bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystal Structures of Pyrophosphatase from Acinetobacter baumannii: Snapshots of Pyrophosphate Binding and Identification of a Phosphorylated Enzyme Intermediate
Authors: Si Yunlong , Wang Xing , Yang Guosong , Yang Tong , Li Yuying , Ayala Gabriela Jaramillo , Li Xumin , Wang Hao , Su Jiyong
Published: September 2019

All living things have pyrophosphatases that hydrolyze pyrophosphate and release energy. This energetically favorable reaction drives many energetically unfavorable reactions. An accepted catalytic model of pyrophosphatase shows that a water molecule activated by two divalent cations (M1 and M2) within the catalytic center can attack pyrophosphate in an SN2 mechanism and thus hydrolyze the molecule. However, our co-crystal structure of Acinetobacter baumannii pyrophosphatase with pyrophosphate shows that a water molecule from the solvent may, in fact, be the actual catalytic water. In the co-crystal structure of the wild-type pyrophosphatase with pyrophosphate, the electron density of the catalytic centers of each monomer are different from one another. This indicates that pyrophosphates in the catalytic center are dynamic. Our mass spectroscopy results have identified a highly conserved lysine residue (Lys30) in the catalytic center that is phosphorylated, indicating that the enzyme could form a phosphoryl enzyme intermediate during hydrolysis. Mutation of Lys30 to Arg abolished the activity of the enzyme. In the structure of the apo wild type enzyme, we observed that a Na+ ion is coordinated by residues within a loop proximal to the catalytic center. Therefore, we mutated three key residues within the loop (K143R, P147G, and K149R) and determined Na+ and K+-induced inhibition on their activities. Compared to the wild type enzyme, P147G is most sensitive to these cations, whereas K143R was inactive and K149R showed no change in activity. These data indicate that monovalent cations could play a role in down-regulating pyrophosphatase activity in vivo. Overall, our results reveal new aspects of pyrophosphatase catalysis and could assist in the design of specific inhibitors of Acinetobacter baumannii growth.
Electrospun Chitosan/Poly (Vinyl Alcohol)/Graphene Oxide Nanofibrous Membrane with Ciprofloxacin Antibiotic Drug for Potential Wound Dressing Application
Authors: Yang Shuai , Zhang Xiaohong , Zhang Dawei
Published: September 2019

In this paper, nanofibrous membranes based on chitosan (CS), poly (vinyl alcohol) (PVA) and graphene oxide (GO) composites, loaded with antibiotic drugs, such as Ciprofloxacin (Cip) and Ciprofloxacin hydrochloride (CipHcl) were prepared via the electrospinning technique. The uniform and defect-free CS/PVA nanofibers were obtained and GO nanosheets, shaping spindle and spherical, were partially embedded into nanofibers. Besides, the antibiotic drugs were effectively loaded into the nanofibers and part of which were absorbed into GO nanosheets. Intriguingly, the release of the drug absorbed in GO nanosheets regulated the drug release profile trend, avoiding the “burst” release of drug at the release initial stage, and the addition of GO slightly improved the drug release ratio. Nanofibrous membranes showed the significantly enhanced antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis after the addition of antibiotic drug. Moreover, the drug-loaded nanofibrous membranes exhibited excellent cytocompatibility with Melanoma cells, indicative to the great potential potential for applications in wound dressing.
Future Needs in Mast Cell Biology
Authors: Varricchi Gilda , de Paulis Amato , Marone Gianni , Galli Stephen J.
Published: September 2019

The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct “subpopulations” of mast cells based on a relatively small number of biochemical characteristics. More recently, “subtypes” of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.
Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities
Authors: Ulu Arzu , Sahoo Prakash K. , Yuil-Valdes Ana G. , Mukherjee Maheswari , Van Ormer Matthew , Muthuraj Philma Glora , Thompson Maranda , Anderson Berry Ann , Hanson Corrine K. , Natarajan Sathish Kumar , Nordgren Tara M.
Published: September 2019

Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue.
The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity
Authors: Heun Yvonn , Grundler Groterhorst Katharina , Pogoda Kristin , Kraemer Bjoern F , Pfeifer Alexander , Pohl Ulrich , Mannell Hanna
Published: September 2019

