bluuebunny/crossref_metadata_2025 huggingface dataset:
Automated Geolocation in Urban Environments Using a Simple Camera-Equipped Unmanned Aerial Vehicle: A Rapid Mapping Surveying Alternative?
Authors: Trigkakis Dimitrios , Petrakis George , Tripolitsiotis Achilleas , Partsinevelos Panagiotis
Published: June 2020

GNSS positioning accuracy can be degraded in areas where the surrounding object geometry and morphology interacts with the GNSS signals. Specifically, urban environments pose challenges to precise GNSS positioning because of signal interference or interruptions. Also, non-GNSS surveying methods, including total stations and laser scanners, involve time consuming practices in the field and costly equipment. The present study proposes the use of an Unmanned Aerial Vehicle (UAV) for autonomous rapid mapping that resolves the problem of localization for the drone itself by acquiring location information of characteristic points on the ground in a local coordinate system using simultaneous localization and mapping (SLAM) and vision algorithms. A common UAV equipped with a camera and at least a single known point, are enough to produce a local map of the scene and to estimate the relative coordinates of pre-defined ground points along with an additional arbitrary point cloud. The resulting point cloud is readily measurable for extracting and interpreting geometric information from the area of interest. Under two novel optimization procedures performing line and plane alignment of the UAV-camera-measured point geometries, a set of experiments determines that the localization of a visual point in distances reaching 15 m from the origin, delivered a level of accuracy under 50 cm. Thus, a simple UAV with an optical sensor and a visual marker, prove quite promising and cost-effective for rapid mapping and point localization in an unknown environment.
Self-Repair in Cacti Branches: Comparative Analyses of Their Morphology, Anatomy, and Biomechanics
Authors: Mylo Max D. , Krüger Friederike , Speck Thomas , Speck Olga
Published: June 2020

Damage-repair is particularly important for the maintenance of the water-storing abilities of succulent plants such as cacti. Comparative morphological, anatomical, and biomechanical analyses of self-repair were performed on artificially wounded branches of Opuntia ficus-indica and Cylindropuntia bigelovii. Macroscopic observations, contrast staining, and lignin-proof staining were used to investigate morphological and anatomical responses after wounding at various time intervals. Two-point bending tests were repeatedly performed on the same branches under unwounded, freshly wounded, and healed conditions by using customized 3D-printed clamping jaws. Morphologically, both species showed a rolling-in of the wound edges, but no mucilage discharge. Anatomically, ligno-suberized peridermal layers developed that covered the wound region, and new parenchyma cells formed, especially in O. ficus-indica. In all samples, the wounding effect directly after damage caused a decrease between 18% and 37% in all the tested mechanical parameters, whereas a positive healing effect after 21 days was only found for C. bigelovii. Based on our data, we hypothesize a high selection pressure on the restoration of structural integrity in the wound area, with a focus on the development of efficient water-retaining mechanisms, whereas the concept of “sufficient is good enough” seems to apply for the restoration of the mechanical properties.
miRNA Clusters with Down-Regulated Expression in Human Colorectal Cancer and Their Regulation
Authors: Pidíkova Paulína , Reis Richard , Herichova Iveta
Published: June 2020

Regulation of microRNA (miRNA) expression has been extensively studied with respect to colorectal cancer (CRC), since CRC is one of the leading causes of cancer mortality worldwide. Transcriptional control of miRNAs creating clusters can be, to some extent, estimated from cluster position on a chromosome. Levels of miRNAs are also controlled by miRNAs “sponging” by long non-coding RNAs (ncRNAs). Both types of miRNA regulation strongly influence their function. We focused on clusters of miRNAs found to be down-regulated in CRC, containing miR-1, let-7, miR-15, miR-16, miR-99, miR-100, miR-125, miR-133, miR-143, miR-145, miR-192, miR-194, miR-195, miR-206, miR-215, miR-302, miR-367 and miR-497 and analysed their genome position, regulation and functions. Only evidence provided with the use of CRC in vivo and/or in vitro models was taken into consideration. Comprehensive research revealed that down-regulated miRNA clusters in CRC are mostly located in a gene intron and, in a majority of cases, miRNA clusters possess cluster-specific transcriptional regulation. For all selected clusters, regulation mediated by long ncRNA was experimentally demonstrated in CRC, at least in one cluster member. Oncostatic functions were predominantly linked with the reviewed miRNAs, and their high expression was usually associated with better survival. These findings implicate the potential of down-regulated clusters in CRC to become promising multi-targets for therapeutic manipulation.
Contribution of Immune Cells to Glucocorticoid Receptor Expression in Breast Cancer
Authors: Gandhi Shipra , Elkhanany Ahmed , Oshi Masanori , Dai Tao , Opyrchal Mateusz , Mohammadpour Hemn , Repasky Elizabeth A. , Takabe Kazuaki
Published: June 2020

