bluuebunny/crossref_metadata_2025 huggingface dataset:
Residual Stress Measurements in a 316L Uniaxial Samples Manufactured by Laser Powder Bed Fusion
Authors: Davies C. M. , Sandmann P. , Ronneberg T. , Hooper P. A. , Kabra Saurabh
Published: October 2020

Uniaxial samples have been manufactured for tension/compression testing from 316L stainless steel by laser powder bed fusion (LPBF). Samples manufactured by LPBF are known to contain high levels of residual stresses. These uniaxial samples were built from a solid cylindrical rod and subsequently machined to reduce the central cross section of the sample to the required gauge diameter and improve the surface finish. Finite element (FE) models have been developed to simulate the LPBF process of the rods, their removal from the build plate and subsequent machining into the tension/compression samples. High tensile residual stresses were predicted at the surface of the samples, balances by similar magnitude compressive stresses along their axis. Post machining however, these stresses were reduced by around 80% or more. Residual stress measurements were performed on the samples post machining using the neutron diffraction techniques. These measurements confirmed that negligible residual stresses remained in the samples post removal from the build plate and machining.
Simulations of Crack Extensions in Arc-Shaped Tension Specimens of Uncharged and Tritium-Charged-and-Decayed Austenitic Stainless Steels Using Cohesive Zone Modeling
Authors: Wu Shengjia , Pan Jwo , Korinko Paul S. , Morgan Michael J.
Published: October 2020

Crack extensions in arc-shaped tension specimens of uncharged and tritium-charged-and-decayed conventionally forged (CF) 21-6-9 austenitic stainless steels are simulated by two-dimensional finite element analyses using the cohesive zone modeling (CZM) approach with the smooth trapezoidal traction-separation law. The J integrals at the deviation loads of the arc-shaped tension specimens are taken as the reference cohesive energies and the maximum opening stresses ahead of the initial crack tips in the arc-shaped tension specimens are taken as the reference cohesive strengths. The cohesive strengths and cohesive energies are then adjusted to match the maximum loads of the experimental load-displacement curves of the arc-shaped tension specimens. The computational results showed that the computational load-displacement, load-crack extension, crack extension-displacement, and J-R curves of the uncharged and tritium-charged-and-decayed CF steel specimens are compared well with the experimental data.
Sustainable Manufacturing and Optimization of Squeeze Stir Cast Rods Using Recycled Aluminum and Alumina Reinforcements
Authors: Christy John Victor , Mourad Abdel-Hamid I. , Arunachalam Ramanathan
Published: October 2020

This work focusses on the production of sustainable metal metrics composites MMCs. The scrap aluminum alloy wheel (SAAW) was used as a metrics and alumina is used as a reinforcement. The process parameters (namely squeeze pressure and time, die preheating temperature and stirrer speed) were optimized using Taguchi method to produce the alumina reinforced-aluminum matrix composites (AMCs). These stir-casted composites were characterized based on their hardness, tensile and compression strengths and wear/tribological properties. The results showed that addition of alumina to aluminum matrix has improved the mechanical and tribological performance. From, Taguchi analysis the optimized 9 approaches (L1 to L9) were obtained and, L5 and L6 methods showed optimum mechanical properties with 100 MPa squeeze pressure, 30 to 40 sec squeeze time, 250 to 350°C die preheating temperature and 450 to 525 rpm stirrer speed process parameters. It was found that properties are process parameters dependent. The produced AMCs have many potential industrial applications including applications in piping industry.
Impact of Grooves in Hydraulically Expanded Tube-to-Tubesheet Joints
Authors: Thekkuden Dinu Thomas , Mourad Abdel-Hamid I. , Bouzid Abdel-Hakim
Published: October 2020

The stress corrosion cracking of tube-to-tubesheet joints is one of the major faults causing heat exchanger failure. After the expansion process, the stresses are developed in a plastically deformed tube around the tube-to-tubesheet joint. These residual stressed joints, exposed to tube and shell side fluids, are the main crack initiation sites. Adequate contact pressure at the tube-to-tubesheet interface is required to produce a quality joint. Insufficient tube-to-tubesheet contact pressure leads to insufficient joint strength. Therefore, a study on the residual stress and contact pressure that have a great significance on the quality of the tube-to-tubesheet joint is highly demanded. In this research, a 2D axisymmetric numerical analysis is performed to study the effect of the presence of grooves in the tubesheet and the expansion pressure length on the distribution of contact pressure and stress during loading and unloading of 400 MPa expansion pressure. The results show that the maximum contact pressure is independent of the expansion pressure length. However, the presence of grooves significantly increased the maximum contact pressure. It is proven that the presence of grooves in the tubesheet is distinguishable from the maximum contact pressure and residual von mises equivalent stress. The tube pull-out strength increases with the expansion pressure and the number of grooves. In conclusion, the presence of the grooves affects the tube-to-tubesheet joints.
Investigation of CGHAZ During Single and Multi Pass Submerged Arc Welding of High Strength Steel
Authors: Sharma Satish Kumar , Maheshwari Sachin
Published: October 2020

