bluuebunny/crossref_metadata_2025 huggingface dataset:
New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
Authors: Cieślak Marcin , Napiórkowska Mariola , Kaźmierczak-Barańska Julia , Królewska-Golińska Karolina , Hawrył Anna , Wybrańska Iwona , Nawrot Barbara
Published: April 2021

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.
Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia
Authors: Guasto Alessandra , Cormier-Daire Valérie
Published: April 2021

Bone development is a tightly regulated process. Several integrated signaling pathways including HH, PTHrP, WNT, NOTCH, TGF-β, BMP, FGF and the transcription factors SOX9, RUNX2 and OSX are essential for proper skeletal development. Misregulation of these signaling pathways can cause a large spectrum of congenital conditions categorized as skeletal dysplasia. Since the signaling pathways involved in skeletal dysplasia interact at multiple levels and have a different role depending on the time of action (early or late in chondrogenesis and osteoblastogenesis), it is still difficult to precisely explain the physiopathological mechanisms of skeletal disorders. However, in recent years, significant progress has been made in elucidating the mechanisms of these signaling pathways and genotype–phenotype correlations have helped to elucidate their role in skeletogenesis. Here, we review the principal signaling pathways involved in bone development and their associated skeletal dysplasia.
Influence of Trace Elements on Neurodegenerative Diseases of The Eye—The Glaucoma Model
Authors: Kamińska Agnieszka , Romano Giovanni Luca , Rejdak Robert , Zweifel Sandrine , Fiedorowicz Michal , Rejdak Magdalena , Bajka Anahita , Amato Rosario , Bucolo Claudio , Avitabile Teresio , Drago Filippo , Toro Mario Damiano
Published: April 2021

Glaucoma is a heterogeneous group of chronic neurodegenerative disorders characterized by a relatively selective, progressive damage to the retinal ganglion cells (RGCs) and their axons, which leads to axon loss and visual field alterations. To date, many studies have shown the role of various elements, mainly metals, in maintaining the balance of prooxidative and antioxidative processes, regulation of fluid and ion flow through cell membranes of the ocular tissues. Based on the earlier and current research results, their relationship with the development and progression of glaucoma seems obvious and is increasingly appreciated. In this review, we aimed to summarize the current evidence on the role of trace elements in the pathogenesis and prevention of glaucomatous diseases. Special attention is also paid to the genetic background associated with glaucoma-related abnormalities of physiological processes that regulate or involve the ions of elements considered as trace elements necessary for the functioning of the cells.
A Highlight on the Inhibition of Fungal Carbonic Anhydrases as Drug Targets for the Antifungal Armamentarium
Authors: Supuran Claudiu T. , Capasso Clemente
Published: April 2021

Carbon dioxide (CO2), a vital molecule of the carbon cycle, is a critical component in living organisms’ metabolism, performing functions that lead to the building of compounds fundamental for the life cycle. In all living organisms, the CO2/bicarbonate (HCO3−) balancing is governed by a superfamily of enzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the pivotal physiological reaction, consisting of the reversible hydration of the CO2 to HCO3− and protons. Opportunistic and pathogenic fungi can sense the environmental CO2 levels, which influence their virulence or environmental subsistence traits. The fungal CO2-sensing is directly stimulated by HCO3− produced in a CA-dependent manner, which directly activates adenylyl cyclase (AC) involved in the fungal spore formation. The interference with CA activity may impair fungal growth and virulence, making this approach interesting for designing antifungal drugs with a novel mechanism of action: the inhibition of CAs linked to the CO2/HCO3−/pH chemosensing and signaling. This review reports that sulfonamides and their bioisosteres as well as inorganic anions can inhibit in vitro the β- and α-CAs from the fungi, suggesting how CAs may be considered as a novel “pathogen protein” target of many opportunistic, pathogenic fungi.
Profiling Colorectal Cancer in the Landscape Personalized Testing—Advantages of Liquid Biopsy
Authors: Verbanac Donatella , Čeri Andrea , Hlapčić Iva , Shakibaei Mehdi , Brockmueller Aranka , Krušlin Božo , Ljubičić Neven , Baršić Neven , Detel Dijana , Batičić Lara , Rumora Lada , Somborac-Bačura Anita , Štefanović Mario , Ćelap Ivana , Demirović Alma , Petlevski Roberta , Petrik József , Grdić Rajković Marija , Hulina-Tomašković Andrea , Rako Ivana , Saso Luciano , Barišić Karmela
Published: April 2021

Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting cytotoxicity. Currently, CEA and CA 19-9 are the only validated blood biomarkers in clinical practice. For this reason, laboratories are trying to identify new specific prognostics and, more importantly, predictive biomarkers for CRC patient profiling. Thus, the unique landscape of personalized biomarker data should have a clinical impact on CRC treatment strategies and molecular genetic screening tests should become the standard method for diagnosing CRC. This review concentrates on recent molecular testing in CRC and discusses the potential modifications in CRC assay methodology with the upcoming clinical application of novel genomic approaches. While mechanisms for analyzing circulating tumor DNA have been proven too inaccurate, detecting and analyzing circulating tumor cells and protein analysis of exosomes represent more promising options. Blood liquid biopsy offers good prospects for the future if the results align with pathologists’ tissue analyses. Overall, early detection, accurate diagnosis and treatment monitoring for CRC with specific markers and targeted molecular testing may benefit many patients.
miR-155 as an Important Regulator of Multiple Sclerosis Pathogenesis. A Review
Authors: Maciak Karina , Dziedzic Angela , Miller Elzbieta , Saluk-Bijak Joanna
Published: April 2021

