine and sensor-based assessments can allow physicians to better observe the evolvement of symptoms over time, in particular with motor fluctuations. In addition, they potentially allow less frequent visits to the expert’s office and facilitate care in rural areas. A variety of systems with different strengths and shortcomings has been investigated in recent years. We designed a multimodal telehealth intervention (TelePark) to mitigate the shortcomings of individual systems and assessed the feasibility of our approach in 12 patients with PD over 12 weeks in preparation for a larger randomized controlled trial. TelePark uses video visits, a smartphone app, a camera system, and wearable sensors. Structured training included setting up the equipment in patients’ homes and group-based online training. Usability was assessed by questionnaires and semi-standardized telephone interviews. Overall, 11 out of 12 patients completed the trial (5 female, 6 male). Mean age was 65 years, mean disease duration 7 years, mean MoCA score 27. Adherence was stable throughout the study and 79% for a short questionnaire administered every second day, 62% for medication confirmation, and 33% for an electronic Hauser diary. Quality of life did not change in the course of the study, and a larger cohort will be required to determine the effect on motor symptoms. Interviews with trial participants identified motivations to use such systems and areas for improvements. These insights can be helpful in designing similar trials.
Signs Indicative of Central Sensitization Are Present but Not Associated with the Central Sensitization Inventory in Patients with Focal Nerve Injury
Authors: Matesanz-García Luis , Cuenca-Martínez Ferran , Simón Ana Isabel , Cecilia David , Goicoechea-García Carlos , Fernández-Carnero Josué , Schmid Annina B.
Published: February 2022

Objective: Carpal tunnel syndrome (CTS) is the most common focal nerve injury. People with CTS may show alterations in central processing of nociceptive information. It remains unclear whether the central sensitization inventory (CSI) is capable of detecting such altered central pain processing. Methods: Thirty healthy volunteers were matched with 30 people with unilateral CTS from the orthopaedic waitlist. Changes to central pain processing were established through psychophysical sensory testing (bilateral pressure pain thresholds (PPT), conditioned pain modulation, temporal summation) and pain distribution on body charts. Patients also completed pain severity and function questionnaires, psychological questionnaires and the CSI. Results: Compared to healthy volunteers, patients with CTS have lower PPTs over the carpal tunnel bilaterally (t = −4.06, p < 0.0001 ipsilateral and t = −4.58, p < 0.0001 contralateral) and reduced conditioned pain modulation efficacy (t = −7.31, p <0.0001) but no differences in temporal summation (t = 0.52, p = 0.60). The CSI was not associated with psychophysical measures or pain distributions indicative of altered central pain processing. However, there was a correlation of the CSI with the Beck Depression Inventory (r = 0.426; p = 0.019). Conclusion: Patients with CTS show signs of altered central pain mechanisms. The CSI seems unsuitable to detect changes in central pain processing but is rather associated with psychological factors in people with focal nerve injuries.
Inhalative Treatment of Laryngitis Sicca in Patients with Sjögren’s Syndrome—A Pilot Study
Authors: Hofauer Benedikt , Kirschstein Lara , Graf Simone , Strassen Ulrich , Johnson Felix , Zhu Zhaojun , Knopf Andreas
Published: February 2022

Xerostomia and keratoconjunctivitis sicca are the main symptoms of Sjögren’s syndrome. Often patients also suffer from laryngeal complaints, but there is a lack of specific treatment options. The aim of this study was to evaluate the effect of a liposomal inhalation therapy. Patients with Sjögren’s syndrome were included and received a two-month period of liposomal inhalation therapy. The effect was evaluated by standardized questionnaires (patient-reported indices) and measurement of unstimulated whole salivary flow and glandular stiffness. Forty-five patients were included in this study. A comparison of baseline and therapeutic values demonstrated a significant improvement of the EULAR Sjögren’s syndrome patient reported index (ESSPRI) with a baseline of 5.0 ± 2.1 and a therapeutic value of 4.1 ± 2.4 (p = 0.012). This improvement was mainly based on the item on dryness within this score. Overall, the therapy was well tolerated. In conclusion, an inhalative application of liposomes had a beneficial effect on the reported dryness in patients with Sjögren’s syndrome. A first insight into the effect of inhalation therapy on laryngeal symptoms could thus be obtained and at the same time the basis was created on which case calculations can be carried out in the future.
Riociguat in Patients with CTEPH and Advanced Age and/or Comorbidities
Authors: Barnikel Michaela , Kneidinger Nikolaus , Arnold Paola , Waelde Andrea , Behr Jürgen , Milger Katrin
Published: February 2022

