bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Non-Coding RNA CsiR Regulates the Ciprofloxacin Resistance in Proteus vulgaris by Interacting with emrB mRNA
Authors: Zhang Hongyang , Song Tongzhen , Qin Chuhan , Xu Haijin , Qiao Mingqiang
Published: October 2021

Bacterial non-coding RNAs (ncRNAs) play important regulatory roles in various physiological metabolic pathways. In this study, a novel ncRNA CsiR (ciprofloxacin stress-induced ncRNA) involved in the regulation of ciprofloxacin resistance in the foodborne multidrug-resistant Proteus vulgaris (P. vulgaris) strain P3M was identified. The survival rate of the CsiR-deficient strain was higher than that of the wild-type strain P3M under the ciprofloxacin treatment condition, indicating that CsiR played a negative regulatory role, and its target gene emrB was identified through further target prediction, quantitative real-time PCR (qRT-PCR), and microscale thermophoresis (MST). Further studies showed that the interaction between CsiR and emrB mRNA affected the stability of the latter at the post-transcriptional level to a large degree, and ultimately affected the ciprofloxacin resistance of P3M. Notably, the base-pairing sites between CsiR and emrB mRNAs were highly conserved in other sequenced P. vulgaris strains, suggesting that this regulatory mechanism may be ubiquitous in this species. To the best of our knowledge, this is the first identification of a novel ncRNA involved in the regulation of ciprofloxacin resistance in P. vulgaris species, which lays a solid foundation for comprehensively expounding the antibiotic resistance mechanism of P. vulgaris.
Trop2 Forms a Stable Dimer with Significant Structural Differences within the Membrane-Distal Region as Compared to EpCAM
Authors: Pavšič Miha
Published: October 2021

Trop2 is a cell-surface transmembrane glycoprotein involved in the maintenance of epithelial tissue integrity and is an important carcinoma marker. It shares similar claudin-interaction capacity with its paralogue EpCAM, and both are implicated in signaling triggered by proteolytic cleavage within the ectodomain. However, the cell proliferation-regulating interactions with IGF-1, neuregulin-1, and α5β1 integrin appear to be Trop2-specific. To illuminate the structural differences between Trop2 and EpCAM, we report the first crystal structure of a Trop2 ectodomain dimer and compare it to the analogous part of EpCAM. While the overall fold of the two proteins is similar, the dimers differ. In Trop2, the inter-subunit contacts are more extensive than in EpCAM, and there are two major differences in the membrane-distal regions. The immunogenic N-terminal domain is in Trop2 almost colinear with the dimer interface plain and consequently more laterally exposed, and the cleft of yet unknown functionality between the two subunits is almost absent. Furthermore, the site of initial signaling-associated proteolytic cleavage in Trop2 is accessible in the dimeric state, while in EpCAM dimer destabilization is required. The structural differences highlight the divergent evolutionary path of the two proteins and pave the way for their structure-based utilization in therapy.
Anti-Osteoporotic Effect of Morroniside on Osteoblast and Osteoclast Differentiation In Vitro and Ovariectomized Mice In Vivo
Authors: Lee Chang Gun , Kim Jeonghyun , Yun Seung Hee , Hwang Seokjin , Jeon Hyoju , Park Eunkuk , Jeong Seon-Yong
Published: October 2021

Bone remodeling is a continuous process of bone synthesis and destruction that is regulated by osteoblasts and osteoclasts. Here, we investigated the anti-osteoporotic effects of morroniside in mouse preosteoblast MC3T3-E1 cells and mouse primary cultured osteoblasts and osteoclasts in vitro and ovariectomy (OVX)-induced mouse osteoporosis in vivo. Morroniside treatment enhanced alkaline phosphatase activity and positively stained cells via upregulation of osteoblastogenesis-associated genes in MC3T3-E1 cell lines and primary cultured osteoblasts. However, morroniside inhibited tartrate-resistant acid phosphatase activity and TRAP-stained multinucleated positive cells via downregulation of osteoclast-mediated genes in primary cultured monocytes. In the osteoporotic animal model, ovariectomized (OVX) mice were administered morroniside (2 or 10 mg/kg/day) for 12 weeks. Morroniside prevented OVX-induced bone mineral density (BMD) loss and reduced bone structural compartment loss in the micro-CT images. Taken together, morroniside promoted increased osteoblast differentiation and decreased osteoclast differentiation in cells, and consequently inhibited OVX-induced osteoporotic pathogenesis in mice. This study suggests that morroniside may be a potent therapeutic single compound for the prevention of osteoporosis.
Preclinical Evaluation of Sodium Selenite in Mice: Toxicological and Tumor Regression Studies after Striatum Implantation of Human Glioblastoma Stem Cells
Authors: Larrouquère Louis , Berthier Sylvie , Chovelon Benoit , Garrel Catherine , Vacchina Véronique , Paucot Hugues , Boutonnat Jean , Faure Patrice , Hazane-Puch Florence
Published: October 2021

Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis; as such, efforts to explore new treatments and GBM’s etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in serum-free medium and proliferating into nude mice when orthotopically grafted). Sodium selenite (SS)—an in vitro attractive agent for cancer therapy against GBM—was evaluated in R2J-GS cells. To go further, we launched a preclinical study: SS was given orally, in an escalation-dose study (2.25 to 10.125 mg/kg/day, 5 days on, 2 days off, and 5 days on), to evaluate (1) the absorption of selenium in plasma and organs (brain, kidney, liver, and lung) and (2) the SS toxicity. A 6.75 mg/kg SS dose was chosen to perform a tumor regression assay, followed by MRI, in R2J-GS cells orthotopically implanted in nude mice, as this dose was nontoxic and increased brain selenium concentration. A group receiving TMZ (5 mg/kg) was led in parallel. Although not reaching statistical significance, the group of mice treated with SS showed a slower tumor growth vs. the control group (p = 0.08). No difference was observed between the TMZ and control groups. We provide new insights of the mechanisms of SS and its possible use in chemotherapy.
Opposing Roles of GSK3α and GSK3β Phosphorylation in Platelet Function and Thrombosis
Authors: Moore Samantha F. , Agbani Ejaife O. , Wersäll Andreas , Poole Alastair W. , Williams Chris M. , Zhao Xiaojuan , Li Yong , Hutchinson James L. , Hunter Roger W. , Hers Ingeborg
Published: October 2021

One of the mechanisms by which PI3 kinase can regulate platelet function is through phosphorylation of downstream substrates, including glycogen synthase kinase-3 (GSK3)α and GSK3β. Platelet activation results in the phosphorylation of an N-terminal serine residue in GSK3α (Ser21) and GSK3β (Ser9), which competitively inhibits substrate phosphorylation. However, the role of phosphorylation of these paralogs is still largely unknown. Here, we employed GSK3α/β phosphorylation-resistant mouse models to explore the role of this inhibitory phosphorylation in regulating platelet activation. Expression of phosphorylation-resistant GSK3α/β reduced thrombin-mediated platelet aggregation, integrin αIIbβ3 activation, and α-granule secretion, whereas platelet responses to the GPVI agonist collagen-related peptide (CRP-XL) were significantly enhanced. GSK3 single knock-in lines revealed that this divergence is due to differential roles of GSK3α and GSK3β phosphorylation in regulating platelet function. Expression of phosphorylation-resistant GSK3α resulted in enhanced GPVI-mediated platelet activation, whereas expression of phosphorylation-resistant GSK3β resulted in a reduction in PAR-mediated platelet activation and impaired in vitro thrombus formation under flow. Interestingly, the latter was normalised in double GSK3α/β KI mice, indicating that GSK3α KI can compensate for the impairment in thrombosis caused by GSK3β KI. In conclusion, our data indicate that GSK3α and GSK3β have differential roles in regulating platelet function.
BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome
Authors: Gorombei Petra , Guidez Fabien , Ganesan Saravanan , Chiquet Mathieu , Pellagatti Andrea , Goursaud Laure , Tekin Nilgun , Beurlet Stephanie , Patel Satyananda , Guerenne Laura , Le Pogam Carole , Setterblad Niclas , de la Grange Pierre , LeBoeuf Christophe , Janin Anne , Noguera Maria-Elena , Sarda-Mantel Laure , Merlet Pascale , Boultwood Jacqueline , Konopleva Marina , Andreeff Michael , West Robert , Pla Marika , Adès Lionel , Fenaux Pierre , Krief Patricia , Chomienne Christine , Omidvar Nader , Padua Rose Ann
Published: October 2021

During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma membrane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regulation of stem cells, differentiation, proliferation, oxidative phosphorylation, mitochondrial function, and apoptosis; relevant in human disease. Spliceosome genes, found to be abnormal in MDS patients and downregulated in our HR-MDS model, such as Rsrc1 and Wbp4, were upregulated by the treatment, as were genes involved in epigenetic regulation, such as DNMT3A and B, upregulated upon disease progression and downregulated upon treatment.
Quinacrine Ameliorates Cisplatin-Induced Renal Toxicity via Modulation of Sirtuin-1 Pathway
Authors: Abo El-Magd Nada F. , Ebrahim Hasnaa Ali , El-Sherbiny Mohamed , Eisa Nada H.
Published: October 2021

Renal toxicity is a serious side effect that hinders the use of cisplatin, a commonly used and effective chemotherapeutic agent. Meanwhile, quinacrine is an FDA approved drug that has been stated for its anti-inflammatory effect. Thus, we investigated the ameliorative effect of quinacrine against cisplatin-induced renal toxicity. Single intraperitoneal (i.p.) 10 mg/kg cisplatin administration induced renal injury in rats. Our results showed that 10 mg/kg/day quinacrine decreased the mortality rate of rats from 46.15% (cisplatin group) to 12.5%, and significantly decreased renal tissue fibrosis, relative kidney to body weight ratio, serum creatinine and urea levels compared with the cisplatin group. Indeed, quinacrine significantly decreased renal malondialdehyde concentration and increased renal total antioxidant capacity, compared with the cisplatin group. Furthermore, quinacrine caused significant upregulation of renal sirtuin-1 (SIRT-1) with significant downregulation of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-α (TNF-α). Moreover, quinacrine significantly blocked cisplatin-induced apoptosis, which was made evident by downregulating renal apoptotic proteins (BAX and p53) and upregulating the renal anti-apoptotic protein BCL2, compared with the cisplatin group. In conclusion, this study demonstrates, for the first time, that quinacrine alleviates cisplatin-induced renal toxicity via upregulating SIRT-1, downregulating inflammatory markers (ICAM-1 and TNF-α), reducing oxidative stress, and inhibiting apoptosis.
Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?
Authors: Franzese Ornella , Torino Francesco , Giannetti Elisa , Cioccoloni Giorgia , Aquino Angelo , Faraoni Isabella , Fuggetta Maria Pia , De Vecchis Liana , Giuliani Anna , Kaina Bernd , Bonmassar Enzo
Published: October 2021