Breast cancer (BC) patients experience increased stress with elevated cortisol levels, increasing risk of cancer recurrence. Cortisol binds to a cytoplasmic receptor, glucocorticoid receptor (GR) encoded by GR gene (NR3C1). We hypothesized that not only cancer cells, but even immune cells in the tumor microenvironment (TME) may contribute to GR expression in bulk tumor and influence prognosis. To test this, mRNA expression data was accessed from METABRIC and TCGA. “High” and “low” expression was based on highest and lowest quartiles of NR3C1 gene expression, respectively. Single-cell sequencing data were obtained from GSE75688 and GSE114725 cohorts. Computer algorithms CIBERSORT, Gene Set Enrichment Analysis and TIMER were used. GR-high BC has better median disease-free and disease-specific survival. Single cell sequencing data showed higher GR expression on immune cells compared to cancer and stromal cells. Positive correlation between GR-high BC and CD8+ T-cells was noted. In GR-high tumors, higher cytolytic activity (CYT) with decreased T-regulatory and T-follicular helper cells was observed. High GR expression was associated with lower proliferation index Ki67, enriched in IL-2_STAT5, apoptosis, KRAS, TGF-β signaling, and epithelial-to-mesenchymal transition. Immune cells significantly contribute to GR expression of bulk BC. GR-high BC has a favorable TME with higher CYT with favorable outcomes.
Bis(maltolato)oxovanadium(IV) Induces Angiogenesis via Phosphorylation of VEGFR2
Authors: Parma Laura , Peters Hendrika A.B. , Johansson Maria E. , Gutiérrez Saray , Meijerink Henk , de Kimpe Sjef , de Vries Margreet R. , Quax Paul H.A.
Published: June 2020

VEGFR2 and VEGF-A play a pivotal role in the process of angiogenesis. VEGFR2 activation is regulated by protein tyrosine phosphatases (PTPs), enzymes that dephosphorylate the receptor and reduce angiogenesis. We aim to study the effect of PTPs blockade using bis(maltolato)oxovanadium(IV) (BMOV) on in vivo wound healing and in vitro angiogenesis. BMOV significantly improves in vivo wound closure by 45% in C57BL/6JRj mice. We found that upon VEGFR2 phosphorylation induced by endogenously produced VEGF-A, the addition of BMOV results in increased cell migration (45%), proliferation (40%) and tube formation (27%) in HUVECs compared to control. In a mouse ex vivo, aortic ring assay BMOV increased the number of sprouts by 3 folds when compared to control. However, BMOV coadministered with exogenous VEGF-A increased ECs migration, proliferation and tube formation by only 41%, 18% and 12% respectively and aortic ring sprouting by only 1-fold. We also found that BMOV enhances VEGFR2 Y951 and p38MAPK phosphorylation, but not ERK1/2. The level of phosphorylation of these residues was the same in the groups treated with BMOV supplemented with exogenous VEGF-A and exogenous VEGF-A only. Our study demonstrates that BMOV is able to enhance wound closure in vivo. Moreover, in the presence of endogenous VEGF-A, BMOV is able to stimulate in vitro angiogenesis by increasing the phosphorylation of VEGFR2 and its downstream proangiogenic enzymes. Importantly, BMOV had a stronger proangiogenic effect compared to its effect in coadministration with exogenous VEGF-A.
In Situ Detection of Endogenous HIV Activation by Dynamic Nuclear Polarization NMR and Flow Cytometry
Authors: Overall Sarah A. , Price Lauren E. , Albert Brice J. , Gao Chukun , Alaniva Nicholas , Judge Patrick T. , Sesti Erika L. , Wender Paul A. , Kyei George B. , Barnes Alexander B.
Published: June 2020

We demonstrate for the first time in-cell dynamic nuclear polarization (DNP) in conjunction with flow cytometry sorting to address the cellular heterogeneity of in-cell samples. Utilizing a green fluorescent protein (GFP) reporter of HIV reactivation, we correlate increased 15N resonance intensity with cytokine-driven HIV reactivation in a human cell line model of HIV latency. As few as 10% GFP+ cells could be detected by DNP nuclear magnetic resonance (NMR). The inclusion of flow cytometric sorting of GFP+ cells prior to analysis by DNP-NMR further boosted signal detection through increased cellular homogeneity with respect to GFP expression. As few as 3.6 million 15N-labeled GFP+ cells could be readily detected with DNP-NMR. Importantly, cell sorting allowed for the comparison of cytokine-treated GFP+ and GFP− cells in a batch-consistent way. This provides an avenue for normalizing NMR spectral contributions from background cellular processes following treatment with cellular modulators. We also demonstrate the remarkable stability of AMUPol (a nitroxide biradical) in Jurkat T cells and achieved in-cell enhancements of 46 with 10 mM AMUPol, providing an excellent model system for further in-cell DNP-NMR studies. This represents an important contribution to improving in-cell methods for the study of endogenously expressed proteins by DNP-NMR.
Complex Characterization of Germline Large Genomic Rearrangements of the BRCA1 and BRCA2 Genes in High-Risk Breast Cancer Patients—Novel Variants from a Large National Center
Authors: Bozsik Anikó , Pócza Tímea , Papp János , Vaszkó Tibor , Butz Henriett , Patócs Attila , Oláh Edit
Published: June 2020

