bluuebunny/crossref_metadata_2025 huggingface dataset:
Demonstrating the Manufacture of Human CAR‐T Cells in an Automated Stirred‐Tank Bioreactor
Authors: Costariol Elena , Rotondi Marco C. , Amini Arman , Hewitt Christopher J. , Nienow Alvin W. , Heathman Thomas R. J. , Rafiq Qasim A.
Published: June 2020

Chimeric antigen receptor T‐cell (CAR‐T) therapies have proven clinical efficacy for the treatment of hematological malignancies. However, CAR‐T cell therapies are prohibitively expensive to manufacture. The authors demonstrate the manufacture of human CAR‐T cells from multiple donors in an automated stirred‐tank bioreactor. The authors successfully produced functional human CAR‐T cells from multiple donors under dynamic conditions in a stirred‐tank bioreactor, resulting in overall cell yields which were significantly better than in static T‐flask culture. At agitation speeds of 200 rpm and greater (up to 500 rpm), the CAR‐T cells are able to proliferate effectively, reaching viable cell densities of >5 × 106 cells ml‐1 over 7 days. This is comparable with current expansion systems and significantly better than static expansion platforms (T‐flasks and gas‐permeable culture bags). Importantly, engineered T‐cells post‐expansion retained expression of the CAR gene and retained their cytolytic function even when grown at the highest agitation intensity. This proves that power inputs used in this study do not affect cell efficacy to target and kill the leukemia cells. This is the first demonstration of human CAR‐T cell manufacture in stirred‐tank bioreactors and the findings present significant implications and opportunities for larger‐scale allogeneic CAR‐T production.
Interactive learning modules with 3D printed models improve student understanding of protein structure–function relationships
Authors: Howell Michelle E. , Booth Christine S. , Sikich Sharmin M. , Helikar Tomáš , van Dijk Karin , Roston Rebecca L. , Couch Brian A.
Published: June 2020

Ensuring undergraduate students become proficient in relating protein structure to biological function has important implications. With current two‐dimensional (2D) methods of teaching, students frequently develop misconceptions, including that proteins contain a lot of empty space, that bond angles for different amino acids can rotate equally, and that product inhibition is equivalent to allostery. To help students translate 2D images to 3D molecules and assign biochemical meaning to physical structures, we designed three 3D learning modules consisting of interactive activities with 3D printed models for amino acids, proteins, and allosteric regulation with coordinating pre‐ and post‐assessments. Module implementation resulted in normalized learning gains on module‐based assessments of 30% compared to 17% in a no‐module course and normalized learning gains on a comprehensive assessment of 19% compared to 3% in a no‐module course. This suggests that interacting with these modules helps students develop an improved ability to visualize and retain molecular structure and function.
Decoration of electrical conductive polyurethane‐polyaniline/polyvinyl alcohol matrixes with mussel‐inspired polydopamine for bone tissue engineering
Authors: Ghorbani Farnaz , Ghalandari Behafarid , Khan Ab Lateef , Li Dejian , Zamanian Ali , Yu Baoqing
Published: June 2020

Electrospinning is a versatile technology for the fabrication of nanofibrous matrixes to regenerate defects. This study aims to develop a functionalized and electroconductive polymeric matrix to improve rat bone marrow mesenchymal stem cell adhesion, proliferation, and differentiation. Herein, the influence of the chemical composition of the substrate on homogeneous modification of the surface with mussel‐inspired polydopamine (PDA) is focused. Accordingly, the deposition of PDA on the surface was proved by Fourier transform infrared spectroscopy. Morphologies of the scaffolds demonstrated homogeneous decoration of the polyvinyl alcohol (PVA)/polyurethane (PU)‐polyaniline (PANI) matrixes with PDA, while a lower density of mussel‐inspired polymer was observed in bare PU‐PANI constructs. Although uniform and dense precipitation of PDA reduced conductivity of scaffolds 1.2 times compared with the samples with a low density of the PDA, 1.1 and 1.2 times enhancement in tensile strength and Young's modulus, respectively, were the strength of the applied process, especially in bone tissue engineering area. Contact angle measurements demonstrated about two times reduction in measured values, which shows improvement in hydrophilicity of PDA‐modified PVA/PU‐PANI fibers compared with PDA‐coated PU‐PANI ones. Swelling ratio and mass loss ratio calculations revealed enhancement in measured values as a function of homogeneous and dense coating, which arise from hydrophilicity of the polymeric substrate. The bioactivity test indicated that a dense layer of PDA strongly supports formations of hydroxyapatite‐like crystals. Moreover, homogeneous decoration of conductive matrixes with PDA showed suitable cell viability, adhesion, and spreading while cell‐scaffolds interactions improved under electrical stimulation. Higher expression of alkaline phosphatase and secretion of Collagen I under the electrical field proved the applicability of modified electroconductive scaffolds for further preclinical and clinical studies to introduce as a reconstructive bone substitute.
Development and validation of a pretreatment nomogram to predict overall survival in gastric cancer
Authors: Bando Etsuro , Ji Xinge , Kattan Michael W. , Seo Ho Seok , Song Kyo Young , Park Cho‐Hyun , Bencivenga Maria , de Manzoni Giovanni , Terashima Masanori
Published: June 2020

Background

Pretreatment clinical staging is essential to select therapy. However, there have been no published pretreatment gastric cancer nomograms constructed using pretreatment clinical prognostic factors, including in nonresection patients. We aimed to develop a new pretreatment gastric cancer nomogram for individualized prediction of overall survival (OS).

