bluuebunny/crossref_metadata_2025 huggingface dataset:
Onion Epithelial Membrane Scaffolds Transfer Corneal Epithelial Layers in Reconstruction Surgery
Authors: Wang Guoliang , Chen Pei , Wang Yanzi , Wang Yixin , Reinach Peter S. , Xue Yuhua , Liu Zuguo , Li Cheng
Published: June 2020

Plants and their extracts have been used especially in China for more than ten centuries for preventing and treating disease. However, there are only few reports describing their use in animal cell culture and tissue transplantation. In this study, onion epithelial membranes (OEM) is used as scaffolds to support cultures of a variety of cells such as fibroblasts and epithelial cells notably; they maintain the phenotypic characteristics of corneal epithelial cells. This improvement includes preservation of the proliferative potential and stemness of rabbit corneal epithelial cells (RCECs). Such an outcome suggests that this cost‐effective technology warrants further evaluation to determine if OEM is a viable candidate for use as scaffolds in corneal epithelial transplantation surgery. To test this possibility, rabbit corneal epithelial cells expanded on OEM are transplanted to treat corneal epithelial defects in limbal stem cell deficient rabbits. This procedure is successful because it shortens the time required for wound healing to restore losses in corneal epithelial integrity, and forms a more compact and stratified epithelium framework than the untreated group. Ultimately, should they be proven to be effective in other relevant animal model systems, their usefulness for treating wounds in a clinical setting warrants consideration.
Electrostatic Intraperitoneal Aerosol Delivery of Nanoparticles: Proof of Concept and Preclinical Validation
Authors: Van de Sande Leen , Rahimi‐Gorji Mohammad , Giordano Silvia , Davoli Enrico , Matteo Cristina , Detlefsen Sönke , D'Herde Katharina , Braet Helena , Shariati Molood , Remaut Katrien , Xie Feifan , Debbaut Charlotte , Ghorbaniasl Ghader , Cosyns Sarah , Willaert Wouter , Ceelen Wim
Published: June 2020

There is an increasing interest in intraperitoneal delivery of chemotherapy as an aerosol in patients with peritoneal metastasis. The currently used technology is hampered by inhomogenous drug delivery throughout the peritoneal cavity because of gravity, drag, and inertial impaction. Addition of an electrical force to aerosol particles, exerted by an electrostatic field, can improve spatial aerosol homogeneity and enhance tissue penetration. A computational fluid dynamics model shows that electrostatic precipitation (EP) results in a significantly improved aerosol distribution. Fluorescent nanoparticles (NPs) remain stable after nebulization in vitro, while EP significantly improves spatial homogeneity of NP distribution. Next, pressurized intraperitoneal chemotherapy with and without EP using NP albumin bound paclitaxel (Nab‐PTX) in a novel rat model is examined. EP does not worsen the effects of CO2 insufflation and intraperitoneal Nab‐PTX on mesothelial structural integrity or the severity of peritoneal inflammation. Importantly, EP significantly enhances tissue penetration of Nab‐PTX in the anatomical regions not facing the nozzle of the nebulizer. Also, the addition of EP leads to more homogenous peritoneal tissue concentrations of Nab‐PTX, in parallel with higher plasma concentrations. In conclusion, EP enhances spatial homogeneity and tissue uptake after intraperitoneal nebulization of anticancer NPs.
The Effect of Thiol Structure on Allyl Sulfide Photodegradable Hydrogels and their Application as a Degradable Scaffold for Organoid Passaging
Authors: Yavitt F. Max , Brown Tobin E. , Hushka Ella A. , Brown Monica E. , Gjorevski Nikolche , Dempsey Peter J. , Lutolf Matthias P. , Anseth Kristi S.
Published: June 2020

