bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing World City Networks by Language: A Complex-Network Approach
Authors: Zhang Wenjia , Zhu Jiancheng , Zhao Pu
Published: April 2021

City networks are multiplex and diverse rather than being regarded as part of a single universal model that is valid worldwide. This study contributes to the debate on multiple globalizations by distinguishing multiscale structures of world city networks (WCNs) reflected in the Internet webpage content in English, German, and French. Using big data sets from web crawling, we adopted a complex-network approach with both macroscale and mesoscale analyses to compare global and grouping properties in varying WCNs, by using novel methods such as the weighted stochastic block model (WSBM). The results suggest that at the macro scale, the rankings of city centralities vary across languages due to the uneven geographic distribution of languages and the variant levels of globalization of cities perceived in different languages. At the meso scale, the WSBMs infer different grouping patterns in the WCNs by language, and the specific roles of many world cities vary with language. The probability-based comparative analyses reveal that the English WCN looks more globalized, while the French and German worlds appear more territorial. Using the mesoscale structure detected in the English WCN to comprehend the city networks in other languages may be biased. These findings demonstrate the importance of scrutinizing multiplex WCNs in different cultures and languages as well as discussing mesoscale structures in comparative WCN studies.
Cytocompatibility and Suitability of Protein-Based Biomaterials as Potential Candidates for Corneal Tissue Engineering
Authors: Romo-Valera Cristina , Guerrero Pedro , Arluzea Jon , Etxebarria Jaime , de la Caba Koro , Andollo Noelia
Published: April 2021

The vision impairments suffered by millions of people worldwide and the shortage of corneal donors show the need of substitutes that mimic native tissue to promote cell growth and subsequent tissue regeneration. The current study focused on the in vitro assessment of protein-based biomaterials that could be a potential source for corneal scaffolds. Collagen, soy protein isolate (SPI), and gelatin films cross-linked with lactose or citric acid were prepared and physicochemical, transmittance, and degradation measurements were carried out. In vitro cytotoxicity, cell adhesion, and migration studies were performed with human corneal epithelial (HCE) cells and 3T3 fibroblasts for the films’ cytocompatibility assessment. Transmittance values met the cornea’s needs, and the degradation profile revealed a progressive biomaterials’ decomposition in enzymatic and hydrolytic assays. Cell viability at 72 h was above 70% when exposed to SPI and gelatin films. Live/dead assays and scanning electron microscopy (SEM) analysis demonstrated the adhesion of both cell types to the films, with a similar arrangement to that observed in controls. Besides, both cell lines were able to proliferate and migrate over the films. Without ruling out any material, the appropriate optical and biological properties shown by lactose-crosslinked gelatin film highlight its potential for corneal bioengineering.
Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function
Authors: Ramos-Ramírez Patricia , Tliba Omar
Published: April 2021

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.
EVs from BALF—Mediators of Inflammation and Potential Biomarkers in Lung Diseases
Authors: Zareba Lukasz , Szymanski Jacek , Homoncik Zuzanna , Czystowska-Kuzmicz Malgorzata
Published: April 2021

Extracellular vesicles (EVs) have been identified as key messengers of intracellular communication in health and disease, including the lung. EVs that can be found in bronchoalveolar lavage fluid (BALF) are released by multiple cells of the airways including bronchial epithelial cells, endothelial cells, alveolar macrophages, and other immune cells, and they have been shown to mediate proinflammatory signals in many inflammatory lung diseases. They transfer complex molecular cargo, including proteins, cytokines, lipids, and nucleic acids such as microRNA, between structural cells such as pulmonary epithelial cells and innate immune cells such as alveolar macrophages, shaping mutually their functions and affecting the alveolar microenvironment homeostasis. Here, we discuss this distinct molecular cargo of BALF-EVs in the context of inducing and propagating inflammatory responses in particular acute and chronic lung disorders. We present different identified cellular interactions in the inflammatory lung via EVs and their role in lung pathogenesis. We also summarize the latest studies on the potential use of BALF-EVs as diagnostic and prognostic biomarkers of lung diseases, especially of lung cancer.
Functional Fine-Tuning of Metabolic Pathways by the Endocannabinoid System—Implications for Health and Disease
Authors: Moreno Estefanía , Cavic Milena , Canela Enric I.
Published: April 2021

The endocannabinoid system (ECS) employs a huge network of molecules (receptors, ligands, and enzymatic machinery molecules) whose interactions with other cellular networks have still not been fully elucidated. Endogenous cannabinoids are molecules with the primary function of control of multiple metabolic pathways. Maintenance of tissue and cellular homeostasis by functional fine-tuning of essential metabolic pathways is one of the key characteristics of the ECS. It is implicated in a variety of physiological and pathological states and an attractive pharmacological target yet to reach its full potential. This review will focus on the involvement of ECS in glucose and lipid metabolism, food intake regulation, immune homeostasis, respiratory health, inflammation, cancer and other physiological and pathological states will be substantiated using freely available data from open-access databases, experimental data and literature review. Future directions should envision capturing its diversity and exploiting pharmacological options beyond the classical ECS suspects (exogenous cannabinoids and cannabinoid receptor monomers) as signaling through cannabinoid receptor heteromers offers new possibilities for different biochemical outcomes in the cell.
ATP-Independent Initiation during Cap-Independent Translation of m6A-Modified mRNA
Authors: Sakharov Pavel A. , Smolin Egor A. , Lyabin Dmitry N. , Agalarov Sultan C.
Published: April 2021