Vascular remodeling and angiogenesis are required to improve the perfusion of ischemic tissues. The hypoxic environment, induced by ischemia, is a potent stimulus for hypoxia inducible factor 1α (HIF-1α) upregulation and activation, which induce pro-angiogenic gene expression. We previously showed that the tyrosine phosphatase SHP-2 drives hypoxia mediated HIF-1α upregulation via inhibition of the proteasomal pathway, resulting in revascularization of wounds in vivo. However, it is still unknown if SHP-2 mediates HIF-1α upregulation by affecting 26S proteasome activity and how the proteasome is regulated upon hypoxia. Using a reporter construct containing the oxygen-dependent degradation (ODD) domain of HIF-1α and a fluorogenic proteasome substrate in combination with SHP-2 mutant constructs, we show that SHP-2 inhibits the 26S proteasome activity in endothelial cells under hypoxic conditions in vitro via Src kinase/p38 mitogen-activated protein kinase (MAPK) signalling. Moreover, the simultaneous expression of constitutively active SHP-2 (E76A) and inactive SHP-2 (CS) in separate hypoxic wounds in the mice dorsal skin fold chamber by localized magnetic nanoparticle-assisted lentiviral transduction showed specific regulation of proteasome activity in vivo. Thus, we identified a new additional mechanism of SHP-2 mediated HIF-1α upregulation and proteasome activity, being functionally important for revascularization of wounds in vivo. SHP-2 may therefore constitute a potential novel therapeutic target for the induction of angiogenesis in ischemic vascular disease.
miR-34a-5p Increases Hepatic Triglycerides and Total Cholesterol Levels by Regulating ACSL1 Protein Expression in Laying Hens
Authors: Tian Wei-Hua , Wang Zhang , Yue Ya-Xin , Li Hong , Li Zhuan-Jian , Han Rui-Li , Tian Ya-Dong , Kang Xiang-Tao , Liu Xiao-Jun
Published: September 2019

Accumulating evidence has shown that miR-34a serves as a posttranscriptional regulatory molecule of lipid metabolism in mammals. However, little studies about miR-34a on lipid metabolism in poultry have been reported until now. To gain insight into the biological functions and action mechanisms of miR-34a on hepatic lipid metabolism in poultry, we firstly investigated the expression pattern of miR-34a-5p, a member of miR-34a family, in liver of chicken, and determined its function in hepatocyte lipid metabolism by miR-34a-5p overexpression and inhibition, respectively. We then validated the interaction between miR-34a-5p and its target using dual-luciferase reporter assay, and explored the action mechanism of miR-34a-5p on its target by qPCR and Western blotting. Additionally, we looked into the function of the target gene on hepatocyte lipid metabolism by gain- and loss-of-function experiments. Our results indicated that miR-34a-5p showed a significantly higher expression level in livers in peak-laying hens than that in pre-laying hens. miR-34a-5p could increase the intracellular levels of triglycerides and total cholesterol in hepatocyte. Furthermore, miR-34a-5p functioned by inhibiting the translation of its target gene, long-chain acyl-CoA synthetase 1 (ACSL1), which negatively regulates hepatocyte lipid content. In conclusion, miR-34a-5p could increase intracellular lipid content by reducing the protein level, without influencing mRNA stability of the ACSL1 gene in chickens.
Lysine Acetylation is an Important Post-Translational Modification that Modulates Heat Shock Response in the Sea Cucumber Apostichopus japonicus
Authors: Xu Dongxue , Wang Xuan
Published: September 2019

Heat stress (HS) is an important factor for the survival of the marine organism Apostichopus japonicus. Lysine acetylation is a pivotal post-translational modification that modulates diverse physiological processes including heat shock response (HSR). In this study, 4028 lysine acetylation sites in 1439 proteins were identified in A. japonicus by acetylproteome sequencing. A total of 13 motifs were characterized around the acetylated lysine sites. Gene Ontology analysis showed that major acetylated protein groups were involved in “oxidation–reduction process”, “ribosome”, and “protein binding” terms. Compared to the control group, the acetylation quantitation of 25 and 41 lysine sites changed after 6 and 48 h HS. Notably, lysine acetyltransferase CREB-binding protein (CBP) was identified to have differential acetylation quantitation at multiple lysine sites under HS. Various chaperones, such as caseinolytic peptidase B protein homolog (CLBP), T-complex protein 1 (TCP1), and cyclophilin A (CYP1), showed differential acetylation quantitation after 48 h HS. Additionally, many translation-associated proteins, such as ribosomal proteins, translation initiation factor (IF), and elongation factors (EFs), had differential acetylation quantitation under HS. These proteins represented specific interaction networks. Collectively, our results offer novel insight into the complex HSR in A. japonicus and provide a resource for further mechanistic studies examining the regulation of protein function by lysine acetylation.
Hybrid Sequencing of Full-Length cDNA Transcripts of the Medicinal Plant Scutellaria baicalensis
Authors: Gao Ting , Xu Zhichao , Song Xiaojun , Huang Kai , Li Ying , Wei Jianhe , Zhu Xunzhi , Ren Hongwei , Sun Chao
Published: September 2019