Riociguat is licensed for the therapy of inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to investigate whether age and comorbidities influence its tolerability and efficacy. Retrospectively, we analyzed data of tolerability, non-invasive, and invasive efficacy at baseline and follow up (FU) of all patients with CTEPH treated with riociguat at the Department of Internal Medicine V, University of Munich (n = 47), grouping patients according to age (<65 versus 65–79 versus ≥80 years) and risk factors for heart failure with preserved ejection fraction (HFpEF) (<2 versus ≥2 risk factors). During dose titration patients >80 years reported side effects more frequently (40%) than the other age groups (23% and 21% for patients <65 years and patients 65–79, respectively). Cessation of riociguat was rare and occurred independent of age. When looking at the total cohort of 47 patients, three patients stopped therapy and three patients had a reduced maintenance dosage, while 41/47 (87%) and all octogenarians reached the highest maintenance dosage of 7.5 mg/d. The frequency of any side effect was similar in patients in both risk factor groups, and hypotension was only observed in those with <2 risk factors. Parameters of efficacy improved significantly under riociguat treatment. Improvement in 6-min walk distance (6 mwd), N-terminal pro brain natriuretic peptide (Nt-proBNP) and hemodynamics did not differ between age or risk factor groups. In this small real-life cohort, riociguat was well-tolerated and effective in advanced age and risk factors for HFpEF.
Pancreatic Stone Protein: Review of a New Biomarker in Sepsis
Authors: Fidalgo Pedro , Nora David , Coelho Luis , Povoa Pedro
Published: February 2022

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to an infection that may evolve rapidly into septic shock and multiple organ failure. Management of sepsis relies on the early recognition and diagnosis of infection and the providing of adequate and prompt antibiotic therapy and organ support. A novel protein biomarker, the pancreatic stone protein (PSP), has recently been studied as a biomarker of sepsis and the available evidence suggests that it has a higher diagnostic performance for the identification of infection than the most used available biomarkers and adds prognostic value. This review summarizes the clinical evidence available for PSP in the diagnosis and prognosis of sepsis.
Changes in Fat Oxidation and Body Composition after Combined Exercise Intervention in Sedentary Obese Chinese Adults
Authors: Cao Jingguo , Lei Siman , Zhao Tong , Xie Yuting , Zhou Zunqiang , Cheng Sulin , Wang Xiuqiang
Published: February 2022

(1) Background: Evidence suggests that aerobic exercise and high-intensity interval training (HIIT) might increase fat oxidation and reduce fat. However, limited research has examined the effects of combining progressive aerobic exercise and HIIT interventions in sedentary adults with overweight and obesity, and differences in its effects between men and women remain unclear. The purpose of this study was to investigate the effects of combined progressive aerobic exercise and HIIT (CAEH) on fat oxidation and fat reduction in sedentary Chinese adults and compare sex differences in sedentary adults after seven weeks. (2) Methods: Eighty-four sedentary obese adults were enrolled and allocated to two groups in baseline (experimental (EXP) group:42; control (CON) group:42), and fifty-six subjects (EXP:31; CON:25) completed the experiments and were included in the final analysis. Subjects in the EXP group performed CAEH three times per week for seven weeks. Subjects in the CON group were advised to continue with their normal daily activities. Anthropometric, lipid profile, cardiorespiratory fitness, and fat oxidation outcomes were assessed before and after the intervention. (3) Results: After seven weeks of the CAEH intervention, compared with the CON group, the EXP group showed significant increases in fat oxidation at rest (FO_rest) (+0.03 g/min, p < 0.01), maximal fat oxidation (MFO) (+0.05 g/min, p < 0.01), and maximal oxygen intake (VO2max) (+3.2 mL/kg/min, p < 0.01). The changes in the percentages of the FO_rest (+57%) and the VO2max (+16%) were significantly greater (+20%, +6%) in males than in females (p < 0.05, p < 0.05). The body mass index (BMI) (−1.2 kg/m2, p < 0.01), body fat percentage (−3.2%, p < 0.001), visceral fat area (−12.8 cm2, p < 0.001), and total cholesterol (TC) levels (−0.4 mmol/L, p < 0.05) were significantly decreased in the EXP group. (4) Conclusions: Seven weeks of the CAEH intervention effectively improved FO_rest, MFO, and VO2max in sedentary obese adults, and the improvements in FO_rest and VO2max were more pronounced in males than in females. CAEH also improved body composition and TC levels in sedentary obese adults.