bluuebunny/crossref_metadata_2025 huggingface dataset:
Technologie‐Migranten aus der Fabrikautomation
Authors: Aust Alexander
Published: April 2021

Pepperl+Fuchs hat Hightech‐Sensoren, die sich in diskreten Anwendungen bewährt haben, mittels Ex‐Schutz für die Verfahrenstechnik in den Zonen 1/21 und 2/22 fit gemacht.
Ringsysteme neu gedacht
Authors: Equit Alexander
Published: April 2021

In der pharmazeutischen und biotechnischen Industrie steigt der Druck, Anlagen zu optimieren und neue Verfahren in der Produktion zu etablieren. Der demografische Wandel und der daraus resultierende Fachkräftemangel werden diese Entwicklung verstärken. Zu
Maschinen überwachen
Authors: Ikan Amal
Published: April 2021

Mit dem Überwachungssystem i‐ALERT2 werden jetzt fast alle Baureihen der Rheinhütte Pumpen ausgestattet. Unzulässige Betriebszustände können so rechtzeitig erkannt werden
Ferndosierung
Authors: Schmitz Dirk
Published: April 2021

Die App Chempairing Suite ist ein Remote Access‐Tool, das sich als Grundlage attraktiver digitaler Geschäftsmodelle bspw. für die Chemikalien‐Distribution eignet.
Hochleistungs‐Wälzkolbenpumpen
Authors: Würz Andreas
Published: April 2021

Die Wälzkolbenpumpen HiLobe bieten ein breites Spektrum an Saugvermögen und Einsatzmöglichkeiten. Sie decken zahlreiche industrielle Vakuumanwendungen wie Elektronenstrahlschweißen, Vakuumöfen oder Gefriertrocknung ab. Durch ihre individuelle Drehzahlrege
Erdgasförderung vor der Küste Afrikas
Authors: Kochenburger Nicole
Published: April 2021

Lewa Nikkiso America erhielt den Auftrag, sechs Triplex‐Pumpen des Typs G3U mit M800‐Pumpenkopf für eine Unterwasser‐Anlage zur Gastrocknung zu liefern.
Intelligent integriert
Authors: Rockmann Ina
Published: April 2021

Die Aufbereitung von Druckluft mittels Kältetrockner gehört mittlerweile zum Standard in vielen Anwendungsbereichen. Die neuen Schraubenkompressoren mit integriertem Trockner von Boge sind in den Leistungsbereichen von 55 bis 110 kW erhältlich. Anwender p
Radikal verbessert
Authors: Mendiberry William
Published: April 2021

Atlas Copco hat eine Serie Drucklufttrockner vorgestellt, die mit dem neuen strukturierten Trockenmittel Cerades arbeiten. Die Produktreihe mit der Typenbezeichnung CD 20+‐335+ bietet dem Druckluftanwender eine deutlich bessere Luftqualität, niedrigere En
Circularly Polarized Luminescence from Chiral p‐Terphenylene‐Based Supramolecular Aggregates
Authors: Xie Titi , Yuan Wei , Li Xiaopei , Li Mengwei , Chen Yulan
Published: April 2021

Main observation and conclusion

Circularly polarized luminescent (CPL) materials with intense emission and high luminescence dissymmetry factor (glum) are highly desirable for their promising applications in communication technologies, nanotechnologies, innovative materials, etc. Motivated by benefits in supramolecular chemistry and aggregation‐induced emission (AIE) materials for the development of advanced luminescent materials, herein, we report a new class of CPL‐active AIE luminogens (AIEgens) by incorporating the p‐terphenylene (TP) with chiral alkoxyl chains. Aggregation‐induced emission and supramolecular chirality have been realized by hierarchical self‐assembly of these TP cored coil‐rod‐coil molecules under the synergistic effect of π‐π stacking, hydrogen bonding and van der Waals forces. Helical nanofibers with length up to several microns and tunable handedness in different condensed states, such as in poor solvents, thin films and gel states are produced, which exhibit strong CPL signals (glum) of ca. 10–2 and fluorescence quantum yields up to 56.7%. The well‐defined one‐component self‐assembly of AIEgens from a concise molecular design is expected to pave a general avenue to fabricate chiroptical materials with both strong emission and high glum, which would be practically important for advanced modern technologies.
Multifunctional Fire‐Resistant Paper Based on Ultralong Hydroxyapatite Nanowires†
Authors: Zhu Ying‐Jie
Published: April 2021