The methylation of adenosine in the N6 position (m6A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m6A-modified mRNAs are not fully known. In this study, we used toeprinting and translation in a cell-free system to confirm that m6A-modified mRNAs can be translated in conditions of suppressed cap-dependent translation. We show for the first time that m6A-modified mRNAs display not only decreased elongation, but also a lower efficiency of translation initiation. Additionally, we report relative resistance of m6A-mRNA translation initiation in the absence of ATP and inhibited eIF4A activity. Our novel findings indicate that the scanning of m6A-modified leader sequences is performed by a noncanonical mechanism.
Symbiotic NCR Peptide Fragments Affect the Viability, Morphology and Biofilm Formation of Candida Species
Authors: Szerencsés Bettina , Gácser Attila , Endre Gabriella , Domonkos Ildikó , Tiricz Hilda , Vágvölgyi Csaba , Szolomajer János , Howan Dian H. O. , Tóth Gábor K. , Pfeiffer Ilona , Kondorosi Éva
Published: April 2021

The increasing rate of fungal infections causes global problems not only in human healthcare but agriculture as well. To combat fungal pathogens limited numbers of antifungal agents are available therefore alternative drugs are needed. Antimicrobial peptides are potent candidates because of their broad activity spectrum and their diverse mode of actions. The model legume Medicago truncatula produces >700 nodule specific cysteine-rich (NCR) peptides in symbiosis and many of them have in vitro antimicrobial activities without considerable toxicity on human cells. In this work we demonstrate the anticandidal activity of the NCR335 and NCR169 peptide derivatives against five Candida species by using the micro-dilution method, measuring inhibition of biofilm formation with the XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) assay, and assessing the morphological change of dimorphic Candida species by microscopy. We show that both the N- and C-terminal regions of NCR335 possess anticandidal activity as well as the C-terminal sequence of NCR169. The active peptides inhibit biofilm formation and the yeast-hypha transformation. Combined treatment of C. auris with peptides and fluconazole revealed synergistic interactions and reduced 2-8-fold the minimal inhibitory concentrations. Our results demonstrate that shortening NCR peptides can even enhance and broaden their anticandidal activity and therapeutic potential.
Can miRNA Indicate Risk of Illness after Continuous Exposure to M. tuberculosis?
Authors: Silva Cleonardo Augusto , Ribeiro-dos-Santos Arthur , Gonçalves Wanderson Gonçalves , Pinto Pablo , Pantoja Rafael Pompeu , Vinasco-Sandoval Tatiana , Ribeiro-dos-Santos André Maurício , Hutz Mara Helena , Vidal Amanda Ferreira , Araújo Gilderlanio Santana , Ribeiro-dos-Santos Ândrea , Santos Sidney
Published: April 2021

The role of regulatory elements such as small ncRNAs and their mechanisms are poorly understood in infectious diseases. Tuberculosis is one of the oldest infectious diseases of humans and it is still a challenge to prevent and treat. Control of the infection, as well as its diagnosis, are still complex and current treatments used are linked to several side effects. This study aimed to identify possible biomarkers for tuberculosis by applying NGS techniques to obtain global miRNA expression profiles from 22 blood samples of infected patients with tuberculosis (n = 9), their respective healthy physicians (n = 6) and external healthy individuals as controls (n = 7). Samples were run through a pipeline consisting of differential expression, target genes, gene set enrichment and miRNA–gene network analyses. We observed 153 altered miRNAs, among which only three DEmiRNAs (hsa-let-7g-5p, hsa-miR-486-3p and hsa-miR-4732-5p) were found between the investigated patients and their respective physicians. These DEmiRNAs are suggested to play an important role in granuloma regulation and their immune physiopathology. Our results indicate that miRNAs may be involved in immune modulation by regulating gene expression in cells of the immune system. Our findings encourage the application of miRNAs as potential biomarkers for tuberculosis.
Fenofibrate Regulates Visceral Obesity and Nonalcoholic Steatohepatitis in Obese Female Ovariectomized C57BL/6J Mice
Authors: Shin Yujin , Lee Mijeong , Lee Dongju , Jang Joonseong , Shin Soon Shik , Yoon Michung
Published: April 2021