Owing to its fine structure and high strength to weight ratio, high strength low alloy (HSLA) steel, API X80, is most preferred grade for application in oil and gas pipeline fabrication. Coarse grain heat affected zone (CGHAZ) formed during fabrication of pipelines using high heat input welding operation like submerged arc welding (SAW) is the crucial area for failure during the application of welded structure. Large detrimental changes occur in mechanical behavior and microstructural characteristics of HAZ due to thermal cycles of the welding operation. In this study, CGHAZ built during first-pass of SAW and when it gets reheated during second-pass as well as third-pass is investigated at each stage for mechanical properties (impact toughness and hardness) as well as microstructural changes. Peak temperature of CGHAZ is determined using upper critical temperature limit of steel. For identifying the lower and upper critical temperature for this steel, dilatometry tests were performed and values were found in well agreement with theoretically determined ones. Comparative analysis of mechanical properties as well as microstructure in simulated HAZ with parent material is also discussed. It is found that subsequent reheating of CGHAZ (formed during first-pass of welding) because of second and third-pass of welding has beneficial effect. Work of this study will guide the engineers to put the limit on heat input in terms of number of passes during welding of such high strength pipeline steels.
Addressing Low Pressure Transients
Authors: Marroquin Amy , Lang Scott
Published: October 2020

Low transient pressures in piping systems are different in many ways to high transient pressures. While high pressures can obviously burst pipes or damage components, low pressures can collapse pipes, pull in environmental contaminants, bring components out of solution, or induce transient cavitation, a particular concern for hydrocarbon liquids. This paper will use examples of computer modeling to reveal how common system events such as pump trips or valve closures induce low pressure transient waves that have potential to be just as destructive as more intuitive high pressure waves.

Fluid transient studies and literature often focus on high pressures, or do not clearly demonstrate how liquids with low vapor pressures (such as many hydrocarbons) can be affected. Even discerning a pipe’s negative pressure rating through codes and standards can be a challenge. It is shown that low pressure transients are a potential issue in any liquid system. It is further demonstrated that “Rule of Thumb” or typical simplified calculations are not sufficient to capture these effects, and cannot be used to properly locate and size equipment.
A stunt flying hawk-inspired drone
Authors: Lau Gih-Keong
Published: October 2020

A winged drone demonstrates aggressive and agile flight by morphing its wings and tail.
Mohawk is a transcription factor that promotes meniscus cell phenotype and tissue repair and reduces osteoarthritis severity
Authors: Lee Kwang Il , Gamini Ramya , Olmer Merissa , Ikuta Yasunari , Hasei Joe , Baek Jihye , Alvarez-Garcia Oscar , Grogan Shawn P. , D’Lima Darryl D. , Asahara Hiroshi , Su Andrew I. , Lotz Martin K.
Published: October 2020

Mohawk is enriched in meniscal tissue and promotes meniscus cell phenotype, enhances repair, and protects against cartilage destruction in mice.
A modified drug regimen clears active and dormant trypanosomes in mouse models of Chagas disease
Authors: Bustamante Juan M. , Sanchez-Valdez Fernando , Padilla Angel M. , White Brooke , Wang Wei , Tarleton Rick L.
Published: October 2020

A modified regimen of benznidazole prevents
Trypanosoma cruzi
dormancy-dependent treatment failure in several mouse models of Chagas disease.
Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis
Authors: Panjasawatwong Navarat , Wattanakul Thanaporn , Hoglund Richard M. , Bang Nguyen Duc , Pouplin Thomas , Nosoongnoen Wichit , Ngo Vi Nguyen , Day Jeremy N. , Tarning Joel
Published: October 2020

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen.
Genome Sequences of Four Strains of Acinetobacter bereziniae Isolated from Human Milk Pumped with a Personal Breast Pump and Hand-Washed Milk Collection Supplies
Authors: Reyes Sarah M. , Bolettieri Emilienne , Allen Dainelle , Hay Anthony G.
Published: October 2020

Acinetobacter bereziniae
, formerly
Acinetobacter
genomospecies 10, is an opportunistic pathogen possessing resistance to multiple antibiotics, and it has been reported to be responsible for hospital-associated infections in immunocompromised individuals. We report the draft genome sequences of four
Acinetobacter bereziniae
strains that were isolated from a single human milk sample collected with a personal breast pump and a hand-washed milk collection kit.
Metagenomes and Metatranscriptomes of a Glucose-Amended Agricultural Soil
Authors: Chuckran Peter F. , Huntemann Marcel , Clum Alicia , Foster Brian , Foster Bryce , Roux Simon , Palaniappan Krishnaveni , Varghese Neha , Mukherjee Supratim , Reddy T. B. K. , Daum Chris , Copeland Alex , Ivanova Natalia N. , Kyrpides Nikos C. , del Rio Tijana Glavina , Eloe-Fadrosh Emiley A. , Morrissey Ember M. , Schwartz Egbert , Fofanov Viacheslav , Hungate Bruce , Dijkstra Paul
Published: October 2020