The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients’ quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in the near future. In view of the crucial role that is played by tumor immunity, the present review provides essential information on the immune-mediated effects potentially generated by the interplay between ionizing radiation and cytotoxic antitumor agents when interacting with target malignant cells. Therefore, the radiation-dependent abscopal effect (i.e., a biological effect of ionizing radiation that occurs outside the irradiated field), the influence of cancer chemotherapy on the antigenic pattern of target neoplastic cells, and the immunogenic cell death (ICD) caused by anticancer agents are the main topics of this presentation. It is widely accepted that tumor immunity plays a fundamental role in generating an abscopal effect and that anticancer drugs can profoundly influence not only the host immune responses, but also the immunogenic pattern of malignant cells. Remarkably, several anticancer drugs impact both the abscopal effect and ICD. In addition, certain classes of anticancer agents are able to amplify already expressed tumor-associated antigens (TAA). More importantly, other drugs, especially triazenes, induce the appearance of new tumor neoantigens (TNA), a phenomenon that we termed drug-induced xenogenization (DIX). The adoption of the abscopal effect is proposed as a potential therapeutic modality when properly applied concomitantly with drug-induced increase in tumor cell immunogenicity and ICD. Although little to no preclinical or clinical studies are presently available on this subject, we discuss this issue in terms of potential mechanisms and therapeutic benefits. Upcoming investigations are aimed at evaluating how chemical anticancer drugs, radiation, and immunotherapies are interacting and cooperate in evoking the abscopal effect, tumor xenogenization and ICD, paving the way for new and possibly successful approaches in cancer therapy.
PPAR-α Hypermethylation in the Hippocampus of Mice Exposed to Social Isolation Stress Is Associated with Enhanced Neuroinflammation and Aggressive Behavior
Authors: Matrisciano Francesco , Pinna Graziano
Published: October 2021

Social behavioral changes, including social isolation or loneliness, increase the risk for stress-related disorders, such as major depressive disorder, posttraumatic stress disorder (PTSD), and suicide, which share a strong neuroinflammatory etiopathogenetic component. The peroxisome-proliferator activated receptor (PPAR)-α, a newly discovered target involved in emotional behavior regulation, is a ligand-activated nuclear receptor and a transcription factor that, following stimulation by endogenous or synthetic ligands, may induce neuroprotective effects by modulating neuroinflammation, and improve anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. How stress affects epigenetic mechanisms with downstream effects on inflammation and emotional behavior remains poorly understood. We studied the effects of 4-week social isolation, using a mouse model of PTSD/suicide-like behavior, on hippocampal PPAR-α epigenetic modification. Decreased PPAR-α expression in the hippocampus of socially isolated mice was associated with increased levels of methylated cytosines of PPAR-α gene CpG-rich fragments and deficient neurosteroid biosynthesis. This effect was associated with increased histone deacetylases (HDAC)1, methyl-cytosine binding protein (MeCP)2 and decreased ten-eleven translocator (TET)2 expression, which favor hypermethylation. These alterations were associated with increased TLR-4 and pro-inflammatory markers (e.g., TNF-α,), mediated by NF-κB signaling in the hippocampus of aggressive mice. This study contributes the first evidence of stress-induced brain PPAR-α epigenetic regulation. Social isolation stress may constitute a risk factor for inflammatory-based psychiatric disorders associated with neurosteroid deficits, and targeting epigenetic marks linked to PPAR-α downregulation may offer a valid therapeutic approach.
Transcriptomic Profiling of Adult-Onset Asthma Related to Damp and Moldy Buildings and Idiopathic Environmental Intolerance
Authors: Suojalehto Hille , Ndika Joseph , Lindström Irmeli , Airaksinen Liisa , Karvala Kirsi , Kauppi Paula , Lauerma Antti , Toppila-Salmi Sanna , Karisola Piia , Alenius Harri
Published: October 2021