Intestinal organoids are useful in vitro models for basic and translational studies aimed at understanding and treating disease. However, their routine culture relies on animal‐derived matrices that limit translation to clinical applications. In fact, there are few fully defined, synthetic hydrogel systems that allow for the expansion of intestinal organoids. Here, an allyl sulfide photodegradable hydrogel is presented, achieving rapid degradation through radical addition‐fragmentation chain transfer (AFCT) reactions, to support routine passaging of intestinal organoids. Shear rheology to first characterize the effect of thiol and allyl sulfide crosslink structures on degradation kinetics is used. Irradiation with 365 nm light (5 mW cm−2) in the presence of a soluble thiol (glutathione at 15 × 10−3 m), and a photoinitiator (lithium phenyl‐2,4,6‐trimethylbenzoylphosphinate at 1 × 10−3 m), leads to complete hydrogel degradation in less than 15 s. Allyl sulfide hydrogels are used to support the formation of epithelial colonies from single intestinal stem cells, and rapid photodegradation is used to achieve repetitive passaging of stem cell colonies without loss in morphology or organoid formation potential. This platform could support long‐term culture of intestinal organoids, potentially replacing the need for animal‐derived matrices, while also allowing systematic variations to the hydrogel properties tailored for the organoid of interest.
Interface Engineering of Si Hybrid Nanostructures for Chemical and Biological Sensing
Authors: Li Jinghua , Rogers John A.
Published: June 2020

Opportunities for quantitative, real‐time monitoring of gases, ions, and biomolecules in the environment and in the human body motivate programs of fundamental and applied research on chemically selective sensors with fast response times. In this context, silicon field‐effect transistors are of considerable interest as label‐free, scalable platforms for detecting a variety of chemical and biological species. Herein, recent progress and research directions in this area are reviewed. The focus of this article is on operational parameters, device architectures, schemes for surface chemical functionalization, and methods for bio‐integration across a variety of use cases. The content includes strategies that combine Si with other functional materials to create hybrid structures for enhanced sensing performance. The final section highlights some remaining challenges and provides perspectives on the future of basic research and engineering development in this field.
Novel Solvent Systems for Biomass Fractionation Based on Hydrogen‐Bond Interaction: A Minireview
Authors: Wang Chenguang , Yang Shaoqi , Song Xiangbo , Pi Qifeng , Zhang Qi , Liu Qiying , Xu Ying , Chen Lungang , Ma Longlong
Published: June 2020

Exploring more efficient solvent systems is important for biomass fractionation that can significantly boost the efficiency of biomass catalytic conversion. Ionic liquids (ILs) and deep eutectic solvents (DESs) as novel hydrogen bond based solvents have attracted more and more attention. Research shows that the hydrogen bond between solvents and biomass is the main factor for their excellent performance in biomass fractionation. The cation or anion of ILs can form strong hydrogen bonding with biomass components during the pretreatment processes, which weakens the hydrogen bond interactions between biomass components, and further promotes the destruction of the biomass hydrogen bond network. Similar to ILs, with their designed hydrogen bond donors and acceptors, DESs can also form strong hydrogen bonds with biomass components for fractionation. Herein, this review outlines the recent development of biomass fractionation research through hydrogen‐bond interactions by using ILs and DESs with biomass. This work provides a framework for future investigation of biomass fractionation mechanisms, understanding the effect of ILs/DESs, and exploring more novel efficient biomass catalytic conversion systems.
Local Doxorubicin Delivery via 3D‐Printed Porous Scaffolds Reduces Systemic Cytotoxicity and Breast Cancer Recurrence in Mice
Authors: Dang Hoang Phuc , Shafiee Abbas , Lahr Christoph A. , Dargaville Tim R. , Tran Phong A.
Published: June 2020

The concept of using macroscale porous scaffolds as local drug reservoirs to prevent cancer recurrence has received little attention. To extend the use of these scaffolds as drug delivery devices, the morphology needs to be optimized. Here, a porous scaffold that can work as efficient drug reservoirs is developed. A combination of additive manufacturing and salt leaching techniques to produce scaffolds of medical grade poly(ε‐caprolactone) that has macroscale pores of 300–500 µm and intrastrut microscale pores of 5–35 µm in size is used. The chemotherapeutic drug, doxorubicin (DOX), is loaded onto the porous scaffolds by soaking with the loading efficacy as high as 90%. The DOX‐loaded scaffolds display a biphasic monotonic drug release up to 28 d, and a dose‐dependent chemotherapeutic effect against breast cancer cells, MDA‐MB‐231. Compared to one‐time intravenous injection of 40 µg DOX, implantation of scaffolds containing only 2 or 8 µg of DOX after tumor removal in mice shows lower cardio‐cytotoxicity, reduced local cancer recurrence, and is correlated with a lower metastasis progression in lungs, liver, and spleen in 28 d of treatment. These bimodal scaffolds are thus promising in the development of scaffolds in breast cancer after tumor removal.
Closely related winter wheat cultivar performance in U.S. Great Plains acid soils
Authors: Gillespie Christopher J. , Marburger David A. , Carver Brett F. , Zhang Hailin
Published: June 2020