Large genomic rearrangements (LGRs) affecting one or more exons of BRCA1 and BRCA2 constitute a significant part of the mutation spectrum of these genes. Since 2004, the National Institute of Oncology, Hungary, has been involved in screening for LGRs of breast or ovarian cancer families enrolled for genetic testing. LGRs were detected by multiplex ligation probe amplification method, or next-generation sequencing. Where it was possible, transcript-level characterization of LGRs was performed. Phenotype data were collected and analyzed too. Altogether 28 different types of LGRs in 51 probands were detected. Sixteen LGRs were novel. Forty-nine cases were deletions or duplications in BRCA1 and two affected BRCA2. Rearrangements accounted for 10% of the BRCA1 mutations. Three exon copy gains, two complex rearrangements, and 23 exon losses were characterized by exact breakpoint determinations. The inferred mechanisms for LGR formation were mainly end-joining repairs utilizing short direct homologies. Comparing phenotype features of the LGR-carriers to that of the non-LGR BRCA1 mutation carriers, revealed no significant differences. Our study is the largest comprehensive report of LGRs of BRCA1/2 in familial breast and ovarian cancer patients in the Middle and Eastern European region. Our data add novel insights to genetic interpretation associated to the LGRs.
Putative Roles for Peptidylarginine Deiminases in COVID-19
Authors: Arisan Elif Damla , Uysal-Onganer Pinar , Lange Sigrun
Published: June 2020

Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to protein moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in infection and immunomodulation are known to some extent, including in viral infections. In the current study we describe putative roles for PADs in COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI isozymes in the patients’ tissue biopsies, including lung, in response to SARS-CoV-2 infection, while PADI2 and PADI4 mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to mRNA levels for the different PADI isozymes. In vitro lung epithelial and adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4 mRNA levels were elevated, but PADI3 and PADI6 mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2 mRNA was elevated, PADI3 and PADI6 mRNA was downregulated, and no effect was observed on the PADI4 or PADI6 mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to SARS-CoV-2 infection. PADI isozyme 1–6 expression in other organ biopsies also reveals putative links to COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in COVID-19.
Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes
Authors: Bezzerri Valentino , Api Martina , Allegri Marisole , Fabrizzi Benedetta , Corey Seth J. , Cipolli Marco
Published: June 2020

Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS.
Aldosterone Induces DNA Damage and Activation of Nrf2 Mainly in Tubuli of Mouse Kidneys
Authors: Balhorn Ronja , Hartmann Christina , Schupp Nicole
Published: June 2020

Hypertensive patients have an increased risk of developing chronic kidney disease (CKD). Many of these patients have increased levels of the blood pressure regulating mineralocorticoid aldosterone. As a protection against aldosterone-induced damage, kidney cells can upregulate key regulators of the antioxidant defense, such as nuclear factor-erythroid-2-related factor 2 (Nrf2). In the present study aldosterone-induced kidney damage and Nrf2 activation in kidney cells of mice treated with three different concentrations of aldosterone for 4 weeks was localized. Increased albumin and neutrophil gelatinase-associated lipocalin (NGAL) in urine revealed an impaired kidney function of the aldosterone-infused mice. Localization of aldosterone-induced oxidative damage (in the form of DNA lesions) in specific kidney cells showed an increase in proximal tubuli and to an even greater extend in distal tubuli. Phosphorylated Nrf2 was increased in distal tubule cells after aldosterone-infusion. Nrf2 activation in proximal tubuli or in glomeruli after aldosterone-treatment could not be observed. Nrf2 target genes and proteins analyzed, paradoxically, showed a downregulation in the whole kidney. Aldosterone-treated mice exhibited an increased kidney injury and DNA damage in distal and proximal tubuli. Nrf2 seemed only to be specifically activated in distal tubule cells, where we also detected the highest amount of oxidative damage.
Complete Mitogenomes of Three Carangidae (Perciformes) Fishes: Genome Description and Phylogenetic Considerations
Authors: Li Zhenhai , Li Min , Xu Shannan , Liu Li , Chen Zuozhi , Zou Keshu
Published: June 2020

Carangidae are ecologically and economically important marine fish. The complete mitogenomes of three Carangidae species (Alectis indicus, Decapterus tabl, and Alepes djedaba) were sequenced, characterized, and compared with 29 other species of the family Carangidae in this study. The length of the three mitogenomes ranged from 16,530 to 16,610 bp, and the structures included 2 rRNA genes (12S rRNA and 16S rRNA), 1 control region (a non-coding region), 13 protein-coding genes, and 22 tRNA genes. Among the 22 tRNA genes, only tRNA-Ser (GCT) was not folded into a typical cloverleaf secondary structure and had no recognizable DHU stem. The full-length sequences and protein-coding genes (PCGs) of the mitogenomes of the three species all had obvious AT biases. The majority of the AT-skew and GC-skew values of the PCGs among the three species were negative, demonstrating bases T and C were more plentiful than A and G. Analyses of Ka/Ks and overall p-genetic distance demonstrated that ATP8 showed the highest evolutionary rate and COXI/COXII were the most conserved genes in the three species. The phylogenetic tree based on PCGs sequences of mitogenomes using maximum likelihood and Bayesian inference analyses showed that three clades were divided corresponding to the subfamilies Caranginae, Naucratinae, and Trachinotinae. The monophyly of each superfamily was generally well supported. The divergence time analyses showed that Carangidae evolved during three geological periods, the Cretaceous, Paleogene, and Neogene. A. indicus began to differentiate from other species about 27.20 million years ago (Mya) in the early Miocene, while D. tabl (21.25 Mya) and A. djedaba (14.67 Mya) differentiated in the middle Oligocene.
Vascular Homeostasis and Inflammation in Health and Disease—Lessons from Single Cell Technologies
Authors: Bondareva Olga , Sheikh Bilal N.
Published: June 2020