Scutellaria baicalensis is a well-known medicinal plant that produces biologically active flavonoids, such as baicalin, baicalein, and wogonin. Pharmacological studies have shown that these compounds have anti-inflammatory, anti-bacterial, and anti-cancer activities. Therefore, it is of great significance to investigate the genetic information of S. baicalensis, particularly the genes related to the biosynthetic pathways of these compounds. Here, we constructed the full-length transcriptome of S. baicalensis using a hybrid sequencing strategy and acquired 338,136 full-length sequences, accounting for 93.3% of the total reads. After the removal of redundancy and correction with Illumina short reads, 75,785 nonredundant transcripts were generated, among which approximately 98% were annotated with significant hits in the protein databases, and 11,135 sequences were classified as lncRNAs. Differentially expressed gene (DEG) analysis showed that most of the genes related to flavonoid biosynthesis were highly expressed in the roots, consistent with previous reports that the flavonoids were mainly synthesized and accumulated in the roots of S. baicalensis. By constructing unique transcription models, a total of 44,071 alternative splicing (AS) events were identified, with intron retention (IR) accounting for the highest proportion (44.5%). A total of 94 AS events were present in five key genes related to flavonoid biosynthesis, suggesting that AS may play important roles in the regulation of flavonoid biosynthesis in S. baicalensis. This study provided a large number of highly accurate full-length transcripts, which represents a valuable genetic resource for further research of the molecular biology of S. baicalensis, such as the development, breeding, and biosynthesis of active ingredients.
Twist1 Inactivation in Dmp1-Expressing Cells Increases Bone Mass but Does Not Affect the Anabolic Response to Sclerostin Neutralization
Authors: Lewis Karl J. , Choi Roy B-J , Pemberton Emily Z. , Bullock Whitney A. , Firulli Anthony B. , Robling Alexander G.
Published: September 2019

Wnt signaling plays a major role in bone metabolism. Advances in our understanding of secreted regulators of Wnt have yielded several therapeutic targets to stimulate osteoanabolism—the most promising of which is the Wnt inhibitor sclerostin. Sclerostin antibody recently gained approval for clinical use to treat osteoporosis, but the biology surrounding sclerostin antagonism is still incompletely understood. Numerous factors regulate the efficacy of sclerostin inhibition on bone formation, a process known as self-regulation. In previous communications we reported that the basic helix-loop-helix transcription factor Twist1—a gene know to regulate skeletal development—is highly upregulated among the osteocyte cell population in mice treated with sclerostin antibody. In this communication, we tested the hypothesis that preventing Twist1 upregulation by deletion of Twist1 from late-stage osteoblasts and osteocytes would increase the efficacy of sclerostin antibody treatment, since Twist1 is known to restrain osteoblast activity in many models. Twist1-floxed loss-of-function mice were crossed to the Dmp1-Cre driver to delete Twist1 in Dmp1-expressing cells. Conditional Twist1 deletion was associated with a mild but significant increase in bone mass, as assessed by dual energy x-ray absorptiometry (DXA) and microCT (µCT) for many endpoints in both male and female mice. Biomechanical properties of the femur were not affected by conditional mutation of Twist1. Sclerostin antibody improved all bone properties significantly, regardless of Twist1 status, sex, or endpoint examined. No interactions were detected when Twist1 status and antibody treatment were examined together, suggesting that Twist1 upregulation in the osteocyte population is not an endogenous mechanism that restrains the osteoanabolic effect of sclerostin antibody treatment. In summary, Twist1 inhibition in the late-stage osteoblast/osteocyte increases bone mass but does not affect the anabolic response to sclerostin neutralization.
IBR5 Regulates Leaf Serrations Development via Modulation of the Expression of PIN1
Authors: Kong Xiuzhen , Huang Guoqiang , Xiong Yali , Zhao Chunyan , Wang Jun , Song Xiaoyun , Giri Jitender , Zuo Kaijing
Published: September 2019

Biodiversity in plant shape is mainly attributable to the diversity of leaf shape, which is largely determined by the transient morphogenetic activity of the leaf margin that creates leaf serrations. However, the precise mechanism underlying the establishment of this morphogenetic capacity remains poorly understood. We report here that INDOLE-3-BUTYRIC ACID RESPONSE 5 (IBR5), a dual-specificity phosphatase, is a key component of leaf-serration regulatory machinery. Loss-of-function mutants of IBR5 exhibited pronounced serrations due to increased cell area. IBR5 was localized in the nucleus of leaf epidermis and petiole cells. Introducing a C129S mutation within the highly conserved VxVHCx2GxSRSx5AYLM motif of IBR5 rendered it unable to rescue the leaf-serration defects of the ibr5-3 mutant. In addition, auxin reporters revealed that the distribution of auxin maxima was expanded ectopically in ibr5-3. Furthermore, we found that the distribution of PIN1 on the plasma membrane of the epidermal and cells around the leaf vein was compromised in ibr5-3. We concluded that IBR5 is essential for the establishment of PIN-FORMED 1 (PIN1)-directed auxin maxima at the tips of leaf serration, which is vital for the elaborated regulation during its formation.
The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer’s Disease and Parkinson’s Disease and Models of Mild Cognitive Impairment
Authors: Hwang Jeannie , Estick Candice M. , Ikonne Uzoma S. , Butler David , Pait Morgan C. , Elliott Lyndsie H. , Ruiz Sarah , Smith Kaitlan , Rentschler Katherine M. , Mundell Cary , Almeida Michael F. , Bear Nicole Stumbling , Locklear James P. , Abumohsen Yara , Ivey Cecily M. , Farizatto Karen L.G. , Bahr Ben A.
Published: September 2019

Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer’s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson’s disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid β 42 (Aβ42) degradation product Aβ38, and this indicator of Aβ42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aβ42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aβ deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.
In Search for the Membrane Regulators of Archaea
Authors: Salvador-Castell Marta , Tourte Maxime , Oger Philippe M.
Published: September 2019

Membrane regulators such as sterols and hopanoids play a major role in the physiological and physicochemical adaptation of the different plasmic membranes in Eukarya and Bacteria. They are key to the functionalization and the spatialization of the membrane, and therefore indispensable for the cell cycle. No archaeon has been found to be able to synthesize sterols or hopanoids to date. They also lack homologs of the genes responsible for the synthesis of these membrane regulators. Due to their divergent membrane lipid composition, the question whether archaea require membrane regulators, and if so, what is their nature, remains open. In this review, we review evidence for the existence of membrane regulators in Archaea, and propose tentative location and biological functions. It is likely that no membrane regulator is shared by all archaea, but that they may use different polyterpenes, such as carotenoids, polyprenols, quinones and apolar polyisoprenoids, in response to specific stressors or physiological needs.
Genetic Dissection of Seed Storability and Validation of Candidate Gene Associated with Antioxidant Capability in Rice (Oryza sativa L.)
Authors: Yuan Zhiyang , Fan Kai , Xia Laifu , Ding Xiali , Tian Li , Sun Wenqiang , He Hanzi , Yu Sibin
Published: September 2019

Seed storability, defined as the ability to remain alive during storage, is an important agronomic and physiological characteristic, but the underlying genetic mechanism remains largely unclear. Here, we report quantitative trait loci (QTLs) analyses for seed storability using a high-density single nucleotide polymorphism linkage map in the backcross recombinant inbred lines that was derived from a cross of a japonica cultivar, Nipponbare, and an indica cultivar, 9311. Seven putative QTLs were identified for seed storability under natural storage, each explaining 3.6–9.0% of the phenotypic variation in this population. Among these QTLs, qSS1 with the 9311 alleles promoting seed storability was further validated in near-isogenic line and its derived-F2 population. The other locus (qSS3.1) for seed storability colocalized with a locus for germination ability under hydrogen peroxide, which is recognized as an oxidant molecule that causes lipid damage. Transgenic experiments validated that a candidate gene (OsFAH2) resides the qSS3.1 region controlling seed storability and antioxidant capability. Overexpression of OsFAH2 that encodes a fatty acid hydroxylase reduced lipid preoxidation and increased seed storability. These findings provide new insights into the genetic and physiological bases of seed storability and will be useful for the improvement of seed storability in rice.
An Internet of Things-Based Low-Power Integrated Beekeeping Safety and Conditions Monitoring System
Authors: Kontogiannis Sotirios
Published: September 2019

This paper proposes a holistic management and control system for the apiculture industry (Integrated Beekeeping System of holistic Management and Control – IBSMC). This integrated beehive array system mainly focuses on the regulation of bees living conditions, targeting both minimizing bee swarm mortality and maximizing productivity. Within the proposed IBSMC system architecture, additional security functionalities are implemented for bee monitoring, low energy consumption and incidents response. As a complete unit, the proposed IBSMC system is both a hive conditions monitoring and safety system. It communicates with the outer world using low power RF data transmission and the LoRaWAN transceivers. This paper presents the proposed IBSMC architecture consisting of new beehive cells embedded with functionalities for integrated conditions regulation and security provisions, as well as the communication protocols used for facility-conditions management, incidents’ acquisition and incidents’ response.
Comparative Volume Analysis of Alveolar Defects by 3D Simulation
Authors: Chou Pang-Yun , Denadai Rafael , Hallac Rami R. , Dumrongwongsiri Sarayuth , Hsieh Wei-Chuan , Pai Betty CJ , Lo Lun-Jou
Published: September 2019