Aluminum‐tolerant wheat (Triticum aestivum L.) cultivars are often employed to damper the yield‐limiting impacts of Al toxicity in acidic soils. Tolerance is often facilitated by the Al‐activated malate transporter 1 (ALMT1) gene, which increases anion permeability of wheat roots and exudes malate in the presence of Al. However, few studies have explored the phenotypic incongruities of closely related genotypes with ALMT1(+) or without ALMT1(−). A field study initiated in Stillwater, OK, on an Easpur loam (fine‐loamy, mixed, superactive, thermic Fluventic Haplustolls) was established to determine the Al tolerance of eight related winter wheat cultivars chosen for presence or absence of ALMT1 [Duster (+), Lonerider (+), OK14319 (+), Jagger (+), Iba (−), Gallagher (−), Spirit Rider (−), Smith's Gold (−)]. Significant differences were found among cultivars in their forage yield responses to Al concentration and soil acidity. Duster (first), Spirit Rider (second), and Gallagher (third) were the most acid tolerant and consistent in forage yield across study years. However, no such trend was observed in the grain yields of any of the cultivars, as there was no clear semblance of acid tolerance in grain yields between study years. Despite the similarity of genetic backgrounds, forage and grain yield productivity of cultivars in this study varied between years and was not wholly dependent on the presence or absence of the ALMT1 gene. Nevertheless, the utilization of acid‐tolerant winter wheat cultivars has the potential to significantly reduce forage yield loss under acidic soil conditions with high Al concentrations.
The clinical impact of time to response in de novo accelerated‐phase chronic myeloid leukemia
Authors: Ohanian Maro , Kantarjian Hagop M. , Shoukier Mahran , Dellasala Sara , Musaelyan Arine , Nogueras Gonzalez Graciela M. , Jabbour Elias , Abruzzo Lynne , Verstovsek Srdan , Borthakur Gautam , Ravandi Farhad , Garcia‐Manero Guillermo , Tamamyan Gevorg , Champlin Richard , Pierce Sherry , Ferrajoli Alessandra , Kadia Tapan , Cortes Jorge E.
Published: June 2020

We aimed to describe the impact of time to response on the outcomes of 75 patients with accelerated‐phase chronic myeloid leukemia (CML‐AP) at diagnosis. Patients had at least 1 feature of AP: blasts ≥15% (n = 2), basophils ≥20% (n = 19), platelets <100 × 109/L (n = 7), cytogenetic clonal evolution (n = 34), or more than one factor (n = 13). Thirty‐three patients received imatinib; 42 received a second‐generation tyrosine kinase inhibitor (2GTKI) (19 dasatinib and 23 nilotinib). We used chi‐square and Kaplan‐Meier analyses to determine the impact of various degrees of molecular and cytogenetic response at early time points (3 and 6 months) on rates of overall cytogenetic and molecular response, overall survival (OS), event‐free survival (EFS), transformation‐free survival (TFS), and failure‐free survival (FFS). After a median follow‐up of 96 months (range: 18‐224 months), the overall rate of complete cytogenetic response was 79%, of major molecular response, 71%, and of molecular reponse (MR)4.5, 59%. Patients who achieved a major cytogenetic response (MCyR) (n = 49) at 3 months had significantly better 3‐year OS (94% vs 75%; P = .002), TFS (98% vs 73%; P < .001), EFS (93% vs 42%; P < .001), and FFS (83% vs 25%; P < .001) rates than patients who did not have MCyR at 3 months. Most (67%) who eventually achieved sustained MR4.5 had achieved MCyR at 3 months. In de novo CML‐AP, early response at 3 and 6 months is a strong determinant of long‐term outcome.
Synthesis and molecular interaction of tung oil‐based anionic waterborne polyurethane dispersion
Authors: Jiang Lei , Ren Zhiyong , Liu Wentao , Liu Hao , Zhu Chengshen
Published: June 2020

