bluuebunny/crossref_metadata_2025 huggingface dataset:
Ensuring chemical resistance of pile foundations when they are installed in permanently and seasonally frozen soils with aggressive environments
Authors: Zhusupbekov A Zh , Montayeva A S , Montayev S A , Montayeva N S
Published: April 2020

The analysis of soil and groundwater chemical composition in Kazakhstan has showed that they contain soluble salts of various concentrations. Therefore, one of the problematic tasks in constructing pile foundations on seasonally frozen soils with aggressive media is not only about to ensure proper pile driving, but also to ensure their chemical resistance against soluble salts. The main factors affecting the pile foundations when driving their permanently and seasonally frozen soils have been identified. It was established that as the main factors in the technology of driving pile foundations in frozen soils are the depth of freezing soil and appropriate method of driving piles. It has been established that in many cases construction is carried out in soils with aggressive environments, which raises new challenges for ensuring the chemical resistance of pile foundations. To ensure the chemical stability of pile foundations, new chemically active additives are proposed in the form of siliceous rock - flask and thermolitic sand. The results of the studies, it has been found that the use of siliceous rock-flask in the form of a filler in the composition of cement binder and thermolithic sand increases the chemical resistance of concrete in conditions of high-intensity salt and acid aggression by almost 1.5-3 times, respectively, in comparison with concrete on quartz sand.
Typical defects and damage to the industrial buildings’ facades
Authors: Krahmalny T A , Evtushenko S I
Published: April 2020

During the life cycle of the industrial building, defects and damages associated with the production process or their operating conditions accumulate in the construction structures. Defects of facades, such as destruction of the protective layer of concrete, exposure of the wall panels working reinforcement, destruction of the concrete of the carnal slabs, absence of glazing on the windows, corrosion of metal fire ladders, destruction of the wall and mechanical damage to the wall panels by motor vehicles, are repeated at different objects and have common causes of occurrence. The authors have identified 5 characteristic zones of defect. The article contains recommendations for the elimination of detected defects and damages. Defects and damages are proposed to be combined according to the above groups during surveys or monitoring of façade condition. This will allow to monitor the dynamics of negative processes development and to carry out major repairs in a timely manner during scheduled annual inspections of facades.
Aerodynamic and thermal interference between two building models
Authors: Korobkov S , Gnyrya A , Terekhov V
Published: April 2020

the paper considers aerodynamic and thermal interference of separated flows between two square prisms arranged at a short distance from each other. It is shown how relative positions of the square prisms affect the specific phenomena caused by the airflow interactions. This work is the experimental study of aerodynamic and thermal interference effects on two square prisms or building models depending on their relative positions. A strong difference is shown between aerodynamic and thermal interferences observed in the airflow behind two tandem models. The thermal interference effect turns to be rather conservative as compared to the aerodynamic. Using the interference parameters one can easily analyze the extreme values of the pressure and thermal flows interfering with the building models depending on many factors, including relative model positions.
Use of two-parameter distributions for a joint assessment of the residual resource of building structures and engineering systems of buildings and structures
Authors: Korolkov D I , Chernykh A G , Kazakevich T N , Mamedov S M , Gravit M V
Published: April 2020

The article describes the use of two-parameter distributions for assessing the residual resource of engineering systems and building structures of buildings and structures. To estimate the residual resource, the authors propose using the Weibull distribution, beta distribution, gamma distribution, and student distribution. Scopes of each distribution are shown. In particular cases, these distributions turn into normal or exponential distributions, which are widely used to estimate the residual resource of building structures and engineering systems of buildings and structures. The authors proposed an algorithm for using two-parameter distributions for a joint assessment of the residual resource of building structures and engineering systems of buildings and structures. In this algorithm, the authors present the parameters by which it is necessary to choose one or another two-parametric distribution. Further, the authors determined how to estimate the element failure rate in the presence and absence of data on the number of failures. The authors also proposed a procedure for assigning the final value of the residual resource when using several distributions at once. The advantages and disadvantages of using two-parameter distributions for a joint assessment of the residual resource of building structures and engineering systems of buildings and structures are given. The authors also proposed ways to further improve it.
Features of preliminary stresses in wooden constructions
Authors: Chernyh A G , Moskalev M B
Published: April 2020

Unlike reinforced concrete and metal, prestressing is used much less frequently in wood. Wood began to apply in 1860 and continued to be used in prestressed structures. But at the same time it faced some problems. To minimize the impact of these factors it is recommended to take the following measures: 1) To use special knots with the most increased contact surface for prevention of wood deformation in them. For such a node, the author of this article received a patent for a utility model; 2) carefully control the humidity and prevent it from changing during operation; 3) prestress is set with some margin due to the rheological properties of wood, or during operation to increase it.
Value of additional vertical deformations of foundations depending on injection grouting conditions
Authors: Osokin A I , Kalach F N , Diakonov I P , Remizova N V
Published: April 2020

The possibilities of new construction in the center of Saint Petersburg are quite limited by the requirements for preserving the historical center and by the height restrictions, so the construction of underground space is of great importance for the developing city. Investors are ready to deepen basements and to excavate foundation pits in the courtyards of existing buildings to increase usable space, but before starting such works, a number of compensatory measures are required, one of which is strengthening of foundation bed and foundation body of affected buildings.
Geodesy and modern technologies
Authors: Pozdysheva O N , Taldykina V V
Published: April 2020