Multiple sclerosis (MS) is a chronic, immune-mediated disease and the leading cause of disability among young adults. MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of gene expression. Of them, miR-155 is a crucial regulator of inflammation and plays a role in modulating the autoimmune response in MS. miR-155 is involved in blood–brain barrier (BBB) disruption via down-regulation of key junctional proteins under inflammatory conditions. It drives demyelination processes by contributing to, e.g., microglial activation, polarization of astrocytes, and down-regulation of CD47 protein and affecting crucial transcription factors. miR-155 has a huge impact on the development of neuropathic pain and indirectly influences a regulatory T (Treg) cell differentiation involved in the alleviation of pain hypersensitivity. This review also focused on neuropsychiatric symptoms appearing as a result of disease-associated stressors, brain atrophy, and pro-inflammatory factors. Recent studies revealed the role of miR-155 in regulating anxiety, stress, inflammation in the hippocampus, and treatment-resistant depression. Inhibition of miR-155 expression was demonstrated to be effective in preventing processes involved in the pathophysiology of MS. This review aimed to support the better understanding the great role of miR-155 dysregulation in various aspects of MS pathophysiology and highlight future perspectives for this molecule.
Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders
Authors: Koyama Yutaka
Published: April 2021

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.
A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity
Authors: Cuenca-Bermejo Lorena , Pizzichini Elisa , Gonçalves Valeria , Guillén-Díaz María , Aguilar-Moñino Elena , Sánchez-Rodrigo Consuelo , González-Cuello Ana-María , Fernández-Villalba Emiliano , Herrero María
Published: April 2021

The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson’s disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100β were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.
Estrogen-Related Receptor Influences the Hemolymph Glucose Content by Regulating Midgut Trehalase Gene Expression in the Last Instar Larvae of Bombyx mori
Authors: Shen Guanwang , Wu Jinxin , Lin Ying , Hua Xiaoting , Xia Qingyou , Zhao Ping
Published: April 2021

The expression of trehalase in the midgut of insects plays an important role in glucose supply to the hemolymph. Energy metabolism is usually regulated by the estrogen-related receptor (ERR). A decrease in ATP levels is caused by the ERR hindering glycolysis. However, the relationship between trehalose accumulation and ERR expression is still unclear. Here, we found that silkworm ERR (BmERR) is concentrated and BmERR expression is strongly correlated with trehalase in the midgut during the last instar silkworm larval stage. We cloned the promoter of the trehalase from Bombyx mori (BmTreh) and found that the ERR bound directly to the core response elements of the promoter. Cell level interference and the overexpression of ERR can reduce or enhance BmTreh transcription and promoter activity. Overexpressed transgenic BmERR can significantly increase the expression of BmTreh in the midgut of the last instar silkworm larvae, thereby hydrolyzing trehalose into glucose and releasing it into the hemolymph. Additionally, increased hemolymph glucose content reduces silkworm pupa weight but does not affect silk protein production from the silk gland. Our results suggest a novel function for BmERR through its involvement in BmTreh regulation and expand the understanding of ERR functions in insect trehalose metabolism.
Rational Design of Resveratrol O-methyltransferase for the Production of Pinostilbene
Authors: Herrera Daniela P. , Chánique Andrea M. , Martínez-Márquez Ascensión , Bru-Martínez Roque , Kourist Robert , Parra Loreto P. , Schüller Andreas
Published: April 2021

Pinostilbene is a monomethyl ether analog of the well-known nutraceutical resveratrol. Both compounds have health-promoting properties, but the latter undergoes rapid metabolization and has low bioavailability. O-methylation improves the stability and bioavailability of resveratrol. In plants, these reactions are performed by O-methyltransferases (OMTs). Few efficient OMTs that monomethylate resveratrol to yield pinostilbene have been described so far. Here, we report the engineering of a resveratrol OMT from Vitis vinifera (VvROMT), which has the highest catalytic efficiency in di-methylating resveratrol to yield pterostilbene. In the absence of a crystal structure, we constructed a three-dimensional protein model of VvROMT and identified four critical binding site residues by applying different in silico approaches. We performed point mutations in these positions generating W20A, F24A, F311A, and F318A variants, which greatly reduced resveratrol’s enzymatic conversion. Then, we rationally designed eight variants through comparison of the binding site residues with other stilbene OMTs. We successfully modified the native substrate selectivity of VvROMT. Variant L117F/F311W showed the highest conversion to pinostilbene, and variant L117F presented an overall increase in enzymatic activity. Our results suggest that VvROMT has potential for the tailor-made production of stilbenes.
Development of an Australian Bread Wheat Nested Association Mapping Population, a New Genetic Diversity Resource for Breeding under Dry and Hot Climates
Authors: Chidzanga Charity , Fleury Delphine , Baumann Ute , Mullan Dan , Watanabe Sayuri , Kalambettu Priyanka , Pontre Robert , Edwards James , Forrest Kerrie , Wong Debbie , Langridge Peter , Chalmers Ken , Garcia Melissa
Published: April 2021