A precise volumetric assessment of maxillary alveolar defects in patients with cleft lip and palate can reduce donor site morbidity or allow accurate preparation of bone substitutes in future applications. However, there is a lack of agreement regarding the optimal volumetric technique to adopt. This study measured the alveolar bone defects by using two cone-beam computed tomography (CBCT)-based surgical simulation methods. Presurgical CBCT scans from 32 patients with unilateral or bilateral clefts undergoing alveolar bone graft surgery were analyzed. Two hands-on CBCT-based volumetric measurement methods were compared: the 3D real-scale printed model-based surgical method and the virtual surgical method. Different densities of CBCT were compared. Intra- and inter-examiner reliability was assessed. For patients with unilateral clefts, the average alveolar defect volumes were 1.09 ± 0.24 and 1.09 ± 0.25 mL (p > 0.05) for 3D printing- and virtual-based models, respectively; for patients with bilateral clefts, they were 2.05 ± 0.22 and 2.02 ± 0.27 mL (p > 0.05), respectively. Bland–Altman analysis revealed that the methods were equivalent for unilateral and bilateral alveolar cleft defect assessment. No significant differences or linear relationships were observed between adjacent different densities of CBCT for model production to obtain the measured volumes. Intra- and inter-examiner reliability was moderate to good (intraclass correlation coefficient (ICC) > 0.6) for all measurements. This study revealed that the volume of unilateral and bilateral alveolar cleft defects can be equally quantified by 3D-printed and virtual surgical simulation methods and provides alveolar defect-specific volumes which can serve as a reference for planning and execution of alveolar bone graft surgery.
Simultaneous Depression of Immunological Synapse and Endothelial Injury is Associated with Organ Dysfunction in Community-Acquired Pneumonia
Authors: Menéndez Rosario , Méndez Raúl , Almansa Raquel , Ortega Alicia , Alonso Ricardo , Suescun Marta , Ferrando Ana , Feced Laura , Bermejo-Martin Jesús F.
Published: September 2019

Rationale: A depressed expression of antigen presentation is, along with endothelial dysfunction, a recognized signature of severe community-acquired pneumonia (CAP). We aimed to evaluate the expression of a number of genes involved in the immunological synapse in non-critically ill CAP patients with or without organ dysfunction and to profile endothelial biomarkers such as proendothelin-1 (proET1) and proadrenomedullin (proADM). Methods: A nested study in a prospective cohort in CAP patients was performed. Expression levels of major histocompatibility complex class II DR alpha (HLA-DRA), CD40 ligand (CD40LG), CD3E, CD28, and inducible T-cell costimulator (ICOS) were quantified by using droplet digital polymerase chain reaction and endothelial biomarkers by immunofluorescence. Results: Ninety-four patients were included, 44.7% of whom had organ failure in one or more organs. A significant decrease in the expression of the five genes with increased levels of proadrenomedullin (proADM) and proendothelin-1 (proET1) was found in CAP with organ failure. The depressed expression of HLA-DRA (odds ratio (OR), 2.94), CD40LG (OR, 3.90), and CD28 (OR, 3.48) was independently associated with organ failure after adjustment for age, Charlson score, and severity. Conclusions. CAP with organ failure showed depressed expression of immunological synapse genes with increased levels of biomarkers denoting endothelial damage. Simultaneous profiling of immunological and endothelial signatures could help in the early identification of organ failure in CAP and in the implementation of personalized treatment.
Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease
Authors: Cabasso Or , Paul Sumit , Dorot Orly , Maor Gali , Krivoruk Olga , Pasmanik-Chor Metsada , Mirzaian Mina , Ferraz Maria , Aerts Johannes , Horowitz Mia
Published: September 2019

Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, type 2 and type 3, forms. We studied the two fly GBA1 orthologs, GBA1a and GBA1b. Each contains a Minos element insertion, which truncates its coding sequence. In the GBA1am/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, GBA1bm/m mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. GBA1bm/m mutant flies showed activation of the Unfolded Protein Response (UPR) and presented inflammation and neuroinflammation that culminated in development of a neuronopathic disease. Treatment with ambroxol did not rescue GCase activity or reduce substrate accumulation; however, it ameliorated UPR, inflammation and neuroinflammation, and increased life span. Our results highlight the resemblance between the phenotype of the GBA1bm/m mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities.
Blood Vessel Patterning on Retinal Astrocytes Requires Endothelial Flt-1 (VEGFR-1)
Authors: Chappell John C. , Darden Jordan , Payne Laura Beth , Fink Kathryn , Bautch Victoria L.
Published: September 2019

Feedback mechanisms are critical components of many pro-angiogenic signaling pathways that keep vessel growth within a functional range. The Vascular Endothelial Growth Factor-A (VEGF-A) pathway utilizes the decoy VEGF-A receptor Flt-1 to provide negative feedback regulation of VEGF-A signaling. In this study, we investigated how the genetic loss of flt-1 differentially affects the branching complexity of vascular networks in tissues despite similar effects on endothelial sprouting. We selectively ablated flt-1 in the post-natal retina and found that maximum induction of flt-1 loss resulted in alterations in endothelial sprouting and filopodial extension, ultimately yielding hyper-branched networks in the absence of changes in retinal astrocyte architecture. The mosaic deletion of flt-1 revealed that sprouting endothelial cells flanked by flt-1−/− regions of vasculature more extensively associated with underlying astrocytes and exhibited aberrant sprouting, independent of the tip cell genotype. Overall, our data support a model in which tissue patterning features, such as retinal astrocytes, integrate with flt-1-regulated angiogenic molecular and cellular mechanisms to yield optimal vessel patterning for a given tissue.
Psychometric Network Analysis of the Hungarian WAIS
Authors: Schmank Christopher J. , Goring Sara Anne , Kovacs Kristof , Conway Andrew R. A.
Published: September 2019

