bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Performance of Flamelet Generated Manifold Model With That of Finite Rate Combustion Model for Hydrogen Blended Flames
Authors: Shrivastava Sourabh , Verma Ishan , Yadav Rakesh , Nakod Pravin , Orsino Stefano
Published: September 2021

International Air Transport Association (IATA) sets a 50% reduction in 2005 CO2 emissions levels by 2050, with no increase in net emissions after 2020 [1]. The association also expects the global aviation demand to double to 8.2 billion passengers per year by 2037. These issues have prompted the aviation industry to focus intensely on adopting sustainable aviation fuels (SAF). Further, reduction in CO2 emission is also an active area of research for land-based power generation gas turbine engines. And fuels with high hydrogen content or hydrogen blends are regarded as an essential part of future power plants. Therefore, clean hydrogen and other hydrogen-based fuels are expected to play a critical role in reducing greenhouse gas emissions in the future. However, the massive difference in hydrogen’s physical properties compared to hydrocarbon fuels, ignition, and flashback issues are some of the major concerns, and a detailed understanding of hydrogen combustion characteristics for the conditions at which gas turbines operate is needed. Numerical combustion analyses can play an essential role in exploring the combustion performance of hydrogen as an alternative gas turbine engine fuel. While several combustion models are available in the literature, two of the most preferred models in recent times are the flamelet generated manifold (FGM) model and finite-rate (FR) combustion model. FGM combustion model is computationally economical compared to the detailed/reduced chemistry modeling using a finite-rate combustion model. Therefore, this paper aims to understand the performance of the FGM model compared to detailed chemistry modeling of turbulent flames with different levels of hydrogen blended fuels. In this paper, a detailed comparison of different combustion characteristics like temperature, species, flow, and NOx distribution using FGM and finite rate combustion models is presented for three flame configurations, including the DLR Stuttgart jet flame [2], Bluff body stabilized Sydney HM1 flame [3] and dry-low-NOx hydrogen micro-mix combustion chamber [4]. One of the FGM model’s essential parameters is to select a suitable definition of the reaction progress variable. The reaction progress variable should monotonically increase from the unburnt region to the burnt region. The definition is first studied using a 1D premixed flame with different blend ratios and then used for the actual cases. 2D/3D simulations for the identified flames are performed using FGM and finite rate combustion models. Numerical results from both these models are compared with the available experimental data to understand FGM’s applicability. The results show that the FGM model performs reasonably well for pure hydrogen and hydrogen blended flames.
Influence of Yawed Wind Flow on the Blade Forces/Bending Moments and Blade Elastic Torsion for an Axial-Flow Wind Turbine
Authors: Ahmadi Mohammad H. B. , Yang Zhiyin
Published: September 2021

Effects of yawed incoming flow on wind turbine blades forces and root bending moments (RBMs) are not fully understood. To advance our current understanding, numerical studies of a small-scale three-bladed horizontal axis wind turbine at TSR = 6.7 with yaw angles of zero and 45° have been carried out to examine the variations of blade and rotor loading due to the yawed incoming flow. An approach combining Large Eddy Simulation (LES) with Actuator Line Modelling (ALM) has been employed in the present study. The predicted phase-averaged blade forces reveal that the blade tangential force, in-plane RBM and power coefficient are much more sensitive to the upstream streamwise velocity variations and are much more strongly affected than the blade axial force, out-of-plane RBM and thrust coefficient. It also shows that for yawed incoming flows the blade axial force to the blade tangential force ratio fluctuates significantly during one rotor revolution, resulting in large variations of the blade elastic torsion and that the total blade force (magnitude and direction) undergoes a non-linear change in the circumferential and radial directions, which will likely lead to the reduction in the turbine operational life significantly, especially for long lightweight blades of large size wind turbines.
Modeling and Testing of a Novel Ultra-Low Temperature sCO2 Opposing Piston Expander
Authors: Schmitt Joshua , Nielson Jordan
Published: September 2021

Southwest Research Institute (SwRI) along with Thermal Tech Holdings (TTH) have modeled, built, and tested a piston expander for generating power from low temperature heat sources. The piston was developed with the goal of creating an engine that operates as a recuperated sCO2 Ericsson cycle. A cycle model based on fluid properties from REFPROP is applied for various hot and cold temperatures to demonstrate the potential of the novel expander to improve cycle efficiency. Cycle modeling results demonstrate the potential improvements in cycle efficiency when compared to the sCO2 Brayton cycle. Small-scale bench testing is used to validate the novel piston concept for achieving a sCO2 Ericsson cycle. The concept is scaled up to a full-sized, opposing piston cylinder that acts as an expander in the theoretical Ericsson cycle. Testing is performed on the full-scale piston cylinder for a variety of inlet temperatures and pressures. The full-scale tests are run continuously to track the transient effects. The results of the full-scale test are discussed. The expander piston cylinder test results show high temperatures at the outlet, better than the ideal sCO2 Brayton cycle, but less than an ideal recuperated sCO2 Ericsson cycle. Comparisons are made to demonstrate the projected cycle efficiency improvements over a sCO2 Brayton cycle.
Gas Turbine Based Fuel Cell Vehicle Charging Station
Authors: Ganiger Manjush , Pandey Maneesh , Wagh Rahul , Govindasamy Rakesh
Published: September 2021

Hydrogen as fuel for transportation sector is going to play a prominent role when it comes combating the climate change, as its only by-products are heat and water. Rapid surge in adoption rate for fuel cell vehicle (FCV) could be driven by improvements in fuel cell technology, as well as rise in number of Fuel Cell Vehicle Charging Station (FCVCS).