Fibrates, including fenofibrate, are a class of hypolipidemic drugs that activate peroxisome proliferator-activated receptor α (PPARα), which in-turn regulates the expression of lipid and lipoprotein metabolism genes. We investigated whether fenofibrate can reduce visceral obesity and nonalcoholic fatty liver disease via adipose tissue PPARα activation in female ovariectomized (OVX) C57BL/6J mice fed a high-fat diet (HFD), a mouse model of obese postmenopausal women. Fenofibrate reduced body weight gain (−38%, p < 0.05), visceral adipose tissue mass (−46%, p < 0.05), and visceral adipocyte size (−20%, p < 0.05) in HFD-fed obese OVX mice. In addition, plasma levels of alanine aminotransferase and aspartate aminotransferase, as well as free fatty acids, triglycerides, and total cholesterol, were decreased. Fenofibrate also inhibited hepatic lipid accumulation (−69%, p < 0.05) and infiltration of macrophages (−72%, p < 0.05), while concomitantly upregulating the expression of fatty acid β-oxidation genes targeted by PPARα and decreasing macrophage infiltration and mRNA expression of inflammatory factors in visceral adipose tissue. These results suggest that fenofibrate inhibits visceral obesity, as well as hepatic steatosis and inflammation, in part through visceral adipose tissue PPARα activation in obese female OVX mice.
Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy
Authors: Mencias Mark , Levene Michelle , Blighe Kevin , Bax Bridget ,   on behalf of the Project Group
Published: April 2021

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Quantitative PCR (qPCR) was used to profile miRNAs in serum and/or plasma samples collected for the discovery, validation and performance phases, and next generation sequencing (NGS) analysis was applied to serum samples assigned to the candidate screening phase. Forty-one differentially expressed candidate miRNAs were identified in the sera of patients (p < 0.05, log2 fold change > 1). The validation cohort revealed that of those, 27 miRNAs were upregulated in plasma and three miRNAs were upregulated in sera (p < 0.05). Through binary logistic regression analyses, five plasma miRNAs (miR-192-5p, miR-193a-5p, miR-194-5p, miR-215-5p and miR-34a-5p) and three serum miRNAs (miR-192-5p, miR-194-5p and miR-34a-5p) were shown to robustly distinguish MNGIE from healthy controls. Reduced longitudinal miRNA expression of miR-34a-5p was observed in all four patients treated with EE-TP and coincided with biochemical and clinical improvements. We recommend the inclusion of the plasma exploratory miRNA biomarker panel in future clinical trials of investigational therapies for MNGIE; it may have prognostic value for assessing clinical status.
Rho GTPases in Retinal Vascular Diseases
Authors: Uemura Akiyoshi , Fukushima Yoko
Published: April 2021

The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell–cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular formation and permeability. While these Rho GTPases are broadly expressed in various types of cells, RhoJ is enriched in angiogenic ECs. Semaphorin 3E (Sema3E) releases RhoJ from the intracellular domain of PlexinD1, by which RhoJ induces actin depolymerization through competition with Cdc42 for their common effector proteins. RhoJ further mediates the Sema3E-induced association of PlexinD1 with vascular endothelial growth factor receptor (VEGFR) 2 and the activation of p38. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, leading to the prevention of VEGFR2 degradation and the maintenance of intracellular signal transduction. These pleiotropic roles of RhoJ are required for directional EC migration in retinal angiogenesis. This review highlights the latest insights regarding Rho GTPases in the field of vascular biology, as it will be informative to consider their potential as targets for the treatment of aberrant angiogenesis and hyperpermeability in retinal vascular diseases.
Arginase Activity in Eisenia andrei Coelomocytes: Function in the Earthworm Innate Response
Authors: Homa Joanna , Klosowska Alina , Chadzinska Magdalena
Published: April 2021

Arginase is the manganese metalloenzyme catalyzing the conversion of l-arginine to l-ornithine and urea. In vertebrates, arginase is involved in the immune response, tissue regeneration, and wound healing and is an important marker of alternative anti-inflammatory polarization of macrophages. In invertebrates, data concerning the role of arginase in these processes are very limited. Therefore, in the present study, we focused on the changes in arginase activity in the coelomocytes of Eisenia andrei. We studied the effects of lipopolysaccharide (LPS), hydrogen peroxide (H2O2), heavy metals ions (e.g., Mn2+), parasite infection, wound healing, and short-term fasting (5 days) on arginase activity. For the first time in earthworms, we described arginase activity in the coelomocytes and found that it can be up-regulated upon in vitro stimulation with LPS and H2O2 and in the presence of Mn2+ ions. Moreover, arginase activity was also up-regulated in animals in vivo infected with nematodes or experiencing segment amputation, but not in fasting earthworms. Furthermore, we confirmed that the activity of coelomocyte arginase can be suppressed by l-norvaline. Our studies strongly suggest that similarly to the vertebrates, also in the earthworms, coelomocyte arginase is an important element of the immune response and wound healing processes.
Thermal Preferences of Cowpea Seed Beetles (Callosobruchus maculatus): Effects of Sex and Nuptial Gift Transfers
Authors: Małek Dariusz Krzysztof , Czarnoleski Marcin
Published: April 2021