The vascular system is critical infrastructure that transports oxygen and nutrients around the body, and dynamically adapts its function to an array of environmental changes. To fulfil the demands of diverse organs, each with unique functions and requirements, the vascular system displays vast regional heterogeneity as well as specialized cell types. Our understanding of the heterogeneity of vascular cells and the molecular mechanisms that regulate their function is beginning to benefit greatly from the rapid development of single cell technologies. Recent studies have started to analyze and map vascular beds in a range of organs in healthy and diseased states at single cell resolution. The current review focuses on recent biological insights on the vascular system garnered from single cell analyses. We cover the themes of vascular heterogeneity, phenotypic plasticity of vascular cells in pathologies such as atherosclerosis and cardiovascular disease, as well as the contribution of defective microvasculature to the development of neurodegenerative disorders such as Alzheimer’s disease. Further adaptation of single cell technologies to study the vascular system will be pivotal in uncovering the mechanisms that drive the array of diseases underpinned by vascular dysfunction.
MnO2 Heterostructure on Carbon Nanotubes as Cathode Material for Aqueous Zinc-Ion Batteries
Authors: Khamsanga Sonti , Nguyen Mai Thanh , Yonezawa Tetsu , Thamyongkit Patchanita , Pornprasertsuk Rojana , Pattananuwat Prasit , Tuantranont Adisorn , Siwamogsatham Siwaruk , Kheawhom Soorathep
Published: June 2020

Due to their cost effectiveness, high safety, and eco-friendliness, zinc-ion batteries (ZIBs) are receiving much attention nowadays. In the production of rechargeable ZIBs, the cathode plays an important role. Manganese oxide (MnO2) is considered the most promising and widely investigated intercalation cathode material. Nonetheless, MnO2 cathodes are subjected to challenging issues viz. limited capacity, low rate capability and poor cycling stability. It is seen that the MnO2 heterostructure can enable long-term cycling stability in different types of energy devices. Herein, a versatile chemical method for the preparation of MnO2 heterostructure on multi-walled carbon nanotubes (MNH-CNT) is reported. Besides, the synthesized MNH-CNT is composed of δ-MnO2 and γ-MnO2. A ZIB using the MNH-CNT cathode delivers a high initial discharge capacity of 236 mAh g−1 at 400 mA g−1, 108 mAh g−1 at 1600 mA g−1 and excellent cycling stability. A pseudocapacitive behavior investigation demonstrates fast zinc ion diffusion via a diffusion-controlled process with low capacitive contribution. Overall, the MNH-CNT cathode is seen to exhibit superior electrochemical performance. This work presents new opportunities for improving the discharge capacity and cycling stability of aqueous ZIBs.
New Biomarkers in Acute Tubulointerstitial Nephritis: A Novel Approach to a Classic Condition
Authors: Martinez Valenzuela Laura , Draibe Juliana , Fulladosa Xavier , Torras Juan
Published: June 2020

Acute tubulointerstitial nephritis (ATIN) is an immunomediated cause of acute kidney injury. The prevalence of ATIN among the causes of acute kidney injury (AKI) is not negligible, especially those cases related to certain drugs. To date, there is a lack of reliable non-invasive diagnostic and follow-up markers. The gold standard for diagnosis is kidney biopsy, which shows a pattern of tubulointerstitial leukocyte infiltrate. The urinalysis findings can aid in the diagnosis but are no longer considered sensitive or specific. Atthe present time, there is a rising attentiveness tofinding trustworthy biomarkers of the disease, with special focus in urinary cytokines and chemokines that may reflect kidney local inflammation. Cell-based tests are of notable interest to identify the exact drug involved in hypersensitivity reactions to drugs, manifesting as ATIN. Certain single-nucleotide polymorphisms in HLA or cytokine genes may confer susceptibility to the disease according to pathophysiological basis. In this review, we aim to critically examine and summarize the available evidence on this topic.
Effect of Acupuncture on the p38 Signaling Pathway in Several Nervous System Diseases: A Systematic Review
Authors: Wei Tzu-Hsuan , Hsieh Ching-Liang
Published: June 2020