The positive manifold—the finding that cognitive ability measures demonstrate positive correlations with one another—has led to models of intelligence that include a general cognitive ability or general intelligence (g). This view has been reinforced using factor analysis and reflective, higher-order latent variable models. However, a new theory of intelligence, Process Overlap Theory (POT), posits that g is not a psychological attribute but an index of cognitive abilities that results from an interconnected network of cognitive processes. These competing theories of intelligence are compared using two different statistical modeling techniques: (a) latent variable modeling and (b) psychometric network analysis. Network models display partial correlations between pairs of observed variables that demonstrate direct relationships among observations. Secondary data analysis was conducted using the Hungarian Wechsler Adult Intelligence Scale Fourth Edition (H-WAIS-IV). The underlying structure of the H-WAIS-IV was first assessed using confirmatory factor analysis assuming a reflective, higher-order model and then reanalyzed using psychometric network analysis. The compatibility (or lack thereof) of these theoretical accounts of intelligence with the data are discussed.
Microparticles in Table Salt: Levels and Chemical Composition of the Smallest Dimensional Fraction
Authors: Renzi Monia , Grazioli Eleonora , Bertacchini Eleonora , Blašković Andrea
Published: September 2019

This study evaluates the chemical composition of microplastic materials (MPs) and non-synthetic particles in different table salts of marine origin by the µFT-IR technique. This research focuses on the microparticles fraction within 10–150 µm of size. Eleven commercial trademarks coming from Italy (IT = 6) and Croatia (CRO = 5) were grouped in two different cost ranges, cheap (n = 5) and expensive (n = 6) and were analysed in replicates (n = 3). Levels and chemical composition of microparticles measured in commercial products were correlated on a statistical basis to some factors of variability of potential scientific interest (geographical origin of marine salt, cost of commercial products, etc.). Results of analyses performed on the tested size fraction of microparticles (10–150 µm) evidence that: (i) levels of MPs are within 0.17–0.32 items/g (IT) and 0.07–0.20 items/g (CRO); (ii) non-synthetic particles detected are mostly made by fibres made of cellulose acetate; (iii) Nations show a different chemical composition of MPs recovered in analysed trademarks (PET and PVC from Italy; PA, PP, and nylon from Croatia); (iv) the annual amount ingested by humans from marine salt consumption ranges between 131.4–372.3 items/y (CRO) and 306.6–580.35 items/y (IT) considering a dose of 5 g of salt per day; (v) statistics performed on factors of interest evidenced that the geographical origin of marine salt do not affect neither levels nor chemical composition of MPs in tested trademarks; while slight correlations are recorded with non-synthetic particles. Further studies are needed to better explore on statistical basis if both levels and chemical composition of MPs in table salts of marine origin can be used or not as good indicators of marine pollution.
Stability Assessment of Rubble Mound Breakwaters Using Extreme Learning Machine Models
Authors: Wei Xianglong , Liu Huaixiang , She Xiaojian , Lu Yongjun , Liu Xingnian , Mo Siping
Published: September 2019

The stability number of a breakwater can determine the armor unit’s weight, which is an important parameter in the breakwater design process. In this paper, a novel and simple machine learning approach is proposed to evaluate the stability of rubble-mound breakwaters by using Extreme Learning Machine (ELM) models. The data-driven stability assessment models were built based on a small size of training samples with a simple establishment procedure. By comparing them with other approaches, the simulation results showed that the proposed models had good assessment performances. The least user intervention and the good generalization ability could be seen as the advantages of using the stability assessment models.
The Late(r) Bird Gets the Verb? Effects of Age of Acquisition of English on Adult Heritage Speakers’ Knowledge of Subjunctive Mood in Spanish
Authors: Giancaspro David
Published: September 2019