Methods

The nomogram was developed using data of 5231 Japanese gastric cancer patients, and it was created with a Cox regression model. Fifteen clinical variables, which were obtained at pretreatment, were collected and registered. Data of two independent cohorts of patients from Seoul St. Mary's Hospital (1001 patients), and the University of Verona (389 patients) formed the external validation cohorts. The model was validated internally and externally using measures of discrimination (Harrell's C‐index), calibration, and decision curve analysis.

Results

The developed nomogram showed good discrimination, with a C‐index of 0.855; that of the American Joint Committee on Cancer (AJCC) clinical stage was 0.819. In the external validation procedure, the C‐indexes were 0.856 (AJCC, 0.795) in the Seoul St. Mary's cohort and 0.714 (AJCC, 0.648) in the University of Verona cohort. The nomogram performed well in the calibration and decision curve analyses when applied to both the internal and external validation cohorts. A stage‐specific subset survival analysis of the three risk groups calculated using the nomogram also showed the superiority of nomogram‐prediction when compared to AJCC.

Conclusion

This new pretreatment model accurately predicts OS in gastric cancer and can be used for patient counseling in clinical practice and stratification in clinical trials.
Development and validation of an immune‐related prognostic signature in lung adenocarcinoma
Authors: Sun Sijin , Guo Wei , Wang Zhen , Wang Xin , Zhang Guochao , Zhang Hao , Li Renda , Gao Yibo , Qiu Bin , Tan Fengwei , Gao Yushun , Xue Qi , Gao Shugeng , He Jie
Published: June 2020

Background

Lung adenocarcinomas (LUAD) is the most common histological subtype of lung cancers. Tumor immune microenvironment (TIME) is involved in tumorigeneses, progressions, and metastases. This study is aimed to develop a robust immune‐related signature of LUAD.

Methods

A total of 1774 LUAD cases sourced from public databases were included in this study. Immune scores were calculated through ESTIMATE algorithm and weighted gene co‐expression network analysis (WGCNA) was applied to identify immune‐related genes. Stability selections and Lasso COX regressions were implemented to construct prognostic signatures. Validations and comparisons with other immune‐related signatures were conducted in independent Gene Expression Omnibus (GEO) cohorts. Abundant infiltrated immune cells and pathway enrichment analyses were carried out, respectively, through ImmuCellAI and gene set enrichment analysis (GSEA).

Results

In Cancer Genome Atlas (TCGA) LUAD cohorts, immune scores of higher levels were significantly associated with better prognoses (P < .05). Yellow (n = 270) and Blue (n = 764) colored genes were selected as immune‐related genes, and after univariate Cox regression analysis (P < .005), a total of 133 genes were screened out for subsequent model constructions. A four‐gene signature (ARNTL2, ECT2, PPIA, and TUBA4A) named IPSLUAD was developed through stability selection and Lasso COX regression. It was suggested by multivariate and subgroup analyses that IPSLUAD was an independent prognostic factor. It was suggested by Kaplan‐Meier survival analysis that eight out of nine patients in high‐risk groups had significantly worse prognoses in validation data sets (P < .05). IPSLUAD outperformed other signatures in two independent cohorts.

Conclusions

A robust immune‐related prognostic signature with great performances in multiple LUAD cohorts was developed in this study.
Client attendance measures in counselling psychology trainees
Authors: Meier Scott T.
Published: June 2020

Counselling supervisors and educators have yet to reach a consensus about standard measures for evaluating the performance of graduate student therapists. Compared to self‐reports and rater judgements, client attendance records provide low‐inference behavioural data partially reflective of clients’ engagement with therapists. This naturalistic study evaluates client attendance data using archival records of 92 doctoral students in beginning and advanced counselling practica who produced data for 771 clients, 3,949 scheduled sessions and 3,186 attended sessions. Providing evidence of the sample representativeness for clinicians, results indicated that the mean number of sessions attended per client for student therapists (5.65) was very similar to that reported in the literature for outpatient therapists (<6). As expected because of structural differences in client assignment, beginning and advanced students evidenced statistically significant differences on attendance variables such as number of clients and scheduled sessions. In contrast, attendance ratios were equivalent across counsellor experience, suggesting that these individual difference variables could be useful for evaluation of therapist competencies related to client engagement.
Impact of lesion preparation strategies on outcomes of left main PCI: The EXCEL trial
Authors: Beohar Nirat , Chen Shmuel , Lembo Nicholas J. , Banning Adrian P. , Serruys Patrick W. , Leon Martin B. , Morice Marie‐Claude , Généreux Philippe , Kandzari David E. , Kappetein Arie Pieter , Sabik Joseph F. , Dressler Ovidiu , McAndrew Thomas , Zhang Zixuan , Stone Gregg W.
Published: June 2020

Objectives

We examined outcomes according to lesion preparation strategy (LPS) in patients with left main coronary artery (LMCA) percutaneous coronary intervention (PCI) in the EXCEL trial.

Background

The optimal LPS for LMCA PCI is unclear.

Methods

We categorized LPS hierarchically (high to low) as: (a) rotational atherectomy (RA); (b) cutting or scoring balloon (CSB); (c) balloon angioplasty (BAL); and d) direct stenting (DIR). The primary endpoint was 3‐year MACE; all‐cause death, stroke, or myocardial infarction.