In the present work, four types of anionic waterborne polyurethane dispersions (APUD) based on polytetramethylene ether glycol (PTMG) and two aliphatic diisocyanates, dicyclohexylmethane diisocyanate (HMDI) or isophorone diisocyanate (IPDI), were prepared by polymerization methods which for the first time controlled the location (soft or hard segment) of hydroxylated tung oil (HTO) incorporation into the final APUD. The resulting HTO‐containing APUD polymers (HTO‐APUDs) with postpolymerization crosslinking capability were characterized using FTIR, DMA, AFM and water imbibition methods, and compared to model compounds synthesized to have the same parts of chemical structural linkages for band assignment. A common PUD sample, as well as polypropylene oxide (PPG) with molecular weight similar to HTO (Mn = 400), was used to replace it for preparing control samples to highlight the role of long branched chains and conjugated double bonds in HTO. Based on the analysis of multiple H‐bond interactions, the relationship of HTO location in the APUD polymer structure to the soft/hard segment compatibility and the diisocyanate structure was further studied. This work is expected to provide basic data for properties regulation in practical applications by adjusting the chain and phase structure, as well as the intermolecular interactions, in these APUDs.
Loosen control without losing control: Formalization and decentralization within commons‐based peer production
Authors: Rozas David , Huckle Steven
Published: June 2020

This study considers commons‐based peer production (CBPP) by examining the organizational processes of the free/libre open‐source software community, Drupal. It does so by exploring the sociotechnical systems that have emerged around both Drupal's development and its face‐to‐face communitarian events. There has been criticism of the simplistic nature of previous research into free software; this study addresses this by linking studies of CBPP with a qualitative study of Drupal's organizational processes. It focuses on the evolution of organizational structures, identifying the intertwined dynamics of formalization and decentralization, resulting in coexisting sociotechnical systems that vary in their degrees of organicity.
Grafting Molecular Cobalt‐oxo Cubane Catalyst on Polymeric Carbon Nitride for Efficient Photocatalytic Water Oxidation
Authors: Zhen Wenlong , Yuan Xu , Shi Xiangyan , Xue Can
Published: June 2020

In this work, we have successfully constructed a cobalt–oxo (CoIII4O4) cubane complex on polymeric carbon nitride (PCN) through pyridine linkage. The covalently grafted CoIII4O4 cubane units were uniformly distributed on the PCN surface. The product exhibited greatly enhanced photocatalytic activities for water oxidation under visible‐light irradiation. Further characterizations and spectroscopic analyses revealed that the grafted CoIII4O4 cubane units could effectively capture the photogenerated holes from excited PCN, lower the overpotential of oxygen evolution reaction (OER), and serve as efficient catalysts to promote the multi‐electron water oxidation process. This work provides new insight into the future development of efficient photocatalysts by grafting molecular catalysts for artificial photosynthesis.
CRISPR with a Happy Ending: Non‐Templated DNA Repair for Prokaryotic Genome Engineering
Authors: Finger‐Bou Max , Orsi Enrico , van der Oost John , Staals Raymond H. J.
Published: June 2020

The exploration of microbial metabolism is expected to support the development of a sustainable economy and tackle several problems related to the burdens of human consumption. Microorganisms have the potential to catalyze processes that are currently unavailable, unsustainable and/or inefficient. Their metabolism can be optimized and further expanded using tools like the clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR‐Cas) systems. These tools have revolutionized the field of biotechnology, as they greatly streamline the genetic engineering of organisms from all domains of life. CRISPR‐Cas and other nucleases mediate double‐strand DNA breaks, which must be repaired to prevent cell death. In prokaryotes, these breaks can be repaired through either homologous recombination, when a DNA repair template is available, or through template‐independent end joining, of which two major pathways are known. These end joining pathways depend on different sets of proteins and mediate DNA repair with different outcomes. Understanding these DNA repair pathways can be advantageous to steer the results of genome engineering experiments. In this review, we discuss different strategies for the genetic engineering of prokaryotes through either non‐homologous end joining (NHEJ) or alternative end joining (AEJ), both of which are independent of exogenous DNA repair templates.
Concentration and Magnetic Field Effects on Thermal Fluctuation of Magnetic Weight of Magnetite Nanoparticles During Agglomeration Under Magnetic Field
Authors: Jin Daeseong , Kim Sung Hoon , Kim Hackjin
Published: June 2020