This paper explores how a gas turbine from the Baker Hughes™ portfolio can be used to create a circular economy model for hydrogen fueling stations. Solid Oxide Electrolyzer (SOE) and carbon capture unit are the two prime components that are integrated to the gas turbine. The SOE unit, powered by the gas turbine, generates hydrogen for refueling the FCVs and to use for itself as a blended fuel, bringing down the carbon footprint.

Proposed FCVCS solution can refuel about 250 FCVs in half a day of operation (50% power split). Economic analysis shows that the solution is lucrative with attractive return on investment. The solution is flexible to incorporate Power-to-X conversions. Modular nature of the solution makes it easy to implement in city limits as well as in remote locations, along the highways, where grid availability is a challenge.
Physical Modal for Acoustic Resonance Based on the Circular Cavity Structure in the Compressor
Authors: Fengtong Zhao , Jianfei Chen , Mingsui Yang , Yundong Sha , Xiaochi Luan
Published: September 2021

On the basis of the rectangular cavity plate model, the Parker resonance phenomenon is investigated by using the present calculation method, which verifies the effectiveness of the numerical calculation method adopted in the paper. Acoustic resonance occurs in the multistage compressor. The acoustic resonance frequency will be locked in a specific range which presents no variation in the rotating speed. The propagation status of the sound source of the acoustic resonance frequency should be from back to forward with a helical shape. The research method of the characteristics and mechanism of the acoustic resonance is proposed based on the annular cavity structure with the numerical simulation. The calculation models of the flow field and the sound field are established. The criterion of the sound resonating with the cavity and the characteristic condition when acoustic resonance occurred in the annular cavity structure is confirmed. The theoretical model of the acoustic resonance which is developed in the paper will be useful for the the three-dimensional model investigation into the acoustic resonance in the compressor, which can provide the better exhibition of the coupling relationship between the acoustic mode in the cavity and the vibration mode of the structure when the acoustic resonance occurs.
Constituent and Ply Level Understanding of Electrical Resistance in Si-Containing SiC/SiC Composites
Authors: El Rassi Joseph , Morscher Gregory N.
Published: September 2021

Electrical resistance, also known as direct current potential drop (DCPD), has been demonstrated as an enabling means to monitor damage evolution in SiC-based ceramic matrix composites. For laminate composites, it has become apparent that the location and orientation of SiC fibers, free Si and in some cases insertion of C rods can greatly affect the measured resistance. In addition, the nature of crack growth through the different plies which consist of different constituents will have different effects on the change in resistance. Therefore, both experimental and modeling approaches as to the resistance and change in resistance for different laminate architectures based on the nature of constituent content and orientation are needed to utilize and optimize electrical resistance as a health-monitoring technique. In this work, unidirectional and cross-ply laminate composites have been analyzed using a ply-based electrical model. Based on a ply-level circuit model, the change in resistance was modeled for damage development. It is believed that this can serve as a basis for tailoring the architecture/constituent content to create a “smarter” composite.
An azimuthal Fourier domain formulation of the Ffowcs Williams and Hawkings equation
Authors: Chen Zhibo , Towne Aaron
Published: September 2021

The acoustic field of high-speed turbulent jets is dominated by a small number of low-wavenumber azimuthal Fourier modes. Accordingly, it is of interest to directly obtain individual azimuthal modes of the acoustic field from simulation data or models of the jet near-field. To this end, we manipulate the Ffowcs Williams and Hawkings (FW–H) equation to obtain a new formulation that lives entirely in the azimuthal Fourier domain—it delivers individual azimuthal modes of the acoustic field as a function of the same azimuthal modes of the near-field FW–H source term or, upon linearization of the source terms, as a function of the same azimuthal modes of the near-field flow variables. As an added benefit, all surface integrals are converted into line integrals in the streamwise–radial plane. After verifying and validating our formulation using a monopole problem with an exact solution and large-eddy simulation data, respectively, we show how our method can be used to efficiently and naturally compute the acoustic field associated with resolvent modes of a Mach 1.5 jet, thus avoiding the need to compute the modes on a large computational domain to capture their acoustic radiation.
Association Between Inspiratory Muscle Function and Balance Ability in Older People: A Pooled Data Analysis Before and After Inspiratory Muscle Training
Authors: Ferraro Francesco V. , Gavin James P. , Wainwright Thomas W. , McConnell Alison K.
Published: September 2021