Paper was one of the greatest inventions in ancient China, and it greatly promoted the rapid development of human civilization. Even in today's electronic information age, paper and paper‐derived products are still indispensable to people's daily work and life. However, the traditional paper based on cellulose fibers from plants has some problems. For instance: (1) papermaking consumes a large amount of precious natural resources such as trees; (2) the papermaking industry causes environmental pollution; (3) the traditional paper consisting of organic cellulose fibers is highly flammable and easy to burn; (4) the traditional paper based on cellulose fibers turns to yellow color with time; (5) the lifetime of the traditional paper is relatively short because of the degradation of cellulose fibers. More efforts are needed to investigate and solve these problems facing the traditional paper. In recent years, a new kind of multifunctional fire‐resistant paper based on ultralong hydroxyapatite nanowires has been developed and investigated for various applications, and many research findings have been documented in the literature. This review article provides a comprehensive summary and discussion on recent research advances for this new kind of multifunctional fire‐resistant paper based on ultralong hydroxyapatite nanowires, including the synthesis, properties, applications, and future perspectives.
Surface expression of the immunotherapeutic target GD2 in osteosarcoma depends on cell confluency
Authors: Wiebel Malena , Kailayangiri Sareetha , Altvater Bianca , Meltzer Jutta , Grobe Kay , Kupich Sabine , Rossig Claudia
Published: April 2021

Background

Chimeric antigen receptor (CAR) T‐cell therapy of pediatric sarcomas is challenged by the paucity of targetable cell surface antigens. A candidate target in osteosarcoma (OS) is the ganglioside GD2, but heterogeneous expression of GD2 limits its value.

Aim

We aimed to identify mechanisms that upregulate GD2 target expression in OS.

Methods and results

GD2 surface expression in OS cells, studied by flow cytometry, was found to vary both among and within individual OS cell lines. Pharmacological approaches, including inhibition of the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) and modulation of the protein kinase C, failed to increase GD2 expression. Instead, cell confluency was found to be associated with higher GD2 expression levels both in monolayer cultures and in tumor spheroids. The sensitivity of OS cells to targeting by GD2‐specific CAR T cells was compared in an in vitro cytotoxicity assay. Higher cell confluencies enhanced the sensitivity of OS cells to GD2‐antigen specific, CAR T‐cell‐mediated in vitro cytolysis. Mechanistic studies revealed that confluency‐dependent upregulation of GD2 expression in OS cells is mediated by increased de novo biosynthesis, through a yet unknown mechanism.

Conclusion

Expression of GD2 in OS cell lines is highly variable and associated with increasing cell confluency in vitro. Strategies for selective upregulation of GD2 are needed to enable effective therapeutic targeting of this antigen in OS.
Differential diagnosis of borderline personality disorder and bipolar disorder: Self‐concept, identity and self‐esteem
Authors: Wright Livia , Lari Lisa , Iazzetta Stefania , Saettoni Marco , Gragnani Andrea
Published: April 2021

Symptoms of borderline personality disorder (BPD) and bipolar disorder (BD) often overlap. In some cases, it is difficult to conduct a differential diagnosis based only on current diagnostic criteria Therefore, it is important to find clinical factors with high discriminatory specificity that, used together with structured or semi‐structured interviews, could help improve diagnostic practice.

We propose that a clinical analysis of identity, self‐concept and self‐esteem may help distinguish the two disorders, when they are not co‐morbid. Our review of the studies that analyse these constructs in BD and BPD, separately, points in the direction of qualitative differences between the two disorders. In BPD, there is a well‐documented identity diffusion, and the self‐concept appears predominantly negative; shifts in self‐concept and self‐esteem are often tied to interpersonal triggers. In BD, patients struggle with their identity, but narrative identity might be less compromised compared with BPD; the shifts in self‐concept and self‐esteem appear more linked to internal (i.e. mood and motivational) factors. We end the paper by discussing the implications for clinicians and ideas for future comparative research.
Evaluation of Switch‐to‐Brand Rates as a Potential Signal for Therapeutic Equivalency of Generic Antidepressants: A Real‐World Retrospective Cohort Study
Authors: Kalaria Shamir , Spence O’Mareen , Hong Kyungwan , dosReis Susan , Gopalakrishnan Mathangi
Published: April 2021

Negative clinical outcomes after switching from brand to generic antidepressants have raised concerns regarding therapeutic equivalency. This research aims to estimate the prevalence of switching and to identify predictors for generic to brand switching for various antidepressants. This retrospective cohort study utilized data from a 10% random sample of enrollees in the IQVIA PharMetrics Plus claims database from 2007–2015. The base cohort consisted of commercially insured patients who were prescribed escitalopram, duloxetine, or venlafaxine extended release (ER) anytime from the year prior to the generic launch through December 2014. The primary outcome was defined as a switch from generic to a brand within 14 days of sustained generic use in a 1‐year follow‐up period. Adjusted logistic regression and generalized estimating equations for repeated measures estimated the drug specific and overall odds of switch‐to‐brand among brand initiators relative to generic initiators, respectively. A total of 102,831 unique patients across 3 drug products contributed to the final analytic sample. The overall prevalence of switch from generic to brand was 0.74%. Across all three antidepressants, brands initiators were more likely to experience a switch‐to‐brand: escitalopram (odds ratio (OR): 14.41, 95% confidence interval (CI): 11.14–18.64), duloxetine (OR: 8.08, 95% CI: 4.85–13.41) and venlafaxine ER (OR: 16.46, 95% CI: 11.56–23.46). The pooled odds of a switch‐to‐brand in brand vs. generic initiators was 13.77 (95% CI: 11.35–16.71). This study suggests a low overall switch‐to‐brand prevalence and may support therapeutic equivalence between brand and generic antidepressants. Initiating with a brand product was the strongest predictor for switching back to brand and suggests that patient experience may play a role in drug utilization.
Banks and environmental, social and governance drivers: Follow the market or the authorities?
Authors: La Torre Mario , Leo Sabrina , Panetta Ida Claudia
Published: April 2021