Genetic diversity, knowledge of the genetic architecture of the traits of interest and efficient means of transferring the desired genetic diversity into the relevant genetic background are prerequisites for plant breeding. Exotic germplasm is a rich source of genetic diversity; however, they harbor undesirable traits that limit their suitability for modern agriculture. Nested association mapping (NAM) populations are valuable genetic resources that enable incorporation of genetic diversity, dissection of complex traits and providing germplasm to breeding programs. We developed the OzNAM by crossing and backcrossing 73 diverse exotic parents to two Australian elite varieties Gladius and Scout. The NAM parents were genotyped using the iSelect wheat 90K Infinium SNP array, and the progeny were genotyped using a custom targeted genotyping-by-sequencing assay based on molecular inversion probes designed to target 12,179 SNPs chosen from the iSelect wheat 90K Infinium SNP array of the parents. In total, 3535 BC1F4:6 RILs from 125 families with 21 to 76 lines per family were genotyped and we found 4964 polymorphic and multi-allelic haplotype markers that spanned the whole genome. A subset of 530 lines from 28 families were evaluated in multi-environment trials over three years. To demonstrate the utility of the population in QTL mapping, we chose to map QTL for maturity and plant height using the RTM-GWAS approach and we identified novel and known QTL for maturity and plant height.
A Phrase-Level User Requests Mining Approach in Mobile Application Reviews: Concept, Framework, and Operation
Authors: Yang Cheng , Wu Lingang , Yu Chunyang , Zhou Yuliang
Published: April 2021

Mobile application (app) reviews are feedback about experiences, requirements, and issues raised after users have used the app. The iteration of an app is driven by bug reports and user requirements analyzed and extracted from app reviews, which is a problem that app designers and developers are committed to solving. However, a great number of app reviews vary in quality and reliability. It is a difficult and time-consuming challenge to analyze app reviews using manual methods. To address this, a novel approach is proposed as an automated method to predict high priority user requests with fourteen extracted features. A semi-automated approach is applied to annotate requirements with high or low priority with the help of app changelogs. Reviews from six apps were retrieved from the Apple App Store to evaluate the feasibility of the approach and interpret the principles. The performance comparison results of the approach greatly exceed the IDEA method, with an average precision of 75.4% and recall of 70.4%. Our approach can be applied to specific app development to assist app developers in quickly locating user requirements and implement app maintenance and evolution.
Visualisation of Control Software for Cyber-Physical Systems
Authors: Melatti Igor , Mari Federico , Salvo Ivano , Tronci Enrico
Published: April 2021

Cyber-physical systems are typically composed of a physical system (plant) controlled by a software (controller). Such a controller, given a plant state s and a plant action u, returns 1 iff taking action u in state s leads to the physical system goal or at least one step closer to it. Since a controller K is typically stored in compressed form, it is difficult for a human designer to actually understand how “good” K is. Namely, natural questions such as “does K cover a wide enough portion of the system state space?”, “does K cover the most important portion of the system state space?” or “which actions are enabled by K in a given portion of the system space?” are hard to answer by directly looking at K. This paper provides a methodology to automatically generate a picture of K as a 2D diagram, starting from a canonical representation for K and relying on available open source graphing tools (e.g., Gnuplot). Such picture allows a software designer to answer to the questions listed above, thus achieving a better qualitative understanding of the controller at hand.
Host-Plant Variations Affect the Biotic Potential, Survival, and Population Projection of Myzus persicae (Hemiptera: Aphididae)
Authors: Ali Muhammad Yasir , Naseem Tayyaba , Arshad Muhammad , Ashraf Ijaz , Rizwan Muhammad , Tahir Muhammad , Rizwan Misbah , Sayed Samy , Ullah Muhammad Irfan , Khan Rashad Rasool , Amir Muhammad Bilal , Pan Mingzhen , Liu Tong-Xian
Published: April 2021