Inspiratory muscle training (IMT) improved balance ability and respiratory muscle function in healthy older adults. The current study is a retrospective analysis to explore the relationship between inspiratory muscle function, balance ability, and adaptation to IMT. All participants (total = 129; IMT = 60; age range = 65–85 years) performed inspiratory and balance assessments, including the mini-balance evaluation system test, maximal inspiratory pressure, and peak inspiratory flow tests. Baseline inspiratory muscle function was positively related to balance ability (p < .05), and IMT-induced improvements in inspiratory function (23.3% in maximal inspiratory pressure, 8.0% in peak inspiratory flow rate, 14.9% in maximal peak inspiratory power) were related to improvements in balance (10.6% in mini-balance evaluation system test), with the greatest improvements (17.0%) observed in the oldest participants (76–85 years old,p < .05). In conclusion, with or without IMT, positive associations between inspiratory function and balance ability exist, with greater improvements in inspiratory muscle function related to greater improvements in balance ability.
Serum amyloid A delivers retinol to intestinal myeloid cells to promote adaptive immunity
Authors: Bang Ye-Ji , Hu Zehan , Li Yun , Gattu Sureka , Ruhn Kelly A. , Raj Prithvi , Herz Joachim , Hooper Lora V.
Published: September 2021

SAAving vitamin A–mediated immunity

The vitamin A metabolite retinol is critical for B and T cell development and homing to the gut. Intestinal myeloid cells such as dendritic cells and macrophages take up retinol and process it into retinoic acid (RA), which in turn initiates RA-dependent gene expression programs in lymphocytes. Bang
et al
. identified LDL receptor-related protein 1 (LRP1) as a myeloid cell surface receptor for retinol. LRP1 binds retinol chaperoned by serum amyloid A (SAA) proteins, and SAA–retinol complexes are then endocytosed and metabolized by myeloid cells. Mice lacking either Saa or myeloid-specific Lrp1 exhibited profound impairments in vitamin A–mediated immunity. B and T cell trafficking to the intestine, immunoglobulin A production by B cells, and protection from enteric
Salmonella
Typhimurium infection were all diminished when either of these crucial players was missing. —STS
Reproductive innovations and pulsed rise in plant complexity
Authors: Leslie Andrew B. , Simpson Carl , Mander Luke
Published: September 2021

Morphological complexity is a notable feature of multicellular life, although whether it evolves gradually or in early bursts is unclear. Vascular plant reproductive structures, such as flowers, are familiar examples of complex morphology. In this study, we use a simple approach based on the number of part types to analyze changes in complexity over time. We find that reproductive complexity increased in two pulses separated by ~250 million years of stasis, including an initial rise in the Devonian with the radiation of vascular plants and a pronounced increase in the Late Cretaceous that reflects flowering plant diversification. These pulses are associated with innovations that increased functional diversity, suggesting that shifts in complexity are linked to changes in function regardless of whether they occur early or late in the history of vascular plants.
Chromosome-Level Genome Sequence of Aspergillus chevalieri M1, Isolated from Katsuobushi
Authors: Kadooka Chihiro , Mori Kazuki , Okutsu Kayu , Yoshizaki Yumiko , Takamine Kazunori , Tashiro Kosuke , Tamaki Hisanori , Futagami Taiki
Published: September 2021

In this study, we report the chromosome-level genome sequence of the osmophilic filamentous fungus
Aspergillus chevalieri
M1, which was isolated from a dried bonito, katsuobushi. This fungus plays a significant role in the fermentation and ripening process. Thus, elucidating the sequence data for this fungus will aid in subsequent genomic research on the fungi involved in katsuobushi production.
Complete Genome Sequence of Dickeya dadantii subsp.
dieffenbachiae
Strain S3-1, Isolated from a White-Flowered Calla Lily in Taiwan
Authors: Lee Yung-An , Chen Kuan-Pei
Published: September 2021

Erwinia chrysanthemi
S3-1 is a bacterial soft rot pathogen of the white-flowered calla lily. The complete genome sequence of the strain was determined and used to reclassify the strain as
Dickeya dadantii
subsp.
dieffenbachiae
. The sequence will be useful to study plant host-driven speciation in strains of
D. dadantii
.
Draft Genome Sequence of a Multidrug-Resistant Escherichia coli Sequence Type 1193 Pandemic Clone Isolated from Wastewater in Austria
Authors: Cabal Adriana , Peischl Nadine , Rab Gerhard , Stöger Anna , Springer Burkhard , Sucher Jasmin , Allerberger Franz , Ruppitsch Werner
Published: September 2021

Extraintestinal
Escherichia coli
sequence type 1193 (ST1193) is an important source of fluoroquinolone resistance, which has emerged in recent years. We report the first draft genome sequence and annotation of a multidrug-resistant
E. coli
ST1193 strain obtained from a wastewater treatment plant in Austria.
Shape of the OGTT glucose response curve: relationship with β-cell function and differences by sex, race, and BMI in adults with early type 2 diabetes treated with metformin
Authors: Utzschneider Kristina M , Younes Naji , Rasouli Neda , Barzilay Joshua I , Banerji Mary Ann , Cohen Robert M , Gonzalez Erica V , Ismail-Beigi Faramarz , Mather Kieren J , Raskin Philip , Wexler Deborah J , Lachin John M , Kahn Steven E
Published: September 2021

Introduction

The shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone.