This paper goes beyond the relationship between a bank ESG performance (ESGP) and corporate financial performance (CFP). Here, the link between ESG factors and financial benchmarks is analysed to verify whether banks may find in the market reaction sufficient stimuli (higher CFP) to adopt ESG conduct spontaneously. Using panel estimation methods on European banks listed in STOXX Europe 600, between 2008 and 2019, this paper tests the relationship between ESGP and CFP considering different dimensions of financial performance at once, both accounted‐based (ROA and ROE) and market‐based (Capitalisation to Book Value, Tobin's Q). Besides, we employ VBM (EVA Spread) not previously considered. The main findings support the current approach of banking authorities, focusing on bank ESG risks, more than ESG opportunities, in order to “force” banks into adopting a new ESG business model, at this early stage of transition to sustainability.
Complement factor D haplodeficiency is associated with a reduced complement activation speed and diminished bacterial killing
Authors: Langereis Jeroen D , van der Molen Renate G , de Kat Angelino Corrie , Henriet Stefanie S , de Jonge Marien I , Joosten Irma , Simons Annet , Schuurs‐Hoeijmakers Janneke HM , van Deuren Marcel , van Aerde Koen , van der Flier Michiel
Published: April 2021

Objectives

Complete deficiency of alternative pathway (AP) complement factors, explained by homozygous mutations, is a well‐known risk factor for invasive bacterial infections; however, this is less obvious for heterozygous mutations. We describe two siblings with a heterozygous NM_001928.3(CFD):c.125C>A p.(Ser42*) mutation in the complement factor D (fD) gene having a history of recurrent bacterial infections. We determined the effect of heterozygous fD deficiency on AP complement activity.

Methods

We determined the effect of fD levels on complement activation as measured by AP activity, complement C3 binding to the bacterial surface of Neisseria meningitidis (Nm), Streptococcus pneumoniae (Sp) and non‐typeable Haemophilus influenzae (NTHi), and complement‐mediated killing of Nm and NTHi. In addition, we measured the effect of vaccination of complement C3 binding to the bacterial surface and killing of Nm.

Results

Reconstitution of fD‐deficient serum with fD increased AP activity in a dose‐ and time‐dependent way. Reconstitution of patient serum with fD to normal levels increased complement C3 binding to Sp, Nm and NTHi, as well as complement‐mediated killing of Nm and NTHi. Vaccination increased complement C3 binding and resulted in complete killing of Nm without fD reconstitution.

Conclusion

We conclude that low fD serum levels (< 0.5 μg mL−1) lead to a reduced speed of complement activation, which results in diminished bacterial killing, consistent with recurrent bacterial infections observed in our index patients. Specific antibodies induced by vaccination are able to overcome the diminished bacterial killing capacity in patients with low fD levels.
DZIP1 regulates mammalian cardiac valve development through a Cby1‐β‐catenin mechanism
Authors: Guo Lilong , Beck Tyler , Fulmer Diana , Ramos‐Ortiz Sandra , Glover Janiece , Wang Christina , Moore Kelsey , Gensemer Cortney , Morningstar Jordan , Moore Reece , Schott Jean‐Jacques , Le Tourneau Thierry , Koren Natalie , Norris Russell A.
Published: April 2021

Background

Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood.

Results

A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and β‐catenin. Co‐expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of β‐catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of β‐catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non‐syndromic MVP. This novel mutation and our previously identified DZIP1S24R variant resulted in reduced DZIP1 and CBY1 stability and increased β‐catenin activities. The β‐catenin target gene, MMP2 was up‐regulated in the Dzip1S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype.

Conclusion

Dzip1 functions to restrain β‐catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear β‐catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.
Prediction of eating disorder treatment response trajectories via machine learning does not improve performance versus a simpler regression approach
Authors: Espel‐Huynh Hallie , Zhang Fengqing , Thomas J. Graham , Boswell James F. , Thompson‐Brenner Heather , Juarascio Adrienne S. , Lowe Michael R.
Published: April 2021

Objective

Patterns of response to eating disorder (ED) treatment are heterogeneous. Advance knowledge of a patient's expected course may inform precision medicine for ED treatment. This study explored the feasibility of applying machine learning to generate personalized predictions of symptom trajectories among patients receiving treatment for EDs, and compared model performance to a simpler logistic regression prediction model.

Method

Participants were adolescent girls and adult women (N = 333) presenting for residential ED treatment. Self‐report progress assessments were completed at admission, discharge, and weekly throughout treatment. Latent growth mixture modeling previously identified three latent treatment response trajectories (Rapid Response, Gradual Response, and Low‐Symptom Static Response) and assigned a trajectory type to each patient. Machine learning models (support vector, k‐nearest neighbors) and logistic regression were applied to these data to predict a patient's response trajectory using data from the first 2 weeks of treatment.