A subset of adult-onset asthma patients attribute their symptoms to damp and moldy buildings. Symptoms of idiopathic environmental intolerance (IEI) may resemble asthma and these two entities overlap. We aimed to evaluate if a distinct clinical subtype of asthma related to damp and moldy buildings can be identified, to unravel its corresponding pathomechanistic gene signatures, and to investigate potential molecular similarities with IEI. Fifty female adult-onset asthma patients were categorized based on exposure to building dampness and molds during disease initiation. IEI patients (n = 17) and healthy subjects (n = 21) were also included yielding 88 study subjects. IEI was scored with the Quick Environmental Exposure and Sensitivity Inventory (QEESI) questionnaire. Inflammation was evaluated by blood cell type profiling and cytokine measurements. Disease mechanisms were investigated via gene set variation analysis of RNA from nasal biopsies and peripheral blood mononuclear cells. Nasal biopsy gene expression and plasma cytokine profiles suggested airway and systemic inflammation in asthma without exposure to dampness (AND). Similar evidence of inflammation was absent in patients with dampness-and-mold-related asthma (AAD). Gene expression signatures revealed a greater degree of similarity between IEI and dampness-related asthma than between IEI patients and asthma not associated to dampness and mold. Blood cell transcriptome of IEI subjects showed strong suppression of immune cell activation, migration, and movement. QEESI scores correlated to blood cell gene expression of all study subjects. Transcriptomic analysis revealed clear pathomechanisms for AND but not AAD patients. Furthermore, we found a distinct molecular pathological profile in nasal and blood immune cells of IEI subjects, including several differentially expressed genes that were also identified in AAD samples, suggesting IEI-type mechanisms.
Upstream Open Reading Frame Mediated Translation of WNK8 Is Required for ABA Response in Arabidopsis
Authors: Li Zhiyong , Fu Yajuan , Shen Jinyu , Liang Jiansheng
Published: October 2021

With no lysine (K) (WNK) kinases comprise a family of serine/threonine kinases belonging to an evolutionary branch of the eukaryotic kinome. These special kinases contain a unique active site and are found in a wide range of eukaryotes. The model plant Arabidopsis has been reported to have 11 WNK members, of which WNK8 functions as a negative regulator of abscisic acid (ABA) signaling. Here, we found that the expression of WNK8 is post-transcriptionally regulated through an upstream open reading frame (uORF) found in its 5′ untranslated region (5′-UTR). This uORF has been predicted to encode a conserved peptide named CPuORF58 in both monocotyledons and dicotyledons. The analysis of the published ribosome footprinting studies and the study of the frameshift CPuORF58 peptide with altered repression capability suggested that this uORF causes ribosome stalling. Plants transformed with the native WNK8 promoter driving WNK8 expression were comparable with wild-type plants, whereas the plants transformed with a similar construct with mutated CPuORF58 start codon were less sensitive to ABA. In addition, WNK8 and its downstream target RACK1 were found to synergistically coordinate ABA signaling rather than antagonistically modulating glucose response and flowering in plants. Collectively, these results suggest that the WNK8 expression must be tightly regulated to fulfill the demands of ABA response in plants.
Diverse Coordination Numbers and Geometries in Pyridyl Adducts of Lanthanide(III) Complexes Based on β-Diketonate
Authors: Mautner Franz A. , Bierbaumer Florian , Fischer Roland C. , Torvisco Ana , Vicente Ramon , Font-Bardía Mercè , Tubau Ànnia , Speed Saskia , Massoud Salah S.
Published: October 2021

Ten mononuclear rare earth complexes of formula [La(btfa)3(H2O)2] (1), [La(btfa)3(4,4′-Mt2bipy)] (2), [La(btfa)3(4,4′-Me2bipy)2] (3), [La(btfa)3(5,5′-Me2bipy)2] (4), [La(btfa)3(terpy)] (5), [La(btfa)3(phen)(EtOH)] (6), [La(btfa)3(4,4′-Me2bipy)(EtOH)] (7), [La(btfa)3(2-benzpy)(MeOH)] (8), [Tb(btfa)3(4,4′-Me2bipy)] (9) and (Hpy)[Eu(btfa)4] (10), where btfa = 4,4,4-trifuoro-1-phenylbutane-1,3-dionato anion, 4,4′-Mt2bipy = 4,4′-dimethoxy-2,2′-bipyridine, 4,4′-Me2bipy = 4,4′-dimethyl-2,2′-bipyridine, 5,5′-Me2bipy = 5,5′-dimethyl-2,2′-bipyridine, terpy = 2,2′:6′,2′-terpyridine, phen = 1,10-phenathroline, 2-benzpy = 2-(2-pyridyl)benzimidazole, Hpy = pyridiniumH+ cation) have been synthesized and structurally characterized. The complexes display coordination numbers (CN) eight for 1, 2, 9, 10, nine for 5, 6, 7, 8 and ten for 3 and 4. The solid-state luminescence spectra of Tb-9 and Eu-10 complexes showed the same characteristic bands predicted from the Tb(III) and Eu(III) ions. The Overall Quantum Yield measured (ϕTOT) at the excitation wavelength of 371 nm for both compounds yielded 1.04% for 9 and up to 34.56% for 10.
De Novo Genome Assembly of Chinese Plateau Honeybee Unravels Intraspecies Genetic Diversity in the Eastern Honeybee, Apis cerana
Authors: Lan Lan , Shi Peng , Song Huali , Tang Xiangyou , Zhou Jianyang , Yang Jiandong , Yang Mingxian , Xu Jinshan
Published: October 2021