The addition of glucose to soil has long been used to study the metabolic activity of microbes in soil; however, the response of the microbial ecophysiology remains poorly characterized. To address this, we sequenced the metagenomes and metatranscriptomes of glucose-amended soil microbial communities in a laboratory incubation.
An Improved Caulobacter crescentus Operon Annotation Based on Transcriptome Data
Authors: Bharmal Mohammed-Husain , Aretakis James R. , Schrader Jared M.
Published: October 2020

Caulobacter crescentus
is a model alphaproteobacterium with a well-studied genetic network controlling its cell cycle. Essential for such studies is an accurate map of the expressed features of its genome. Here, we provide an updated map of the expressed RNAs by integrative analysis of 5′ global rapid amplification of cDNA ends, transcriptome sequencing, rifampicin treatment RNA sequencing, and RNA end-enriched sequencing data sets.
Lifetime duration of lactation and chronic inflammation among middle-aged women with a history of gestational diabetes
Authors: Ley Sylvia H , Chavarro Jorge E , Hinkle Stefanie N , Li Mengying , Tsai Michael Y , Hu Frank B , Zhang Cuilin
Published: October 2020

Introduction

Longer duration of lactation is associated with lower cardiometabolic disease risk, but pathogenic pathways involved in the disease progression are unclear, especially among high-risk women. We aimed to examine the associations of lifetime lactation duration with cardiometabolic biomarkers among middle-aged women with a history of gestational diabetes (GDM).

Research design and methods

Women with a history of GDM participating in the Nurses’ Health Study II, a prospective cohort study, were identified and followed through biennial questionnaires beginning in 1991. Lactation history was asked in three follow-up questionnaires to calculate lifetime duration. In 2012–2014, fasting blood samples were collected through the Diabetes & Women’s Health Study to measure inflammatory (C-reactive protein (CRP), interleukin (IL) 6), liver enzyme (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase), and lipid biomarkers (total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol).

Results

At follow-up blood collection, women were at median age 58.2 (95% CI 51 to 65) years and 26.3 (95% CI 15.7 to 34.1) years since GDM index pregnancy. After multiple adjustment including prepregnancy body mass index (BMI), longer duration of lactation was significantly associated with lower CRP (least squares (LS) mean 1.90 mg/L (95% CI 1.47 to 2.45) for 0-month lactation, 1.98 mg/L (95% CI 1.68 to 2.32) for up to 12-month lactation, 1.67 mg/L (95% CI 1.42 to 1.97) for 12–24 month lactation, and 1.39 mg/L (95% CI 1.19 to 1.62) for >24-month lactation; p trend=0.003) and IL-6 (1.25 pg/L (95% CI 0.94 to 1.68), 1.19 pg/L (95% CI 0.99 to 1.42), 1.04 pg/L (95% CI 0.87 to 1.25), and 0.93 pg/L (95% CI 0.78 to 1.11); p trend=0.04). Longer duration of lactation was associated with lower risk for chronic inflammation using CRP 3 mg/L cut-off in middle-aged women (OR 0.81 (95% CI 0.69 to 0.940 per 1-year increase) with multiple adjustment.

Conclusions

Longer lifetime duration of lactation was associated with favorable inflammatory biomarker concentrations in middle-aged women with a history of GDM. Chronic inflammatory pathways may be responsible for previously reported associations between lactation and long-term risk for cardiometabolic diseases.
Metabolic recovery after weight loss surgery is reflected in serum microRNAs
Authors: Sangiao-Alvarellos Susana , Theofilatos Konstantinos , Barwari Temo , Gutmann Clemens , Takov Kaloyan , Singh Bhawana , Juiz-Valiña Paula , Varela-Rodríguez Bárbara María , Outeiriño-Blanco Elena , Duregotti Elisa , Zampetaki Anna , Lunger Lukas , Ebenbichler Christoph , Tilg Herbert , García-Brao María Jesús , Willeit Peter , Mena Enrique , Kiechl Stefan , Cordido Fernando , Mayr Manuel
Published: October 2020

Introduction

Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue.

Research design and methods

We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up.

Results

Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction.