Currently, a lot of geodetic instruments and new geodetic technologies have been created, which are fundamentally different from traditional ones. In previous years, each type of measurement had its own type of instrument: for the angular measurements, the theodolite, for high-altitude measurements - a level, for linear measurements - a tape measure and rangefinder. Each device, depending on the intended use, had its own accuracy characteristics. Over time, science is developing and technologies are moving forward, the devices used in the field of engineering and geodetic works are improving. A modern geodetic instrument is a product of new technologies that embodies the latest achievements in optics and modern satellite technologies. This article provides a classification of devices according to their purpose and describes their application.
Overall stability of steel web-tapered frame members
Authors: Belyy G I , Askinazi V U
Published: April 2020

The solution to the problem of fully nonlinear stability analysis of web-tapered I-shaped members is presented in the paper. In order to accelerate the analysis, an analytical- numerical approach was applied in the solution. Nonlinear stability analysis in the elastic range is carried out by the use of the analytical procedure (so-called “Member” procedure) which is based on the combination of the results of buckling and linear analyses. The growth of the plastic deformations is taken into account by adding extra displacements in the “Member” procedure. These displacements are determined numerically in the process of incremental loading (so-called “Section” procedure). The proposed approach allows the calculation of all displacements at each load step and the estimating of the member’s overall stability capacity, rapidly (up to 20 times faster than using shell-FEM) and accurately enough. The overall stability calculation results, depending on the different variables (slenderness, load eccentricities and their ratios, rigidity variations) under different load cases, are given in the paper. The stability capacity comparison between tapered and prismatic members is presented. Also the comparison with existent experimental researches’ results is provided in the paper.
Classification and Treatment of Glabella-Radix Deficiency in Primary Augmentation Rhinoplasty
Authors: Chang Ray-Hon , Chang Yean-Lu
Published: April 2020

Background

A systematic approach to treating glabella-radix deficiency is lacking, and the management of brow-tip aesthetic lines remains technically challenging.

Objectives

The authors describe implantation of a customized Gore-Tex prosthesis combined with primary augmentation rhinoplasty to address the glabella-radix deficiency.

Methods

Fifty Asian patients with glabella-radix deficiency who received implantation and primary augmentation rhinoplasty were retrospectively evaluated in an 8-year period. Patients were assigned to categories based on brow-tip contour lines and symmetry patterns, and implant dimensions were ascertained from the contour type and from simulated postoperative results.

Results

Eleven men and 39 women were included in the study; the mean patient age was 27.22 years, and mean follow-up was 22.8 months. Seven of the patients were assigned to the type I/Ia category, 24 to type II/IIa, and 19 to type III/IIIa. Forty-five patients were considered to have satisfactory surgical results, with curved, symmetric, and normally spaced brow-tip lines on front view and a smooth frontonasal transition on profile view. Complications occurred in 5 patients and included infection (1 patient), inadequate augmentation (2), and palpable margin folding of the Gore-Tex device (2).

Conclusions

Deformities of brow-tip contour lines coincide with glabella-radix deficiencies in terms of severity. Knowledge of the patterns of brow-tip lines, combined with postoperative image simulation, can help the surgeon design an appropriate glabella-radix prosthesis. When placed in conjunction with other augmentation rhinoplasty procedures, the glabella-radix implant yields sufficient, predictable nasal projection and a harmonious facial aesthetic.

Level of Evidence: 4
Extensive cytonuclear discordance in a crested newt from the Balkan Peninsula glacial refugium
Authors: Wielstra Ben , Arntzen Jan W
Published: April 2020

Integration of multilocus data and species distribution modelling into phylogeography allows mitochondrial DNA (mtDNA)-based scenarios to be fine-tuned. We address the question of whether extensive mtDNA substructuring in the crested newt Triturus macedonicus from the Balkan Peninsula is matched in the nuclear genome. We determine the intraspecific population structure based on 52 nuclear DNA markers and project a species distribution model on climate layers for the Last Glacial Maximum. We show that T. macedonicus accumulated nuclear DNA population structure in an area predicted to have been climatically stable during the Pleistocene, with four nuclear DNA groups in the western part of the species range. The distribution of these nuclear DNA groups shows little agreement with that of mtDNA structuring, which shows three highly distinct species-specific clades and a fourth one introgressed from another crested newt species. This cytonuclear discordance conveys that historical biogeographical scenarios based on mtDNA exclusively should be interpreted with caution. Our findings further highlight the important role the Balkan Peninsula has played in the evolution and preservation of European biodiversity.
Inflammatory Cutaneous Lesions in Inflammatory Bowel Disease Treated With Vedolizumab or Ustekinumab: An ECCO CONFER Multicentre Case Series
Authors: Phillips Frank M , Verstockt Bram , Sebastian Shaji , Ribaldone Davide , Vavricka Stephan , Katsanos Konstantinos , Slattery Eoin , de Suray Nicholas , Flores Cristina , Fries Walter , Vincenzi Francesca , Capoferro Elvira , Bachmann Oliver , Kopylov Uri
Published: April 2020