The green peach aphid, Myzus persicae Sulzer (Hemiptera: Aphididae), a polyphagous insect pest is a major threat to a wide range of crops worldwide. Aiming to evaluate the life history traits of M. persicae, feeding on different host plants, we used five vegetables: cabbage, Brassica oleracea (Brassicaceae); chinese cabbage, B. rapa (Brassicaceae); chili pepper, Capsicum annum (Solanaceae); crown daisy, Chrysanthemum coronarium (Asteraceae); and eggplant, Solanum melongena (Solanaceae). TWOSEX-MSchart software was used for the statistical analysis about the age-stage, two-sex life table theory. The highest fecundity (69.65 individuals) rate of M. persicae, intrinsic rate of increase (r = 0.425 d−1), finite rate of increase (λ = 1.531 d−1), net reproductive rate (R0 = 69.65 offspring), and shortest mean generation time (T = 9.964 d) were recorded on the chili pepper plant. Whereas, lower fitness occurred on cabbage. The findings attained from population growth parameters indicate that chili pepper is the most susceptible plant, while cabbage is resistant to aphids. Population projection results also supported this statement, as the final total population size on cabbage was significantly lower than other plants. The reported information would be useful for devising integrated pest management programs, particularly those involving M. persicae. This information also suggests the adaptability of M. persicae causing economic damage to these vegetable cultivars.
Efficacy and Safety of Inhalation Sedation during Office Probing for Congenital Nasolacrimal Duct Obstruction
Authors: Lee Chunghyun , Jeong Su-Min , Kim Gye Jung , Joo Eun-Young , Song Myung Hee , Sa Ho-Seok
Published: April 2021

We compared the effectiveness of inhaled sevoflurane versus physical restraint during probing in children with congenital nasolacrimal duct obstruction (CNLDO). We performed a retrospective review of children with CNLDO who underwent office probing procedures by a single surgeon under sedation or restraint. Patients’ characteristics at the time of probing, including age, sex, laterality, previous non-surgical treatment, presence of dacryocystitis, outcomes of probing, and complications were compared between the sedation and restraint groups. A multivariable logistic regression analysis was performed to investigate the prognostic factors associated with the success of probing. A subgroup analysis by 12 months of age was also conducted. The overall success rate was 88.6% in 202 eyes of 180 consecutive children (mean age, 15.1 ± 7.7 months). The sedation group had a marginally higher success rates than the restraint group (93.8% vs. 85.1%, p = 0.056). The success rate was not significantly different between the two groups in children aged <12 months (90.9% vs. 93.1%, p = 0.739), but it was significantly higher in the sedation group (94.7% vs. 77.8%. p = 0.006) in children aged ≥12 months. Inhalation sedation was the most potent factor associated with success (adjusted odds ratio = 5.56, 95% confidence interval = 1.33–23.13, p = 0.018) in children aged ≥12 months. There were no surgical or sedation-related complications intra- and postoperatively. Inhaled sevoflurane sedation resulted in more successful, controlled, painless probing, particularly in children aged ≥12 months. It represents a safe, efficient alternative to general anesthesia.
Heart Failure with Preserved Ejection Fraction: An Urgent Need for Precision Medicine
Authors: Miñana Gema , Núñez Julio
Published: April 2021

Heart failure with preserved (HFpEF) and mid-range ejection fraction (HFmrEF) constitute two heart failure categories, representing about 50–70% of the total [...]
Mechanical Thrombectomy in Stroke. Experience from Switching from Stent Retriever Only to Stent Retriever Combined with Aspiration Catheter
Authors: Meder Grzegorz , Żuchowski Paweł , Skura Wojciech , Palacz-Duda Violetta , Świtońska Milena , Nowaczewska Magdalena , Sokal Paweł
Published: April 2021

Endovascular treatment is a rapidly evolving technique; therefore, there is a constant need to evaluate this method and its modifications. This paper discusses a single-center experience and the results of switching from the stent retriever only (SO) mechanical thrombectomy (MT) to the combined approach (CA), with a stent retriever and aspiration catheters. Methods: The study involved a retrospective analysis of 70 patients undergoing MT with the use of either SO or CA. The primary endpoint was the frequency of perfect reperfusion defined as grade 3 of the modified Thrombolysis in Cerebral Infarction scale (mTICI) after the first pass. The secondary endpoints were the procedure success, defined as mTICI grades 2b-3; time of the procedure; clinical outcome, measured by 90 days’ modified Rankin Scale (mRS) score; Δ NIHSS, defined as the difference between National Institutes of Health Stroke Scale (NIHSS) score at patients’ admission and discharge; and the total number of device passes. Results: Out of the 70 patients included, 33 were treated with SO and 37 with CA. In both groups, a total number of 42 patients received intravenous recombined tissue plasminogen activator (iv-rTPA: 20 patients (60.6%) in the SO group and 22 patients (59.5%) in the CA group (p = 1.000). There was a significant difference between the groups regarding first-pass success rate, with 46% in the CA group and 18% in the SO group, (OR 3.83, 95% CI 1.28 to 11.44, p = 0.016). Complete procedure success tended to be more frequent in the CA group than in the SO group—94.6% vs. 84.8% (OR 3.13, 95% CI 0.56 to 17.34, p = 0.193)—and CA tended to require a lower number of passes than SO (mean 1.76 vs. 2.09 passes per procedure, p = 0.114), yet these differences did not reach statistical significance. Mean duration of the procedure was significantly shorter in the CA group than in the SO group (49 min vs. 64 min, p = 0.017). There was a significant difference in clinical outcomes, with higher Δ NIHSS (9.3 in the CA group vs. 6.7 in the SO group, p = 0.025) after the procedure and 90-day mRS (median 2 in the CA group vs. 4 in the SO group, p = 0.031). Conclusions: Combining stent retrievers with aspiration catheters may offer a beneficial effect on angiographic results and clinical outcomes in stroke patients undergoing endovascular treatment.
Accuracy and Repeatability of Spatiotemporal Gait Parameters Measured with an Inertial Measurement Unit
Authors: Posada-Ordax Jorge , Cosin-Matamoros Julia , Losa-Iglesias Marta Elena , Becerro-de-Bengoa-Vallejo Ricardo , Esteban-Gonzalo Laura , Martin-Villa Carlos , Calvo-Lobo César , Rodriguez-Sanz David
Published: April 2021