Conclusions

Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.
Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events
Authors: Lingvay Ildiko , Hansen Thomas , Macura Stanislava , Marre Michel , Nauck Michael A , de la Rosa Raymond , Woo Vincent , Yildirim Emre , Wilding John
Published: October 2020

Introduction

Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Weight loss (WL) is slightly greater in people who experience GI AEs than those who do not. A previous mediation analysis of the SUSTAIN 1–5 trials indicated minor contribution of nausea/vomiting to the greater WL with once-weekly semaglutide versus comparators. Semaglutide demonstrated superior glycated hemoglobin and body weight (BW) reductions versus other GLP-1RAs in SUSTAIN 3 (versus exenatide extended release 2.0 mg), SUSTAIN 7 (versus dulaglutide) and SUSTAIN 10 (liraglutide 1.2 mg). The objective of this analysis was to assess if significantly greater WL with semaglutide versus other GLP-1RAs is mediated by nausea/vomiting and other GI AEs (diarrhea, constipation, dyspepsia) during dose escalation (baseline to week 12, when GI AEs are generally most prevalent) and from baseline to end of treatment (EOT: week 56 (SUSTAIN 3), 40 (SUSTAIN 7) or 30 (SUSTAIN 10)).

Research design and methods

Subjects within trials were subdivided into those who reported (yes/no) nausea/vomiting or any other GI AE. Change from baseline in BW was assessed within each trial and subgroup. A mediation analysis separated WL into direct or indirect (mediated by GI AEs) effects.

Results

From baseline to week 12 or EOT, the nausea/vomiting-mediated difference in WL was, respectively: 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3); 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10).

Conclusions

In SUSTAIN 3, 7 and 10, nausea/vomiting by week 12 (end of dose escalation) or throughout treatment contributed minimally (<0.1 kg) to the superior WL with semaglutide versus GLP-1RA comparators at EOT.
Bridging research integrity and global health epidemiology (BRIDGE) guidelines: explanation and elaboration
Authors: Alba Sandra , Lenglet Annick , Verdonck Kristien , Roth Johanna , Patil Rutuja , Mendoza Walter , Juvekar Sanjay , Rumisha Susan F
Published: October 2020

Over the past decade, two movements have profoundly changed the environment in which global health epidemiologists work: research integrity and research fairness. Both ought to be equally nurtured by global health epidemiologists who aim to produce high quality impactful research. Yet bridging between these two aspirations can lead to practical and ethical dilemmas. In the light of these reflections we have proposed the BRIDGE guidelines for the conduct of fair global health epidemiology, targeted at stakeholders involved in the commissioning, conduct, appraisal and publication of global health research. The guidelines follow the conduct of a study chronologically from the early stages of study preparation until the dissemination and communication of findings. They can be used as a checklist by research teams, funders and other stakeholders to ensure that a study is conducted in line with both research integrity and research fairness principles. In this paper we offer a detailed explanation for each item of the BRIDGE guidelines. We have focused on practical implementation issues, making this document most of interest to those who are actually conducting the epidemiological work.
Healthcare utilisation and costs for temporomandibular disorders: a descriptive, cross-sectional study
Authors: Seo Hyejin , Jung Boyoung , Yeo Jiyoon , Kim Koh-Woon , Cho Jae-Heung , Lee Yoon Jae , Ha In-Hyuk
Published: October 2020

Objective

Temporomandibular joint disorder (TMD) requires long-term management and can be a financial burden for patients. Here, we investigated the treatment received by people diagnosed with TMD and its relevant costs.

Design

A descriptive, cross-sectional study.

Setting and participants

We performed secondary data analysis of health insurance claims data provided by the Health Insurance Assessment and Review (HIRA) of the Republic of Korea. We reviewed the records of 10 041 patients who were diagnosed with TMD and who utilised outpatient healthcare service at least once between January and December 2017.

Primary and secondary outcome measures

Data on use of medical services, hospitalisations, sociodemographic factors, treatment and medication were retrieved and analysed. Cost was defined as the cost of care incurred by a health insurance beneficiary at a care facility.

Results

We reported the characteristics as medians, frequencies and percentages and found that most TMD patients were outpatients, women (58.9%) and in their 20s (46.4%). For visit type, 85.9% of all patients had an outpatient dental medical visit, with most visiting dental clinics and dental hospitals. Western medicine (WM; 9.8%) was prescribed more often, followed by Korean medicine (KM; 8.2%). The median expense per patient was highest among those in their 20s (58.00, 23.90, 53.40, 65.90 US$ for overall, WM, dental medicine (DM) and KM, respectively). Consultation fees accounted for the greatest percentage (42.8%) of DM and WM care expenses, while injection/non-surgical intervention fees accounted for the greatest percentage of KM care expenses. The most commonly used treatments for TMD were temporomandibular joint stimulation therapy (51.1%) and acupuncture (19.9%), considered as the most basic care for TMD. Psychosomatic agents (86.4%) were the most commonly used medications in outpatients.