Many previous studies have found that adult heritage speakers exhibit significant variability in their production and comprehension of mood morphology in Spanish. Nonetheless, it remains unclear what specific factors predict heritage speakers’ likelihood of exhibiting such variability. The present study contributes to this question by testing the effect of both (a) age-of-acquisition of English and (b) Spanish proficiency on heritage speakers’ productive and receptive knowledge of mood morphology. Seventeen “early” heritage speakers (age of acquisition of English: 0 to 3.5 years), 20 “late” heritage speakers (age of acquisition of English: 4 to 6 years), and 18 later childhood immigrants (age of arrival in the US: 8 to 12 years) completed a Contextualized Elicited Production Task and a Mood Preference Task. Results of the two experiments suggest that the later childhood immigrants, despite “overusing” subjunctive in +Presupposition adjectival relative clauses, are significantly more likely than “early” and “late” heritage speakers to produce and prefer subjunctive mood in expected subjunctive contexts (with para que and in -Presupposition adjectival relative clauses). Within the heritage speaker groups, however, Spanish proficiency was a stronger predictor of subjunctive knowledge than age of acquisition of English, a finding with implications for both heritage language research and pedagogy.
2-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenyl)-1-propyl-1H-benzo[d]imidazole-5-carboxamide
Authors: Bhaskar Prakash , Kumar Vasantha , Tholappanavara Hanumanthappa Suresha Kumara , Haliwana Banakara Vijaykumar Sowmya
Published: September 2019

2-(3,4-Dimethoxyphenyl)-N-(4-methoxyphenyl)-1-propyl-1H-benzo[d]imidazole-5-carboxamide was synthesized by the ‘one-pot’ reductive cyclization of N-(4-methoxyphenyl)-3-nitro-4-(propylamino)benzamide with 3,4-dimethoxybenzaldehyde, using sodium dithionite as a reductive cyclizing agent using DMSO as a solvent. The structure of newly synthesized compound was elucidated based on IR, 1H-NMR, 13C-NMR, and LC-MS data.
Field Programmable Gate Array-Based Linear Shaft Motor Drive System Design in Terms of the Trapezoidal Velocity Profile Consideration
Authors: Lai Chiu-Keng , Lai Hsiang-Yueh , Tang Yong-Xiang , Chang En-Shen
Published: September 2019

Owing to the benefits of programmable and parallel processing of the field programmable gate arrays (FPGAs), they have been widely used to the realization of digital controllers and motor drive systems. In this study, we adopt the FPGA chip to realize the Linear Shaft Motor (LSM) drive system which includes the position, speed and current vector controls. Linear shaft motor is a special motor which has the magnet as the shaft and stator coils are on the forcer. Thus, it reveals a small mechanical time constant. In addition, the electrical side can be looked as a general three-phase Alternating Current (AC) system which can be powered by inverter and vector control technique can be applied to the system. The designed system needs high performance calculation ability about position/speed control and vector current control loops. The mathematical model of linear shaft motor drive system is first built and simulated by MATLAB/Simulink and the accuracy about the effect from the speed estimation method is proposed. The resulting digital model of the drive system is stored into Verilog Hardware Description Language (Verilog HDL) codes and realized by FPGA. At last, the hardware circuits as well as the power module are used to test the performance of the developed hardware system in terms of the trapezoidal velocity profile. The experimental results show that the designed system realized by FPGA has attained the desired performance.
Queueing Network with Moving Servers as a Model of Car Sharing Systems
Authors: Kim Chesoong , Dudin Sergei , Dudina Olga
Published: September 2019

We consider a queueing network with a finite number of nodes and servers moving between the nodes as a model of car sharing. The arrival process of customers to various nodes is defined by a marked Markovian arrival process. The customer that arrives at a certain node when there is no idle server (car) is lost. Otherwise, he/she is able to start the service. With known probability, which depends on the node and the number of available cars, this customer can balk the service and leave the system. The service time of a customer has an exponential distribution. Location of the server in the network after service completion is random with the known probability distribution. The behaviour of the network is described by a multi-dimensional continuous-time Markov chain. The generator of this chain is derived which allows us to compute the stationary distribution of the network states. The formulas for computing the key performance indicators of the system are given. Numerical results are presented. They characterize the dependence of some performance measures of the network and the nodes on the total number of cars (fleet size of the car sharing system) and correlation in the arrival process.
Hydrodynamic and Acoustic Performance Analysis of Marine Propellers by Combination of Panel Method and FW-H Equations
Authors: Ebrahimi Abouzar , Seif Mohammad Saeed , Nouri-Borujerdi Ali
Published: September 2019

The noise emitted by ships is one of the most important noises in the ocean, and the propeller noise is one of the major components of the ship noise. Measuring the propeller noise in a laboratory, despite the high accuracy and good reliability, has high costs and is very time-consuming. For this reason, the calculation of propeller noise using numerical methods has been considered in recent years. In this study, the noise of a propeller in non-cavitating conditions is calculated by the combination of the panel method (boundary element method) and solving the Ffowcs Williams-Hawkings (FW-H) equations. In this study, a panel method code is developed, and the results are validated by the experimental results of the model tests carried out in the cavitation tunnel of the Sharif University of Technology. Software for numerical calculation of propeller noise, based on FW-H equations, is also developed and the results are validated by experimental results. This study shows that the results of the panel method code have good agreement with experimental results, and that the maximum error of this code for the thrust and torque coefficients is 4% and 7%, respectively. The results of the FW-H noise code are also in good agreement with the experimental data.
Organised Versus Opportunistic Cervical Cancer Screening in Urban and Rural Regions of Lithuania
Authors: Paulauskiene Justina , Ivanauskiene Rugile , Skrodeniene Erika , Petkeviciene Janina
Published: September 2019