Agglomeration process of the magnetic nanoparticles under the magnetic field is studied by monitoring the magnetic weight of the sample, the magnetic force that the magnetic sample experiences under the magnetic field. The magnetic weight of the single domain magnetite nanoparticles in aqueous solution increases slowly with fluctuation as the nanoparticles agglomerate. The fluctuation of the magnetic weight coincides with the temperature change. We observe the thermal fluctuation of the magnetic weight of the samples of different concentrations at different magnetic fields. We employ the energy distribution function in order to simulate the thermal fluctuation of the magnetic weight. The simulation results suggest that the interparticle interactions, which restrict the motions of nanoparticles, play important roles in the agglomeration of high concentration samples at high magnetic fields. The interparticle interactions make the effective temperature lower than the experimental temperature by raising the magnetic anisotropy energy barrier.
Insights from 20 years of the Molecule of the Month
Authors: Goodsell David S. , Zardecki Christine , Berman Helen M. , Burley Stephen K.
Published: June 2020

For 20 years, Molecule of the Month articles have highlighted the functional stories of 3D structures found in the Protein Data Bank (PDB). The PDB is the primary archive of atomic structures of biological molecules, currently providing open access to more than 150,000 structures studied by researchers around the world. The wealth of knowledge embodied in this resource is remarkable, with structures that allow exploration of nearly any biomolecular topic, including the basic science of genetic mechanisms, mechanisms of photosynthesis and bioenergetics, and central biomedical topics like cancer therapy and the fight against infectious disease. The central motivation behind the Molecule of the Month is to provide a user‐friendly introduction to this rich body of data, charting a path for users to get started with finding and exploring the many available structures. The Molecule of the Month and related materials are updated regularly at the education portal PDB‐101 (http://pdb101.rcsb.org/), offering an ongoing resource for molecular biology educators and students around the world.
Evaluation of the safety and efficacy of the Cobra PzF NanoCoated coronary stent in routine, consecutive, prospective, and high‐risk patients: The e‐Cobra study
Authors: Maillard Luc , de Labriolle Axel , Brasselet Camille , Faurie Benjamin , Durel Nicolas , de Poli Fabien , Bosle Sébastien , Madiot Hend , Berland Jacques , Belle Loic
Published: June 2020

Background

The Cobra PzF coronary stent is cobalt chromium with flat thin struts, nano‐coated with Polyzene‐F that enhance rapid reendothelialization and reduce the risk of stent thrombosis and restenosis. It is designed to overcome shortfalls of BMS and DES in patients requiring short DAPT duration.

Aims

To report procedural and 1‐year clinical outcomes following Cobra PzF stent implantation in routine practice PCI.

Methods

e‐Cobra registry is a multicenter prospective study to evaluate Cobra PzF stent in routine practice in patients deemed appropriate for short DAPT after PCI. The primary endpoint was MACE rate at 12 months (Cardiac death, MI, TLR). The secondary endpoint was definite stent thrombosis at 12 months.

Results

Among 940 patients (72% men, 72.8 ± 13.4 years) with multiple co‐morbidities, 47% had acute coronary syndromes, and 62% were defined as high bleeding risk. A total of 1,229 lesions were treated with 1,314 stents. 36% of patients had lesion type B2 or C classification. Angiographic success was achieved in all cases. One‐year follow‐up was available for 97% of patients. The primary endpoint occurred in 9.0% of patients, including cardiac death 3.7%, MI 4.8%, and TLR 4.3%. Definite stent thrombosis occurred in six out of 915 (0.7%).