The thermal environment influences insect performance, but the factors affecting insect thermal preferences are rarely studied. We studied Callosobruchus maculatus seed beetles and hypothesized that thermal preferences are influenced by water balance, with individuals with limited water reserves preferring cooler habitats to reduce evaporative water loss. Adult C. maculatus, in their flightless morph, do not consume food or water, but a copulating male provides a female with a nuptial gift of ejaculate containing nutrients and water. We hypothesized that gift recipients would prefer warmer habitats than gift donors and that both sexes would plastically adjust their thermal preferences according to the size of the transferred gift. We measured the thermal preference in each sex in individuals that were mated once or were unmated. In the mated group, we measured the sizes of the nuptial gifts and calculated proportional body mass changes in each mate during copulation. Supporting the role of water balance in thermal preference, females preferred warmer habitats than males. Nevertheless, thermal preferences in either sex were not affected by mating status or gift size. It is likely that high rates of mating and gift transfers in C. maculatus living under natural conditions promoted the evolution of constitutive sex-dependent thermal preferences.
The Insect Type 1 Tyramine Receptors: From Structure to Behavior
Authors: Finetti Luca , Roeder Thomas , Calò Girolamo , Bernacchia Giovanni
Published: April 2021

Tyramine is a neuroactive compound that acts as neurotransmitter, neuromodulator, and neurohormone in insects. Three G protein-coupled receptors, TAR1-3, are responsible for mediating the intracellular pathway in the complex tyraminergic network. TAR1, the prominent player in this system, was initially classified as an octopamine receptor which can also be activated by tyramine, while it later appeared to be a true tyramine receptor. Even though TAR1 is currently considered as a well-defined tyramine receptor and several insect TAR1s have been characterized, a defined nomenclature is still inconsistent. In the last years, our knowledge on the structural, biochemical, and functional properties of TAR1 has substantially increased. This review summarizes the available information on TAR1 from different insect species in terms of basic structure, its regulation and signal transduction mechanisms, and its distribution and functions in the brain and the periphery. A special focus is given to the TAR1-mediated intracellular signaling pathways as well as to their physiological role in regulating behavioral traits. Therefore, this work aims to correlate, for the first time, the physiological relevance of TAR1 functions with the tyraminergic system in insects. In addition, pharmacological studies have shed light on compounds with insecticidal properties having TAR1 as a target and on the emerging trend in the development of novel strategies for pest control.
Reproductive Chances of Men with Azoospermia Due to Spermatogenic Dysfunction
Authors: Kang Caroline , Punjani Nahid , Schlegel Peter N.
Published: April 2021

Non-obstructive azoospermia (NOA), or lack of sperm in the ejaculate due to spermatogenic dysfunction, is the most severe form of infertility. Men with this form of infertility should be evaluated prior to treatment, as there are various underlying etiologies for NOA. While a significant proportion of NOA men have idiopathic spermatogenic dysfunction, known etiologies including genetic disorders, hormonal anomalies, structural abnormalities, chemotherapy or radiation treatment, infection and inflammation may substantively affect the prognosis for successful treatment. Despite the underlying etiology for NOA, most of these infertile men are candidates for surgical sperm retrieval and subsequent use in intracytoplasmic sperm injection (ICSI). In this review, we describe common etiologies of NOA and clinical outcomes following surgical sperm retrieval and ICSI.
Longitudinal Changes on Optical Coherence Tomography Angiography in Retinal Vein Occlusion
Authors: Tripathy Swetapadma , Le Hong-Gam , Cicinelli Maria Vittoria , Gill Manjot K.
Published: April 2021

Background: To evaluate the longitudinal changes on optical coherence tomography angiography (OCTA) in retinal vein occlusion (RVO). Methods: Retrospective study of patients with RVO treated with intravitreal anti-vascular endothelial growth factors (VEGF) for macular edema. Foveal avascular zone (FAZ) area, vessel density (VD), vessel length density (VLD), and adjusted flow index (AFI) were calculated. The unaffected eye of each participant was used as a control. Results: Twelve RVO eyes were included, receiving 6 ± 3 anti-VEGF injections over a follow-up of 10.4 ± 3.1 months. Compared to fellow eyes, RVO eyes had lower VD and VLD at inclusion (p = 0.07 and p = 0.04) and last visit (p = 0.002 and p < 0.001). VD, AFI, and VLD did not change over time, while FAZ area increased in RVO eyes (+0.016 ± 0.024 mm2, p = 0.04). AFI correlated with duration of disease (r = 0.63, p = 0.02). Visual acuity was inversely related to VD and VLD over the follow-up. Conclusions: OCTA parameters remained stable with sustained anti-VEGF treatment in RVO, while changes in the FAZ area may suggest capillary remodeling after RVO.
Changes in Neutrophil–Lymphocyte or Platelet–Lymphocyte Ratios and Their Associations with Clinical Outcomes in Idiopathic Pulmonary Fibrosis
Authors: Nathan Steven D. , Mehta Jayesh , Stauffer John , Morgenthien Elizabeth , Yang Ming , Limb Susan L. , Bhorade Sangeeta
Published: April 2021