Conclusions

While people with TMD most commonly received temporomandibular stimulation therapy, the costs and duration of treatment varied significantly for these patients.
External validation and clinical usefulness of three commonly used cardiovascular risk prediction scores in an Emirati population: a retrospective longitudinal cohort study
Authors: Al-Shamsi Saif , Govender Romona Devi , King Jeffrey
Published: October 2020

Objectives

Cardiovascular disease (CVD) risk prediction models are useful tools for identifying those at high risk of cardiovascular events in a population. No studies have evaluated the performance of such risk models in an Arab population. Therefore, in this study, the accuracy and clinical usefulness of two commonly used Framingham-based risk models and the 2013 Pooled Cohort Risk Equation (PCE) were assessed in a United Arab Emirates (UAE) national population.

Design

A 10-year retrospective cohort study.

Setting

Outpatient clinics at a tertiary care hospital, Al-Ain, UAE.

Participants

The study cohort included 1041 UAE nationals aged 30–79 who had no history of CVD at baseline. Patients were followed until 31 December 2019. Eligible patients were grouped into the PCE and the Framingham validation cohorts.

Exposure

The 10-year predicted risk for CVD for each patient was calculated using the 2008 Framingham risk model, the 2008 office-based Framingham risk model, and the 2013 PCE model.

Primary outcome measure

The discrimination, calibration and clinical usefulness of the three models for predicting 10-year cardiovascular risk were assessed.

Results

In women, the 2013 PCE model showed marginally better discrimination (C-statistic: 0.77) than the 2008 Framingham models (C-statistic: 0.74–0.75), whereas all three models showed moderate discrimination in men (C-statistic: 0.69‒0.70). All three models overestimated CVD risk in both men and women, with higher levels of predicted risk. The 2008 Framingham risk model (high-risk threshold of 20%) classified only 46% of women who subsequently developed incident CVD within 10 years as high risk. The 2013 PCE risk model (high-risk threshold of 7.5%) classified 74% of men who did not develop a cardiovascular event as high risk.

Conclusions

None of the three models is accurate for predicting cardiovascular risk in UAE nationals. The performance of the models could potentially be improved by recalibration.
Strengthening palliative care in the hospital setting: a codesign study
Authors: Virdun Claudia , Luckett Tim , Davidson Patricia M , Phillips Jane
Published: October 2020

Objective

To identify actions required to strengthen the delivery of person and family centred hospital-based palliative care so that it addressed the domains of care identified as important for inpatients with palliative care needs and their families.

Methods

A codesign study involving a workshop with palliative care and acute hospital policy, consumer and clinical representatives in Australia. A modified nominal group process generated a series of actions, which were thematically analysed and refined, before being circulated to participants to gain consensus.

Results

More than half (n=30, 58%) of the invited representatives (n=52) participated in the codesign process. Nine actions were identified as required to strengthen inpatient palliative care provision being: (a) evidence-informed practice and national benchmarking; (b) funding reforms; (c) securing executive level support; (d) mandatory clinical and ancillary education; (e) fostering greater community awareness; (f) policy reviews of care of the dying; (g) better integration of advance care planning; (h) strengthen nursing leadership; and (i) develop communities of practice for improving palliative care.

Conclusions

Changes to policy, practice, education and further research are required to optimise palliative care within hospital settings, in accordance with the domains inpatients with palliative care needs and their families consider to be important. Achieving these changes will require a whole of sector approach and significant national and jurisdictional leadership.
Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma
Authors: He Xiran , Du Yang , Wang Zhijie , Wang Xin , Duan Jianchun , Wan Rui , Xu Jiachen , Zhang Pei , Wang Di , Tian Yanhua , Han Jiefei , Fei Kailun , Bai Hua , Tian Jie , Wang Jie
Published: October 2020

Background

The survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored.

Methods

Cell lines, syngeneic immunocompetent mouse models, and patients’ peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized.

Results

Low-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8+T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic.

Conclusions

We first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.
Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response
Authors: Qi Xiaoqiang , Yang Ming , Ma Lixin , Sauer Madeline , Avella Diego , Kaifi Jussuf T , Bryan Jeffrey , Cheng Kun , Staveley-O’Carroll Kevin F , Kimchi Eric T , Li Guangfu
Published: October 2020

Background

Minimally invasive radiofrequency ablation (RFA) is used as a first-line treatment option for hepatocellular cancer (HCC) with the weaknesses of incomplete ablation, tumor recurrence, and inferior outcomes. To overcome this limitation, we proposed to develop sunitinib-RFA integrated therapy with a potential of activating anti-HCC immune response.

Methods

Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib–RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling; immune reaction was defined by flow cytometry; and signaling molecules were examined with real-time PCR (qPCR), western blot, and immunohistochemical staining.