Results

Among 938 patients undergoing LMCA PCI, RA was performed in 6.0%, CSB 9.5%, BAL 71.3%, and DIR 13.2%. In patients treated with DIR, BAL, CSB, and RA, respectively, there was a progressive increase in SYNTAX score, LMCA complex bifurcation, trifurcation or calcification, number of stents, and total stent length. Any procedural complication occurred in 10.4% of cases overall, with the lowest rate in the DIR (7.4%) and highest in the RA group (16.1%) (ptrend = .22). There were no significant differences in the 3‐year rates of MACE (from RA to DIR: 17.9%, 20.2%, 14.5%, 14.7%; p = .50) or ischemia‐driven revascularization (from RA to DIR: 16.8%, 10.8%, 12.3%, 14.2%; p = .65). The adjusted 3‐year rates of MACE did not differ according to LPS.

Conclusions

The comparable 3‐year outcomes suggest that appropriate lesion preparation may be able to overcome the increased risks of complex LMCA lesion morphology.
The contribution of fiber components to water absorption of wheat grown in the UK
Authors: Lovegrove Alison , Wood Abigail J. , Hassall Kirsty L. , Howes Liz , Poole Mervin , Tosi Paola , Shewry Peter
Published: June 2020

Background and objectives

The water absorption (WA) of white wheat flour is a major factor affecting processing quality, and millers, therefore, process their wheat to achieve the required level. Although it is likely that WA is determined by the amounts and compositions of three major grain components, starch, protein, and arabinoxylan, the contribution of the latter is not agreed and not recognized in the widely used Farrand equation.

Findings

We have measured a range of parameters related to fiber amount and composition and tested the ability of these to improve the prediction of WA using a modified Farrand equation. The addition of a range of single fiber traits improved the prediction of WA from a baseline of 82.98% to a maximum of 86.78%, but inclusion of all fiber traits as PCs resulted in a further improvement to 90%. Inclusion of the PCs also accounted for variation in WA between harvest years. The greatest improvement from inclusion of a single trait was observed with β‐glucan, the inclusion of arabinogalactan peptide (AGP) also resulted in improved prediction of WA.

Conclusions

The study shows that fiber components contribute to variation in WA, including differences between harvest years, but that β‐glucan and AGP have similar or greater impacts than AX.

Significance and novelty

The study dissects the contributions of AX amount and composition to WA and demonstrates a contribution of b‐glucan for the first time.
In vitro antioxidant and angiotensin I‐converting enzyme inhibitory properties of enzymatically hydrolyzed quinoa (Chenopodium quinoa) and kiwicha (Amaranthus caudatus) proteins
Authors: Chirinos Rosana , Pedreschi Romina , Velásquez‐Sánchez Margoth , Aguilar‐Galvez Ana , Campos David
Published: June 2020

Background and objectives

This study investigated the in vitro antioxidant and angiotensin I‐converting enzyme (ACE‐I) inhibitory properties of quinoa (QPH) and kiwicha (KPH) protein hydrolysates.

Findings

Enzymatic treatments with Neutrase for 120 min for quinoa and sequential Alcalase‐Neutrase hydrolysis for 240 min for kiwicha protein, both at 50°C, presented high antioxidant activities and ACE‐I inhibition (1.50 and 1.67 μmol TE/mg of protein and 89.2 and 72.8%, respectively) and the lowest IC50 values (0.08 and 0.29 mg/ml, respectively). After simulated gastrointestinal digestion (pepsin–pancreatin), both protein hydrolysates did not display significant changes in their antioxidant and ACE‐I inhibition properties.

Conclusions

The in vitro antioxidant and antihypertensive properties (ACE‐I inhibition) of QPH and KPH obtained via enzymatic hydrolysis using food‐grade commercial enzymes were demonstrated. In addition, tested in vitro bioactive properties did not change after simulated gastrointestinal digestion.

Significance and novelty

The results of this research might be used to obtain QPH and KPH with bioactive properties and/or as starting material for subsequent processes of separation and purification to obtain bioactive peptides.
Application of chemometrics to prediction of some wheat quality factors by near‐infrared spectroscopy
Authors: Williams Phil C.
Published: June 2020

Background and objectives

Physical quality parameters of wheat include kernel texture and test weight, which affect classification, grading, and price. Physicochemical factors are associated with flour functionality. The objective of the work was to determine the effectiveness with which these factors could be predicted in early generations using near‐infrared spectroscopy (NIRS). Wheat breeders need to know how their new genetic lines carry these factors, which carry no identifiable absorbers in the NIR region, can be predicted in early generations, by experts in the use of NIRS and its associated chemometrics.

Findings

With the exception of protein content, for which absorbers are plentiful, and was included to verify the spectral quality of the sample sets, none of the strictly physical factors could be reliably predicted with the most widely used chemometric options in the hands of experts in their use. Random forest algorithms were capable of prediction of all physicochemical factors, except Farinograph development time, with a reasonable degree of reliability.

Conclusions

Reliable predictions of quality factors in wheat that can be predicted by NIRS with satisfactory reliability are limited to chemical and physicochemical factors for which absorbers exist in the NIR region.