In recent years, interest in finding alternatives for the evaluation of mobility has increased. Inertial measurement units (IMUs) stand out for their portability, size, and low price. The objective of this study was to examine the accuracy and repeatability of a commercially available IMU under controlled conditions in healthy subjects. A total of 36 subjects, including 17 males and 19 females were analyzed with a Wiva Science IMU in a corridor test while walking for 10 m and in a threadmill at 1.6 km/h, 2.4 km/h, 3.2 km/h, 4 km/h, and 4.8 km/h for one minute. We found no difference when we compared the variables at 4 km/h and 4.8 km/h. However, we found greater differences and errors at 1.6 km/h, 2.4 km/h and 3.2 km/h, and the latter one (1.6 km/h) generated more error. The main conclusion is that the Wiva Science IMU is reliable at high speeds but loses reliability at low speeds.
Depression as a Risk Factor for Alzheimer’s Disease: A Systematic Review of Longitudinal Meta-Analyses
Authors: Sáiz-Vázquez Olalla , Gracia-García Patricia , Ubillos-Landa Silvia , Puente-Martínez Alicia , Casado-Yusta Silvia , Olaya Beatriz , Santabárbara Javier
Published: April 2021

Alzheimer’s disease (AD) is the most frequent cause of dementia, linked to morbidity and mortality among elderly patients. Recently, several clinical studies suggested that depression is a potential risk factor for cognitive decline and AD. A review of meta-analyses was performed, calculating pooled odds ratios to estimate the risk of AD in people with a prior diagnosis (or clinically significant symptoms) of depression. A total of six meta-analyses which represented 28 individual studies were analyzed. A significant association between depression and AD was found (OR = 1.54, 95% CI [1.02–2.31]; p = 0.038). The results showed that heterogeneity across studies was substantial. We found a significant positive effect size for clinical measures of depression, but not for symptomatic rating scales, in the association of depression with risk of AD. The type of rating scale used to assess depression and the cut-off criteria selected also moderated the relationship between depression and AD risk. We found that studies that used clinically significant criteria for diagnosis of depression had more consistent and significant results than studies that used symptomatic scales.
Acute Responses to Oxygen Delivery via High Flow Nasal Cannula in Patients with Severe Chronic Obstructive Pulmonary Disease—HFNC and Severe COPD
Authors: Attaway Amy H. , Faress Jihane , Jacono Frank , Dasarathy Srinivasan
Published: April 2021

Differences in oxygen delivery methods to treat hypoxemia have the potential to worsen CO2 retention in chronic obstructive lung disease (COPD). Oxygen administration using high flow nasal cannula (HFNC) has multiple physiological benefits in treating respiratory failure including reductions in PaCO2 in a flow-dependent manner. We hypothesized that patients with COPD would develop worsening hypercapnia if oxygen fraction was increased without increasing flow rate. We evaluated the acute response to HFNC in subjects with severe COPD when flow remained constant and inspired oxygen was increased. In total, 11 subjects with severe COPD (FEV1 < 50%) on supplemental oxygen with baseline normocapnia (PaCO2 < 45 mm Hg; n = 5) and hypercapnia (PaCO2 ≥ 45 mm Hg; n = 6) were studied. Arterial blood gas responses were studied at three timepoints: Baseline, HFNC at a flow rate of 30 L/min at resting oxygen supplementation for 1 h, and FiO2 30% above baseline with the same flow rate for the next hour. The primary endpoint was the change in PaCO2 from baseline. No significant changes in PaCO2 were noted in response to HFNC applied at baseline FiO2 in the normocapnic and hypercapnic group. At HFNC with FiO2 30% above baseline, the normocapnic group did not show a change in PaCO2 (baseline: 38.9 ± 1.8 mm Hg; HFNC at higher FiO2: 38.8 ± 3.1 mm Hg; p = 0.93), but the hypercapnic group demonstrated significant increase in PaCO2 (baseline: 58.2 ± 9.3 mm Hg; HFNC at higher FiO2: 63.3 ± 10.9 mm Hg; p = 0.025). We observed worsening hypercapnia in severe COPD patients and baseline hypercapnia who received increased oxygen fraction when flow remained constant. These data show the need for careful titration of oxygen therapy in COPD patients, particularly those with baseline hypercapnia when flow rate is unchanged.
Screening for TB in Hospitalised Patients with Inflammatory Bowel Disease before Anti-TNF Therapy: Is QuantiFERON® Gold Testing Useful?
Authors: Lovatt Jessica , Gascoyne-Binzi Deborah , Hussey Thomas , Garside Maya , McGill Fiona , Selinger Christian P.
Published: April 2021