Acupuncture is clinically used to treat various diseases and exerts positive local and systemic effects in several nervous system diseases. Advanced molecular and clinical studies have continually attempted to decipher the mechanisms underlying these effects of acupuncture. While a growing understanding of the pathophysiology underlying several nervous system diseases shows it to be related to inflammation and impair cell regeneration after ischemic events, the relationship between the therapeutic mechanism of acupuncture and the p38 MAPK signal pathway has yet to be elucidated. This review discusses the latest advancements in the identification of the effect of acupuncture on the p38 signaling pathway in several nervous system diseases. We electronically searched databases including PubMed, Embase, and the Cochrane Library from their inception to April 2020, using the following keywords alone or in various combinations: “acupuncture”, “p38 MAPK pathway”, “signaling”, “stress response”, “inflammation”, “immune”, “pain”, “analgesic”, “cerebral ischemic injury”, “epilepsy”, “Alzheimer’s disease”, “Parkinson’s disease”, “dementia”, “degenerative”, and “homeostasis”. Manual acupuncture and electroacupuncture confer positive therapeutic effects by regulating proinflammatory cytokines, ion channels, scaffold proteins, and transcription factors including TRPV1/4, Nav, BDNF, and NADMR1; consequently, p38 regulates various phenomena including cell communication, remodeling, regeneration, and gene expression. In this review article, we found the most common acupoints for the relief of nervous system disorders including GV20, GV14, ST36, ST37, and LI4. Acupuncture exhibits dual regulatory functions of activating or inhibiting different p38 MAPK pathways, contributing to an overall improvement of clinical symptoms and function in several nervous system diseases.
Conjugates of Ciprofloxacin and Levofloxacin with Cell-Penetrating Peptide Exhibit Antifungal Activity and Mammalian Cytotoxicity
Authors: Ptaszyńska Natalia , Gucwa Katarzyna , Olkiewicz Katarzyna , Heldt Mateusz , Serocki Marcin , Stupak Anna , Martynow Dorota , Dębowski Dawid , Gitlin-Domagalska Agata , Lica Jan , Łęgowska Anna , Milewski Sławomir , Rolka Krzysztof
Published: June 2020

Seven conjugates composed of well-known fluoroquinolone antibacterial agents, ciprofloxacin (CIP) or levofloxacin (LVX), and a cell-penetrating peptide transportan 10 (TP10-NH2) were synthesised. The drugs were covalently bound to the peptide via an amide bond, methylenecarbonyl moiety, or a disulfide bridge. Conjugation of fluoroquinolones to TP10-NH2 resulted in congeners demonstrating antifungal in vitro activity against human pathogenic yeasts of the Candida genus (MICs in the 6.25–100 µM range), whereas the components were poorly active. The antibacterial in vitro activity of most of the conjugates was lower than the activity of CIP or LVX, but the antibacterial effect of CIP-S-S-TP10-NH2 was similar to the mother fluoroquinolone. Additionally, for two representative CIP and LVX conjugates, a rapid bactericidal effect was shown. Compared to fluoroquinolones, TP10-NH2 and the majority of its conjugates generated a relatively low level of reactive oxygen species (ROS) in human embryonic kidney cells (HEK293) and human myeloid leukemia cells (HL-60). The conjugates exhibited cytotoxicity against three cell lines, HEK293, HepG2 (human liver cancer cell line), and LLC-PK1 (old male pig kidney cells), with IC50 values in the 10–100 µM range and hemolytic activity. The mammalian toxicity was due to the intrinsic cytoplasmic membrane disruption activity of TP10-NH2 since fluoroquinolones themselves were not cytotoxic. Nevertheless, the selectivity index values of the conjugates, both for the bacteria and human pathogenic yeasts, remained favourable.
Sleep Inertia Countermeasures in Automated Driving: A Concept of Cognitive Stimulation
Authors: Wörle Johanna , Kenntner-Mabiala Ramona , Metz Barbara , Fritzsch Samantha , Purucker Christian , Befelein Dennis , Prill Andy
Published: June 2020

When highly automated driving is realized, the role of the driver will change dramatically. Drivers will even be able to sleep during the drive. However, when awaking from sleep, drivers often experience sleep inertia, meaning they are feeling groggy and are impaired in their driving performance―which can be an issue with the concept of dual-mode vehicles that allow both manual and automated driving. Proactive methods to avoid sleep inertia like the widely applied ‘NASA nap’ are not immediately practicable in automated driving. Therefore, a reactive countermeasure, the sleep inertia counter-procedure for drivers (SICD), has been developed with the aim to activate and motivate the driver as well as to measure the driver’s alertness level. The SICD is evaluated in a study with N = 21 drivers in a level highly automation driving simulator. The SICD was able to activate the driver after sleep and was perceived as “assisting” by the drivers. It was not capable of measuring the driver’s alertness level. The interpretation of the findings is limited due to a lack of a comparative baseline condition. Future research is needed on direct comparisons of different countermeasures to sleep inertia that are effective and accepted by drivers.
Flowers in Conservation Reserve Program (CRP) Pollinator Plantings and the Upper Midwest Agricultural Landscape Supporting Honey Bees
Authors: McMinn-Sauder Harper , Richardson Rodney , Eaton Tyler , Smith Mike , Johnson Reed
Published: June 2020