This was a multicentre case series supported by the European Crohn’s and Colitis Organisation [ECCO] and performed as part of the Collaborative Network of Exceptionally Rare case reports [CONFER] project. The aim was to report on whether cutaneous lesions associated with inflammatory bowel disease [IBD] and refractory to standard medical therapy including anti-tumour necrosis factors [anti-TNFs], would respond to the newer biologic agents ustekinumab [UST] or vedolizumab [VDZ]. This report includes 28 patients with cutaneous lesions from 14 centres, all of whom had failed immunomodulator and anti-TNF therapy. Metastatic Crohn’s disease [MCD] was diagnosed in 10 patients: UST led to remission in five cases and partial response in four cases, with a single report of VDZ inducing remission. All cases of MCD treated with UST responded after the first or second dose, and the median time for the five cases that attained remission was 5 months. Pyoderma gangrenosum [PG] was diagnosed in four cases: three of these attained remission with UST [median time to remission 4 months] and one case did not respond to VDZ. There were seven cases of erythema nodosum [EN]: UST led to remission in four cases and partial response in 1 case whilst VDZ had partial response in 2 cases and non-response in two cases. There were seven single cases of other inflammatory lesions. In summary, UST appears to be useful for different cutaneous lesions including MCD, PG, and EN, whereas VDZ does not appear to be useful for lesions that are independent of disease activity.
Local factors drive bacterial and microeukaryotic community composition in lake surface sediment collected across an altitudinal gradient
Authors: Pearman John K , Biessy Laura , Thomson-Laing Georgia , Waters Sean , Vandergoes Marcus J , Howarth Jamie D , Rees Andrew , Moy Chris , Pochon Xavier , Wood Susanna A
Published: April 2020

Lake surface sediments are dominated by microorganisms that play significant roles in biogeochemical cycling within lakes. There is limited knowledge on the relative importance of local environmental factors and altitude on bacterial and microeukaryotic community richness and composition in lake sediments. In the present study, surface sediment samples were collected from 40 lakes along an altitude gradient (2–1215 m). Microbial communities were characterized using 16S (bacteria) and 18S (microeukaryotes) rRNA gene metabarcoding. Bacterial and microeukaryotic richness were not correlated with altitude but instead to environmental variables (e.g. area of water in the catchment (bacteria: R = −0.43). For both bacteria and microeukaryotes, dissimilarity in the community structure had a higher correlation to combined environmental variables (without altitude) (bacteria: R = 0.53; microeukaryotes: R = 0.55) than altitude alone (bacteria: R = 0.34; microeukaryotes: R = 0.47). Sediment sulfur and productive grassland were important variables in determining the relative abundance of sulfate reducing bacteria. Nitrospira, was positively related to altitude but negatively to water column total organic carbon and the proportion of productive grassland in the catchment. Little overlap in amplicon sequence variants was shown amongst lakes. This has important considerations for management decisions, suggesting that to protect biodiversity, conservation of numerous lakes and lake types is required.
Ideas on royal power in the French Wars of Religion: the influence of René Choppin’s De Domanio Franciae (1574)
Authors: Nicholls Sophie
Published: April 2020

René Choppin (1537–1606) was one of the most cited French lawyers of the sixteenth century, and yet his contribution to intellectual history has gone curiously unexamined. This article considers the reception of his most important work, De Domanio Franciae (1574), in the political thought of the 1570s and early 1580s. It shows that Choppin was particularly influential in two key areas: the question of the inalienability of the French domain, and the role of the Paris parlement in guarding the laws of the country. It also assesses the question of his membership of the Holy League and thereby seeks to establish and clarify the complex nature of the position of Choppin’s works within the broader context of conceptions of royal power in this era.
Sprouty1 Prevents Cellular Senescence Maintaining Proliferation and Differentiation Capacity of Human Adipose Stem/Progenitor Cells
Authors: Mandl Markus , Wagner Sonja A , Hatzmann Florian M , Ejaz Asim , Ritthammer Heike , Baumgarten Saphira , Viertler Hans P , Springer Jochen , Zwierzina Marit E , Mattesich Monika , Brucker Camille , Waldegger Petra , Pierer Gerhard , Zwerschke Werner
Published: April 2020

The role of Ras-Mitogen-activated protein kinase (MAPK) signaling in cellular aging is not precisely understood. Recently, we identified Sprouty1 (SPRY1) as a weight-loss target gene in human adipose stem/progenitor cells (ASCs) and showed that Sprouty1 is important for proper regulation of adipogenesis. In the present study, we show that loss-of-function of Sprouty1 by CRISPR/Cas9-mediated genome editing in human ASCs leads to hyper-activation of MAPK signaling and a senescence phenotype. Sprouty1 knockout ASCs undergo an irreversible cell cycle arrest, become enlarged and stain positive for senescence-associated β-galactosidase. Sprouty1 down-regulation leads to DNA double strand breaks, a considerably increased number of senescence-associated heterochromatin foci and induction of p53 and p21Cip1. In addition, we detect an increase of hypo-phosphorylated Retinoblastoma (Rb) protein in SPRY1 knockout ASCs. p16Ink4A is not induced. Moreover, we show that Sprouty1 knockout leads to induction of a senescence-associated secretory phenotype as indicated by the activation of the transcription factors NFκB and C/EBPβ and a significant increase in mRNA expression and secretion of interleukin-8 (IL-8) and CXCL1/GROα. Finally, we demonstrate that adipogenesis is abrogated in senescent SPRY1 knockout ASCs. In conclusion, this study reveals a novel mechanism showing the importance of Sprouty1 for the prevention of senescence and the maintenance of the proliferation and differentiation capacity of human ASCs.
Metabolic flux analysis of the neural cell glycocalyx reveals differential utilization of monosaccharides
Authors: Wong Maurice , Xu Gege , Barboza Mariana , Maezawa Izumi , Jin Lee-Way , Zivkovic Angela , Lebrilla Carlito B
Published: April 2020