Identification of prognostic and predictive biomarkers in idiopathic pulmonary fibrosis (IPF) could aid assessment of disease severity and prediction of progression and response to treatment. This analysis examined reference ranges for neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) in IPF, and the relationship between NLR or PLR changes and clinical outcomes over 12 months. This post hoc analysis included patients with IPF from the Phase III, double-blind trials of pirfenidone, ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729). The relationship between change from baseline to Month 12 in NLR or PLR (divided into quartiles (Q1–Q4)) and outcomes (mortality, respiratory hospitalization, declines in lung function, exercise capacity and quality of life) was assessed. Estimated reference ranges at baseline for all patients analyzed (n = 1334) were 1.1–6.4 for NLR and 56.8–250.5 for PLR. Significant trends were observed across NLR and PLR quartiles for all outcomes in placebo-treated patients, with patients manifesting the greatest NLR or PLR changes experiencing the worst outcomes. These results suggest that the greatest NLR or PLR changes over 12 months were associated with worse clinical outcomes. Further research is needed to determine the utility of NLR and PLR as prognostic biomarkers in IPF.
CGRP Receptor Antagonists and 5-HT1F Receptor Agonist in the Treatment of Migraine
Authors: Capi Matilde , De Angelis Valerio , De Bernardini Donatella , De Luca Ottavia , Cipolla Fabiola , Lionetto Luana , Simmaco Maurizio , Martelletti Paolo
Published: April 2021

Discovering that calcitonin-related peptide (CGRP) plays a key role in the complex pathophysiology of migraine has allowed us to make great strides in the development of new approaches for acute and preventive treatment. This evidence has led to the development of small molecules antagonist molecules of the CGRP receptor (“gepants”) and of a new class of medications called “Ditans”. This review presents the data from clinical trials reporting the efficacy, safety, and tolerability of the new drugs used in the treatment of migraines. Evidences show that therapeutic approaches targeted to CGRP have the potential to transform the clinical management of migraine, even though its appropriate place has yet to be determined with accuracy.
Pre-Processing Method for Contouring the Uptake Levels of [18F] FDG for Enhanced Specificity of PET Imaging of Solitary Hypermetabolic Pulmonary Nodules
Authors: Szumowski Piotr , Szklarzewski Artur , Żukowski Łukasz , Abdelrazek Saeid , Mojsak Małgorzata , Porębska Katarzyna , Sierko Ewa , Myśliwiec Janusz
Published: April 2021

Background: The paper presents a pre-processing method which, based on positron-emission tomography (PET) images of 18F-fluorodeoxyglucose ([18F] FDG) hypermetabolic pulmonary nodules, makes it possible to obtain additional visual characteristics and use them to enhance the specificity of imaging. Material and Methods: A retrospective analysis of 69 FDG-PET/CT scans of solitary hypermetabolic pulmonary nodules (40 cases of lung cancer and 29 benign tumours), where in each case, the standardised uptake value of the hottest voxel within the defined volume of interest was greater than 2.5 (SUVmax > 2.5). No diagnosis could be made based on these SUVmax values. All of the PET DICOM images were transformed by means of the pre-processing method for contouring the uptake levels of [18F] FDG (PCUL-FDG). Next, a multidimensional comparative analysis was conducted using a synthetic variable obtained by calculating the similarities based on the generalised distance measure for non-metric scaling (GDM2) from the pattern object. The calculations were performed with the use of the R language. Results: The PCUL-FDG method revealed 73.9% hypermetabolic nodules definitively diagnosed as either benign or malignant lesions. As for the other 26.1% of the nodules, there was uncertainty regarding their classification (some had features suggesting malignancy, while the characteristics of others made it impossible to confirm malignancy with a high degree of certainty). Conclusions: Application of the PCUL-FDG method enhances the specificity of PET in imaging solitary hypermetabolic pulmonary nodules. Images obtained using the PCUL-FDG method can serve as point of departure for automatic analysis of PET data based on convolutional neural networks.
Comparison of the Effects of Laparoscopic and Open Surgery on Postoperative Acute Kidney Injury in Patients with Colorectal Cancer: Propensity Score Analysis
Authors: Sim Ji Hoon , Kang Sa-Jin , Bang Ji-Yeon , Song Jun-Gol
Published: April 2021