Results

The best‐performing machine learning model (evaluated via area under the receiver operating characteristics curve [AUC]) was the radial‐kernel support vector machine (AUCRADIAL = 0.94). However, the more computationally‐intensive machine learning models did not improve predictive power beyond that achieved by logistic regression (AUCLOGIT = 0.93). Logistic regression significantly improved upon chance prediction (MAUC[NULL] = 0.50, SD = .01; p <.001).

Discussion

Prediction of ED treatment response trajectories is feasible and achieves excellent performance, however, machine learning added little benefit. We discuss the need to explore how advance knowledge of expected trajectories may be used to plan treatment and deliver individualized interventions to maximize treatment effects.
Distribution and habitat attributes associated with the Himalayan red panda in the westernmost distribution range
Authors: Shrestha Saroj , Thapa Arjun , Bista Damber , Robinson Natasha , Sherpa Ang Phuri , Acharya Krishna Prasad , Jnawali Shant Raj , Lama Sonam Tashi , Lama Sony
Published: April 2021

The Himalayan red panda (Ailurus fulgens), a recently confirmed distinct species in the red panda genus, is distributed in Nepal, India, Bhutan, and south Tibet. Nepal represents the westernmost distribution of the Himalayan red panda. This study aims to determine important habitat features influencing the distribution of red panda and recommend possible habitat corridors. This manuscript described current potential habitat of 3,222 km2 with the relative abundance of 3.34 signs/km in Nepal. Aspect, canopy cover, bamboo cover, and distance to water were the important habitat attributes. It suggested five potential corridors in western Nepal. Overall, the study has important implications for conservation of the Himalayan red panda in western distribution range.
Mixing tree species associated with arbuscular or ectotrophic mycorrhizae reveals dual mycorrhization and interactive effects on the fungal partners
Authors: Heklau Heike , Schindler Nicole , Buscot François , Eisenhauer Nico , Ferlian Olga , Prada Salcedo Luis D. , Bruelheide Helge
Published: April 2021

Recent studies found that the majority of shrub and tree species are associated with both arbuscular mycorrhizal (AM) and ectomycorrhizal (EM) fungi. However, our knowledge on how different mycorrhizal types interact with each other is still limited. We asked whether the combination of hosts with a preferred association with either AM or EM fungi increases the host tree roots’ mycorrhization rate and affects AM and EM fungal richness and community composition.

We established a tree diversity experiment, where five tree species of each of the two mycorrhiza types were planted in monocultures, two‐species and four‐species mixtures. We applied morphological assessment to estimate mycorrhization rates and next‐generation molecular sequencing to quantify mycobiont richness.

Both the morphological and molecular assessment revealed dual‐mycorrhizal colonization in 79% and 100% of the samples, respectively. OTU community composition strongly differed between AM and EM trees. While host tree species richness did not affect mycorrhization rates, we observed significant effects of mixing AM‐ and EM‐associated hosts in AM mycorrhization rate. Glomeromycota richness was larger in monotypic AM tree combinations than in AM‐EM mixtures, pointing to a dilution or suppression effect of AM by EM trees. We found a strong match between morphological quantification of AM mycorrhization rate and Glomeromycota richness.

Synthesis. We provide evidence that the combination of hosts differing in their preferred mycorrhiza association affects the host's fungal community composition, thus revealing important biotic interactions among trees and their associated fungi.
Tests of hypotheses for group formation in the subtropical leaf‐dwelling bat, Kerivoula furva
Authors: Hsu Chia‐Wei , Kao Mei‐Ting , Chou Cheng‐Han , Cheng Hsi‐Chi , Liu Jian‐Nan
Published: April 2021

Investigating factors that promote group living in animals can help us to understand the evolution of sociality. The dark woolly bat, Kerivoula furva, forms small groups and uses furled leaves of banana (Musa formosana) as day roosts in subtropical Taiwan. In this study, we reported on the roosting ecology and social organization of K. furva. We examined whether ecological constraints, demographic traits, and physiological demands contributed to its sociality. From July 2014 to May 2016, we investigated the daily roost occupation rate, group size, and composition of each roost, and we calculated association indices in pairs. The results showed K. furva lived in groups throughout the year, and the average daily roost occupation rate was approximately 6.7% of all furled leaves that were suitable for roosting. The size of roosting groups of adults in each roost varied between 1 and 13; group size was independent of air temperature during both reproductive and nonreproductive seasons. The vast majority of roosting groups was composed of females and their young, and males frequently roosted solitarily or in a bachelor group. Forty adult bats were captured ≥4 times during the study period. The association indices in pairs of these 40 bats ranged between 0 and 0.83 with an average of 0.05 ± 0.14 (n = 780). The average association index of female–female pairs was significantly higher than that of female–male pairs and male–male pairs. Based on the association indices, the 40 bats were divided into seven social groups with social group sizes that varied between 2 and 10. Despite changing day roosts frequently, the relatively stable social bonds were maintained year‐round. Our results that groups of K. furva were formed by active aggregation of multiple generation members supported the demographic traits hypothesis.
Distributive stress: individually variable responses to hypoxia expand trophic niches in fish
Authors: Steube Tyler R. , Altenritter Matthew E. , Walther Benjamin D.
Published: April 2021