Saccharides in our diet are major sources of carbon for the formation of biomass such as proteins, lipids, nucleic acids and glycans. Among the dietary monosaccharides, glucose occupies a central role in metabolism, but human blood contains regulated levels of other monosaccharides as well. Their influence on metabolism and how they are utilized have not been explored thoroughly. Applying metabolic flux analysis on glycan synthesis can reveal the pathways that supply glycosylation precursors and provide a snapshot of the metabolic state of the cell. In this study, we traced the incorporation of six 13C uniformly labeled monosaccharides in the N-glycans, O-glycans and glycosphingolipids of both pluripotent and neural NTERA-2 cells. We gathered detailed isotopologue data for hundreds of glycoconjugates using mass spectrometry methods. The contributions of de novo synthesis and direct incorporation pathways for glucose, mannose, fructose, galactose, N-acetylglucosamine and fucose were determined based on their isotope incorporation. Co-feeding studies revealed that fructose incorporation is drastically decreased by the presence of glucose, while mannose and galactose were much less affected. Furthermore, increased sialylation slowed down the turnover of glycans, but fucosylation attenuated this effect. Our results demonstrated that exogenous monosaccharide utilization can vary markedly depending on the cell differentiation state and monosaccharide availability, and that the incorporation of carbons can also differ among different glycan structures. We contend that the analysis of metabolic isotope labeling of glycans can yield new insights about cell metabolism.
Social Determinants Associated with Pediatric Burn Injury: A Population-Based, Case–Control Study
Authors: Padalko Adam , Gawaziuk Justin , Chateau Dan , Sareen Jitender , Logsetty Sarvesh
Published: April 2020

Social determinants of health (SDoH) influence risk of injury. We conducted a population-based, case–control study to identify which social determinants influence burn injury in children. Children (≤16 years of age) admitted to a Canadian regional burn center between January 1, 1999 and March 30, 2017 were matched based on age, sex, and geographic location 1:5 with an uninjured control cohort from the general population. Population-level administrative data describing the SDoH at the Manitoba Center for Health Policy (MCHP) were compared between the cohorts. Specific SDoH were chosen based on a published systematic review conducted by the research team. In the final multivariable model, children from a low-income household odds ratio (OR) (95% confidence interval) 1.97 (1.46, 2.65), in care 1.57 (1.11, 2.21), from a family that received income assistance 1.71 (1.33, 2.19) and born to a teen mother 1.43 (1.13, 1.81) were significantly associated with an increased risk of pediatric burn injury. This study identified SDoH that are associated with an increased risk of burn injury. This case–control study supports the finding that children from a low-income household, children in care, from a family that received income assistance, and children born to a teen mother are at an elevated risk of burn injury. Identifying children at increased potential risk allows targeting of burn risk reduction and home safety programs.
Efficacy of Topical Antimicrobial Agents Against Bacterial Isolates From Burn Wounds
Authors: Nethery William , Warner Petra , Durkee Paula , Dwyer Angela , Zembrodt Jacquelyn , Fowler Laura
Published: April 2020

Topically applied antimicrobials are key to the prevention of infection and mortality in the acute burn population. The purpose of this study was to determine the in vitro effectiveness of commercially available topical antimicrobials, as well as topical preparations that were compounded in our burn care institution. One-hundred twenty microorganisms were tested against these topical antimicrobials and in vitro effectiveness was observed. Results showed that compounded preparations of 1:1:1 + Double Antibiotic (1 part bacitracin: 1 part silver sulfadiazine: 100,000 units/g nystatin + 5 mg/g neomycin sulfate + 500 units/g polymyxin B) and 3:1 + Double Antibiotic (3 part bacitracin: 1 part silver sulfadiazine + 5mg/g neomycin sulfate + 500 units/g polymyxin B) were effective against 100% of the isolates tested. Other topical agents showed moderate effectiveness, thus demonstrating the need for multiple topical agents to reach a broad spectrum of microorganisms. However, the development of topical antimicrobial resistance needs further study.
Magnetic-field evolution with large-scale velocity circulation in a neutron-star crust
Authors: Kojima Yasufumi , Suzuki Kazuki
Published: April 2020

We examine the effects of plastic flow that appear in a neutron-star crust when a magnetic stress exceeds the threshold. The dynamics involved are described using the Navier–Stokes equation comprising the viscous-flow term, and the velocity fields for the global circulation are determined using quasi-stationary approximation. We simulate the magnetic-field evolution by taking into consideration the Hall drift, Ohmic dissipation, and fluid motion induced by the Lorentz force. The decrease in the magnetic energy is enhanced, as the energy converts to the bulk motion energy and heat. It is found that the bulk velocity induced by the Lorentz force has a significant influence in the low-viscosity and strong-magnetic-field regimes. This effect is crucial near magnetar surfaces.
A census of young stellar population associated with the Herbig Be star HD 200775
Authors: Saha Piyali , Gopinathan Maheswar , Kamath Umanath , Lee Chang Won , Puravankara Manoj , Mathew Blesson , Sharma Ekta
Published: April 2020