Significance and novelty

Chemical, physicochemical, and physical factors can be predicted with acceptable reliability by NIRS using a computerized spectrophotometer in association with Random Forest software. Farinograph development time remains a challenge for NIRS application.
A case of drug‐induced Stevens‐Johnson syndrome‐like eruption predominating in mucosa: A case report
Authors: Ishiguro Akihiro , Shibata Tomoyuki , Yanagishita Takeshi , Takama Hiroyuki , Uchida Rimi , Ohshima Yuichiro , Watanabe Daisuke
Published: June 2020

Atypical Stevens‐Johnson syndrome (SJS) is a variant of SJS with complete absence of or only few cutaneous manifestations. It usually affects children with Mycoplasma‐induced respiratory infection. It was unique because our case was induced by drug and occurred in an adult.
An Artificial Hemoprotein with Inducible Peroxidase‐ and Monooxygenase‐Like Activities
Authors: Kariyawasam Kalani , Di Meo Thibault , Hammerer Fabien , Valerio‐Lepiniec Marie , Sciortino Giuseppe , Maréchal Jean‐Didier , Minard Philippe , Mahy Jean‐Pierre , Urvoas Agathe , Ricoux Rémy
Published: June 2020

A novel inducible artificial metalloenzyme obtained by covalent attachment of a manganese(III)‐tetraphenylporphyrin (MnTPP) to the artificial bidomain repeat protein, (A3A3′)Y26C, is reported. The protein is part of the αRep family. The biohybrid was fully characterized by MALDI‐ToF mass spectrometry, circular dichroism and UV/Vis spectroscopies. The peroxidase and monooxygenase activities were evaluated on the original and modified scaffolds including those that have a) an additional imidazole, b) a specific αRep bA3‐2 that is known to induce the opening of the (A3A3′) interdomain region and c) a derivative of the αRep bA3‐2 inducer extended with a His6‐Tag (His6‐bA3‐2). Catalytic profiles are highly dependent on the presence of co‐catalysts with the best activity obtained with His6‐bA3‐2. The entire mechanism was rationalized by an integrative molecular modeling study that includes protein–ligand docking and large‐scale molecular dynamics. This constitutes the first example of an entirely artificial metalloenzyme with inducible peroxidase and monooxygenase activities, reminiscent of allosteric regulation of natural enzymatic pathways.
LGBTQ+ in STEM: Visibility and Beyond
Authors: Unsay Joseph D.
Published: June 2020

Lesbian, gay, bisexual, trans, queer (LGBTQ+, “+”=plus other sexes, gender identities, and sexual orientation) people in the STEM fields (STEM=science, technology, engineering, and mathematics) continue to experience discrimination in their workplace. In the last decade, the clamor for safe and diverse spaces continue to rise. Indeed, social media plays a huge part on increasing visibility of the LGBTQ+ community in STEM. LGBTQ+ scientists have not only promoted discourse and raised concerns to the online community, but more importantly, supported each other in platforms such as Twitter. Beyond social media, work at the institutes by LGBTQ+ individuals are also bearing fruit. This piece explores the grassroots work of scientists as they work hand‐in‐hand with their institute staff and leadership to promote diversity and inclusivity within and beyond their community.
Simulation of binary particle segregation for bubbling fluidized beds using polydispersed structure‐based drag model extended from a monodispersed model
Authors: Jia Jibin , Li Hongzhong , Zou Zheng , Liu Wenming , Zhu Qingshan
Published: June 2020

A bubble structure‐based drag model developed for the monodispersed system has been extended to simulate bi‐dispersed bubbling fluidized beds. Both dense phase and dilute phase are considered to be comprised of two types of particles with different sizes. The derivation of the structure‐based drag coefficient for individual particle based on the force equilibrium principle is proved to be independent of the volume fractions (εsi) of particle i. The multi‐fluid model in the commercial software Ansys Fluent is employed to evaluate the polydispersed drag model for the segregation of binary gas‐particle flows in a bubbling fluidized bed. It is shown that the simulation results predicted by the new structure‐based drag model are in reasonable agreement with experimental data with a 6.34% root mean square error (RMSE). The new structure‐based model can capture the particle distribution at the top region of the fluidized bed well. The bubble behaviour can also be captured by the new model well.
Development of Biomimetic Synthesis of Propindilactone G†
Authors: Wang Yu , Chen Bo , He Xubiao , Gui Jinghan
Published: June 2020

Summary of main observation and conclusion

The natural product propindilactone G is a complex Schisandra nortriterpenoid with a unique 5/5/7/6/5 pentacyclic framework. This full paper describes the development of concise biomimetic synthesis of propindilactone G from a known steroid lactone. The key C19‐OH intermediate was synthesized via Breslow and Suárez radical remote C—H functionalizations. Wagner‐Meerwein rearrangement was subsequently utilized for the expansion of the B ring. To invert the configuration of the C10 tertiary alcohol, an intramolecular peroxide cyclization catalyzed by BF3·Et2O was devised. The 5/5 fused lactone system was then assembled in a biomimetic transesterification/oxa‐Michael addition sequence. Our work should provide experimental support for the proposed biosynthetic pathway and facilitate investigation of the biological activities of propindilactone G.
Hypothesis‐free deep survival learning applied to the tumour microenvironment in gastric cancer
Authors: Meier Armin , Nekolla Katharina , Hewitt Lindsay C , Earle Sophie , Yoshikawa Takaki , Oshima Takashi , Miyagi Yohei , Huss Ralf , Schmidt Günter , Grabsch Heike I
Published: June 2020