Environmental stress can reshape trophic interactions by excluding predators or rendering prey vulnerable, depending on the relative sensitivity of species to the stressor. Classical models of food web responses to stress predict either complete predator exclusion from stressed areas or complete prey vulnerability if predators are stress tolerant. However, if the consumer response to the stress is individually variable, the result may be a distributive stress model (DSM) whereby predators distribute consumption pressure across a range of prey guilds and their trophic niche is expanded. We test these models in one of the largest hypoxic “Dead Zones” in the world, the northern Gulf of Mexico, by combining geochemical tracers of hypoxia exposure and isotope ratios to assess individual‐level trophic responses. Hypoxia‐exposed fish occupied niche widths that were 14.8% and 400% larger than their normoxic counterparts in two different years, consistent with variable displacement from benthic to pelagic food webs. The degree of isotopic displacement depended on the magnitude of hypoxia exposure. These results are consistent with the DSM and highlight the need to account for individually variable sublethal effects when predicting community responses to environmental stress.
Brown meets green: light and nutrients alter detritivore assimilation of microbial nutrients from leaf litter
Authors: Price Taylor L. , Harper Jennifer , Francoeur Steven N. , Halvorson Halvor M. , Kuehn Kevin A.
Published: April 2021

In aquatic detrital‐based food webs, research suggests that autotroph‐heterotroph microbial interactions exert bottom‐up controls on energy and nutrient transfer. To address this emerging topic, we investigated microbial responses to nutrient and light treatments during Liriodendron tulipifera litter decomposition and fed litter to the caddisfly larvae Pycnopsyche sp. We measured litter‐associated algal, fungal, and bacterial biomass and production. Microbes were also labeled with 14C and 33P to trace distinct microbial carbon (C) and phosphorus (P) supporting Pycnopsyche assimilation and incorporation (growth). Litter‐associated algal and fungal production rates additively increased with higher nutrient and light availability. Incorporation of microbial P did not differ across diets, except for higher incorporation efficiency of slower‐turnover P on low‐nutrient, shaded litter. On average, Pycnopsyche assimilated fungal C more efficiently than bacterial or algal C, and Pycnopsyche incorporated bacterial C more efficiently than algal or fungal C. Due to high litter fungal biomass, fungi supported 89.6–93.1% of Pycnopsyche C growth, compared to 0.2% to 3.6% supported by bacteria or algae. Overall, Pycnopsyche incorporated the most C in high nutrient and shaded litter. Our findings affirm others' regarding autotroph‐heterotroph microbial interactions and extend into the trophic transfer of microbial energy and nutrients through detrital food webs.
A Phase II study of autologous mesenchymal stromal cells and c‐kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT‐HF trial
Authors: Bolli Roberto , Mitrani Raul D. , Hare Joshua M. , Pepine Carl J. , Perin Emerson C. , Willerson James T. , Traverse Jay H. , Henry Timothy D. , Yang Phillip C. , Murphy Michael P. , March Keith L. , Schulman Ivonne H. , Ikram Sohail , Lee David P. , O'Brien Connor , Lima Joao A. , Ostovaneh Mohammad R. , Ambale‐Venkatesh Bharath , Lewis Gregory , Khan Aisha , Bacallao Ketty , Valasaki Krystalenia , Longsomboon Bangon , Gee Adrian P. , Richman Sara , Taylor Doris A. , Lai Dejian , Sayre Shelly L. , Bettencourt Judy , Vojvodic Rachel W. , Cohen Michelle L. , Simpson Lara , Aguilar David , Loghin Catalin , Moyé Lem , Ebert Ray F. , Davis Barry R. , Simari Robert D. ,   for the Cardiovascular Cell Therapy Research Network (CCTRN)
Published: April 2021

Aims

CONCERT‐HF is an NHLBI‐sponsored, double‐blind, placebo‐controlled, Phase II trial designed to determine whether treatment with autologous bone marrow‐derived mesenchymal stromal cells (MSCs) and c‐kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.

Methods and results

Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (−22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6‐min walking distance, and peak oxygen consumption did not differ significantly among groups.