Results

A significantly reduced tumor growth and extended lift span were observed in the mice receiving combined treatment with RFA and sunitinib. This combined treatment significantly increased the frequency of CD8+ T cell, memory CD8+ T cell, and dendritic cells (DCs); decreased the frequency of regulatory T cells; and activated tumor-specific antigen (TSA) immune response in tumor microenvironment. We found that RFA caused PD-1 upregulation in tumor-infiltrated T cells by boosting hepatocyte growth factor (HGF) expression, which was suppressed by sunitinib treatment. We have also demonstrated that sunitinib suppressed VEGF’s effect in enhancing PD-L1 expression in DCs and attenuated heat-sink effect. The results indicate that RFA induced tumor destruction and release of in situ TSAs which can activate a tumoricidal immune response in sunitinib-treated mice, significantly improving anti-HCC therapeutic efficacy.

Conclusions

Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib–RFA as a synergistic therapeutic approach significantly suppresses HCC growth.
PD-1 inhibitor inducing exosomal miR-34a-5p expression mediates the cross talk between cardiomyocyte and macrophage in immune checkpoint inhibitor–related cardiac dysfunction
Authors: Xia Wenzheng , Chen Hanbin , Chen Didi , Ye Yijia , Xie Congying , Hou Meng
Published: October 2020

Background

Immune checkpoint inhibitors (ICIs) have been an important therapeutic advancement in the field of cancer medicine. Recent reports provided greater insights into the cardiovascular adverse events, which prohibited the use of ICIs. Cardiovascular adverse events occur in different forms, such as myocarditis and cardiomyopathy, myocardial fibrosis, heart failure and pericardial disease. Cardiac aging overlapped with the occurrence of some cardiac diseases. Exosomes mediate cell–cell cross talk in cardiac diseases by transferring a variety of biomolecules, including microRNAs (miRs). miR-34a-5p is a well-known miR associated with the cardiac senescence. This study aimed to investigate whether cardiovascular adverse effects of the programmed cell death 1 (PD-1) inhibitor, a widely used ICI, were related to exosomal-transferred miR-34a-5p in cardiac senescence in a mouse model.

Methods and results

The upregulation of miR-34a-5p in cardiomyocytes induced by exosomes derived from PD-1 inhibitor–treated macrophages, accompanied by cardiac senescence, caused cardiac injury in mouse hearts. miR-34a-5p was identified as an exosomal transfer RNA to induce cardiac senescence–related injury. Inhibiting miR-34a-5p in macrophages attenuated the exosomePD-1 inhibitor-induced pro-senescent effect in cardiomyocytes. TargetScan and luciferase assay showed that miR-34a-5p targeted the serine/threonine-protein phosphatase 1 regulatory subunit 10 (PNUTS) 3′-untranslated region.

Conclusions

Exosomes derived from PD-1 inhibitor–treated macrophages exerted a pro-senescent effect by modulating the miR-34a-5p/PNUTS signaling pathway. The findings might supply new targets to ameliorate cardiac injury in patients with cancer receiving PD-1 inhibitor treatment.
Patient’s experience of psoriatic arthritis: a conceptual model based on qualitative interviews
Authors: Ogdie Alexis , Michaud Kaleb , Nowak Miroslawa , Bruce Rachel , Cantor Sarah , Hintzen Carlijn , Mease Philip J
Published: October 2020

Introduction

Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory musculoskeletal disorder that manifests as peripheral arthritis, dactylitis, enthesitis and spondylitis. PsA results in significant burden that impacts quality of life of patients. We examined the signs, symptoms and impacts reported by patients with PsA, to characterise the patient experience of PsA and develop a conceptual model representing this patient experience.

Methods

Semi-structured interviews were conducted with patients with PsA recruited through the FORWARD databank. Spontaneous and probed signs, symptoms and impacts of PsA were assessed. Patients rated the disturbance of these concepts on their lives using a scale from 0 (‘does not disturb’) to 10 (‘greatly disturbs’). Signs, symptoms and impacts reported by >80% of patients with a disturbance rating of ≥5 were defined as salient concepts. Recruitment continued until concept saturation was achieved.

Results

19 patients with PsA were interviewed. The interviews elicited 42 symptoms of which 8 had not been identified in a previous literature review encompassing 15 relevant articles. The most salient signs and symptoms elicited in the interviews were joint pain, skin symptoms, stiffness, swollen/inflamed joints and fatigue all with moderate to high disturbance ratings (range: 5.5–7.8). The most salient impacts were sleep disturbance, physical disability, effects on daily activities and feelings of frustration with also moderate to high disturbance ratings (range: 6.1–7.4).