Postoperative acute kidney injury (AKI) is a serious complication that increases patient morbidity and mortality. However, few studies have evaluated the effect of laparoscopic surgery on postoperative AKI. This study compared the incidence of postoperative AKI between laparoscopic and open surgery in patients with colorectal cancer. This study retrospectively analyzed 3637 patients who underwent colorectal cancer surgery between June 2008 and February 2012. The patients were classified into laparoscopic (n = 987) and open (n = 2650) surgery groups. We performed multivariable regression analysis to assess the risk factors for AKI and propensity score matching analysis to compare the incidence of AKI between the two groups. We also assessed postoperative intensive care unit (ICU) admission, complications, hospital stay, and 1-year mortality. We observed no significant differences in the incidence of postoperative AKI between the two groups before (8.8% vs. 9.1%, p = 0.406) and after (8.8% vs. 7.7%, p = 0.406) matching. Laparoscopic surgery was not associated with AKI even after adjusting for intraoperative variables (adjusted odds ratio (OR): 1.17, 95% confidence interval (CI): 0.84–1.62, p = 0.355). Body mass index, diabetes mellitus, hypertension, and albumin were risk factors for AKI. ICU admission (0.6% vs. 2.5%, p = 0.001), complications (0.2% vs. 1.5%, p = 0.002), hospital stay (6.89 days vs. 8.61 days, p < 0.001), and 1-year mortality (0.1% vs. 0.9%, p = 0.021) were significantly better in the laparoscopic than in the open group. The incidence of postoperative AKI did not differ significantly between laparoscopic and open surgery. However, considering its better surgical outcomes, laparoscopic surgery may be recommended for patients with colorectal cancer.
Re-Operative Laparoscopic Colorectal Surgery: A Systematic Review
Authors: Halkias Constantine , Zoikas Athanasios , Garoufalia Zoe , Konstantinidis Michalis K. , Ioannidis Argyrios , Wexner Steven
Published: April 2021

Introduction: Re-operative laparoscopic colorectal surgery is becoming increasingly common. It can be a challenging procedure, but its benefits can outweigh the associated risks. Methods: A systematic review of the literature reporting re-operative laparoscopic surgery was carried out. Retrospective and prospective cohort studies and case series were included, with case reports being excluded. Results: Seventeen articles dated from 2007 to 2020 were included in the systematic review. In total, 1555 patients were identified. Five hundred and seventy-four of them had a laparoscopic procedure and 981 an open re-operation. One hundred and eighty-three women had a laparoscopic operation. The median age ranged from to 44.9 years to 68.7 years. In seven studies, the indication of the index operation was malignancy, one study regarded re-laparoscopy for excision of lateral pelvic lymph nodes, and one study looked at redo surgery of ileal J pouch anal anastomosis. There were 16 mortalities in the laparoscopic arm (2.78%) and 93 (9.4%) in the open surgery arm. One hundred and thirty-seven morbidities were recorded in the open arm and 102 in the laparoscopic arm. Thirty-nine conversions to open occurred. The median length of stay ranged from 5.8 days to 19 days in laparoscopy and 9.7 to 34 days in the open surgery arm. Conclusions: Re-operative laparoscopic colorectal surgery is safe when performed by experienced hands. The management of complications, recurrence of malignancy, and lateral pelvic floor dissection can be safely performed. The complication rate is low, with conversion to open procedures being relatively uncommon.
Investigating the Potential of Network Optimization for a Constrained Object Detection Problem
Authors: Ophoff Tanguy , Gullentops Cédric , Van Beeck Kristof , Goedemé Toon
Published: April 2021

Object detection models are usually trained and evaluated on highly complicated, challenging academic datasets, which results in deep networks requiring lots of computations. However, a lot of operational use-cases consist of more constrained situations: they have a limited number of classes to be detected, less intra-class variance, less lighting and background variance, constrained or even fixed camera viewpoints, etc. In these cases, we hypothesize that smaller networks could be used without deteriorating the accuracy. However, there are multiple reasons why this does not happen in practice. Firstly, overparameterized networks tend to learn better, and secondly, transfer learning is usually used to reduce the necessary amount of training data. In this paper, we investigate how much we can reduce the computational complexity of a standard object detection network in such constrained object detection problems. As a case study, we focus on a well-known single-shot object detector, YoloV2, and combine three different techniques to reduce the computational complexity of the model without reducing its accuracy on our target dataset. To investigate the influence of the problem complexity, we compare two datasets: a prototypical academic (Pascal VOC) and a real-life operational (LWIR person detection) dataset. The three optimization steps we exploited are: swapping all the convolutions for depth-wise separable convolutions, perform pruning and use weight quantization. The results of our case study indeed substantiate our hypothesis that the more constrained a problem is, the more the network can be optimized. On the constrained operational dataset, combining these optimization techniques allowed us to reduce the computational complexity with a factor of 349, as compared to only a factor 9.8 on the academic dataset. When running a benchmark on an Nvidia Jetson AGX Xavier, our fastest model runs more than 15 times faster than the original YoloV2 model, whilst increasing the accuracy by 5% Average Precision (AP).
Epidemiology of Candidemia: Three-Year Results from a Croatian Tertiary Care Hospital
Authors: Mareković Ivana , Pleško Sanja , Rezo Vranješ Violeta , Herljević Zoran , Kuliš Tomislav , Jandrlić Marija
Published: April 2021