Conclusions

This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline‐directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.
CCR4 in cutaneous T‐cell lymphoma: Therapeutic targeting of a pathogenic driver
Authors: Nicolay Jan P. , Albrecht Jana D. , Alberti‐Violetti Silvia , Berti Emilio
Published: April 2021

New treatments are needed for patients with cutaneous T‐cell lymphoma (CTCL), particularly for advanced mycosis fungoides (MF) and Sezary syndrome (SS). The immunopathology of MF and SS is complex, but recent advances in tumor microenvironment understanding have identified CCR4 as a promising therapeutic target. CCR4 is widely expressed on malignant T cells and Tregs in the skin and peripheral blood of patients with MF and SS. The interaction of CCR4 with its dominant ligands CCL17 and CCL22 plays a critical role in the development and progression of CTCL, facilitating the movement into, and accumulation of, CCR4‐expressing T cells in the skin, and recruiting CCR4‐expressing Tregs into the tumor microenvironment. Expression of CCR4 is upregulated at all stages of MF and in SS, increasing with advancing disease. Several CCR4‐targeted therapies are being evaluated, including “chemotoxins” targeting CCR4 via CCL17, CCR4‐directed chimeric antigen receptor‐modified T‐cell therapies, small‐molecule CCR4 antagonists, and anti‐CCR4 monoclonal antibodies. Only one is currently approved: mogamulizumab, a defucosylated, fully humanized, anti‐CCR4, monoclonal antibody for the treatment of relapsed/refractory MF and SS. Clinical trial da1ta confirm that mogamulizumab is an effective and well‐tolerated treatment for relapsed/refractory MF or SS, demonstrating the clinical value of targeting CCR4.
Modulating oxidative stress counteracts specific antigen‐induced regulatory T‐cell apoptosis in mice
Authors: Zhang Yuan‐Yi , Feng Bai‐Sui , Zhang Huanping , Yang Gui , Jin Qiao‐Ruo , Luo Xiang‐Qian , Ma Na , Huang Qin‐Miao , Yang Li‐Teng , Zhang Guo‐Hao , Liu Da‐Bo , Yu Yong , Liu Zhi‐Gang , Zheng Peng‐Yuan , Yang Ping‐Chang
Published: April 2021

Treg are known to have a central role in orchestrating immune responses, but less is known about the destiny of Treg after being activated by specific Ags. This study aimed to investigate the role of superoxide dismutase, an active molecule in the regulation of oxidative stress in the body, in the prevention of Treg apoptosis induced by specific Ags. Ag‐specific Tregs were isolated from the DO11.10 mouse intestine. A food allergy mouse model was developed with ovalbumin as the specific Ag and here, we observed that exposure to specific Ag induced Treg apoptosis through converting the precursor of TGF‐β to its mature form inside the Tregs. Oxidative stress was induced in Tregs upon exposure to specific Ags, in which Smad3 bound the latency‐associated peptide to induce its degradation, converting the TGF‐β precursor to its mature form, TGF‐β. Suppressing oxidative stress in Tregs alleviated the specific Ag‐induced Treg apoptosis in in vitro experiments and suppressed experimental food allergy by preventing the specific Ag‐induced Treg apoptosis in the intestine. In conclusion, exposure to specific Ags induces Treg apoptosis and it can be prevented by upregulating superoxide dismutase or suppressing reactive oxidative species in Tregs.
Effect of magnetic field on electroosmotic flow of viscoelastic fluids in a microchannel
Authors: Wang Xiaoping , Qiao Yanli , Qi Haitao , Xu Huanying
Published: April 2021

Electroosmotic flow is an efficient transportation technology driven by applying an external electric field across the microchannel, which has a great potential for future application. This work is presented to study the unsteady electroosmotic flow of viscoelastic fluids combined with a constant pressure gradient and a vertical magnetic field through a parallel plate microchannel. For the reason that the upper and bottom walls of the parallel plate microchannel in microfluidic devices can be made of different materials, this leads to different hydrophobic properties, asymmetric zeta wall potentials, and different slip boundary conditions. The Navier slip model with different slip coefficients at walls is considered. The generalized Maxwell fluid with fractional derivative is adopted for the constitutive equation of the fluid. The analytical and numerical solutions of velocity are derived by employing the integral transform method and finite difference method, respectively. Excellent agreement is found between the numerical solutions and analytical solutions. Finally, the effects of fractional parameter , relaxation time , slip coefficients and , the ratio of wall zeta potentials , Hartmann number , and electrical field strength parameter on velocity profiles are interpreted graphically in detail.
Preparation of lignosulfonate‐based nanofiltration membranes with improved water desalination performance
Authors: Liu Wangqu , Geng Xin , Li Saisai , Zhan Xia , Li Jiding , Wang Luying , Lei Jiandu
Published: April 2021

Pulping and papermaking generate large amounts of waste in the form of lignosulfonates which have limited valorized applications so far. Herein, we report a novel lignosulfonate‐based nanofiltration membrane, prepared by using polyethylenimine (PEI) and sodium lignosulfonate (SL) via a layer‐by‐layer (LbL) self‐assembly. As a low‐cost and renewable natural polyelectrolyte, SL is selected to replace the synthetic polyelectrolyte commonly used in the conventional LbL fabrication for composite membranes. The prepared LbL (PEI/SL)7 membranes were crosslinked by glutaraldehyde (GA) to obtain (PEI/SL)7‐GA membranes with compact selective layer. We characterized (PEI/SL)7 and (PEI/SL)7‐GA membranes to study the chemical compositions, morphologies, and surface hydrophilicity. To improve the nanofiltration performances of the (PEI/SL)7‐GA membranes for water desalination, we investigated the effects of the crosslinking time, GA concentration and the NaCl supporting electrolyte on membrane structure and performance. The optimized (PEI/SL)7‐GA membrane exhibited a permeating flux up to 39.6 L/(m2·h) and a rejection of 91.7% for the MgSO4 aqueous solution 2.0 g/L concentration, showing its promising potential for water desalination. This study provides a new approach to applying the underdeveloped lignin‐based biomass as green membrane materials for water treatment.
Truncated generalized extreme value distribution‐based ensemble model output statistics model for calibration of wind speed ensemble forecasts
Authors: Baran Sándor , Szokol Patrícia , Szabó Marianna
Published: April 2021