Background and Objectives: In 2004, Lithuania started the Nationwide Cervical Cancer Screening Programme. However, screening is more opportunistic than population-wide and the programme’s coverage is insufficient. The aim of this study was to assess the effect of systematic personal invitation on coverage of cervical cancer (CC) screening in urban and rural regions of Lithuania. Materials and Methods: The study was conducted in an urban primary healthcare centre (PHCC) and in a rural PHCC, where prevailing CC screening practice was highly opportunistic. Over the first year, all women aged 25–60 who had not received a Pap smear test within the last three years in urban (n = 1591) and rural (n = 1843) PHCCs received a personal invitation letter to participate in the screening. Over the second year, the reminder letter was sent to the non-attendees (n = 1042 in urban and n = 929 in rural PHCCs). A random sample of women (n = 93), who did not attend for screening after two letters, was contacted by phone in order to identify the barriers of non-attendance. Results: Before the study, only 9.6% of the target population in urban and 14.7% in rural PHCCs participated in CC screening. After the first invitation letter, the participation in CC screening increased up to 24.6% in urban and 30.8% in rural areas (p < 0.001). After the reminder letter, the attendance was 16.4% in urban and 22.2% in rural PHCCs (p < 0.001). The most common barriers for the non-attendance were lack of time, long waiting time for family doctor’s appointment, worries that a Pap test might be unpleasant and preventive gynaecological examination outside of the screening program. Conclusions: A systematic personal invitation with one reminder letter significantly increased the coverage of CC screening and was more effective in rural regions than in urban regions. The assessed barriers for non-attendance can be used to improve the coverage of screening.
Current Evidence of the Oncological Benefit-Risk Profile of Hormone Replacement Therapy
Authors: D’Alonzo Marta , Bounous Valentina Elisabetta , Villa Michela , Biglia Nicoletta
Published: September 2019

Hormone replacement therapy (HRT) remains the most effective treatment for menopausal symptoms and has been shown to prevent bone loss and fracture. The progestogen is added to provide endometrial protection in women with an intact uterus. After the publication of the initial WHI (Women’s Health Initiative) results in 2002 reporting an overall increased risk of breast cancer, many women discontinued HRT. Despite the re-analysis of the results by subgroups of patients and updates with extended follow-up, much controversy remains, which we will analyze later in the text. Different types of estrogen or progestogen, as well as different formulations, doses, and durations, may play a role in HRT’s effects on breast tissue. Evidence states that conjugated equine estrogen (CEE), compared to estro-progestin therapy, shows a better profile risk (HR 0.79, CI 0.65–0.97) and that, among different type of progestins, those structurally related to testosterone show a higher risk (RR 3.35, CI 1.07–10.4). Chronic unopposed endometrial exposure to estrogen increases the risk of endometrial hyperplasia and cancer, whereas the association with progestins, especially in continuous combined regimen, seems to reduce the risk (RR 0.71, CI 0.56–0.90). HRT was also associated with a protective effect on colon cancer risk (HR 0.61, CI 0.42–0.87). Data about ovarian and cervical cancer are still controversial.
Single Incision Pediatric Endoscopic Surgery: From Myth to Reality a Case Series
Authors: Wallace Bradley J. , Vuille-dit-Bille Raphael N. , Marwan Ahmed I.
Published: September 2019

Laparoscopic surgery has continued to evolve to minimize access sites and scars in both the adult and pediatric populations. In children, single-incision pediatric endoscopic surgery (SIPES) has been shown to be effective, feasible, and safe with comparative results to multiport equivalents. Thus, the use of SIPES continues over increasingly complex cases, however, conceptions of its efficacy continue to vary greatly. In the present case series and discussion, we review the history of SIPES techniques and its current application today. We present this in the setting of five common myths about SIPES techniques: limitations against complex cases, restrictions to specialized training, increased morbidity outcomes, increased operative lengths, and increased operative costs. Regarding the myth of SIPES being limited in application to simple cases, examples were highlighted throughout the literature in addition to the authors’ own experience with three complex cases including resection of a lymphatic malformation, splenectomy with cholecystectomy, and distal pancreatectomy with splenectomy. A review of SIPES learning curves shows equivalent operative outcomes to multiport learning curves and advancements towards practical workshops to increase trainee familiarity can help assuage these aptitudes. In assessing comorbidities, adult literature reveals a slight increase in incisional hernia rates, but this does not correlate with single-incision pediatric data. In experienced hands, operative SIPES times average approximate multiport laparoscopic equivalents. Finally, regarding expenses, SIPES represents an equivalent alternative to laparoscopic techniques.