Research design and methods

This is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed <10 years who underwent 2-hour 75 g OGTT at baseline as part of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Insulin sensitivity (homeostasis model of insulin sensitivity, HOMA2-S) and β-cell function (early, late, and total incremental insulin and C peptide responses adjusted for HOMA2-S) were calculated. Glucose curve shape was classified as monophasic, biphasic, or continuous rise.

Results

The monophasic profile was the most common (67.8% monophasic, 5.5% biphasic, 26.7% continuous rise). The monophasic subgroup was younger, more likely male and white, and had higher body mass index (BMI), while the continuous rise subgroup was more likely female and African American/black. HOMA2-S and fasting glucose did not differ among the subgroups. The biphasic subgroup had the highest early, late, and total insulin and C peptide responses (all p<0.05 vs monophasic and continuous rise). Compared with the monophasic subgroup, the continuous rise subgroup had similar early insulin (p=0.3) and C peptide (p=0.6) responses but lower late insulin (p<0.001) and total insulin (p=0.008) and C peptide (p<0.001) responses.

Conclusions

Based on the large multiethnic GRADE cohort, sex, race, age, and BMI were found to be important determinants of the shape of the glucose response curve. A pattern of a continuously rising glucose at 2 hours reflected reduced β-cell function and may portend increased glycemic failure rates.

Trial registration number

NCT01794143.
Incidence of ‘new-onset’ constipation and associated factors during lockdown due to the COVID-19 pandemic
Authors: Remes-Troche Jose Maria , Coss-Adame Enrique , Amieva-Balmori Mercedes , Velarde-Ruiz Velasco José Antonio , Gómez-Castaños Paulo César , Flores-Rendón Ricardo , Gómez-Escudero Octavio , Rodríguez-Leal María Celina , Durán-Rosas Cristina , Pinto-Gálvez Samanta Mayanin , Priego-Parra Bryan Adrián , Triana-Romero Arturo
Published: September 2021

Objective

A minimum of physical activity and low liquid intake are factors that have been associated with constipation. The health emergency brought on by the COVID-19 pandemic has resulted in adopting behaviour, such as sheltering-in-place (less mobility) and dietary changes, creating a scenario we believe to be an adequate model for examining the appearance of symptoms of constipation and its associated factors.

Design

A cross-sectional and descriptive study was conducted on an open population, applying an electronic survey (4 weeks after lockdown due to COVID-19 in Mexico) to evaluate demographic characteristics, physical activity, water and fibre intake, appearance of constipation symptoms (including stool consistency), and quality of life.

Results

Out of 678 subjects evaluated, 170 (25%, 95% CI: 21.7 to 28.4) developed symptoms of ‘new-onset’ constipation, with a significant decrease in the number of daily bowel movements (p<0.05) and stool consistency (p<0.05) during lockdown. Furthermore, in the ‘new-onset’ constipation population there was a higher proportion of subjects (79 (47%) of 170) who stopped exercising during the pandemic compared with the subjects who did not develop constipation symptoms (187 (37%) of 508, p=0.03, OR: 1.49, 95% CI: 1.0 to 2.1). The multivariate analysis (logistic regression) showed that female sex (p=0.001), water intake (p=0.039), and physical activity (p=0.012) were associated with ‘new-onset’ constipation.

Conclusions

In our study on an open population in Mexico, we found that one-fourth of the population developed ‘new-onset’ constipation symptoms during the lockdown imposed due to the COVID-19 pandemic. A reduction of physical activity and less water consumption were associated factors.
Route of oxytocin administration for preventing blood loss at caesarean section: a systematic review with meta-analysis
Authors: Torloni Maria Regina , Siaulys Monica , Riera Rachel , Martimbianco Ana Luiza Cabrera , Pacheco Rafael Leite , Latorraca Carolina de Oliveira Cruz , Widmer Mariana , Betran Ana Pilar
Published: September 2021

Objectives

Assess the effects of different routes of prophylactic oxytocin administration for preventing blood loss at caesarean section (CS).

Design

Systematic review and meta-analysis.

Methods

Medline, EMBASE, CINAHL, Cochrane Library, BVS, SciELO and Global Index Medicus were searched through 24 May 2020 for randomised controlled trials (RCTs) comparing different routes of prophylactic oxytocin administration during CS. Study selection, data extraction and quality assessment were conducted by two investigators independently. We pooled results in fixed effects meta-analyses and calculated average risk ratio (RR), mean difference (MD) and 95% CI. We used GRADE to assess the overall quality of evidence for each outcome.