Invasive candidosis is the most common invasive fungal infection in hospitalized patients and is associated with a high mortality rate. This is the first study from a Croatian tertiary care hospital describing epidemiology, risk factors and species distribution in patients with candidemia. A three-year retrospective observational study, from 2018 to 2020, was performed at the University Hospital Centre Zagreb, Zagreb, Croatia. A total of 160 patients with candidemia (n = 170 isolates) were enrolled. Candidemia incidence increased from 0.47 to 0.69 per 1000 admissions in 2018 and 2020, respectively. Ninety-five patients (58.38%) were in the intensive care unit. The main risk factors for candidemia were central venous catheter (CVC) (84.38%), previous surgical procedure (56.88%) and invasive mechanical ventilation (42.50%). Candida albicans was identified in 43.53% of isolates, followed by C. parapsilosis (31.76%) and C. glabrata (12.36%), C. krusei (5.29%), C. tropicalis (2.35%) and C. lusitaniae (2.35%). The study discovered a shift to non-albicansCandida species, particularly C. parapsilosis, and made it possible to determine the main tasks we should focus on to prevent candidemia in the hospital, these being mainly infection control measures directed towards prevention of catheter-related bloodstream infections, specifically comprising hand hygiene and CVC bundles of care. The potential benefit of fluconazole prophylaxis in certain populations of surgical patients could also be considered.
Personalized, Predictive, Participatory, Precision, and Preventive (P5) Medicine in Rotator Cuff Tears
Authors: Longo Umile Giuseppe , Carnevale Arianna , Massaroni Carlo , Lo Presti Daniela , Berton Alessandra , Candela Vincenzo , Schena Emiliano , Denaro Vincenzo
Published: April 2021

Rotator cuff (RC) disease is a common musculoskeletal disorder of the shoulder entailing pain, with reduced functionality and quality of life. The main objective of this study was to present a perspective of the current scientific evidence about personalized, predictive, participatory, precision, and preventive approaches in the management of RC diseases. The personalized, predictive, participatory, precision and preventive (P5) medicine model is an interdisciplinary and multidisciplinary approach that will provide researchers and clinicians with a comprehensive patrimony of knowledge in the management of RC diseases. The ability to define genetic predispositions in conjunction with the evaluation of lifestyle and environmental factors may boost the tailoring of diagnosis and therapy in patients suffering from RC diseases.
Diagnosis and Management of Glioblastoma: A Comprehensive Perspective
Authors: Gilard Vianney , Tebani Abdellah , Dabaj Ivana , Laquerrière Annie , Fontanilles Maxime , Derrey Stéphane , Marret Stéphane , Bekri Soumeya
Published: April 2021

Glioblastoma is the most common malignant brain tumor in adults. The current management relies on surgical resection and adjuvant radiotherapy and chemotherapy. Despite advances in our understanding of glioblastoma onset, we are still faced with an increased incidence, an altered quality of life and a poor prognosis, its relapse and a median overall survival of 15 months. For the past few years, the understanding of glioblastoma physiopathology has experienced an exponential acceleration and yielded significant insights and new treatments perspectives. In this review, through an original R-based literature analysis, we summarize the clinical presentation, current standards of care and outcomes in patients diagnosed with glioblastoma. We also present the recent advances and perspectives regarding pathophysiological bases as well as new therapeutic approaches such as cancer vaccination and personalized treatments.
CD24 for Cardiovascular Researchers: A Key Molecule in Cardiac Immunology, Marker of Stem Cells and Target for Drug Development
Authors: Sagiv Eyal , Portman Michael A.
Published: April 2021

The study of the membrane protein, CD24, and its emerging role in major disease processes, has made a huge leap forward in the past two decades. It appears to have various key roles in oncogenesis, tumor progression and metastasis, stem cell maintenance and immune modulation. First described in the 1980s as the homologous human protein to the mouse HSA (Heat Stable Antigen), it was reported as a surface marker in developing hematopoietic cell lines. The later discovery of its overexpression in a large number of human neoplasms, lead cancer researchers to discover its various active roles in critical checkpoints during cancer development and progression. Targeting CD24 in directed drug development showed promising results in cancer treatment. More recently, the chimeric CD24-Fc protein has shown exciting results in clinical trials as a specific modulator of auto-inflammatory syndromes. This report is aimed to summarize the relevant literature on CD24 and tie it together with recent advancements in cardiovascular research. We hypothesize that CD24 is a promising focus of research in the understanding of cardiovascular disease processes and the development of novel biological therapies.
The Exposure of French and South Korean Firm Stock Returns to Exchange Rates and the COVID-19 Pandemic
Authors: Thorbecke Willem
Published: April 2021