A present goal of the Conservation Reserve Program (CRP) is to manage land in agricultural landscapes to increase pollinator abundance and diversity. CP42, or the pollinator seed mix, is planted and managed to support foraging pollinators with blooming flowers present at all points in the foraging season. This high-quality habitat provides an excellent opportunity to study honey bee nutrition and determine whether honey bees located near CRP sites use known resources included in planting seed mixes. This study aims to highlight the primary sources of honey bee forage in the northern Midwest as well as to assess honey bee utilization of the floral resources provided by the pollinator seed mix used for CRP plantings. We received pollen samples collected using pollen traps by beekeepers in Ohio, South Dakota, Indiana, Illinois, and Michigan. Metabarcoding methods were used to identify and quantify pollen collected at different points in the season. The results indicate that honey bees frequently used major mass flowering resources such as Glycine, Trifolium, and Symphiotrichum throughout the season. In addition, flowers included in the CRP pollinator seed mix were used modestly. These results have implications for pollinator seed mix design.
Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development
Authors: Dhuri Karishma , Bechtold Clara , Quijano Elias , Pham Ha , Gupta Anisha , Vikram Ajit , Bahal Raman
Published: June 2020

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets the disease source at the RNA level and offers a promising alternative to therapies targeting downstream processes. To translate ASO-based therapies into a clinical success, it is crucial to overcome the challenges associated with off-target side effects and insufficient biological activity. In this regard, several chemical modifications and diverse delivery strategies have been explored. In this review, we systematically discuss the chemical modifications, mechanism of action, and optimized delivery strategies of several different classes of ASOs. Further, we highlight the recent advances made in development of ASO-based drugs with a focus on drugs that are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical applications. We also discuss various promising ASO-based drug candidates in the clinical trials, and the outstanding opportunity of emerging microRNA as a viable therapeutic target for future ASO-based therapies.
Early Predictors of Employment Status One Year Post Injury in Individuals with Traumatic Brain Injury in Europe
Authors: Arango-Lasprilla Juan , Zeldovich Marina , Olabarrieta-Landa Laiene , Forslund Marit , Núñez-Fernández Silvia , von Steinbuechel Nicole , Howe Emilie , Røe Cecilie , Andelic Nada ,   CENTER-TBI Participants and Investigators
Published: June 2020

Sustaining a traumatic brain injury (TBI) often affects the individual’s ability to work, reducing employment rates post-injury across all severities of TBI. The objective of this multi-country study was to assess the most relevant early predictors of employment status in individuals after TBI at one-year post-injury in European countries. Using a prospective longitudinal non-randomized observational cohort (The Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) project), data was collected between December 2014–2019 from 63 trauma centers in 18 European countries. The 1015 individuals who took part in this study were potential labor market participants, admitted to a hospital and enrolled within 24 h of injury with a clinical TBI diagnosis and indication for a computed tomography (CT) scan, and followed up at one year. Results from a binomial logistic regression showed that older age, status of part-time employment or unemployment at time of injury, premorbid psychiatric problems, and higher injury severity (as measured with higher Injury severity score (ISS), lower Glasgow Coma Scale (GCS), and longer length of stay (LOS) in hospital) were associated with higher unemployment probability at one-year after injury. The study strengthens evidence for age, employment at time of injury, premorbid psychiatric problems, ISS, GCS, and LOS as important predictors for employment status one-year post-TBI across Europe.
Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results
Authors: Brinkmann Folke , Hanusch Beatrice , Ballmann Manfred , Mayorandan Sebene , Bollenbach Alexander , Chobanyan-Jürgens Kristine , Jansen Kathrin , Schmidt-Choudhury Anjona , Derichs Nico , Tsikas Dimitrios , Lücke Thomas
Published: June 2020

Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients’ lungs and in connection with malnutrition. The aim of the present study was to investigate markers of the Arg/NO pathway in the plasma and urine of CF patients and to identify possible risk factors, especially associated with malnutrition. We measured the major NO metabolites nitrite and nitrate, Arg, a semi-essential amino acid and NO precursor, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) in plasma and urine samples of 70 pediatric CF patients and 78 age-matched healthy controls. Biomarkers were determined by gas chromatography–mass spectrometry and high-performance liquid chromatography. We observed higher plasma Arg (90.3 vs. 75.6 µM, p < 0.0001), ADMA (0.62 vs. 0.57 µM, p = 0.03), Arg/ADMA ratio (148 vs. 135, p = 0.01), nitrite (2.07 vs. 1.95 µM, p = 0.03) and nitrate (43.3 vs. 33.1 µM, p < 0.001) concentrations, as well as higher urinary DMA (57.9 vs. 40.7 µM/mM creatinine, p < 0.001) and nitrate (159 vs. 115 µM/mM creatinine, p = 0.001) excretion rates in the CF patients compared to healthy controls. CF patients with pancreatic sufficiency showed plasma concentrations of the biomarkers comparable to those of healthy controls. Malnourished CF patients had lower Arg/ADMA ratios (p = 0.02), indicating a higher NO synthesis capacity in sufficiently nourished CF patients. We conclude that NO production, protein-arginine dimethylation, and ADMA metabolism is increased in pediatric CF patients. Pancreas and liver function influence Arg/NO metabolism. Good nutritional status is associated with higher NO synthesis capacity and lower protein-arginine dimethylation.
Role of Exocrine and Endocrine Insufficiency in the Management of Patients with Chronic Pancreatitis
Authors: Diéguez-Castillo Carmelo , Jiménez-Luna Cristina , Martín-Ruiz Jose Luis , Martínez-Galán Joaquina , Prados José , Torres Carolina , González-Ramírez Amanda Rocío , Caba Octavio
Published: June 2020