Conclusions

The interviews highlighted the adverse impact PsA has on the patient’s life and may inform on outcome variables or areas suitable to be assessed in PsA studies.
Advances in visualizing transcription factor – DNA interactions
Authors: Price Rachel M. , Budzyński Marek A. , Kundra Shivani , Teves Sheila S.
Published: October 2020

At the heart of the transcription process is the specific interaction between transcription factors (TFs) and their target DNA sequences. Decades of molecular biology research have led to unprecedented insights into how TFs access the genome to regulate transcription. In the last 20 years, advances in microscopy have enabled scientists to add imaging as a powerful tool in probing two specific aspects of TF–DNA interactions: structure and dynamics. In this review, we examine how applications of diverse imaging technologies can provide structural and dynamic information that complements insights gained from molecular biology assays. As a case study, we discuss how applications of advanced imaging techniques have reshaped our understanding of TF behavior across the cell cycle, leading to a rethinking in the field of mitotic bookmarking.
Numerical study of the nanofluid thin film flow past an unsteady stretching sheet with fractional derivatives using the spectral collocation Chebyshev approximation
Authors: Khader M. M.
Published: October 2020

In this work, a mathematical model of fractional-order in fluid will be analyzed numerically to describe and study the influence of thermal radiation on the magnetohydrodynamic flow of nanofluid thin film which moves due to the unsteady stretching surface with viscous dissipation. The set of nonlinear fractional differential equations in the form of velocity, temperature and concentration which describe our proposed problem are tackled through the spectral collocation method based on Chebyshev polynomials of the third-kind. This method reduces the presented model to a system of algebraic equations. The effect of the influence parameters which governs the process of flow and mass heat transfer is discussed. The numerical values of the dimensionless velocity, temperature and concentration are depicted graphically. Also, computations of the values of skin-friction, Nusselt number and Sherwood number have been carried out and presented in the same figures. Finally, our numerical analysis shows that both the magnetic and the unsteadiness parameters can enhance the free surface temperature and nanoparticle volume fraction.
A 32-GS/s Front-End Sampling Circuit Achieving >39 dB SNDR for Time-Interleaved ADCs in 65-nm CMOS
Authors: Zhao Lei , Li Dengquan , Mao Henghui , Ding Ruixue , Zhu Zhangming
Published: October 2020

This paper presents a 32-GS/s front-end sampling circuit (FESC) in 65-nm CMOS. The FESC is designed for a 32-channel time-interleaved analog-to-digital converter (ADC), and the [Formula: see text] two-stage interleaving structure leads to a good trade-off between bandwidth and linearity. The analysis and cancellation of charge injection, clock feedthrough, and signal feedthrough are presented. Inductor peaking technique is adopted to extend the bandwidth of the buffer between the first and the second stage. Based on the simulation results, the proposed FESC consumes 136[Formula: see text]mW at 32 GS/s, and the signal-to-noise ratio (SNDR) is up to 39.55 dB at Nyquist input, achieving a state-of-the-art power efficiency.
Linear instability of Z-pinch in plasma: Viscous case
Authors: Bian Dongfen , Guo Yan , Tice Ian
Published: October 2020

The [Formula: see text]-pinch is a classical steady state for the MHD model, where a confined plasma fluid is separated by vacuum, in the presence of a magnetic field which is generated by a prescribed current along the [Formula: see text]-direction. We develop a scaled variational framework to study its stability in the presence of viscosity effect, and demonstrate that any such [Formula: see text]-pinch is always unstable. We also establish the existence of a largest growing mode, which dominates the linear growth of the linear MHD system.
How close is our ΛCDM physical universe to de Sitter spacetime dS4?
Authors: Fischer Arthur E.
Published: October 2020

We introduce a methodology for quantitatively measuring at all times in its evolution how close our physical spatially flat [Formula: see text] CDM universe with cosmological constant [Formula: see text] is to the de Sitter spacetime [Formula: see text] with de Sitter radius [Formula: see text]. The main idea in this study is to align the respective scale factors [Formula: see text] and [Formula: see text] of these two spacetimes, where de Sitter spacetime is taken with respect to a spatially flat foliation. This goal is accomplished by fine-tuning an adjustable parameter [Formula: see text] that arises naturally in the de Sitter scale factor by requiring that these scale factors be future-asymptotically convergent. Once this parameter is adjusted and the scale factors are aligned, we define a relative error function [Formula: see text] that computes as a function of time [Formula: see text] how close the scale factors of these two spacetimes are to one another. Our results quantify how close our physical [Formula: see text]CDM universe is to its corresponding de Sitter spacetime as both spacetimes converge as they expand. As an example of our results, we show that at the present time [Formula: see text][Formula: see text]Gy, to an accuracy of [Formula: see text], and at [Formula: see text][Formula: see text]Gy, to an accuracy of [Formula: see text], we can use de Sitter spacetime to model our own [Formula: see text]CDM universe. Our results also show by statistical analysis that with a confidence level of 68.3%, for [Formula: see text][Formula: see text]Gy, the scale factor [Formula: see text] of our [Formula: see text] universe and the scale factor [Formula: see text] of the corresponding de Sitter spacetime are indistinguishable to within the accuracy of current cosmological measurements.
Seismic Control of a Self-Anchored Suspension Bridge Using Fluid Viscous Dampers
Authors: Feng Dongming , Wang Jingquan
Published: October 2020