Rogoff predicted that the U.S. dollar will depreciate and that exchange rate volatility will return. The coronavirus crisis has also roiled the world economy. This paper investigates the exposure of French and Korean firm stock returns to exchange rate appreciations and the pandemic. Both France and Korea are major exporters, but Korea has managed the crisis better than France. The results indicate that Korean firms have come through the pandemic better than French firms. The findings also indicate that the Korean economy is less exposed to appreciations than the French economy. This paper concludes with suggestions to increase firms’ resilience to these shocks.
Transcription Factor Activity Inference in Systemic Lupus Erythematosus
Authors: Lopez-Dominguez Raul , Toro-Dominguez Daniel , Martorell-Marugan Jordi , Garcia-Moreno Adrian , Holland Christian , Saez-Rodriguez Julio , Goldman Daniel , Petri Michelle , Alarcon-Riquelme Marta , Carmona-Saez Pedro
Published: April 2021

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE. Methods: In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples. Results: TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets—one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE. Conclusions: These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets.
Development of the Cerebrospinal Fluid in Early Stage after Hemorrhage in the Central Nervous System
Authors: Kelbich Petr , Hejčl Aleš , Krejsek Jan , Radovnický Tomáš , Matuchová Inka , Lodin Jan , Špička Jan , Sameš Martin , Procházka Jan , Hanuljaková Eva , Vachata Petr
Published: April 2021

Extravasation of blood in the central nervous system (CNS) represents a very strong damaged associated molecular patterns (DAMP) which is followed by rapid inflammation and can participate in worse outcome of patients. We analyzed cerebrospinal fluid (CSF) from 139 patients after the CNS hemorrhage. We compared 109 survivors (Glasgow Outcome Score (GOS) 5-3) and 30 patients with poor outcomes (GOS 2-1). Statistical evaluations were performed using the Wilcoxon signed-rank test and the Mann–Whitney U test. Almost the same numbers of erythrocytes in both subgroups appeared in days 0–3 (p = 0.927) and a significant increase in patients with GOS 2-1 in days 7–10 after the hemorrhage (p = 0.004) revealed persistence of extravascular blood in the CNS as an adverse factor. We assess 43.3% of patients with GOS 2-1 and only 27.5% of patients with GOS 5-3 with low values of the coefficient of energy balance (KEB < 15.0) in days 0–3 after the hemorrhage as a trend to immediate intensive inflammation in the CNS of patients with poor outcomes. We consider significantly higher concentration of total protein of patients with GOS 2-1 in days 0–3 after hemorrhage (p = 0.008) as the evidence of immediate simultaneously manifested intensive inflammation, swelling of the brain and elevation of intracranial pressure.
In Situ 3D-Imaging of the Inner Ear Synapses with a Cochlear Implant
Authors: Malfeld Kathrin , Armbrecht Nina , Volk Holger A. , Lenarz Thomas , Scheper Verena
Published: April 2021

In recent years sensorineural hearing loss was found to affect not exclusively, nor at first, the sensory cells of the inner ear. The sensory cells’ synapses and subsequent neurites are initially damaged. Auditory synaptopathies also play an important role in cochlear implant (CI) care, as they can lead to a loss of physiological hearing in patients with residual hearing. These auditory synaptopathies and in general the cascades of hearing pathologies have been in the focus of research in recent years with the aim to develop more targeted and individually tailored therapeutics. In the current study, a method to examine implanted inner ears of guinea pigs was developed to examine the synapse level. For this purpose, the cochlea is made transparent and scanned with the implant in situ using confocal laser scanning microscopy. Three different preparation methods were compared to enable both an overview image of the cochlea for assessing the CI position and images of the synapses on the same specimen. The best results were achieved by dissection of the bony capsule of the cochlea.
Oxidative Stress-Induced Alteration of Plant Central Metabolism
Authors: Savchenko Tatyana , Tikhonov Konstantin
Published: April 2021

Oxidative stress is an integral component of various stress conditions in plants, and this fact largely determines the substantial overlap in physiological and molecular responses to biotic and abiotic environmental challenges. In this review, we discuss the alterations in central metabolism occurring in plants experiencing oxidative stress. To focus on the changes in metabolite profile associated with oxidative stress per se, we primarily analyzed the information generated in the studies based on the exogenous application of agents, inducing oxidative stress, and the analysis of mutants displaying altered oxidative stress response. Despite of the significant variation in oxidative stress responses among different plant species and tissues, the dynamic and transient character of stress-induced changes in metabolites, and the strong dependence of metabolic responses on the intensity of stress, specific characteristic changes in sugars, sugar derivatives, tricarboxylic acid cycle metabolites, and amino acids, associated with adaptation to oxidative stress have been detected. The presented analysis of the available data demonstrates the oxidative stress-induced redistribution of metabolic fluxes targeted at the enhancement of plant stress tolerance through the prevention of ROS accumulation, maintenance of the biosynthesis of indispensable metabolites, and production of protective compounds. This analysis provides a theoretical basis for the selection/generation of plants with improved tolerance to oxidative stress and the development of metabolic markers applicable in research and routine agricultural practice.