Background: Exocrine pancreatic insufficiency results from the destruction of the pancreatic parenchyma and is diagnosed by using direct or indirect tests, both of which have shortcomings. Chronic pancreatitis is the most frequent cause of this pathology in adults. Methods: Patients meeting radiological or histological diagnostic criteria of chronic pancreatitis are enrolled and the stool elastase test is conducted, considering fecal elastase levels >200 µg/g to represent normal pancreatic function, and levels <200 μg/g to indicate the presence of exocrine pancreatic insufficiency. Additionally, we determine the body mass index of the patients and study their nutritional status and main biochemical and hematological variables, including their glucose and hemoglobin A1c (HbA1c) levels. Results: Exocrine pancreatic insufficiency is detected in 60% of the patients. Among these, 83.3% are severe cases, and 72% of the latter also are diagnosed with endocrine pancreatic insufficiency (diabetes mellitus). During the nutritional status study, HbA1c levels are significantly higher, and magnesium and prealbumin levels are significantly lower in patients with exocrine pancreatic insufficiency than in those without this disease. Conclusions: Exocrine and endocrine pancreatic insufficiency are highly prevalent among patients with chronic pancreatitis and an early diagnosis of these diseases is vital to improve the clinical management of these patients and reduce their risk of mortality.
Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome
Authors: Bor Wilbert , Gorog Diana A.
Published: June 2020

Acute coronary syndrome and atrial fibrillation are both common and can occur in the same patient. Combination therapy with dual antiplatelet therapy and oral anticoagulation increases risk of bleeding. Where the two conditions coexist, careful consideration is needed to determine the optimal antithrombotic treatment to reduce the risks of future ischaemic events associated with both conditions. Choices can be made in intraprocedural anticoagulation, type and dosing of oral anticoagulant, duration of combination therapy, and selection of P2Y12 inhibitor including genetic testing. This review article provides an overview of the available evidence to support clinicians in finding the delicate balance between antithrombotic efficacy and bleeding risk in patients with acute coronary syndrome and atrial fibrillation.
Clinical-Forensic Autopsy Findings to Defeat COVID-19 Disease: A Literature Review
Authors: Sessa Francesco , Bertozzi Giuseppe , Cipolloni Luigi , Baldari Benedetta , Cantatore Santina , D’Errico Stefano , Di Mizio Giulio , Asmundo Alessio , Castorina Sergio , Salerno Monica , Pomara Cristoforo
Published: June 2020

The severe acute respiratory syndrome (SARS)-CoV-2 was identified for the first time in China, in December 2019. Confirmed cases of COVID-19 have been reported around the world; indeed, this infection has been declared a pandemic. Consequently, the scientific community is working hard to gain useful information about the history of this virus, its transmission, diagnosis, clinical features, radiological findings, research and development of candidate therapeutics as well as vaccines. This review aims to analyze the diagnostic techniques used to ascertain the COVID-19 infection, critically reviewing positive points and criticism for forensic implications, obviously including autopsy. Finally, this review proposes a practical workflow to be applied in the management of corpses during this outbreak of the COVID-19 infection, which could be useful in cases of future infectious disease emergencies. Analyzing the diagnostic methods, to date, virus nucleic acid RT-PCR represents the standard method used to ascertain the COVID-19 infection in living subjects and corpses, even if this technique has several criticisms: mainly, the staff should be highly specialized, working in high-throughput settings, able to handle high workloads and aware of health risks and the importance of the results. Thus, IgG/IgM serological tests have been developed, overcoming RT-qPCR duration, costs, and management, not requiring highly trained personnel. Nevertheless, serological tests present problems; the WHO recommends the use of these new point-of-care immunodiagnostic tests only in research settings. Furthermore, nothing has yet been published regarding the possibility of applying these methods during post-mortem investigations. In light of this scenario, in this review, we suggest a flow chart for the pathologist called on to ascertain the cause of death of a subject with historical and clinical findings of COVID-19 status or without any anamnestic, diagnostic, or exposure information. Indeed, the literature data confirmed the analytical vulnerabilities of the kits used for laboratory diagnosis of COVID-19, particularly during postmortem examinations. For these reasons, autopsy remains the gold standard method to ascertain the exact cause of death (from or with COVID-19 infection, or other causes), to consequently provide real data for statistical evaluations and to take necessary measures to contain the risks of the infection. Moreover, performing autopsies could provide information on the pathogenesis of the COVID-19 infection with obvious therapeutic implications.
The Complex Relationship Between Serum Uric Acid, Endothelial Function and Small Vessel Remodeling in Humans
Authors: Masi Stefano , Georgiopoulos Georgios , Alexopoulos George , Pateras Konstantinos , Rosada Javier , Seravalle Gino , De Ciuceis Carolina , Taddei Stefano , Borghi Claudio , Grassi Guido , Rizzoni Damiano , Virdis Agostino ,   the Study Groups on the Uric Acid Right for heArt Health (URRAH),   Micro-and Macro-circulation of the Italian Society of Hypertension (SIIA)
Published: June 2020