The biological complexity reflected in histology images requires advanced approaches for unbiased prognostication. Machine learning and particularly deep learning methods are increasingly applied in the field of digital pathology. In this study, we propose new ways to predict risk for cancer‐specific death from digital images of immunohistochemically (IHC) stained tissue microarrays (TMAs). Specifically, we evaluated a cohort of 248 gastric cancer patients using convolutional neural networks (CNNs) in an end‐to‐end weakly supervised scheme independent of subjective pathologist input. To account for the time‐to‐event characteristic of the outcome data, we developed new survival models to guide the network training. In addition to the standard H&E staining, we investigated the prognostic value of a panel of immune cell markers (CD8, CD20, CD68) and a proliferation marker (Ki67). Our CNN‐derived risk scores provided additional prognostic value when compared to the gold standard prognostic tool TNM stage. The CNN‐derived risk scores were also shown to be superior when systematically compared to cell density measurements or a CNN score derived from binary 5‐year survival classification, which ignores time‐to‐event. To better understand the underlying biological mechanisms, we qualitatively investigated risk heat maps for each marker which visualised the network output. We identified patterns of biological interest that were related to low risk of cancer‐specific death such as the presence of B‐cell predominated clusters and Ki67 positive sub‐regions and showed that the corresponding risk scores had prognostic value in multivariate Cox regression analyses (Ki67&CD20 risks: hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.15–1.89,p= 0.002; CD20&CD68 risks: HR = 1.33, 95% CI = 1.07–1.67,p= 0.009). Our study demonstrates the potential additional value that deep learning in combination with a panel of IHC markers can bring to the field of precision oncology.
Review paper on WPW and athletes: Let sleeping dogs lie?
Authors: Leung Lisa W.M. , Gallagher Mark M.
Published: June 2020

Accessory pathways are present in 1 in 300 young individuals. They are often asymptomatic and potentially lethal arrhythmias may be the first presentation. During long‐term follow‐up, up to 20% of asymptomatic individuals with pre‐excitation go on to develop an arrhythmia and the absence of traditional clinical and electrophysiological high‐risk markers does not guarantee the “safe” nature of an accessory pathway. The widespread availability of permanent cure for the condition at low risk by catheter ablation, creates an incentive to screen for accessory pathways with a 12‐lead ECG, particularly in individuals who are perceived to be at increased risk, such as athletes and high‐risk professions. We review the existing literature on the assessment and management of accessory pathways (Wolff‐Parkinson‐White [WPW] syndrome) and discuss its implications for the young athletic population.
Effects of Multiple‐Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin
Authors: Sidharta Patricia N. , Dingemanse Jasper
Published: June 2020

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult‐to‐control (resistant) hypertension. The drug‐drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single‐center, open‐label, single‐sequence study. Twenty healthy male subjects received a single dose of 10‐mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration–time curve from time 0 to time t and area under the plasma concentration–time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25.

Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.
Humanized Mouse Models for Evaluation of PSC Immunogenicity
Authors: Hermsen Jack , Brown Matthew E.
Published: June 2020

New human pluripotent stem cell (hPSC)‐derived therapies are advancing to clinical trials at an increasingly rapid pace. In addition to ensuring that the therapies function properly, there is a critical need to investigate the human immune response to these cell products. A robust allogeneic (or autologous) immune response could swiftly eliminate an otherwise promising cell therapy, even in immunosuppressed patients. In coming years, researchers in the regenerative medicine field will need to utilize a number of in vitro and in vivo assays and models to evaluate and better understand hPSC immunogenicity. Humanized mouse models—mice engrafted with functional human immune cell types—are an important research tool for investigating the mechanisms of the adaptive immune response to hPSC therapies. This article provides an overview of humanized mouse models relevant to the study of hPSC immunogenicity and explores central considerations for investigators seeking to utilize these powerful models in their research. © 2020 Wiley Periodicals LLC.
Design of low power approximate floating‐point adders
Authors: Omidi Reza , Sharifzadeh Sepehr
Published: June 2020

Due to the increasing demands for more power in data intensive computing, low power design methodologies play a very important role in these systems. For noncritical data, the approximate computing that significantly reduces the power can be used. In this paper, an approximate floating‐point adder is proposed by designing an inexact mantissa adder and exponent subtractor. The results indicate that the power consumption and delay of the proposed approximate floating‐point adder have been decreased by 37% and 62% compared with the IEEE‐754 single‐precision floating‐point (FP) adder. Furthermore, compared with a state‐of‐the‐art inexact floating‐point adder, the proposed method provides an improvement of 7% and 21% in terms of the power consumption and delay. In addition, the proposed floating‐point adder has been investigated in terms of error, and the mean error of the proposed floating‐point adder at worst is about 55% less than that of another approximate floating‐point adder considered in this work. High dynamic range (HDR) images are processed using the proposed approximate floating‐point adders to show the performance of the proposed adder. The results show that, on average, peak signal‐to‐noise ratio increased by 9.6 and 18.64 dB, which may be achieved by utilizing the proposed floating‐point adder.
Analysis of alert message propagation on the highway in VANET assuming Markovian vehicle arrival process
Authors: Mahmood Dhari Ali , Horvath Gabor
Published: June 2020