Apis cerana abansis, widely distributed in the southeastern margin of the Qinghai-Tibet Plateau, is considered an excellent model to study the phenotype and genetic variation for highland adaptation of Asian honeybee. Herein, we assembled and annotated the chromosome-scale assembly genome of A. cerana abansis with the help of PacBio, Illumina and Hi-C sequencing technologies in order to identify the genome differences between the A. cerana abansis and the published genomes of different A. cerana strains. The sequencing methods, assembly and annotation strategies of A. cerana abansis were more comprehensive than previously published A. cerana genomes. Then, the intraspecific genetic diversity of A. cerana was revealed at the genomic level. We re-identified the repeat content in the genome of A. cerana abansis, as well as the other three A. cerana strains. The chemosensory and immune-related proteins in different A. cerana strains were carefully re-identified, so that 132 odorant receptor subfamilies, 12 gustatory receptor subfamilies and 22 immune-related pathways were found. We also discovered that, compared with other published genomes, the A. ceranaabansis lost the largest number of chemoreceptors compared to other strains, and hypothesized that gene loss/gain might help different A. cerana strains to adapt to their respective environments. Our work contains more complete and precise assembly and annotation results for the A. cerana genome, thus providing a resource for subsequent in-depth related studies.
Variant A of the Deformed Wings Virus Alters the Olfactory Sensitivity and the Expression of Odorant Binding Proteins on Antennas of Apis mellifera
Authors: Silva Diego , Ceballos Ricardo , Arismendi Nolberto , Dalmon Anne , Vargas Marisol
Published: October 2021

Insects have a highly sensitive sense of smell, allowing them to perform complex behaviors, such as foraging and peer recognition. Their sense of smell is based on the recognition of ligands and is mainly coordinated by odorant-binding proteins (OBPs). In Apis mellifera, behavior can be affected by different pathogens, including deformed wing virus (DWV) and its variants. In particular, it has been shown that variant A of DWV (DWV-A) is capable of altering the ultra-cellular structure associated with olfactory activity. In this study was evaluated olfactory sensitivity and the expression of OBP genes in honey bees inoculated with DWV-A. Electroantennographic analyses (EAG) were carried out to determine the olfactory sensitivity to the essential oils Eucalyptus globulus and Mentha piperita. The expression of nine antenna-specific OBP genes and DWV-A load in inoculated bees was also quantified by qPCR. We observed an inverse relationship between viral load and olfactory sensitivity and the expression of some OBP proteins. Thus, high viral loads reduced olfactory sensitivity to essential oils and the gene expression of the OBP2, OBP5, OBP11, and OBP12 proteins on the antennas of middle- and forager-age bees. These results suggest that DWV-A could have negative effects on the processes of aroma perception by worker bees, affecting their performance in tasks carried out in and outside the colony.
Coping with Environmental Extremes: Population Ecology and Behavioural Adaptation of Erebia pronoe, an Alpine Butterfly Species
Authors: Wendt Martin , Senftleben Nele , Gros Patrick , Schmitt Thomas
Published: October 2021

A mark-recapture study of the nominotypical Erebia pronoe in the Alps was conducted to survey its ecological demands and characteristics. Population structure analysis revealed a combination of protandry (one-week earlier eclosion of males) and serial eclosion. Significant differences between both sexes were found in population density (males: 580/ha ± 37 SE; females: 241/ha ± 66 SE), sex-ratio (2.4) and behaviour (57.7 vs. 11.9% flying). Both sexes used a wide range of nectar plants (Asteraceae, 77.3%; Dipsacaceae, 12.3%; Gentianaceae, 9.7%). The use of nectar plants shows a non-specific spectrum, which, however, completely avoids overlap with the locally co-occurring species Erebia nivalis. Movement patterns show the establishment of homeranges, which significantly limits the migration potential. Due to its broad ecological niche, E. pronoe will probably be able to react plastically to the consequences of climate change. The formation of high population densities, the unconcerned endangerment status, the unspecific resource spectrum and the sedentary character of the species make E. pronoe a potential indicator of the quality and general resource occurrence of alpine rupicolous grasslands.
Bioengineering Systems for Modulating Notch Signaling in Cardiovascular Development, Disease, and Regeneration
Authors: Gomez Angello Huerta , Joshi Sanika , Yang Yong , Tune Johnathan D. , Zhao Ming-Tao , Yang Huaxiao
Published: October 2021

The Notch intercellular signaling pathways play significant roles in cardiovascular development, disease, and regeneration through modulating cardiovascular cell specification, proliferation, differentiation, and morphogenesis. The dysregulation of Notch signaling leads to malfunction and maldevelopment of the cardiovascular system. Currently, most findings on Notch signaling rely on animal models and a few clinical studies, which significantly bottleneck the understanding of Notch signaling-associated human cardiovascular development and disease. Recent advances in the bioengineering systems and human pluripotent stem cell-derived cardiovascular cells pave the way to decipher the role of Notch signaling in cardiovascular-related cells (endothelial cells, cardiomyocytes, smooth muscle cells, fibroblasts, and immune cells), and intercellular crosstalk in the physiological, pathological, and regenerative context of the complex human cardiovascular system. In this review, we first summarize the significant roles of Notch signaling in individual cardiac cell types. We then cover the bioengineering systems of microfluidics, hydrogel, spheroid, and 3D bioprinting, which are currently being used for modeling and studying Notch signaling in the cardiovascular system. At last, we provide insights into ancillary supports of bioengineering systems, varied types of cardiovascular cells, and advanced characterization approaches in further refining Notch signaling in cardiovascular development, disease, and regeneration.
Risk Stratification of Patients with Acute Coronary Syndrome
Authors: Bauer Dávid , Toušek Petr
Published: October 2021