Results

Three trials (180 women) were included in the review. All studies compared intramyometrial (IMY) versus intravenous oxytocin in women having prelabour CS. IMY compared with intravenous oxytocin administration may result in little or no difference in the incidence of postpartum haemorrhage (RR 0.14, 95% CI 0.01 to 2.70; N=100 participants; 1 RCT), hypotension (RR 1.00, 95% CI 0.29 to 3.45; N=40; 1 RCT), headache (RR 3.00, 95% CI 0.13 to 69.52; N=40; 1 RCT) or facial flushing (RR 0.50, 95% CI 0.05 to 5.08; N=40; 1 RCT); IMY oxytocin may reduce nausea/vomiting (RR 0.13, 95% CI 0.02 to 0.69; N=140; 2 RCTs). We are very uncertain about the effect IMY versus intravenous oxytocin on the need for additional uterotonics (RR 0.82; 95% CI 0.25 to 2.69; N=140; 2 RCTs). IMY oxytocin may reduce blood loss slightly (MD −57.40 mL, 95% CI −101.71 to −13.09; N=40; 1 RCT).

Conclusions

There is limited, low to very low certainty evidence on the effects of IMY versus intravenous oxytocin at CS for preventing blood loss. The evidence is insufficient to support choosing one route over another. More trials, including studies that assess intramuscular oxytocin administration, are needed on this relevant question.

PROSPERO registration number

CRD42020186797.
Effect of first-line antifungal treatment on ocular complication risk inCandidaor yeast blood stream infection
Authors: Hautala Nina , Köykkä Hannu , Siiskonen Mira , Saari Juho , Kauranen Jari , Hautala Timo
Published: September 2021

Objectives

Ocular candidiasis (OC) can complicateCandidabloodstream infection (BSI). Antifungal treatment improves the prognosis of patients with BSI, but the effects of choice and timing of first-line medication on OC risk are incompletely understood. We explored the early treatments, risk factors and ocular presentations inCandidaBSI.

Methods and analysis

All patients (n=304) withCandidaBSI during 2008–2017 at Oulu University Hospital were included. Those patients in whom clinical condition was appropriate for ocular examination (OE), including biomicroscopy (n=103), were carefully analysed by ophthalmologists. Criteria for patient selection were considered.Candidaand yeast species, antifungal medications, echocardiography, underlying diseases and clinical properties of the patients withCandidaBSI were analysed.

Results

Clinical condition in 103 patients had been considered appropriate for OE. OC was diagnosed in 33 of the 103 patients.Candida albicanswas the most common finding (88%) in OC. Patients in intensive care, alcohol-related conditions or poor prognosis were less frequently examined. Persistent candidemia increased the risk of OC. Chorioretinitis and endophthalmitis were diagnosed in 94% and 48% of the patients with OC, respectively. Any early antifungal treatment decreased the endophthalmitis risk. Echinocandin lowered the OC risk in those with central venous catheters (CVCs) or abdominal malignancy.

Conclusion

Critical condition of patients withCandidaBSI affects the selection and results of OE. OC was associated withC. albicansBSI especially among those with persistent candidemia, CVC or abdominal malignancy. Any early antifungal treatment reduced endophthalmitis risk. Early echinocandin treatment may reduce the risk of OC in selected patients.
An observational study of patient experiences with a direct-to-patient telehealth abortion model in Australia
Authors: Thompson Terri-ann , Seymour Jane W , Melville Catriona , Khan Zara , Mazza Danielle , Grossman Daniel
Published: September 2021

Background

While abortion care is widely legal in Australia, access to care is often poor. Many Australians must travel long distances or interstate to access abortion care, while others face stigma when seeking care. Telehealth-at-home medical abortion is a potential solution to these challenges. In this study, we compared the experience of accessing an abortion via telehealth-at-home to accessing care in-clinic.

Methods

Over a 20-month period, we surveyed patients who received medical abortion services at Marie Stopes Australia via the telehealth-at-home service or in-clinic. We conducted bivariate analyses to assess differences in reported acceptability and accessibility by delivery model.

Results

In total, 389 patients were included in the study: 216 who received medical abortion services in-clinic and 173 through the telehealth-at-home service. Telehealth-at-home and in-clinic patients reported similarly high levels of acceptability: satisfaction with the service (82% vs 82%), provider interaction (93% vs 84%), and recommending the service to a friend (73% vs 72%). Only 1% of telehealth-at-home patients reported that they would have preferred to be in the same room as the provider. While median time between discovering the pregnancy to first contact with a clinic was similar between groups, median time from first contact to taking the first abortion medication was 7 days longer for telehealth-at-home patients versus in-clinic patients (14 days (IQR 9–21) vs 7 days (IQR 4–14); p<0.01).

Conclusion

The telehealth-at-home medical abortion service has the potential to address some of the challenges with provision of abortion care in Australia.
Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity
Authors: Anfray Clément , Mainini Francesco , Digifico Elisabeth , Maeda Akihiro , Sironi Marina , Erreni Marco , Anselmo Achille , Ummarino Aldo , Gandoy Sara , Expósito Francisco , Redrado Miriam , Serrano Diego , Calvo Alfonso , Martens Marvin , Bravo Susana , Mantovani Alberto , Allavena Paola , Andón Fernando Torres
Published: September 2021

Background

Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments.