Conclusion

The Cobra PzF stent was safe and effective in routine practice patients and seems feasible in situations when short DAPT or Mono Antiplatelet Therapy (MAPT) is needed. One‐year follow‐up was associated with satisfactory clinical outcomes and validate previously reported data.
Functional fat injection in the treatment of dysphagia following surgery
Authors: Mozzanica Francesco , Schindler Antonio , Ottaviani Francesco
Published: June 2020

Functional fat injection under local anesthesia could be useful in the treatment of chronic dysphagia in selected patients with tissue loss secondary to laryngeal surgery.
Klebsiella pneumoniae invasive syndrome in a diabetic patient with gallbladder abscess
Authors: Zheng Shuhua , Florescu Samuel , Mendoza Mari
Published: June 2020

The mortality rates for Klebsiella pneumoniae invasive syndrome range from 4% to 11% with diabetes as a major risk factor. Early diagnosis of KPIS can decrease mortality rate with good outcomes due to sensitivity of K pneumoniae to antibiotics in KPIS.
Mixed connective tissue disease: Not always an obvious diagnosis
Authors: Rahmouni Safa , Maatallah Kaouther , Ferjani Hanene , Abid Leila , Kaffel Dhia , Hamdi Wafa
Published: June 2020

Mixed connective tissue disease (MCTD) is characterized by a mixture of clinical features. The initial presentation is often incomplete, and the features of MCTD usually develop as the disease evolves. We present a 37‐year‐old female patient with overlapping symptoms. The most plausible diagnosis was MCTD.
Supramolecular Assembly of TPE‐Based Glycoclusters with Dicyanomethylene‐4H‐pyran (DM) Fluorescent Probes Improve Their Properties for Peroxynitrite Sensing and Cell Imaging
Authors: Dong Lei , Fu Mengqi , Liu Lifang , Han Hai‐Hao , Zang Yi , Chen Guo‐Rong , Li Jia , He Xiao‐Peng , Vidal Sébastien
Published: June 2020

Two red‐emitting dicyanomethylene‐4H‐pyran (DM) based fluorescent probes were designed and used for peroxynitrite (ONOO−) detection. Nevertheless, the aggregation‐caused quenching effect diminished the fluorescence and restricted their further applications. To overcome this problem, tetraphenylethylene (TPE) based glycoclusters were used to self‐assemble with these DM probes to obtain supramolecular water‐soluble glyco‐dots. This self‐assembly strategy enhanced the fluorescence intensity, leading to an enhanced selectivity and activity of the resulting glyco‐dot comparing to DM probes alone in PBS buffer. The glyco‐dots also exhibited better results during fluorescence sensing of intracellular ONOO− than the probes alone, thereby offering scope for the development of other similar supramolecular glyco‐systems for chemical biological studies.
Enhancing DPCD in Liquid Products by Mechanical Inactivation Effects: Assessment of Feasibility
Authors: Hoferick Ratka , Gockel Frank , Müller Mareike , Schönherr Holger , Barbe Stéphan
Published: June 2020

The enhancement of standard dense phase carbon dioxide (DPCD) pasteurization by additional mechanical effects was assessed in this work. These effects were induced during pasteurization by the sudden depressurization in a narrow minitube. The high flow velocities, moderate pressures (40–80 bar) and low temperatures (25–45 °C) lead to intense degasification and shear stress. The inactivation of the test microorganism Escherichia coli DH5α (E. coli DH5α) was determined before and after depressurization in the minitube, representing entirely chemical DPCD via dissolved CO2 and total inactivation comprising the effects of dissolved CO2 and mechanical effects, respectively. Compared to conventional DPCD pasteurization, which is mostly attributed to chemical effects, the additional mechanical effects increased the inactivation efficiency considerably.
Real‐world use of nonvitamin K antagonist oral anticoagulant in atrial fibrillation patients with liver disease: A meta‐analysis
Authors: Dai Qixin , Deng Xiaohong , Zhou Lin , Zhang Long , Xiao Xiulin , Liao Yonghui
Published: June 2020