The region surrounding the well-known reflection nebula, NGC 7023, illuminated by a Herbig Be star, HD 200775, located in the dark cloud L1174 is studied in this work. Based on the distances and proper motion values from Gaia DR2 of 20 previously known young stellar object (YSO) candidates, we obtained a distance of 335 ± 11 pc to the cloud complex L1172/1174. Using polarization measurements of the stars projected on the cloud complex, we show additional evidence for the cloud to be at ∼335 pc distance. Using this distance and proper motion values of the YSO candidates, we searched for additional comoving sources in the vicinity of HD 200775 and found 20 new sources, which show low infrared excess emission and are of age ∼1 Myr. Among these, 10 YSO candidates and 4 newly identified comoving sources are found to show X-ray emission. Three of the four new sources for which we have obtained optical spectra show H α in emission. About 80 per cent of the total sources are found within ∼1 pc distance from HD 200775. Spatial correlation of some of the YSO candidates with the Herschel dust column density peaks suggests that star formation is still active in the region and may have been triggered by HD 200775.
MicroRNA-93 acts as an “anti-inflammatory tumor suppressor” in glioblastoma
Authors: Hübner Max , Moellhoff Nicholas , Effinger David , Hinske Christian Ludwig , Hirschberger Simon , Wu Tingting , Müller Martin Bernhard , Strauß Gabriele , Kreth Friedrich-Wilhelm , Kreth Simone
Published: April 2020

Background

Inflammation is an important driver of malignant glioma disease. Inflammatory mediators are not only produced by immune cells in the tumor microenvironment, but also by glioblastoma (GBM) cells themselves creating a mutually reinforcing loop. We here aimed at identifying an “anti-inflammatory switch” that allows to dampen inflammation in GBM.

Methods

We used human GBM specimens, primary cultures, and cell lines. The response of GBM cells toward inflammatory stimuli was tested by incubation with supernatant of stimulated human immune cells. Expression levels were measured by whole transcriptome microarrays and qRT-PCR, and protein was quantified by LUMINEX and SDS-PAGE. MicroRNA binding to 3′UTRs was analyzed by luciferase assays. Proliferation rates were determined by flow cytometry, and invasion and angiogenesis were studied using migration and endothelial tube formation assays.

Results

We demonstrated GBM cells to secrete high amounts of proinflammatory mediators in an inflammatory microenvironment. We found miR-93 as a potential “anti-inflammatory tumor suppressor” dramatically downregulated in GBM. Concordantly, cytokine secretion dropped after miR-93 re-expression. Transfection of miR-93 in GBM cells led to down-regulation of hubs of the inflammatory networks, namely, HIF-1α and MAP3K2 as well as IL-6, G-CSF, IL-8, LIF, IL-1β, COX2, and CXCL5. We showed only COX2 and CXCL5 to be indirectly regulated by miR-93 while all other genes are true targets. Phenotypically, re-expression of miR-93 in GBM cells substantially suppressed proliferation, migration, and angiogenesis.

Conclusions

Alleviating GBM-derived inflammation by re-expression of miR-93 may be a powerful tool to mitigate these tumors’ aggressiveness and holds promise for new clinical approaches.
Evaluation of neurapheresis therapy in vitro: a novel approach for the treatment of leptomeningeal metastases
Authors: Ejikeme Tiffany , de Castro George C , Ripple Katelyn , Chen Yutong , Giamberardino Charles , Bartuska Andrew , Smilnak Gordon , Marius Choiselle , Boua Jane-Valeriane , Chongsathidkiet Pakawat , Hodges Sarah , Pagadala Promila , Verbick Laura Zitella , McCabe Aaron R , Lad Shivanand P
Published: April 2020

Background

Leptomeningeal metastases (LM), late-stage cancer when malignant cells migrate to the subarachnoid space (SAS), have an extremely poor prognosis. Current treatment regimens fall short in effectively reducing SAS tumor burden. Neurapheresis therapy is a novel approach employing filtration and enhanced circulation of the cerebrospinal fluid (CSF). Here, we examine the in vitro use of neurapheresis therapy as a novel, adjunctive treatment option for LM by filtering cells and augmenting the distribution of drugs that may have the potential to enhance the current clinical approach.

Methods

Clinically relevant concentrations of VX2 carcinoma cells were suspended in artificial CSF. The neurapheresis system’s ability to clear VX2 carcinoma cells was tested with and without the chemotherapeutic presence (methotrexate [MTX]). The VX2 cell concentration following each filtration cycle and the number of cycles required to reach the limit of detection were calculated. The ability of neurapheresis therapy to circulate, distribute, and maintain therapeutic levels of MTX was assessed using a cranial–spinal model of the SAS. The distribution of a 6 mg dose was monitored for 48 h. An MTX-specific ELISA measured drug concentration at ventricular, cervical, and lumbar sites in the model over time.

Results

In vitro filtration of VX2 cancer cells with neurapheresis therapy alone resulted in a 2.3-log reduction in cancer cell concentration in 7.5 h and a 2.4-log reduction in live-cancer cell concentration in 7.5 h when used with MTX. Cranial–spinal model experiments demonstrated the ability of neurapheresis therapy to enhance the circulation of MTX in CSF along the neuraxis.

Conclusion

Neurapheresis has the potential to act as an adjunct therapy for LM patients and significantly improve the standard of care.
Efficacy and Safety of Peripherally Acting Mu-Opioid Receptor Antagonists for the Treatment of Opioid-Induced Constipation: A Bayesian Network Meta-analysis
Authors: Ouyang Rong , Li Zhongzhuan , Huang Shijiang , Liu Jun , Huang Jiean
Published: April 2020

Objective

To assess the efficacy and safety of peripherally acting mu-opioid receptor antagonists (PAMORAs) for the treatment of opioid-induced constipation (OIC).