Methods

TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein–protein interaction analysis.

Results

Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4+ and CD8+ T cells, accompanied by a reduction of immunosuppressive CD206+ TAMs and FOXP3+/CD4+ T cells. The depletion of both CD4+ and CD8+ T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein–protein-interaction network analysis reveal the key activation of the STAT1 pathway.

Discussion

These findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic.
Simple and effective bacterial-based intratumoral cancer immunotherapy
Authors: Carroll Christina S E , Andrew Erin R , Malik Laeeq , Elliott Kathryn F , Brennan Moira , Meyer James , Hintze Alexander , Almonte Andrew A , Lappin Cassandra , MacPherson Philip , Schulte Klaus-Martin , Dahlstrom Jane E , Tamhane Rohit , Neeman Teresa , Herbert Elizabeth W , Orange Maurice , Yip Desmond , Allavena Rachel , Fahrer Aude M
Published: September 2021

Background

We describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients.

Methods

Efficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient.

Results

Significantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided.

Conclusion

Our data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.
Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor-infiltrating CD8T lymphocytes
Authors: Nishida Mikako , Yamashita Nahoko , Ogawa Taisaku , Koseki Keita , Warabi Eiji , Ohue Tomoyuki , Komatsu Masaaki , Matsushita Hirokazu , Kakimi Kazuhiro , Kawakami Eiryo , Shiroguchi Katsuyuki , Udono Heiichiro
Published: September 2021

Background

Metformin (Met) is the first-line treatment for type 2 diabetes mellitus and plays an effective role in treating various diseases, such as cardiovascular disease, neurodegenerative disease, cancer, and aging. However, the underlying mechanism of Met-dependent antitumor immunity remains to be elucidated.

Methods

MitoTEMPO, a scavenger of mitochondrial superoxide, abolished the antitumor effect of Met, but not antiprogrammed cell death (PD-1) antibody (Ab) treatment. Consequently, we studied the mechanism of the Met-induced antitumor effect. Expressions of glucose transporter (Glut)-1, mitochondrial reactive oxygen species (mtROS), interferon (IFN)-γ, Ki67, autophagy markers, activation markers for NF-E2-related factor 2 (Nrf2), and mammalian target of rapamaycin complex 1 (mTORC1) in CD8+ tumor-infiltrating T lymphocytes (CD8TILs) were examined by flow cytometry analysis. In addition, conditional knockout mice for Nrf2 and p62 were used to detect these markers, together with the monitoring of in vivo tumor growth. RNA sequencing was performed for CD8TILs and tumor cells. Melanoma cells containing an IFN-γ receptor (IFNγR) cytoplasmic domain deletion mutant was overexpressed and used for characterization of the metabolic profile of those tumor cells using a Seahorse Flux Analyzer.

Results

Met administration elevates mtROS and cell surface Glut-1, resulting in the production of IFN-γ in CD8TILs. mtROS activates Nrf2 in a glycolysis-dependent manner, inducing activation of autophagy, glutaminolysis, mTORC1, and p62/SQSTM1. mTORC1-dependent phosphorylation of p62 at serine 351 (p-p62(S351)) is also involved in activation of Nrf2. Conditional deletion of Nrf2 in CD8TILs abrogates mTORC1 activation and antitumor immunity by Met. In synergy with the effect of anti-PD-1 Ab, Met boosts CD8TIL proliferation and IFN-γ secretion, resulting in decreased glycolysis and oxidative phosphorylation in tumor cells. Consequently, Glut-1 is elevated in CD8TILs, together with the expansion of activated dendritic cells. Moreover, tumor cells lacking in IFNγR signaling abolish IFN-γ production and proliferation of CD8TILs.

Conclusions

We found that Met stimulates production of mtROS, which triggers Glut-1 elevation and Nrf2 activation in CD8TILs. Nrf2 activates mTORC1, whereas mTORC1 activates Nrf2 in a p-p62(S351)-dependent manner, thus creating a feedback loop that ensures CD8TILs’ proliferation. In combination with anti-PD-1 Ab, Met stimulates robust proliferation of CD8TILs and IFN-γ secretion, resulting in an IFN-γ-dependent reprogramming of the tumor microenvironment.
Effect of moderate potassium-elevating treatment in long QT syndrome: the TriQarr Potassium Study
Authors: Marstrand Peter , Almatlouh Kasim , Kanters Jørgen K , Graff Claus , Christensen Alex Hørby , Bundgaard Henning , Theilade Juliane
Published: September 2021

Background

In long QT syndrome (LQTS), beta blockers prevent arrhythmias. As a supplement, means to increase potassium has been suggested. We set to investigate the effect of moderate potassium elevation on cardiac repolarisation.