Background—Tumour necrosis factor alpha (TNFα) plays an important role in the pathogenesis of inflammatory bowel disease (IBD) and in immunity to Mycobacterium tuberculosis. Patients should be tested for latent tuberculosis infection using interferon-gamma release assays (IGRA/QF) prior to anti-TNFα therapy. Indeterminate QF results can delay anti-TNFα therapy. We sought to investigate factors associated with indeterminate QF results. Method—Retrospective study of all IGRA tests requested for gastroenterology patients in 2017. We compared inpatients and outpatients and investigated factors potentially associated with QF usefulness (steroid exposure, C-reactive protein (CRP), hypoalbuminaemia, thrombophilia). Results—We included 286 outpatients and 74 inpatients with IBD. Significantly more inpatients had an indeterminate IGRA (52.7% vs. 3.14% in outpatients; p < 0.0001). Laboratory parameters reflecting inflammation (high CRP, low albumin, low haemoglobin and high platelets) were also associated with an indeterminate QF (p < 0.0001). Exposure to steroids was more common in patients with an indeterminate QF (p < 0.0001). A binary logistic regression analysis revealed inpatient status and steroid exposure to be independently predictive of an indeterminate QF (p < 0.0001). Conclusion—There is a high chance of indeterminate QF results in inpatients. QF testing should ideally be performed in the outpatient setting at diagnosis.
Development of a Fundus Image-Based Deep Learning Diagnostic Tool for Various Retinal Diseases
Authors: Kim Kyoung Min , Heo Tae-Young , Kim Aesul , Kim Joohee , Han Kyu Jin , Yun Jaesuk , Min Jung Kee
Published: April 2021

Artificial intelligence (AI)-based diagnostic tools have been accepted in ophthalmology. The use of retinal images, such as fundus photographs, is a promising approach for the development of AI-based diagnostic platforms. Retinal pathologies usually occur in a broad spectrum of eye diseases, including neovascular or dry age-related macular degeneration, epiretinal membrane, rhegmatogenous retinal detachment, retinitis pigmentosa, macular hole, retinal vein occlusions, and diabetic retinopathy. Here, we report a fundus image-based AI model for differential diagnosis of retinal diseases. We classified retinal images with three convolutional neural network models: ResNet50, VGG19, and Inception v3. Furthermore, the performance of several dense (fully connected) layers was compared. The prediction accuracy for diagnosis of nine classes of eight retinal diseases and normal control was 87.42% in the ResNet50 model, which added a dense layer with 128 nodes. Furthermore, our AI tool augments ophthalmologist’s performance in the diagnosis of retinal disease. These results suggested that the fundus image-based AI tool is applicable for the medical diagnosis process of retinal diseases.
An Ex Vivo and In Silico Study Providing Insights into the Interplay of Circulating miRNAs Level, Platelet Reactivity and Thrombin Generation: Looking beyond Traditional Pharmacogenetics
Authors: Garcia Alix , Dunoyer-Geindre Sylvie , Nolli Séverine , Reny Jean-Luc , Fontana Pierre
Published: April 2021

Platelet reactivity (PR), a key pharmacodynamic (PD) component of the action of antiplatelet drugs in cardiovascular disease (CVD) patients, is highly variable. PR is associated with occurrence or recurrence of thrombotic and bleeding events, but this association is modulated by several factors. Conventional pharmacogenetics explains a minor part of this PR variability, and among determinants of PR, circulating microRNAs (miRNAs) have been the focus of attention during these last years as biomarkers to predict PR and clinical outcomes in CVD. This being said, the impact of miRNAs on platelet function and the mechanisms behind it are largely unknown. The level of a set of candidate miRNAs including miR-126-3p, miR-150-5p, miR-204-5p and miR-223-3p was quantified in plasma samples of stable CVD patients and correlated with PR as assessed by light-transmission aggregometry and in vivo thrombin generation markers. Finally, miRNA target networks were built based on genes involved in platelet function. We show that all candidate miRNAs were associated with platelet aggregation, while only miR-126-3p and miR-223-3p were positively correlated with in vivo thrombin generation markers. In silico analysis identified putative miRNA targets involved in platelet function regulation. Circulating miRNAs were associated with different aspects of platelet reactivity, including platelet aggregation and platelet-supported thrombin generation. This paves the way to a personalized antithrombotic treatment according to miRNA profile in CVD patients.
Prolonged P300 Latency in Antipsychotic-Free Subjects with At-Risk Mental States Who Later Developed Schizophrenia
Authors: Higuchi Yuko , Sumiyoshi Tomiki , Tateno Takahiro , Nakajima Suguru , Sasabayashi Daiki , Nishiyama Shimako , Mizukami Yuko , Takahashi Tsutomu , Suzuki Michio
Published: April 2021