Defining the risk factors affecting the prognosis of patients with acute coronary syndrome (ACS) has been a challenge. Many individual biomarkers and risk scores that predict outcomes during different periods following ACS have been proposed. This review evaluates known outcome predictors supported by clinical data in light of the development of new treatment strategies for ACS patients during the last three decades.
Improving the Combustion Properties of Corncob Biomass via Torrefaction for Solid Fuel Applications
Authors: Ibitoye Segun Emmanuel , Jen Tien-Chien , Mahamood Rasheedat Modupe , Akinlabi Esther Titilayo
Published: October 2021

The overdependence on fossils as the primary energy source has led to climate change, global warming, and the emission of greenhouse gas. As a result, the United Nations, while setting the goals for the year 2030, has made the provision of a green environment and energy one of the top priorities. In this study, the suitability of corncob for green energy production was investigated. The improvement of corncob’s thermal and combustion properties via the torrefaction process was considered for solid fuel applications. The raw corncob was collected, sorted, and dried for seven days before being used for the torrefaction experiment. Different torrefaction temperatures (200, 240, and 260 °C) and residence times (20, 40, 60 min) were studied. There was no particle reduction—samples were torrefied as collected (whole corncob). The results show that torrefaction temperature and residence time affect the torrefaction products yields along with their properties. Thermal and combustion properties were improved with an increase in torrefaction temperature and residence time. The higher heating value and energy density of the torrefied corncob varied between 17.26 and 18.89 MJ/kg, and 3.23 and 5.66 GJ/m3, respectively. High torrefaction temperature and residence time lead to low solid yield; however, liquid and gas yields increase with torrefaction temperature and residence time. The solid yields varied from 27.57 to 52.23%, while the liquid and gas yields varied from 31.56 to 44.78% and 16.21 to 27.65%, respectively. The properties of corncob improve after torrefaction and are suitable for solid fuel application.
Carbonization Temperature and Its Effect on the Mechanical Properties, Wear and Corrosion Resistance of Aluminum Reinforced with Eggshell
Authors: Ononiwu Ndudim H. , Ozoegwu Chigbogu G. , Madushele Nkosinathi , Akinlabi Esther T.
Published: October 2021

In this paper, the effect of the carbonization temperature on the mechanical properties, density, wear and corrosion resistance of AA 6063 reinforced with eggshells was investigated. The selected fabrication route for this investigation was stir casting while the weight fraction of the eggshells was kept constant at 5 wt.%. The carbonization temperature was varied at 900, 1000, 1100, and 1200 °C. The microstructure revealed that the eggshells were fairly uniformly dispersed on the individual grains and along the grain boundaries of the base metal. It was also shown that the presence of agglomeration increased with increasing carbonization temperature. The densities of the eggshell-reinforced AMCs were lower than that of the base metal. The analysis of the microhardness showed an improvement of 40.79, 22.93, 25.70, and 29.43% for the 900, 1000, 1100, and 1200 °C carbonized eggshell samples, respectively. The compressive strength studies showed that the addition of carbonized eggshells improved the compressive strength of the composites compared to the base metal. The tribology studies showed that the wear resistance improved for the 900 and 1200 °C samples, while the electrochemical studies revealed that the corrosion resistance improved for the 900 and 1000 °C samples only.
Single-Input Multi-Output U-Net for Automated 2D Foetal Brain Segmentation of MR Images
Authors: Rampun Andrik , Jarvis Deborah , Griffiths Paul D. , Zwiggelaar Reyer , Scotney Bryan W. , Armitage Paul A.
Published: October 2021

In this work, we develop the Single-Input Multi-Output U-Net (SIMOU-Net), a hybrid network for foetal brain segmentation inspired by the original U-Net fused with the holistically nested edge detection (HED) network. The SIMOU-Net is similar to the original U-Net but it has a deeper architecture and takes account of the features extracted from each side output. It acts similar to an ensemble neural network, however, instead of averaging the outputs from several independently trained models, which is computationally expensive, our approach combines outputs from a single network to reduce the variance of predications and generalization errors. Experimental results using 200 normal foetal brains consisting of over 11,500 2D images produced Dice and Jaccard coefficients of 94.2 ± 5.9% and 88.7 ± 6.9%, respectively. We further tested the proposed network on 54 abnormal cases (over 3500 images) and achieved Dice and Jaccard coefficients of 91.2 ± 6.8% and 85.7 ± 6.6%, respectively.
Modelling the Past and Future Evolution of Tidal Sand Waves
Authors: Krabbendam Janneke , Nnafie Abdel , de Swart Huib , Borsje Bas , Perk Luitze
Published: October 2021

This study focuses on the hindcasting and forecasting of observed offshore tidal sand waves by using a state-of-the-art numerical morphodynamic model. The sand waves, having heights of several meters, evolve on timescales of years. Following earlier work, the model has a 2DV configuration (one horizontal and one vertical direction). First, the skill of the model is assessed by performing hindcasts at four transects in the North Sea where sand wave data are available of multiple surveys that are at least 10 years apart. The first transect is used for calibration and this calibrated model is applied to the other three transects. It is found that the calibrated model performs well: the Brier Skill Score is ‘excellent’ at the first two transects and ‘good’ at the last two. The root mean square error of calculated bed levels is smaller than the uncertainty in the measurements, except at the last transect, where the M2 is more elliptical than at the other three transects. The calibrated model is subsequently used to make forecasts of the sand waves along the two transects with the best skill scores.
Buckling Mechanism of Offshore Pipelines: A State of the Art
Authors: Seth Debtanu , Manna Bappaditya , Shahu Jagdish Telangrao , Fazeres-Ferradosa Tiago , Pinto Francisco Taveira , Rosa-Santos Paulo Jorge
Published: October 2021