Methods

Patients with LQTS with a disease-causingKCNQ1orKCNH2variant were included. In addition to usual beta-blocker treatment, patients were prescribed (1) 50 mg spironolactone (low dose) or (2) 100 mg spironolactone and 3 g potassium chloride per day (high dose+). Electrocardiographic measures were obtained at baseline and after 7 days of treatment.

Results

Twenty patients were enrolled (10 low dose and 10 high dose+). One patient was excluded due to severe influenza-like symptoms, and 5 of 19 patients completing the study had mild side effects. Plasma potassium in low dose did not increase in response to treatment (4.26±0.22 to 4.05±0.19 mmol/L, p=0.07). Also, no change was observed in resting QTcF (QT interval corrected using Fridericia's formula) before versus after treatment (478±7 vs 479±7 ms, p=0.9). In high dose+, potassium increased significantly from 4.08±0.29 to 4.48±0.54 mmol/L (p=0.001). However, no difference in QTcF was observed comparing before (472±8 ms) versus after (469±8 ms) (p=0.66) high dose+treatment. No patients developed hyperkalaemia.

Conclusion

In patients with LQTS, high dose+treatment increased plasma potassium by 0.4 mmol/L without cases of hyperkalaemia. However, the potassium increase did not shorten the QT interval and several patients had side effects. Considering the QT interval as a proxy for arrhythmic risk, our data do not support that potassium-elevating treatment has a role as antiarrhythmic prophylaxis in patients with LQTS with normal-range potassium levels.

Trial registration number

NCT03291145.
Efficacy and safety of belimumab in paediatric and adult patients with systemic lupus erythematosus: an across-study comparison
Authors: Brunner Hermine I , Abud-Mendoza Carlos , Mori Masaaki , Pilkington Clarissa A , Syed Reema , Takei Syuji , Viola Diego O , Furie Richard A , Navarra Sandra , Zhang Fengchun , Bass Damon L , Eriksson Gina , Hammer Anne E , Ji Beulah N , Okily Mohamed , Roth David A , Quasny Holly , Ruperto Nicolino
Published: September 2021

Objective

To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE).

Methods

We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score; anti-dsDNA/C3/C4 levels); Week 52 SRI-6 response rate; and time to first severe flare (SELENA-SLEDAI Flare Index) over 52 weeks. Safety data were compared for all aforementioned studies along with adult LBSL02 (phase II) and BLISS-SC (phase III).

Results

SRI-4 response rates were similar across the paediatric and adult studies; more belimumab-treated patients achieved SRI-4 responses versus placebo (PLUTO: 52.8% vs 43.6%; BLISS-52: 57.6% vs 43.6%; BLISS-76: 43.2% vs 33.8%; BLISS-NEA: 53.8% vs 40.1%; EMBRACE: 48.7% vs 41.6%). Across all studies, SRI-4 response rates were generally greater in patients with baseline SELENA-SLEDAI scores ≥10 than in patients with baseline SELENA-SLEDAI scores ≤9. A similar proportion of belimumab-treated patients achieved SRI-6 across all studies (PLUTO: 41.2%; BLISS-52: 46.2%; BLISS-76: 33.1%; BLISS-NEA: 43.9%; EMBRACE: 37.5%). Belimumab reduced the risk of severe flare versus placebo in all studies. The incidence of adverse events was similar across all studies.

Conclusions

These analyses demonstrate consistent efficacy and safety of belimumab plus standard therapy across paediatric and adult patients with SLE.

Trial registration numbers

PLUTO (NCT01649765); BLISS-52 (NCT00424476); BLISS-76 (NCT00410384); BLISS-NEA (NCT01345253); EMBRACE (NCT01632241); BLISS-SC (NCT01484496); and LBSL02 (NCT00071487).
DFT modeling of polyaniline: a computational investigation into the structure and band gap of polyaniline
Authors: Scotland Kevin M. , Strong Oliver K.L. , Parnis J. Mark , Vreugdenhil Andrew J.
Published: September 2021

The band gaps of three forms of polyaniline (PANI) are calculated using the DFT method with the B3LYP functional and SV(P) basis set. This marks the first time that the band gap for this polymer has been calculated using this DFT method. The calculations include an investigation of the effect of varying the benzoid–quinoid structural units, the effect of increasing oligomer length, and the inclusion of Michael’s addition structures, which could be residual in the polymer depending on the chosen synthetic method. All results were compared with the experimentally determined band gap of 1.5 eV as typically reported in the literature. A commonly used structural motif of alternating benzoid–quinoid units and a ratio of 0.5:0.5 benzoid–quinoid resulted in a computed band gap of 1.9 eV. Inclusion of one extra quinoid unit gave rise to a band gap of 1.3 eV. Incorporation of a Michael’s addition structure was found to dominate the band gap calculation, yielding a localized LUMO and a band gap of 1.3 eV that was insensitive to the polymer chain length and composition.
How does strategic choice affect the performance of community forest enterprises? A study in the Cascadia region
Authors: Siegner Meike , Kozak Robert , Panwar Rajat , Nelson Harry
Published: September 2021