We measured P300, an event-related potential, in subjects with at-risk mental states (ARMS) and aimed to determine whether P300 parameter can predict progression to overt schizophrenia. Thirty-three subjects with ARMS, 39 with schizophrenia, and 28 healthy controls participated in the study. All subjects were antipsychotic-free. Subjects with ARMS were followed-up for more than two years. Cognitive function was measured by the Brief assessment of Cognition in Schizophrenia (BACS) and Schizophrenia Cognition Rating Scale (SCoRS), while the modified Global Assessment of Functioning (mGAF) was used to assess global function. Patients with schizophrenia showed smaller P300 amplitudes and prolonged latency at Pz compared to those of healthy controls and subjects with ARMS. During the follow-up period, eight out of 33 subjects with ARMS developed overt psychosis (ARMS-P) while 25 did not (ARMS-NP). P300 latency of ARMS-P was significantly longer than that of ARMS-NP. At baseline, ARMS-P elicited worse cognitive functions, as measured by the BACS and SCoRS compared to ARMS-NP. We also detected a significant relationship between P300 amplitudes and mGAF scores in ARMS subjects. Our results suggest the usefulness of prolonged P300 latency and cognitive impairment as a predictive marker of later development of schizophrenia in vulnerable individuals.
Insuring Hollywood: A Movie Returns Index and the American Stock Market
Authors: Lauria Davide , Phillips Wyatt D.
Published: April 2021

The aim of this paper is the definition of a daily index representing the risk-return on investments in the American film industry. The index should be used to predict the riskiness and the expected return of movie projects at the level of the overall industry and then to determine a premium for insurance for such an investment. Such an index can inform the decision making in relation to risk but also timing. Though not currently legal in the United States, such an index may be relevant at some point in the future or in other countries for film production companies as well as venture capitalists interested in investing in one or a slate of motion picture productions or more broadly in the holdings of a media conglomerate, an exhibition chain, or some other aspect of the media landscape.
Influence of Carbonate-Flysch Contact and Groundwater Dynamics on the Occurrence of Geohazards in Istria, Croatia
Authors: Dugonjić Jovančević Sanja , Rubinić Josip , Ružić Igor , Radišić Maja
Published: April 2021

This research focuses on the analysis of soil-water interaction at the carbonate-flysch contact on the Istrian peninsula in Croatia. As a result of the interaction of surface and groundwater and the position of flysch and carbonate rocks in the geotechnical profile, two problems occur in the study area: numerous instabilities and the occasionally high turbidity of drinking water. As an example, the St. Ivan spring was considered. The paper presents a complex mechanism of groundwater circulation in geological structures at carbonate-flysch contacts, differences in runoff through karst aquifers and flysch rocks during heavy rainfall under current and predicted (climate change) conditions, and the mentioned geohazards as a result of extreme precipitation. The analyses carried out showed the decisive influence of the existing geological structure on the dynamics of infiltration and precipitation runoff, as well as the risks of pronounced spring water turbidity and instability events. The main drivers of these geohazards are continuous long-term precipitation for landslides and intense daily precipitation for turbidity. Possible consequences of climate change are the increase in precipitation intensity, amount and higher variation, which subsequently brings risks such as the increase in maximum runoff, i.e., the expected more frequent occurrence of high turbidity and the more frequent occurrence of higher cumulative precipitation triggering instabilities in the area.
Compared to Individuals with Mild to Moderate Obstructive Sleep Apnea (OSA), Individuals with Severe OSA Had Higher BMI and Respiratory-Disturbance Scores
Authors: Rezaie Leeba , Maazinezhad Soroush , Fogelberg Donald J. , Khazaie Habibolah , Sadeghi-Bahmani Dena , Brand Serge
Published: April 2021

Objective: Individuals with obstructive sleep apnea (OSA) are at increased risk to suffer from further somatic and sleep-related complaints. To assess OSA, demographic, anthropometric, and subjective/objective sleep parameters are taken into consideration, but often separately. Here, we entered demographic, anthropometric, subjective, and objective sleep- and breathing-related dimensions in one model. Methods: We reviewed the demographic, anthropometric, subjective and objective sleep- and breathing-related data, and polysomnographic records of 251 individuals with diagnosed OSA. OSA was considered as a continuous and as categorical variable (mild, moderate, and severe OSA). A series of correlational computations, X2-tests, F-tests, and a multiple regression model were performed to investigate which demographic, anthropometric, and subjective and objective sleep dimensions were associated with and predicted dimensions of OSA. Results: Higher apnea/hypopnea index (AHI) scores were associated with higher BMI, higher daytime sleepiness, a higher respiratory disturbance index, and higher snoring. Compared to individuals with mild to moderate OSA, individuals with severe OSA had a higher BMI, a higher respiratory disturbance index (RDI) and a higher snoring index, while subjective sleep quality and daytime sleepiness did not differ. Results from the multiple regression analysis showed that an objectively shorter sleep duration, more N2 sleep, and a higher RDI predicted AHI scores. Conclusion: The pattern of results suggests that blending demographic, anthropometric, and subjective/objective sleep- and breathing-related data enabled more effective discrimination of individuals at higher risk for OSA. The results are of practical and clinical importance: demographic, anthropometric, and breathing-related issues derived from self-rating scales provide a quick and reliable identification of individuals at risk of OSA; objective assessments provide further certainty and reliability.
Cataract Progression Associated with Modifications in Calcium Signaling in Human Lens Epithelia as Studied by Mechanical Stimulation
Authors: Gosak Marko , Gojić Dajana , Spasovska Elena , Hawlina Marko , Andjelic Sofija
Published: April 2021