In recent years, ensemble weather forecasting has become a routine at all major weather prediction centers. These forecasts are obtained from multiple runs of numerical weather prediction models with different initial conditions or model parametrizations. However, ensemble forecasts can often be underdispersive and also biased, so some kind of postprocessing is needed to account for these deficiencies. One of the most popular state of the art statistical postprocessing techniques is the ensemble model output statistics (EMOS), which provides a full predictive distribution of the studied weather quantity. We propose a novel EMOS model for calibrating wind speed ensemble forecasts, where the predictive distribution is a generalized extreme value (GEV) distribution left truncated at zero (TGEV). The truncation corrects the disadvantage of the GEV distribution‐based EMOS models of occasionally predicting negative wind speed values, without affecting its favorable properties. The new model is tested on four datasets of wind speed ensemble forecasts provided by three different ensemble prediction systems, covering various geographical domains and time periods. The forecast skill of the TGEV EMOS model is compared with the predictive performance of the truncated normal, log‐normal and GEV methods and the raw and climatological forecasts as well. The results verify the advantageous properties of the novel TGEV EMOS approach.
Seismic structural health monitoring using the modal assurance distribution
Authors: Quqa Said , Landi Luca , Diotallevi Pier Paolo
Published: April 2021

Thanks to emerging techniques in the field of signal processing and due to improvements in smart sensing systems which enable the event‐triggered acquisition of high‐fidelity data at the occurrence of strong ground motion events, seismic structural health monitoring has grown considerably in the last few decades. In this paper, the modal assurance distribution, an alternative time‐frequency representation of the modal features of multivariate and multicomponent signals, is extended for application to short‐term nonstationary vibrational structural responses in which the system may manifest its nonlinear behavior. A general procedure for the extraction of the decoupled normal modes is presented, which allows the identification of instantaneous modal parameters in order to investigate in detail the structural behavior during earthquakes. Valuable information that cannot be recovered by means of traditional criteria can thus be exploited for accurate damage assessment. The results obtained for two case studies consisting of a numerical model with softening nonlinear behavior and a full‐scale experimental reinforced concrete benchmark show the potential and applicability of the method proposed for the integrity assessment of civil structures.
Simulating nonstationary and non‐Gaussian vector ground motions with time‐ and frequency‐dependent lagged coherence
Authors: Cui X. Z. , Hong H. P.
Published: April 2021

Seismic ground motions at multiple sites are nonstationary and non‐Gaussian with potentially time‐ and frequency‐dependent coherence, although the nonstationarity or non‐Gaussian or time‐dependent coherence aspects are often neglected because of lack of algorithm or method to take all these aspects into account to simulate synthetic ground motion records at multiple sites. In the present study, an iterative power and amplitude correction algorithm is proposed to simulate the nonstationary and non‐Gaussian vector process and takes into account time‐ and frequency‐dependent coherence. The algorithm usually converges within 10 iterations. It can be viewed as the extension of the well‐known iterative amplitude adjust Fourier transform algorithm for generating a vector of surrogates. The proposed algorithm uses the S‐transform and discrete orthonormal S‐transform rather than the ordinary Fourier transform. The adequacy of the proposed algorithm is validated numerically by using simulated ground motions.
Glial Synaptobrevin mediates peripheral nerve insulation, neural metabolic supply, and is required for motor function
Authors: Böhme Mathias A. , McCarthy Anthony W. , Blaum Natalie , Berezeckaja Monika , Ponimaskine Kristina , Schwefel David , Walter Alexander M.
Published: April 2021