Proponents of decentralized forest governance make a compelling case that community forest enterprises (CFEs) can aid in sustainable and equitable utilization of forest resources. The effectiveness of CFEs is thus dependent on their ability to balance social, environmental, and financial performance. In this paper, we examine the relationship between a commonly recommended differentiation strategy and CFE effectiveness. Using data obtained through a survey administered on 51 CFEs located in the Cascadia region (British Columbia province of Canada; and Oregon and Washington states of the United States), we find that CFEs pursuing a differentiation strategy are able to balance social, environmental, and financial objectives. Further, recognizing that all CFEs cannot pursue a differentiation strategy, and some may not even have a defined strategic orientation, the paper compares social, environmental, and financial performance of CFEs pursuing a differentiation strategy, a hybrid strategy (a combination of differentiation and cost leadership strategy), and no defined strategy. This analysis reveals that CFEs pursuing a hybrid strategy deliver better financial performance than those with no defined strategy but are similar to those pursuing a differentiation strategy.
Simulated winter warming has negligible effects on germination success of Acadian Forest tree species
Authors: Vaughn William R. , Taylor Anthony R. , MacLean David A. , D’Orangeville Loïc
Published: September 2021

Dormant seeds that require long periods of cold stratification to become germinable may be most sensitive to increases in winter temperatures caused by anthropogenic climate change. In this study, we used outdoor plots with infrared heaters to simulate the effects of projected winter warming (+6 °C) for Canada’s Acadian Forest Region and compared seed germination success of tree species with varying stratification requirements. We evaluated four seedlots each of balsam fir (Abies balsamea (L.) Mill.), red spruce (Picea rubens Sarg.), white pine (Pinus strobus L.), red maple (Acer rubrum L.), sugar maple (Acer saccharum Marshall), and yellow birch (Betula alleghaniensis Britton). Three central findings emerged from this study: (i) none of the tested species were significantly affected by warming; (ii) the random effect of seedlot explained more variation in germination success of deciduous species than it did for conifers; and (iii) balsam fir seedlots exhibited considerable differences in their response to warming, implying intraspecific variation in depth of dormancy. These results suggest seed germination success of the tested tree species may not be impeded by their individual seed characteristics under the magnitude of winter warming projected over the coming century in our study area.
Prompt production of the hidden charm pentaquarks in the LHC
Authors: Ling Pan , Dai Xiao-Hu , Du Meng-Lin , Wang Qian
Published: September 2021

Motivated by the observation of the first hidden charm pentaquarks by the LHCb collaboration in 2015 and the updated analysis with an order-of-magnitude larger data set in 2019, we estimate their cross sections for the prompt production as well as their heavy quark spin partners, in the $$\Sigma _c^{(*)}\bar{D}^{(*)}$$

Σ
c

(

∗
)

D

¯

(

∗
)

hadronic molecular picture, at the center-of-mass energy $$7~\text {TeV}$$

7

TeV

in the pp collision. Their cross sections are several $${\mathrm {nb}}$$
nb
and we would expect several tens hidden charm pentaquark events in the LHC based on its current integrated luminosity. The cross sections show a sizable deviation of the cross sections for hidden charm pentaquarks with the third isospin component $$I_z=+\frac{1}{2}$$

I
z

=
+

1
2

($$P_c^+$$

P
c
+

) from those with $$I_z=-\frac{1}{2}$$

I
z

=
-

1
2

($$P_c^0$$

P
c
0

). The cross sections decrease dramatically with the increasing transverse momentum. Our study can also tell where to search for the missing hidden charm pentaquarks. The confirmation of the complete hidden charm pentaquarks in the heavy quark symmetry would further verify their $$\Sigma _c^{(*)}\bar{D}^{(*)}$$

Σ
c

(

∗
)

D

¯

(

∗
)

molecular interpretation. In addition, the relative strength among these cross sections for pentaquarks can help us to identify the quantum numbers of the $$P_c(4440)$$

P
c

(
4440
)

and $$P_c(4457)$$

P
c

(
4457
)

.
On the 3-Extra Connectivity of Enhanced Hypercubes
Authors: Zhai Liyang , Xu Liqiong , Yin Shanshan
Published: September 2021

Reliability evaluation of interconnection networks is of significant importance to the design and maintenance of interconnection networks. The extra connectivity is an important parameter for the reliability evaluation of interconnection networks. Given a graph [Formula: see text] and a positive integer [Formula: see text], the [Formula: see text]-extra connectivity, denoted by [Formula: see text], is the minimum cardinality of a set of vertices in [Formula: see text], if exists, whose deletion disconnects [Formula: see text] and leaves each remaining component with at least [Formula: see text] vertices. In this paper, we show that the 3-extra connectivity of the [Formula: see text]-enhanced hypercube is [Formula: see text] for [Formula: see text] and [Formula: see text]. Some previous results in [IEEE Trans. Comput. 63 (2014) 1594–1600] and [Theor. Comput. Sci. 799 (2019) 22–31] are extended.