Ca2+ homeostasis and signaling disturbances are associated with lens pathophysiology and are involved in cataract formation. Here, we explored the spatiotemporal changes in Ca2+ signaling in lens epithelial cells (LECs) upon local mechanical stimulation, to better understand the LECs’ intercellular communication and its association with cataractogenesis. We were interested in if the progression of the cataract affects the Ca2+ signaling and if modifications of the Ca2+ homeostasis in LECs are associated with different cataract types. Experiments were done on the human postoperative anterior lens capsule (LC) preparations consisting of the monolayer of LECs on the basement membrane. Our findings revealed that the Ca2+ signal spreads radially from the stimulation point and that the amplitude of Ca2+ transients decreases with increasing distance. It is noteworthy that a comparison of signaling characteristics with respect to the degree of cataract progression revealed that, in LCs from more developed cataracts, the Ca2+ wave propagates faster and the amplitudes of Ca2+ signals are lower, while their durations are longer. No differences were identified when comparing LCs with regard to the cataract type. Moreover, experiments with Apyrase have revealed that the Ca2+ signals are not affected by ATP-dependent paracrine communication. Our results indicated that cataract progression is associated with modifications in Ca2+ signaling in LECs, suggesting the functional importance of altered Ca2+ signaling of LECs in cataractogenesis.
Tenderness of the Skin after Chemical Stimulation of Underlying Temporal and Thoracolumbar Fasciae Reveals Somatosensory Crosstalk between Superficial and Deep Tissues
Authors: Magerl Walter , Thalacker Emanuela , Vogel Simon , Schleip Robert , Klein Thomas , Treede Rolf-Detlef , Schilder Andreas
Published: April 2021

Musculoskeletal pain is often associated with pain referred to adjacent areas or skin. So far, no study has analyzed the somatosensory changes of the skin after the stimulation of different underlying fasciae. The current study aimed to investigate heterotopic somatosensory crosstalk between deep tissue (muscle or fascia) and superficial tissue (skin) using two established models of deep tissue pain (namely focal high frequency electrical stimulation (HFS) (100 pulses of constant current electrical stimulation at 10× detection threshold) or the injection of hypertonic saline in stimulus locations as verified using ultrasound). In a methodological pilot experiment in the TLF, different injection volumes of hypertonic saline (50–800 µL) revealed that small injection volumes were most suitable, as they elicited sufficient pain but avoided the complication of the numbing pinprick sensitivity encountered after the injection of a very large volume (800 µL), particularly following muscle injections. The testing of fascia at different body sites revealed that 100 µL of hypertonic saline in the temporal fascia and TLF elicited significant pinprick hyperalgesia in the overlying skin (–26.2% and –23.5% adjusted threshold reduction, p < 0.001 and p < 0.05, respectively), but not the trapezius fascia or iliotibial band. Notably, both estimates of hyperalgesia were significantly correlated (r = 0.61, p < 0.005). Comprehensive somatosensory testing (DFNS standard) revealed that no test parameter was changed significantly following electrical HFS. The experiments demonstrated that fascia stimulation at a sufficient stimulus intensity elicited significant across-tissue facilitation to pinprick stimulation (referred hyperalgesia), a hallmark sign of nociceptive central sensitization.
Preparation and Characterization of Silica Nanoparticles and of Silica-Gentamicin Nanostructured Solution Obtained by Microwave-Assisted Synthesis
Authors: Purcar Violeta , Rădiţoiu Valentin , Nichita Cornelia , Bălan Adriana , Rădiţoiu Alina , Căprărescu Simona , Raduly Florentina Monica , Manea Raluca , Şomoghi Raluca , Nicolae Cristian-Andi , Raut Iuliana , Jecu Luiza
Published: April 2021

In this research work, silica nanoparticles and silica-gentamicin nanostructured solution were synthesized by using the microwave-assisted synthesis, in basic medium, using two silane precursors (tetraethylorthosilicate and octyltriethoxysilane) and the antibiotic (gentamicin sulfate). The prepared materials were characterized through Fourier transform infrared (FTIR) spectroscopy, TGA analysis, transmission electron microscopy (TEM), and atomic force microscopy (AFM) to investigate the morphology and structure. Antimicrobial studies of the silica-gentamicin nanostructured solution versus silica nanoparticles were performed against Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. FTIR spectra showed that the gentamicin has been loaded to the silica nanoparticles. AFM analysis showed that the morphology of the silica-gentamicin nanostructured solution has changed, and agglomerations of particles are present at the surface. Antimicrobial testing, performed using the diffusion method through spot inoculation, indicates that the silica-gentamicin nanostructured solution exhibited activity against the resistant strain. The obtained silica-gentamicin solution can be used as biochemical agent for the prevention and treatment of microorganisms which are deposited on different surfaces (e.g., glass, plastic, ceramic).