Several studies have investigated the effectiveness and safety of nonvitamin K antagonist oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and liver disease. Herein, we conducted a meta‐analysis to compare the effect of NOACs with VKAs in patients with AF and liver disease. We also conducted a subsidiary analysis to compare the risk of liver injury between NOACs and VKA in AF patients. We systematically searched the PubMed and Embase databases from January 2009 to May 2020 for the relevant studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) were selected and pooled using a random‐effects model. A total of six cohorts were included. Compared with VKA use, the use of NOACs was associated with reduced risks of stroke or systemic embolism (HR 0.68, 95% CI 0.49‐0.93), all‐cause death (HR 0.69, 95% CI 0.63‐0.75), and intracranial bleeding (HR 0.49, 95% CI 0.40‐0.59), whereas the outcomes of major bleeding (HR 0.72, 95% CI 0.51‐1.01) and gastrointestinal bleeding (HR 0.84, 95% CI 0.51‐1.36) were not significantly different between groups in AF patients with liver disease. Moreover, compared with VKA use, the use of NOACs was associated with a reduced risk of liver injury (HR 0.72, 95% CI 0.61‐0.84) in AF patients. Compared with VKAs, the use of NOACs was associated with reduced risks of stroke or systemic embolism, all‐cause death, and intracranial bleeding in AF patients with liver disease, and associated with a reduced risk of liver injury in AF patients.
A Primary Evaluation of Potential Small‐Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, a Novel Drug Target in Female Infertility Treatment
Authors: Körschgen Hagen , Jäger Christian , Tan Kathrin , Buchholz Mirko , Stöcker Walter , Ramsbeck Daniel
Published: June 2020

Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin‐B and the cortical granule‐based proteinase ovastacin to be a novel key mechanism in the regulation of fertilization. Upon sperm–egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness, and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this process is controlled by fetuin‐B, an endogenous ovastacin inhibitor. Here we aimed to discover small‐molecule inhibitors of ovastacin that could mimic the effect of fetuin‐B. These compounds could be useful lead structures for the development of specific ovastacin inhibitors that can be used in infertility treatment or in vitro fertilization
Exploring Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Autoproteolysis Process by Molecular Simulations: Hints for Drug Design
Authors: Sgrignani Jacopo , Fassi Enrico M. A. , Lammi Carmen , Roda Gabriella , Grazioso Giovanni
Published: June 2020

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a notable target for the treatment of hypercholesterolemia because it regulates the population of the low‐density lipoprotein receptor (LDLR) on liver cells. The PCSK9 zymogen is a serine protease that spontaneously undergoes a double self‐cleavage step. Available X‐ray structures depict the PCSK9 mature state, but the atomic details of the zymogen state of the enzyme are still unknown. Additionally, why the protease activity of PCSK9 is blocked after the second autoprocessing step remains unclear, as this deviates from other members of the PCSK family. By performing constant‐pH molecular dynamics (MD) simulations, we investigated the protonation state of the catalytic triad of PCSK9 and found that it strongly influences the catalytic properties of the enzyme. Moreover, we determined the final step of the maturation process by classical and steered MD simulations. This study could facilitate the identification of ligands capable of interfering with the PCSK9 maturation process.
Effect of renal function on neutrophil decreases following eribulin administration
Authors: Suzuki Norifumi , Tanaka Hiroyuki , Murakami Hirotoshi , Tomioka Nobumoto , Watanabe Kenichi , Endo Masayuki , Takahashi Masato
Published: June 2020

Background

Eribulin therapy has recently attracted attention from various viewpoints, including quality of life, and is considered a standard therapy for inoperable or recurrent breast cancer. Although a reduction in renal function reportedly decreases total eribulin clearance, its association with dose‐limiting toxicity and the reduction of neutrophils remain unclear.

Aim

This study was aimed at analyzing the association between decreased renal function prior to eribulin administration and the occurrence of neutrophil reduction and time to treatment failure in patients with breast cancer.

Methods and Results

We retrospectively assessed patients with breast cancer, who underwent eribulin therapy between July 2011 and March 2018. Multivariate analysis revealed creatinine clearance <70 mL/min and serum albumin levels <3.9 mg/dL as predictive factors for neutrophil reduction. Even on increasing the relative dose intensity by these factors, no difference in time to treatment failure was observed, suggesting that treatment efficacy is potentially unaffected.