Aims: The relationship between serum uric acid (SUA) and microvascular remodeling in humans remains largely unexplored. We assessed whether SUA provides additional information on the severity of microvascular remodeling than that obtained from the European Heart Score (HS), the patterns of microvascular remodeling associated with changes in SUA levels and the mediation by endothelial function and nitric oxide (NO) availability on this relationship. Methods: A total of 162 patients included in the microvascular dataset of the Italian Society of Hypertension with available information on SUA, media-to-lumen (M/L) ratio, media cross-sectional area (MCSA), endothelial function, NO availability and HS were included in the analysis. The top tertile of M/L ratio and MCSA were used to define severe microvascular remodeling. Results: A U-shaped association was observed between SUA and both M/L ratio and MCSA. Adjustment for HS did not affect these associations. SUA was able to reclassify a significant number of subjects without, and with, severe M/L ratio and MCSA remodeling over the HS alone. The microvascular remodeling associated with SUA levels presented a predominant hypertrophic pattern. SUA was inversely associated with endothelial function and NO availability. Structural equation modeling analysis controlling for the HS suggested that the association of SUA with M/L ratio and MCSA was mediated through changes in endothelial function and NO availability. Conclusions: The addition of SUA to the HS improves the identification of subjects with greater microvascular remodeling. The relationship between SUA and microvascular remodeling is mediated by endothelial function and NO availability.
Bilateral Simultaneous Breast Reconstruction with DIEP- and TMG Flaps: Head to Head Comparison, Risk and Complication Analysis
Authors: Weitgasser Laurenz , Schwaiger Karl , Medved Fabian , Hamler Felix , Wechselberger Gottfried , Schoeller Thomas
Published: June 2020

Background: A two center retrospective cohort study of simultaneous bilateral breast reconstructions using double deep inferior epigastric perforator (DIEP) flaps and double transverse myocutaneous/upper gracilis (TMG) flaps was conducted. The aim of this study was to compare surgical procedures, complications, and overall outcome. Patients and Methods: Two study groups, either receiving a simultaneous bilateral breast reconstruction, with double DIEP flaps (n = 152) in group 1, or double TMG flaps (n = 86) in group 2, were compared. A detailed risk and complication analysis was performed. Patient characteristics, operative time and the need for further operations were evaluated. Results: Double DIEP patients had donor site complications in 23.7% and double TMG patients in 16.3% (p = 0.9075, RR 1.45). Flap loss rates of 3.5% (double TMG) and 2.6% (double DIEP) were recorded (p = 0.7071, RR 1.33). The need for postoperative lipofilling was significantly higher in double TMG patients (65.1% vs. 38.2 %, p = 0.0047, RR 1.71). Conclusion: Complication analysis favors the double DIEP procedure. Donor site morbidity was lower and less severe in the double TMG group. Later fat grafting was more frequently needed after double TMG reconstructions. Further studies, preferably of prospective nature, are needed to evaluate the benefit of bilateral simultaneous breast reconstructions.
Characteristics of Pachychoroid Diseases and Age-Related Macular Degeneration: Multimodal Imaging and Genetic Backgrounds
Authors: Yamashiro Kenji , Hosoda Yoshikatsu , Miyake Masahiro , Ooto Sotaro , Tsujikawa Akitaka
Published: June 2020

The emergence of pachychoroid disease is changing the concept of age-related macular degeneration (AMD). The concept of pachychoroid diseases was developed through clinical observation of multimodal images of eyes with AMD and central serous chorioretinopathy; however, recent genetic studies have provided a proof of concept for pachychoroid spectrum disease, which should be differentiated from drusen-driven AMD. The genetic confirmation of pachychoroid concept further provides novel viewpoints to decode previously reported findings, which facilitates an understanding of the true nature of pachychoroid diseases and AMD. The purpose of this review was to elucidate the relationship between pachychoroid diseases and AMD by interpreting previous findings on pachychoroid diseases and AMD from the novel viewpoints of genetic associations. We confirmed that previous genetic studies supported the concept of pachychoroid diseases. From a genetic viewpoint, the presence of thick choroid and the presence of choroidal vascular hyperpermeability were important characteristics of pachychoroid spectrum diseases. Previous studies have also suggested the classification of polypoidal choroidal vasculopathy (PCV) into two subtypes, pachychoroid neovasculopathy and drusen-driven PCV. Genetic viewpoints will be beneficial to rearrange subtypes of drusen-driven AMD and pachychoroid spectrum diseases. Further genetic studies are needed to investigate pachyvessels, pachydrusen and the significance of polypoidal lesions in pachychoroid neovasculopathy and drusen-driven AMD/PCV.