Vehicular ad hoc networks (VANETs) provide the infrastructure for the intelligent transportation system (ITS). The number of vehicles that are capable of communicating with each other through VANET is increasing. In this paper, we provide several analytical results regarding the message propagation on the highway in VANET. In our scenario, there is a stationary message source (i.e., alert messages are generated at an accident). Vehicles can receive the message and get informed when they reach the radio transmission range of the message source or another informed vehicle. Most papers published on the analysis of message propagation assume that the inter arrival times between vehicles follow a Poisson process; there are very few results available with more general traffic model. In this paper, we show that the Poisson process is not always suitable for modeling vehicle traffic. Instead of the Poisson process, we propose to use the more general Markovian arrival process (MAP) to model the vehicle headway times and derive the probability that the message propagates beyond a certain distance from the accident under this traffic assumption. Through several numerical examples, we demonstrate how much the statistics of the vehicle arrival process impacts the message propagation distance.
Cytomorphology of Mycobacterium avium intracellulare‐associated ascites
Authors: Satturwar Swati , Pantanowitz Liron , Xing Juan , Schoedel Karen , Weber David , Monaco Sara E.
Published: June 2020

Ascites due to Mycobacterium avium intracellulare (MAI) infection is extremely rare and associated with a poor outcome. The cytomorphology of this condition has not been previously reported. We present a unique case of a 45‐year‐old woman with iatrogenic immunodeficiency who developed MAI‐associated chylous ascites. The ascitic fluid cytology showed numerous lymphocytes and foamy histiocytes with abundant intracytoplasmic MAI organisms. The diagnosis was confirmed by tissue biopsy showing MAI mesenteritis. It is important to consider MAI‐associated ascites in the differential diagnosis whenever ascitic fluid shows a predominant population of lymphocytes and macrophages, especially in immunocompromised patients.
Association between circulating follistatin‐like‐1 and metabolic syndrome in middle‐aged and old population: A cross‐sectional study
Authors: Yang Shan , Dai Han , Hu Wenjing , Geng Shan , Li Ling , Li Xinrun , Liu Hua , Liu Dongfang , Li Ke , Yang Gangyi , Yang Mengliu
Published: June 2020

Aim

Follistatin‐like‐1 (FSTL‐1) is considered to be a novel cytokine, and it is associated with metabolic diseases. However, it is necessary to investigate further the association of FSTL‐1 with metabolic syndrome (MetS) and insulin resistance (IR). We performed a cross‐sectional study to investigate the associated of circulating FSTL‐1 with the MetS.

Materials and methods

A cross‐sectional study was performed in 487 Chinese people, including 231 control subjects and 256 patients with MetS. Bioinformatics analysis was used to determine the protein and pathways associated with FSTL‐1. The protein and protein interaction (PPI) network was constructed and analysed. Serum FSTL‐1 concentrations were determined by an ELISA assay. The association of FSTL‐1 with MetS components and IR was assessed.

Results

Serum FSTL‐1 levels were markedly higher in patients with newly diagnosed MetS than in controls (7.5 [5.6‐9.2] vs 5.8 [5.0‐7.7] μg/L, P < .01). According to bioinformatics analysis, the top high‐degree genes were identified as the core genes, including SPARCL1, CYR61, LTBP1, IL‐6, BMP2, BMP4, FBN1, FN1 CHRDL1 and FSTL‐3. These genes are mainly enriched in pathways including TGF‐ß, AGE‐RAGE signalling pathway in diabetic complications, and Hippo signalling pathways; in basal cell carcinoma, cytokine‐cytokine receptor interaction and in amoebic and Yersinia infections. Furthermore, serum FSTL‐1 levels were positively associated with fasting plasma glucose (FPG), waist circumference (WC), blood pressure, triglyceride levels and visceral adiposity index (VAI). We found that serum FSTL‐1 levels were markedly associated with MetS and IR by binary logistic regression analysis.

Conclusions

We conclude that FSTL‐1 may be a novel cytokine related to MetS and IR.
Hydroxychloroquine, COVID‐19 and diabetes. Why it is a different story
Authors: Stoian Anca Pantea , Catrinoiu Doina , Rizzo Manfredi , Ceriello Antonio
Published: June 2020

Hydroxychloroquine has been proposed for the cure of the COVID‐19 due to its anti‐inflammatory and anti‐viral action. People with diabetes are more prone to severe outcome if affected by COVID‐19 and the use of Hydroxychloroquine might have some benefit in this setting. However, the use of Hydroxychloroquine in diabetes deserves particular attention for its documented hypoglycemic action.
Application of a chiral high‐performance liquid chromatography‐tandem mass spectrometry method for the determination of 13 related amphetamine‐type stimulants to forensic samples: Interpretative hypotheses
Authors: Schwelm Hannes M. , Grumann Christina , Auwärter Volker , Neukamm Merja A.
Published: June 2020