Methods

Randomized controlled trials (RCTs) were searched for OIC therapy comparing PAMORAs with placebo. Both a pairwise and network meta-analysis were performed. The surface under the cumulative ranking area (SUCRA) was used to determine the efficacy and safety of OIC treatment using different PAMORAs.

Results

The primary target outcome was a response that achieves an average of three or more bowel movements (BMs) per week. In the network meta-analysis, four PAMORAs (naldemedine, naloxone, methylnaltrexone, and alvimopan) showed a better BM response than the placebo. Naldemedine was ranked first (odds ratio [OR] = 2.8, 95% credible interval [CrI] = 2–4.5, SUCRA = 89.42%), followed by naloxone (OR = 2.9, 95% CrI = 1.6–5.3, SUCRA = 87.44%), alvimopan (OR = 2.2, 95% CrI = 1.3–3.5, SUCRA = 68.02%), and methylnaltrexone (OR = 1.7, 95% CrI = 1.0–2.8, SUCRA = 46.09%). There were no significant differences in safety found between the PAMORAs and the placebo.

Conclusions

We found that PAMORAs are effective and can be safely used for the treatment of OIC. In network meta-analysis, naldemedine and naloxone appear to be the most effective PAMORAs for the treatment of OIC.
Can Strong Creditors Inhibit Entrepreneurial Activity?
Authors: Ersahin Nuri , Irani Rustom M , Waldock Katherine
Published: April 2020

We examine entrepreneurial activity following the staggered adoption of modern-day fraudulent transfer laws in the United States. These laws strengthen unsecured creditors’ rights and are particularly important for entrepreneurs whose personal assets commingle with the firm’s. Using administrative data from the U.S. Census Bureau, we document declines in startup entry—particularly among riskier entrants—and closures of existing firms after these laws pass. Firm financial data shows that entrepreneurs lower leverage by reducing demand for unsecured credit. Our results suggest that strong creditor protections can limit entrepreneurs’ appetite for risk, which may reduce churning along the extensive margin among the smallest firms in the economy.
Leukocyte toll-like receptor expression in pathergy positive and negative Behçet’s disease patients
Authors: van der Houwen Tim B , Dik Willem A , Goeijenbier Marco , Hayat Manizhah , Nagtzaam Nicole M A , van Hagen Martin , van Laar Jan A M
Published: April 2020

Objectives

To investigate whether the auto-inflammatory nature and the pathergic reaction in Behçet’s disease (BD) are driven by a disturbed toll-like receptor (TLR) response.

Methods

We compared both TLR expression by flow-cytometry and TLR response by stimulation assay in 18 BD patients (both pathergy positive and pathergy negative) with 15 healthy controls.

Results

Expression of TLR1 and 2 was significantly elevated in B-lymphocytes of BD patients compared with healthy controls. TLR1, 2 and 4 were significantly more highly expressed in both CD4+ and CD8+ T-lymphocytes of BD patients. Granulocytes of BD patients displayed significantly higher expression of TLR1, 2, 4 and 6. TLR2, 4 and 5 expression was significantly increased on classical monocytes of BD patients. Intermediate monocytes of BD patients showed an increase in expression of TLR2. Furthermore, TLR2 and 5 were significantly more highly expressed in non-classical monocytes of BD patients. In pathergy positive patients, TLR5 was even more highly expressed compared with pathergy negative patients on B- and T-lymphocytes and granulocytes. Furthermore, TLR2 and 5 showed an elevated TNF-α response to stimulation with their cognate ligands.

Conclusion

Immune cells of BD patients overexpress TLR1, 2, 4, 5 and 6. Furthermore, after stimulation of TLR2 and 5, BD patients demonstrate a more potent TNF-α response. Although this is a small cohort, in the pathergy positive patients, TLR5 expression is even further augmented, suggesting that a microbial (flagellin) or damage (HMGB1) associated signal may trigger the exaggerated immune response that is characteristic for the pathergy phenomenon in BD. In conclusion, these results point to an exaggerated TLR response in the auto-inflammatory nature of BD.
The Dynamics of Pseudophosphatase MK‐STYX and HDAC6 Ubiquitination
Authors: Gergel Emma , Hinton Shantá
Published: April 2020

MK‐STYX [mitogen‐activated protein kinase phospho‐serine/threonine/tyrosine binding protein] is a pseudophosphatase and a member of the MAP kinase phosphatase family. Due to the absence of cysteine and histidine residues in the signature active site motif (HCX5R), MK‐STYX is catalytically inactive. Even so, it maintains the ability to bind phosphorylated residues. MK‐STYX is an important molecule in various signaling pathways, including the stress response pathway. Our previous research showed that the expression of MK‐STYX decreases stress granules [SG], which are aggregates of untranslated mRNA and misfolded proteins caused by cellular stress. However, the molecular mechanism by which MK‐STYX decreases SG remains elusive. Histone deacetylase isoform 6 (HDAC6) serves as a major component of SG. Therefore, we investigated whether MK‐STYX affects the dynamics of HDAC6. Our findings showed that MK‐STYX alters the subcellular localization of HDC6, which became nuclear, and decreased and altered the location of HDAC6‐aggregates. Because HDAC6 contains a ubiquitin binding domain, we investigated whether MK‐STYX affects the ubiquitination of HDAC6 and/or the ubiquitin proteasome system. Ubiquitin assays in stressed and unstressed cells showed that ubiquitinated proteins increased in the presence of MK‐STYX. Immunoprecipitation of HDAC6 and ubiquitin assays show that HDAC6‐ubiquitin interactions decreased in the presence of MK‐STYX, when HEK‐293 cells were exposed to MG132, whereas HDAC6‐ubiquitin interaction increased in cells expressing the active mutant of MK‐STYX (MK‐STYX(active)), which dephosphorylates phosphorylated residues. Overall, our research suggests that MK‐STYX affects ubiquitination; however, further studies are important to determine whether the effects of MK‐STYX on HDAC6 are linked to the decrease in stress granules.