Peripheral nerves contain sensory and motor neuron axons coated by glial cells whose interplay ensures function, but molecular details are lacking. SNARE‐proteins mediate the exchange and secretion of cargo by fusing vesicles with target organelles, but how glial SNAREs contribute to peripheral nerve function is largely unknown. We, here, identify non‐neuronal Synaptobrevin (Syb) as the essential vesicular SNARE in Drosophila peripheral glia to insulate and metabolically supply neurons. We show that tetanus neurotoxin light chain (TeNT‐LC), which potently inhibits SNARE‐mediated exocytosis from neurons, also impairs peripheral nerve function when selectively expressed in glia, causing nerve disintegration, defective axonal transport, tetanic muscle hyperactivity, impaired locomotion, and lethality. While TeNT‐LC disrupts neural function by cleaving neuronal Synaptobrevin (nSyb), it targets non‐neuronal Synaptobrevin (Syb) in glia, which it cleaves at low rates: Glial knockdown of Syb (but not nSyb) phenocopied glial TeNT‐LC expression whose effects were reverted by a TeNT‐LC‐insensitive Syb mutant. We link Syb‐necessity to two distinct glial subtypes: Impairing Syb function in subperineurial glia disrupted nerve morphology, axonal transport, and locomotion, likely, because nerve‐isolating septate junctions (SJs) could not form as essential SJ components (like the cell adhesion protein Neurexin‐IV) were mistargeted. Interference with Syb in axon‐encircling wrapping glia left nerve morphology and locomotion intact but impaired axonal transport, likely because neural metabolic supply was disrupted due to the mistargeting of metabolite shuffling monocarboxylate transporters. Our study identifies crucial roles of Syb in various glial subtypes to ensure glial‐glial and glial‐neural interplay needed for proper nerve function, animal motility, and survival.
Co‐culture of exogenous oligodendrocytes with unmyelinated cerebella: Revisiting ex vivo models and new tools to study myelination
Authors: Baudouin Lucas , Adès Noémie , Kanté Kadia , Czarnecki Antonny , Bachelin Corinne , Baskaran Asha , Langui Dominique , Millécamps Aymeric , Gurchenkov Basile , Velut Yoan , Duarte Kévin , Barnier Jean‐Vianney , Nait Oumesmar Brahim , Bouslama‐Oueghlani Lamia
Published: April 2021

Common in vitro models used to study the mechanisms regulating myelination rely on co‐cultures of oligodendrocyte precursor cells (OPCs) and neurons. In such models, myelination occurs in an environment that does not fully reflect cell–cell interactions and environmental cues present in vivo. To avoid these limitations while specifically manipulating oligodendroglial cells, we developed a reliable ex vivo model of myelination by seeding OPCs on cerebellar slices, deprived of their endogenous oligodendrocytes. We showed that exogenous OPCs seeded on unmyelinated cerebella, efficiently differentiate and form compact myelin. Spectral confocal reflectance microscopy and electron microscopy analysis revealed that the density of compacted myelin sheaths highly increases all along the culture. Importantly, we defined the appropriate culture time frame to study OPC differentiation and myelination, using accurate quantification resources we generated. Thus, this model is a powerful tool to study the cellular and molecular mechanisms of OPC differentiation and myelination. Moreover, it is suitable for the development and validation of new therapies for myelin‐related disorders such as multiple sclerosis and psychiatric diseases.
Development of an assessment measure for sexual disinhibition in dementia
Authors: Chapman Kimberly R. , Tremont Geoffrey , Spitznagel Mary Beth
Published: April 2021

Objective

Sexual disinhibition (SD), a neuropsychiatric symptom characterized by sexually inappropriate comments and/or behaviors, remains under identified in dementia, possibly due to a lack of standardized assessment methods. A recent systematic review of measures used to assess SD proposed four behavioral domains and identified the need for a population‐specific measure. The present study addressed this by examining the underlying factor structure of SD to create a new caregiver‐report measure.

Methods

Dementia caregivers (n = 622) recruited online were randomly assigned to Initial Validation (n = 311) or Cross‐Validation (n = 311) groups.

Results

Initial Validation revealed five behavioral domains that served as provisional scales for cross‐validation, leading to measure development.

Conclusions

The current study is the first to statistically evaluate the underlying factor structure of SD, resulting in a new measure that can help better characterize and identify SD.
Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study
Authors: Jonas Maureen M. , Rhee Susan , Kelly Deirdre A. , Del Valle‐Segarra Antonio , Feiterna‐Sperling Cornelia , Gilmour Susan , Gonzalez‐Peralta Regino P. , Hierro Loreto , Leung Daniel H. , Ling Simon C. , Lobzin Yuri , Lobritto Steven , Mizuochi Tatsuki , Narkewicz Michael R. , Sabharwal Vishakha , Wen Jessica , Kei Lon Hoi , Marcinak John , Topp Andrew , Tripathi Rakesh , Sokal Etienne
Published: April 2021

Background and Aims

Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV‐infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open‐label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years.

Approach and Results

Children with chronic HCV infection, genotype 1‐6, with or without compensated cirrhosis, were divided into three cohorts by age—cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)—and given weight‐based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady‐state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug‐related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults.

Conclusions

A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV‐infected children 3 to < 12 years old.
Saroglitazar, a PPAR‐α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double‐Blind Phase 2 Trial
Authors: Gawrieh Samer , Noureddin Mazen , Loo Nicole , Mohseni Rizwana , Awasty Vivek , Cusi Kenneth , Kowdley Kris V. , Lai Michelle , Schiff Eugene , Parmar Deven , Patel Pankaj , Chalasani Naga
Published: April 2021

Background and Aims

NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor‐α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH.

Approach and Results

A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least‐squares mean percent change from baseline in ALT at week 16 was −25.5% (5.8), −27.7% (5.9), and −45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. −19.7% [5.6]), adiponectin (−0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment–insulin resistance (−1.3 [1.8] vs. −6.3 [1.7]), and triglycerides (−5.3 mg/dL [10.7] vs. −68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well‐tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27).

Conclusions

Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.)