Interpretation of amphetamine‐type stimulant (ATS) findings in urine samples can be challenging without chiral information. We present a sensitive enantioselective high‐performance liquid chromatography–tandem mass spectrometry method for the quantification of (R)‐amphetamine, (S)‐amphetamine, (R)‐methamphetamine, (S)‐methamphetamine, (1R,2R)‐pseudoephedrine, (1S,2S)‐pseudoephedrine, (1R,2S)‐ephedrine, (1S,2R)‐ephedrine, (1R,2S)‐norephedrine, (1S,2R)‐norephedrine, (R)‐cathinone, (S)‐cathinone, and (1S,2S)‐norpseudoephedrine (cathine) in urine. The method was successfully applied to more than 100 authentic urine samples from forensic casework. In addition, samples from a controlled self‐administration of (1S,2S)‐pseudoephedrine (Rinoral, 1200 mg within 6 days) were analyzed. The results strengthen the hypothesis that (1R,2S)‐norephedrine is a minor metabolite of amphetamine and methamphetamine. We suggest cathine and (1S,2R)‐norephedrine as minor metabolites of amphetamine racemate in humans. Small methamphetamine concentrations detected in samples with high concentrations of amphetamine could result from a metabolic formation by methylation of amphetamine although in samples with an (R)/(S) ratio for methamphetamine < 1 an additional (previous) (S)‐methamphetamine consumption seems likely. Our data suggest that even amphetamine concentrations exceeding methamphetamine concentrations in urine can be caused by the biotransformation of methamphetamine to amphetamine as long as no (R)‐amphetamine is detected. However, without chiral information, such findings might be (falsely) assumed as a co‐consumption of both substances. Cathinone enantiomers detected in urine samples with high amphetamine concentrations can be interpreted as metabolites of amphetamine. In addition, the results of the self‐administration study revealed that both cathinone enantiomers are minor metabolites of (1S,2S)‐pseudoephedrine, which is the active ingredient of various medicines used for cold. The enantioselective analysis is a powerful tool to avoid the misinterpretation of ATS findings in urine samples.
Acknowledging uncertainty in evolutionary reconstructions of ecological niches
Authors: Owens Hannah L. , Ribeiro Vivian , Saupe Erin E. , Cobos Marlon E. , Hosner Peter A. , Cooper Jacob C. , Samy Abdallah M. , Barve Vijay , Barve Narayani , Muñoz‐R. Carlos J. , Peterson A. Townsend
Published: June 2020

Reconstructing ecological niche evolution can provide insight into the biogeography and diversification of evolving lineages. However, comparative phylogenetic methods may infer the history of ecological niche evolution inaccurately because (a) species' niches are often poorly characterized; and (b) phylogenetic comparative methods rely on niche summary statistics rather than full estimates of species' environmental tolerances. Here, we propose a new framework for coding ecological niches and reconstructing their evolution that explicitly acknowledges and incorporates the uncertainty introduced by incomplete niche characterization. Then, we modify existing ancestral state inference methods to leverage full estimates of environmental tolerances. We provide a worked empirical example of our method, investigating ecological niche evolution in the New World orioles (Aves: Passeriformes: Icterus spp.). Temperature and precipitation tolerances were generally broad and conserved among orioles, with niche reduction and specialization limited to a few terminal branches. Tools for performing these reconstructions are available in a new R package called nichevol.
Western bumble bee: declines in the continental United States and range‐wide information gaps
Authors: Graves Tabitha A. , Janousek William M. , Gaulke Sarah M. , Nicholas Amy C. , Keinath Douglas A. , Bell Christine M. , Cannings Syd , Hatfield Richard G. , Heron Jennifer M. , Koch Jonathan B. , Loffland Helen L. , Richardson Leif L. , Rohde Ashley T. , Rykken Jessica , Strange James P. , Tronstad Lusha M. , Sheffield Cory S.
Published: June 2020

In recent decades, many bumble bee species have declined due to changes in habitat, climate, and pressures from pathogens, pesticides, and introduced species. The western bumble bee (Bombus occidentalis), once common throughout western North America, is a species of concern and will be considered for listing by the U.S. Fish and Wildlife Service (USFWS) under the Endangered Species Act (ESA). We attempt to improve alignment of data collection and research with USFWS needs to consider redundancy, resiliency, and representation in the upcoming species status assessment. We reviewed existing data and literature on B. occidentalis, highlighting information gaps and priority topics for research. Priorities include increased knowledge of trends, basic information on several life‐history stages, and improved understanding of the relative and interacting effects of stressors on population trends, especially the effects of pathogens, pesticides, climate change, and habitat loss. An understanding of how and where geographic range extent has changed for the two subspecies of B. occidentalis is also needed. We outline data that could be easily collected in other research projects that would increase their utility for understanding range‐wide trends of bumble bees. We modeled the overall trend in occupancy from 1998 to 2018 of Bombus occidentalis within the continental United States using existing data. The probability of local occupancy declined by 93% over 21 yr from 0.81 (95% CRI = 0.43, 0.98) in 1998 to 0.06 (95% CRI = 0.02, 0.16) in 2018. The decline in occupancy varied spatially by landcover and other environmental factors. Detection rates vary in both space and time, but peak detection across the continental United States occurs in mid‐July. We found considerable spatial gaps in recent sampling, with limited sampling in many regions, including most of Alaska, northwestern Canada, and the southwestern United States. We therefore propose a sampling design to address these gaps to best inform the ESA species status assessment through improved assessment of how the spatial distribution of stressors influences occupancy changes. Finally, we request involvement via data sharing, participation in occupancy sampling with repeated visits to distributed survey sites, and complementary research to address priorities outlined in this paper.
Nano‐Ferric Oxide Embedded in Graphene Oxide: High‐performance Electrocatalyst for Nitrogen Reduction at Ambient Condition
Authors: Wang Fei , Xia Lixue , Li Xin , Yang Weixiang , Zhao Yan , Mao Jian
Published: June 2020