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Department of Biology, Integrated Science Center, William and Mary, Williamsburg, VA 23187
Thermal Tolerance and Metabolism of Archocentrus nigrofasciatus Acclimated to a Large Daily Temperature Fluctuation Reflect its Success as an Invasive Species
Authors: Cooper Cassidy Jean , Eme John
Published: April 2020

Fish exhibit thermal tolerance and metabolism correlated to recent thermal history, and more studies should examine species’ responses to large fluctuations in daily temperatures. We compared thermal tolerance and metabolic responses between fish acclimated to constant temperatures and a large, daily thermal cycle of 10°C. Black Convict cichlid (Archocentrus nigrofasciatus) is a freshwater teleost native to Central America, with non‐native populations established in numerous locations. Black Convict cichlid were acclimated for two weeks to constant 20°C or 30°C, or a daily cycle of 20–30°C (“cycling group”, ~0900–1500 hrs). Following acclimation, routine metabolism (oxygen consumption, Mo2) and Critical thermal maxima/minima (CTmax/CTmin) were measured. Critical thermal limits were compared via ANOVA, with the cycling group sampled from both the daily minimum at 20°C (0900 hrs) and daily maximum at 30°C (1600 hrs). CTmax (0.3°C per degree of acclimation) and CTmin (0.4 °C per degree of acclimation) increased with acclimation. CTmax for the cycling group were 0.7°C higher when sampled from the maximum 30°C (39.3°C) of the daily cycle compared to 20°C (38.6°C). CTmin values for the cycling group were 2.2°C higher when sampled from the maximum 30°C (14.6°C) of the daily cycle compared to 20°C (12.4°C). Mo2 was measured acutely at 20°C and 30°C for each acclimation group, with the cycling group sampled from the daily minimum at 20°C (0900 hrs) and daily maximum at 30°C (1600 hrs). ANOVA showed that mass‐specific Mo2 decreased with increasing acclimation temperature for fish measured acutely at 30°C, where fish acclimated to 20°C (Mo2 = 0.329 mg/h/g) demonstrated an 84% higher Mo2 than fish acclimated to 30°C (Mo2 = 0.178 mg/h/g). Mass‐specific Mo2 also decreased with increasing acclimation temperature for fish measured acutely at 20°C, where fish acclimated to 20°C (Mo2 = 0.170 mg/h/g) demonstrated a 139% higher Mo2 than fish acclimated to 30°C (Mo2 = 0.071 mg/h/g). Mo2 was measured continually across the 24h daily thermal acclimation cycle of 20 – 30°C for all groups. Total oxygen consumption across the 24h cycle was highest for the constant 30°C group naively exposed to the cycle and lowest for the cycling group. Black Convict cichlid retains more upper thermal tolerance than lower thermal tolerance with altered thermal acclimation, and this hardy species shows metabolic compensation following high temperature acclimation (30°C) and large, daily cycling temperature acclimation (20 – 30°C). These aspects of fish thermal physiology phenotypes are reflective of a successful invasive fish species that may respond more robustly to impacts from anthropogenic climate change.

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Funding was provided through startup funds to JE from CSUSM.
Comparison of Transcriptomic Analysis between IDH1 Mutant and Wild‐type of Lower Grade Glioma
Authors: Lee MinWook , Jin Hoeyoung , Kim Suwan , Ji SeonYeong , Song SeokJung , Koh DooHyun , Choi JoungWan , Park JeongMan , Lee YunGyeon , Jo GaeHoon , Kim JongIl , Sim JeongMin , Ahn JuWon , Park YoungJoon , Kwack KyuBum
Published: April 2020

Among glioma patients, the existence of isocitrate dehydrogenase (IDH) 1 mutation is critical in their treatment and prognosis. However, effector genes specifically affected by IDH1 mutation are not identified yet, nor their biological mechanisms. Here, we show a few candidate genes selected by informatics methods, and suggest that inflammasome related CASP‐1, and ‐4 as the effector genes of glioma and future possibility of drug relocations. According to Cox regression analysis, 23, 78 genes were confirmed in the groups of protective genes in IDH1 mutant type and wild type, and 68, 170 genes in risk groups in mutant and wild type each. Interestingly, there were only two overlaps between the mutation group and wild type group within the risk factors, and none within the protective factors. These indicate that the pathophysiological mechanisms directed by the IDH1 mutant type and wild type in glioma are different. The results of Cox regression and GO term enrichment showed that many of the pathways in IDH1 wild type risk group are related to inflammation response, which are known to be pathologic in many different types of cancers. Among the genes related to the pathways, we chose CASP‐1 and ‐4, which are involved in inflammasome functions, and were able to find that high expression of the genes are related with the low survival of the patients, according to the Kaplan‐Meier curves. In conclusion, this research suggests new possibilities of treatment targeted to the genes mentioned above, such as drug relocations.