The buckling analysis of an offshore pipeline refers to the analysis of temperature-induced uplift and lateral buckling of pipelines by analytical, numerical, and experimental means. Thus, the current study discusses different research performed on thermal pipe-buckling and the different factors affecting the pipeline’s buckling behaviour. The current study consists of the dependency of the pipe-buckling direction on the seabed features and burial condition; the pre-buckling and post-buckling load-displacement behaviour of the pipeline; the effect of soil weight, burial depth, axial resistance, imperfection amplitude, temperature difference, interface tensile capacity, and diameter-to-thickness ratio on the uplift and lateral resistance; and the failure mechanism of the pipeline. Moreover, the effect of external hydrostatic pressure, bending moment, initial imperfection, sectional rigidity, and diameter-to-thickness ratio of the pipeline on collapse load of the pipeline during buckling were also included in the study. This work highlights the existing knowledge on the topic along with the main findings performed up to recent research. In addition, the reference literature on the topic is given and analysed to contribute to a broad perspective on buckling analysis of offshore pipelines. This work provides a starting point to identify further innovation and development guidelines for professionals and researchers dealing with offshore pipelines, which are key infrastructures for numerous maritime applications.
Deregulation of N6-Methyladenosine RNA Modification and Its Erasers FTO/ALKBH5 among the Main Renal Cell Tumor Subtypes
Authors: Guimarães-Teixeira Catarina , Barros-Silva Daniela , Lobo João , Soares-Fernandes Diana , Constâncio Vera , Leite-Silva Pedro , Silva-Santos Rui , Braga Isaac , Henrique Rui , Miranda-Gonçalves Vera , Jerónimo Carmen
Published: October 2021

(1) Background: Methylation of N6-adenosine (m6A) is the most abundant messenger RNA (mRNA) modification in eukaryotes. We assessed the expression profiles of m6A regulatory proteins in renal cell carcinoma (RCC) and their clinical relevance, namely, as potential biomarkers. (2) Methods: In silico analysis of The Cancer Genome Atlas (TCGA) dataset was use for evaluating the expression of the m6A regulatory proteins among RCC subtypes and select the most promising candidates for further validation. ALKBH5 and FTO transcript and protein expression were evaluated in a series of primary RCC (n = 120) and 40 oncocytomas selected at IPO Porto. (3) Results: In silico analysis of TCGA dataset disclosed altered expression of the major m6A demethylases among RCC subtypes, particularly FTO and ALKBH5. Furthermore, decreased FTO mRNA levels associated with poor prognosis in ccRCC and pRCC. In IPO Porto’s cohort, FTO and ALKBH5 transcript levels discriminated ccRCC from oncocytomas. Furthermore, FTO and ALKBH5 immunoexpression differed among RCC subtypes, with higher expression levels found in ccRCC comparatively to the other RCC subtypes and oncocytomas. (4) Conclusion: We conclude that altered expression of m6A RNA demethylases is common in RCC and seems to be subtype specific. Specifically, FTO and ALKBH5 might constitute new candidate biomarkers for RCC patient management, aiding in differential diagnosis of renal masses and prognostication.
Propagation of International Supply-Chain Disruptions between Firms in a Country
Authors: Inoue Hiroyasu
Published: October 2021

This study shows how import and export shocks propagate through domestic supply chains using actual Japanese supply-chain data and a world input-output table (WIOT) based on firm-level agent-based simulations. We propose three different models with which to connect the domestic firms to a WIOT. Then, we estimate the value-added losses of Japanese firms caused by shocks of different magnitudes and durations originating in China, in the EU and the US, and globally. The volume and rates at which losses increase are very different across the connection models, which indicates that the assignment of international connections to firms matters greatly. The losses increase sublinearly as the duration expands, which indicates that the shock propagation ultimately saturates the economy. Rates of saturation differ substantially depending on the assignment of international connections. The losses increase superlinearly as the initial reduction rate increases. This occurs because there is a greater probability of one supplier being replaced by other suppliers if the reduction is smaller.
Spatial-Temporal Divergence and Driving Mechanisms of Urban-Rural Sustainable Development: An Empirical Study Based on Provincial Panel Data in China
Authors: Wei Chao , Zhang Zuo , Ye Sheng , Hong Mengxi , Wang Wenwen
Published: October 2021