Nitrogen (N2) fixation at ambient condition by electrochemical N2 reduction reaction (NRR) is energy‐efficient and eco‐friendly as compared to the traditional Harber–Bosch process, but it is extremely challenging. Development and design of high‐performance NRR electrocatalysts are indispensable to achieve the goal. In this work, a strongly coupled hybrid of nano‐Fe3O4 with reduced graphene oxide (rGO) is synthesized via an in situ redox hydrothermal approach, and the synthesized Fe3O4@rGO hybrid has excellent activity, selectivity, and stability as an NRR catalyst. The NH3 yield rate of 28.01 μg h‐1 mg‐1 at −0.3 V and the Faradaic efficiency (FE) of 19.12% at −0.1 V are obtained in 0.1 M Na2SO4 solutions at ambient conditions. The superior NRR performance is attributed to the chemical coupling effect between rGO and nano‐Fe3O4 particles, which leads to the enhancement of the binding affinity to N2 molecules, improvement of the conductivity, and lowering the free energy of reaction for the limiting reaction step. This work provides a facile route in fabricating hybrid NRR catalysts with superior performance and shed lights on the reaction mechanism with theoretical mechanistic calculations.
Growth differentiation factor 15 as mortality predictor in heart failure patients with non‐reduced ejection fraction
Authors: Mendez Fernandez Ana Belen , Ferrero‐Gregori Andreu , Garcia‐Osuna Alvaro , Mirabet‐Perez Sonia , Pirla‐Buxo Maria Jose , Cinca‐Cuscullola Juan , Ordonez‐Llanos Jordi , Roig Minguell Eulàlia
Published: June 2020

Aims

The prognostic value of biomarkers in patients with heart failure (HF) and mid‐range (HFmrEF) or preserved ejection fraction (HFpEF) has not been widely addressed. The aim of this study was to assess whether the prognostic value of growth differentiation factor 15 (GDF‐15) is superior to that of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) in patients with HFmrEF or HFpEF.

Methods and results

Heart failure patients with either HFpEF or HFmrEF were included in the study. During their first visit to the HF unit, serum samples were obtained and stored for later assessment of GDF‐15 and NT‐proBNP concentrations. Patients were followed up by the HF unit. The main endpoint was all‐cause mortality. A total of 311 patients, 90 (29%) HFmrEF and 221 (71%) HFpEF, were included. Mean age was 72 ± 13 years, and 136 (44%) were women. No differences were found in GDF‐15 or NT‐proBNP concentrations between both HF groups. During a median follow‐up of 15 months (Q1–Q3: 9–30 months), 98 patients (32%) died, most (71%) of cardiovascular causes. Patients who died had higher median concentrations of GDF‐15 (4085 vs. 2270 ng/L, P < 0.0001) and NT‐proBNP (1984 vs. 1095 ng/L, P < 0.0001). A Cox multivariable model identified New York Heart Association Functional Class III (P = 0.04), systolic blood pressure (P = 0.01), left atrial diameter (P = 0.03), age >65 years (P < 0.0001), and GDF‐15 concentrations (P = 0.01) but not NT‐proBNP as independent predictors of all‐cause mortality. The area under the curve was 0.797 for the basic model including NT‐proBNP, and the area under the curve comparing the overall model was 0.819, P = 0.016 (DeLong's test). Integrated discrimination improvement index after the inclusion of GDF‐15 in the model with the mortality risk factors was 0.033; that is, the ability to predict death increased by 3.3% (P = 0.004). Net reclassification improvement was 0.548 (P < 0.001); that is, the capacity to improve the classification of the event (mortality) was 54.8%. GDF‐15 concentrations were divided in tertiles (<1625, 1625–4330, and >4330 ng/L), and survival curves were evaluated using the Kaplan–Meier technique. Patients in the highest tertile had the poorest 5 year survival, at 16%, whereas the lowest tertile had the best survival, of 78% (P < 0.001).

Conclusions

Growth differentiation factor 15 was superior to NT‐proBNP for assessing prognosis in patients with HFpEF and HFmrEF. GDF‐15 emerges as a strong, independent biomarker for identifying HFmrEF and HFpEF patients with worse prognosis.
Left‐dominant arrhythmogenic cardiomyopathy with a nonsense mutation in DSP
Authors: Tsuruta Yuichiro , Sueta Daisuke , Takashio Seiji , Oda Seitaro , Sakamoto Kenij , Kaikita Koichi , Kato Koichi , Ohno Seiko , Horie Minoru , Tsujita Kenichi
Published: June 2020

A 74‐year‐old man had abnormal left ventricular (LV) function according to a perioperative test at a local hospital and was transferred to our institution for further evaluation and treatment. His electrocardiogram demonstrated the presence of premature ventricular contraction with a QRS complex of the right bundle branch block type and superior axis. His echocardiography showed systolic dysfunction of the LV (LV ejection fraction, 44.6%). Cardiac computed tomography imaging revealed banded and patchy densities observed frequently from the middle to epicardial layer of the LV wall. Cardiac magnetic resonance imaging showed fat signals on fat‐selective images and late gadolinium enhancement in the mid‐wall to subepicardial layers in the LV myocardium. Endomyocardial biopsy revealed the histological presence of fibrofatty replacement. A genetic analysis revealed a nonsense mutation in the desmoplakin gene. Thus, he was diagnosed with left‐dominant arrhythmogenic cardiomyopathy. To prevent fatal ventricular arrhythmias, an implantable cardioverter defibrillator was successfully implanted.