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This study was supported by grants of Basic Research Project in Science and Engineering, funded by the Ministry of Science, Technology and Information, Republic of Korea (Grant no. 2019R1F1A1054920) and of the University Innovation Support Project (UISP) through the National Research Foundation (NRF) funded by MOE.
Early Hepatic Gene Expression Profile of Lipid Metabolism of Mice on High Fat Diet after Treatment with Anti‐Obesity Drugs
Authors: Rizk Nasser M. , Saleh Amina , Elsayegh Dina , Algamal Abdelrahman
Published: April 2020

Obesity is a multifactorial disorder of global scale. The liver plays a vital role in fat metabolism. Disorder of hepatic fat metabolism is associated with obesity and fatty liver disease. This study aimed to detect the effects of anti‐obesity drugs (sulforaphane; SFN and leptin) on hepatic gene expression of fat metabolism in mice that were fed HFD during an early time of DIO.

Thirty‐two wild type (WT) ten‐week‐old CD1 male mice were fed high fat diet for four weeks in order to induce diet‐induced obesity (DIO). The mice were treated with a vehicle, or SFN for one week and then each group is treated with leptin or saline for 24 hours. Four groups of treatment were obtained; control group (vehicle + saline), group 2 (vehicle + leptin), group 3 (SFN + saline), and group 4 (SFN + leptin). Body weight and food intake were monitored during the treatment period. Following the treatments, liver tissue was collected, and total RNA was extracted to assess the expression of 84 genes involved in hepatic fat metabolism using RT‐PCR profiler array technique.

Leptin treatment upregulated the genes involved in fatty acid beta‐oxidation (Acsbg2, Acsm4) and fatty acyl‐CoA biosynthesis (Acot6, Acsl6), and down‐regulated the fatty acid transport gene (Slc27a2). SFN upregulated acyl‐CoA hydrolase (Acot3) and long chain fatty acid activation for lipids synthesis and beta‐oxidation (Acsl1). Leptin + SFN upregulated fatty acid beta‐oxidation‐related genes (Acad11, Acam) and acyl‐CoA hydrolases (Acot3, Acot7), and downregulated fatty acid elongation gene, Acot2. As a result, treatment with both SFN and leptin has a more profound effect in ameliorating the pathways involved in hepatic lipogenesis and TG accumulation and body weight gain than other types of intervention.

We conclude that early intervention of obesity pathogenesis could ameliorate the metabolic changes of fat metabolism in the liver, as observed in mice on HFD in response to SFN anti‐obesity treatment.

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This publication was made possible by NPRP Grant No. 9‐351‐3‐075 from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors. Qatar university grant QUST‐1‐CHS‐2019‐3
Heterogeneity in Insulin‐Stimulated Glucose Uptake Among Different Muscle Groups in People
Authors: Koh Han-Chow E. , van Vliet Stephan , Meyer Gretchen A. , Laforest Richard , Gropler Robert J. , Klein Samuel , Mittendorfer Bettina
Published: April 2020

Insulin‐stimulated glucose uptake in skeletal muscles is the major mechanism for postprandial glucose disposal. Insulin‐stimulated glucose uptake is greater in type I than in type II muscles in rats. The cellular capacity for glucose uptake and disposal (insulin receptor, GLUT4, hexokinase, and glycogen synthase expression) is also greater in isolated human type I compared with type II fibers. The goal of the present study was to test the hypothesis that insulin‐stimulated glucose uptake rate varies among different muscle groups and is greater in trunk (erector spinae, rectus abdominis, obliques) than leg (quadriceps, hamstrings) muscles and greater in the hamstrings than the quadriceps because trunk muscles generally have a greater percentage of type I fibers than leg muscles and the hamstrings have a greater percentage of type I fibers than quadriceps muscles. We determined abdominal and thigh muscle glucose uptake rates in 10 healthy lean women (age: 43±13 years, BMI: 23±2 kg/m2; mean±SD) by using a hyperinsulinemic‐euglycemic clamp procedure in conjunction with dynamic positron emission tomography imaging after bolus injection of 18F‐fluorodeoxyglucose. In addition, [6,6‐2H2]glucose was infused to determine whole‐body glucose disposal rate per kg fat‐free mass, which is commonly used as an index of muscle glucose uptake, and a muscle biopsy from the vastus lateralis was obtained to determine myofiber composition. Glucose uptake rate in the erector spinae (128±30 μmol/kg/min) was nearly twice as great as in the rectus abdominis (66±14 μmol/kg/min; P<0.01) and approximately 50% greater than in the obliques (88±23 μmol/kg/min; P<0.05). Quadriceps and hamstring glucose uptake rates were not different from each other (85±42 and 91±37 μmol/kg/min, respectively; P>0.05) and not different from glucose uptake rates in the rectus abdominis and obliques but less than in the erector spinae (P<0.05). No significant correlation between fiber type composition and muscle glucose uptake rate in the quadriceps was detected. Whole body insulin stimulated glucose disposal rate was 93±28 μmol/kg fat‐free mass/min. We conclude that: i) insulin‐stimulated muscle glucose uptake is heterogeneous among muscle groups, ii) it is unlikely that differences in fiber type composition among muscles are responsible for the heterogeneity in glucose uptake rates, and iii) whole‐body glucose disposal rate per kg fat‐free mass does not accurately reflect glucose uptake rates in individual muscles.

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NIH DK115400, DK56341 (Nutrition Obesity Research Center), DK020579 (Diabetes Research Center), and UL1TR000448 (Clinical Translational Science Award), and ADA 1‐18‐ICTS‐119.