China’s long-standing urban-rural dichotomy has led to a widening gap between urban and rural areas, posing a huge challenge to the sustainable development of Chinese society. This paper adopted the subjective-objective weighting method, coupled coordination degree model, and geographically weighted regression model to conduct urban-rural sustainable development research on 31 provincial administrative regions in China and discussed their spatial-temporal divergence and driving mechanisms during 2007–2018. The results showed that (1) the quality of both rural revitalization and new urbanization improved during the study period, and the gap between them showed a trend of increasing after fluctuations. Both of them had significant spatial and temporal divergence characteristics. (2) The urban-rural coupling coordination degree in China continued to increase during the study period and showed an overall pattern of “high in the east-west and low in the north and southwest”. The changes of relative development type indicated that new urbanization had far surpassed rural revitalization during the study period. (3) The coefficients of driving factors varied significantly in space, showing a hierarchical band distribution. Seven of the eight driving factors showed a strong positive correlation in the vast majority of regions. The results and suggestions of this research can further promote the organic combination of rural revitalization and new urbanization strategy, which is of great practical significance for narrowing the urban-rural gap and realizing sustainable urban-rural development. Likewise, it can be a reference for other developing countries around the world.
Delimitating the Ecological Spaces for Water Conservation Services in Jilin Province of China
Authors: Wang Huan , Zhang Chao , Li Li , Yun Wenju , Ma Jiani , Gao Lulu
Published: October 2021

Mastering the spatial distribution of water retention capacity and scientifically delineating the ecological space for water conservation are of great significance to the management of regional land and water resources. In this paper, a water conservation ecological spatial delimitation framework suitable for water-deficient areas was put forward. The water retention capacity of the study area in 1983, 1990, 2000, 2010, and 2016 was evaluated by using the InVEST Water Yield model and water balance method, respectively. On this basis, a flexible inflection point model based on the contribution degree of functional units was established. Then the ecological space for water conservation was delimited. The framework was applied to the delimitation of the key water conservation areas in Jilin province, China. The results showed that: (1) the spatial distribution pattern of water conservation in Jilin province gradually decreased from east to west. The spatial difference was significant. The maximum value of water conservation in Jilin province was 730 mm. From 1983 to 2016, water conservation, which accounted for 75.71% of the area, showed an upward trend. The overall water retention capacity showed the characteristics of the overall increase and the local decline. (2) From the absolute amount of the effect of unit area change on water conservation, the intensity from the high to the low was forestland, cultivated land, grassland, unused land, buildings, and water. (3) The area of water conservation less than 474 mm accounted for more than 80% of the total study area. The overall water retention capacity was low. High importance ecological space area of water conservation was comprehensively defined as 36.97%, which was mainly distributed in the natural forest area of Changbai Mountain in the east and the south of Song Liao Plain. Therefore, this study provided a basic layout of relatively concentrated ecological spatial distribution for water conservation types at different levels in Jilin province. The study results and conclusions of this paper will provide a reference for water conservation assessment and the regional land’s natural resources management.
NMR Reveals the Conformational Changes of Cytochrome C upon Interaction with Cardiolipin
Authors: Zhan Jianhua , Zhang Guangqing , Chai Xin , Zhu Qinjun , Sun Peng , Jiang Bin , Zhou Xin , Zhang Xu , Liu Maili
Published: October 2021

Conformational change of cytochrome c (cyt c) caused by interaction with cardiolipin (CL) is an important step during apoptosis, but the underlying mechanism is controversial. To comprehensively clarify the structural transformations of cyt c upon interaction with CL and avoid the unpredictable alias that might come from protein labeling or mutations, the conformation of purified yeast iso–1 cyt c with natural isotopic abundance in different contents of CL was measured by using NMR spectroscopy, in which the trimethylated group of the protein was used as a natural probe. The data demonstrate that cyt c has two partially unfolded conformations when interacted with CL: one with Fe–His33 coordination and the other with a penta–coordination heme. The Fe–His33 coordination conformation can be converted into a penta–coordination heme conformation in high content of CL. The structure of cyt c becomes partially unfolded with more exposed heme upon interaction with CL, suggesting that cyt c prefers a high peroxidase activity state in the mitochondria, which, in turn, makes CL easy to be oxidized, and causes the release of cyt c into the cytoplasm as a trigger in apoptosis.
Comparison of the Effect of Unfractionated Heparin and Enoxaparin Sodium at Different Doses on the Course of COVID-19-Associated Coagulopathy
Authors: Oliynyk Oleksandr , Barg Wojciech , Slifirczyk Anna , Oliynyk Yanina , Dubrov Serhij , Gurianov Vitaliy , Rorat Marta
Published: October 2021

Background: COVID-19-associated coagulopathy (CAC) exacerbates the course of coronavirus infection and contributes to increased mortality. Current recommendations for CAC treatment include the use of low-molecular weight heparins (LMWH) at prophylactic or therapeutic doses, as well as the use of unfractionated heparin (UFH). Methods: A randomised, controlled trial enrolled 126 patients hospitalised in the intensive care unit with severe COVID-19 complicated by CAC. The effects of LMWH at preventive and therapeutic doses and UFH at therapeutic doses on mortality and intubation rates were compared. Results: The number of intubations and deaths showed no significant difference depending on the anticoagulant therapy used. However, multivariate logistic regression models revealed an increased risk of intubation (p = 0.026, odds ratio (OR) = 3.33, 95% confidence interval (CI) 1.15–9.59), and an increased risk of death (p = 0.046, OR = 3.01, 95% CI 1.02–8.90), for patients treated with LMWH at a prophylactic dose but not at a therapeutic dose as compared to patients treated with UFH when controlling for other risk factors. Conclusions: The use of unfractionated heparin in the treatment of COVID-19-associated coagulopathy seems to be more effective at reducing the risk of intubation and death than enoxaparin at prophylactic doses.