A self-anchored suspension bridge balances forces internally without external anchorage requirements, making it suitable for sites where anchorages would be difficult to construct. It often adopts either a full-floating or a semi-floating tower-girder connection system, which may result in large displacement responses along bridge longitudinal direction during earthquakes. This study investigated the efficacy of using the fluid viscous damper (FVD) for seismic control of a single-tower self-anchored suspension bridge. First, the energy dissipation behaviors of the FVD under sinusoidal excitations were studied. It revealed that besides the damper parameters (i.e. damping coefficient and velocity exponent) of an FVD itself, the energy dissipation capacity also relies on the characteristics of external excitations. Therefore, optimum damper parameters added to a structure should be determined on a case-by-case basis. Parametric study was then carried out on the prototype bridge, which indicated a tendency of decreasing the longitudinal deck/tower displacements and tower forces with increasing damping coefficient [Formula: see text] and decreasing velocity exponent [Formula: see text]. Compared with the linear FVD, the nonlinear FVD with a smaller velocity exponent can develop more rectangular force-displacement loops and thus achieve better energy dissipation performance. With selected optimum damper parameters (i.e. [Formula: see text][Formula: see text]kN[Formula: see text]m[Formula: see text][Formula: see text]s[Formula: see text] and [Formula: see text]) for the two FVDs added between the deck and the tower, the longitudinal deck and tower displacements could be reduced by 54%, while the peak bending moment and shear force at the tower base could be reduced by 30% and 19%, respectively. It is concluded that the nonlinear FVD can provide a simple and efficient solution to reduce displacement responses of self-anchored suspension bridges while simultaneously reducing the bending moment and shear force in the tower.
Arithmetic modules over generalized Dedekind domains
Authors: Wijayanti Indah Emilia , Marubayashi Hidetoshi , Ernanto Iwan , Sutopo
Published: October 2020

Let [Formula: see text] be a finitely generated torsion-free module over a generalized Dedekind domain [Formula: see text]. It is shown that if [Formula: see text] is a projective [Formula: see text]-module, then it is a generalized Dedekind module and [Formula: see text]-multiplication module. In case [Formula: see text] is Noetherian it is shown that [Formula: see text] is either a generalized Dedekind module or a Krull module. Furthermore, the polynomial module [Formula: see text] is a generalized Dedekind [Formula: see text]-module (a Krull [Formula: see text]-module) if [Formula: see text] is a generalized Dedekind module (a Krull module), respectively.
Enhancing adversarial attack transferability with multi-scale feature attack
Authors: Sun Caixia , Zou Lian , Fan Cien , Shi Yu , Liu Yifeng
Published: October 2020

Deep neural networks are vulnerable to adversarial examples, which can fool models by adding carefully designed perturbations. An intriguing phenomenon is that adversarial examples often exhibit transferability, thus making black-box attacks effective in real-world applications. However, the adversarial examples generated by existing methods typically overfit the structure and feature representation of the source model, resulting in a low success rate in a black-box manner. To address this issue, we propose the multi-scale feature attack to boost attack transferability, which adjusts the internal feature space representation of the adversarial image to get far to the internal representation of the original image. We show that we can select a low-level layer and a high-level layer of the source model to conduct the perturbations, and the crafted adversarial examples are confused with original images, not just in the class but also in the feature space representations. To further improve the transferability of adversarial examples, we apply reverse cross-entropy loss to reduce the overfitting further and show that it is effective for attacking adversarially trained models with strong defensive ability. Extensive experiments show that the proposed methods consistently outperform the iterative fast gradient sign method (IFGSM) and momentum iterative fast gradient sign method (MIFGSM) under the challenging black-box setting.
Backward bifurcation in a fractional-order and two-patch model of tuberculosis epidemic with incomplete treatment
Authors: Jafari Mohsen , Kheiri Hossein , Jabbari Azizeh
Published: October 2020

In this paper, we consider a tuberculosis model with incomplete treatment and extend the model to a Caputo fractional-order and two-patch version with exogenous re-infection among the treated individuals, in which only susceptible individuals can travel freely between the patches. The model has multiple equilibria. We determine conditions that lead to the appearance of a backward bifurcation. The results show that the TB model can have exogenous reinfection among the treated individuals and, at the same time, does not exhibit backward bifurcation. Also, conditions that lead to the global asymptotic stability of the disease-free equilibrium are obtained. In case without reinfection, the model has four equilibria. In this case, the global asymptotic stability of the equilibria is established using the Lyapunov function theory together with the LaSalle invariance principle for fractional differential equations (FDEs). Numerical simulations confirm the validity of the theoretical results.