Conclusions

For continuous eribulin therapy, eribulin may need to be administered to individual patients in accordance with renal function and albumin levels before treatment initiation.
A High‐Performing Metal‐Free Photoactivatable Nitric Oxide Donor with a Green Fluorescent Reporter
Authors: Parisi Cristina , Seggio Mimimorena , Fraix Aurore , Sortino Salvatore
Published: June 2020

Abstract: We report herein a novel nitric oxide (NO) donor activatable by visible blue light with an in‐built green fluorescence reporter. This NO photodonor, based on the amino‐nitro‐benzofurazan chromogenic skeleton, releases NO in solution with a quantum yield ΦNO=0.15 which increases up to 0.80 in Pluronic® micelles, the largest values ever reported for nonmetal‐containing NO donors activatable by visible light. Besides, the large contrast between the fluorescence emission of the chromogenic moiety after and before the NO release (>10) permits the easy and in real‐time quantification of the amount of NO released, without the addition of external fluorescent probes. This NO photodonor can also be effectively entrapped in a Pluronic‐based thermoresponsive hydrogel with excellent preservation of its photochemical and photophysical behaviour. These properties, together with the facile synthetic procedure, make the present compound an intriguing candidate for fundamental and potential applicative research studies where spatiotemporally regulated NO delivery is required.
Behavioral constraints on local adaptation and counter‐gradient variation: Implications for climate change
Authors: Quinby Brandon M. , Belk Mark C. , Creighton J. Curtis
Published: June 2020

Resource allocation to growth, reproduction, and body maintenance varies within species along latitudinal gradients. Two hypotheses explaining this variation are local adaptation and counter‐gradient variation. The local adaptation hypothesis proposes that populations are adapted to local environmental conditions and are therefore less adapted to environmental conditions at other locations. The counter‐gradient variation hypothesis proposes that one population out performs others across an environmental gradient because its source location has greater selective pressure than other locations. Our study had two goals. First, we tested the local adaptation and counter‐gradient variation hypotheses by measuring effects of environmental temperature on phenotypic expression of reproductive traits in the burying beetle, Nicrophorus orbicollis Say, from three populations along a latitudinal gradient in a common garden experimental design. Second, we compared patterns of variation to evaluate whether traits covary or whether local adaptation of traits precludes adaptive responses by others. Across a latitudinal range, N. orbicollis exhibits variation in initiating reproduction and brood sizes. Consistent with local adaptation: (a) beetles were less likely to initiate breeding at extreme temperatures, especially when that temperature represents their source range; (b) once beetles initiate reproduction, source populations produce relatively larger broods at temperatures consistent with their local environment. Consistent with counter‐gradient variation, lower latitude populations were more successful at producing offspring at lower temperatures. We found no evidence for adaptive variation in other adult or offspring performance traits. This suite of traits does not appear to coevolve along the latitudinal gradient. Rather, response to selection to breed within a narrow temperature range may preclude selection on other traits. Our study highlights that N. orbicollis uses temperature as an environmental cue to determine whether to initiate reproduction, providing insight into how behavior is modified to avoid costly reproductive attempts. Furthermore, our results suggest a temperature constraint that shapes reproductive behavior.
Mobility costs and energy uptake mediate the effects of morphological traits on species' distribution and abundance
Authors: Pinkert Stefan , Friess Nicolas , Zeuss Dirk , Gossner Martin M. , Brandl Roland , Brunzel Stefan
Published: June 2020

Individuals of large or dark‐colored ectothermic species often have a higher reproduction and activity than small or light‐colored ones. However, investments into body size or darker colors should negatively affect the fitness of individuals as they increase their growth and maintenance costs. Thus, it is unlikely that morphological traits directly affect species’ distribution and abundance. Yet, this simplification is frequently made in trait‐based ecological analyses. Here, we integrated the energy allocation strategies of species into an ecophysiological framework to explore the mechanisms that link species’ morphological traits and population dynamics. We hypothesized that the effects of morphological traits on species’ distribution and abundance are not direct but mediated by components of the energy budget and that species can allocate more energy towards dispersal and reproduction if they compensate their energetic costs by reducing mobility costs or increasing energy uptake. To classify species’ energy allocation strategies, we used easily measured proxies for the mobility costs and energy uptake of butterflies that can be also applied to other taxa. We demonstrated that contrasting effects of morphological traits on distribution and abundance of butterfly species offset each other when species’ energy allocation strategies are not taken into account. Larger and darker butterfly species had wider distributions and were more abundant if they compensated the investment into body size and color darkness (i.e., melanin) by reducing their mobility costs or increasing energy uptake. Adults of darker species were more mobile and foraged less compared to lighter colored ones, if an investment into melanin was indirectly compensated via a size‐dependent reduction of mobility costs or increase of energy uptake. Our results indicate that differences in the energy allocations strategies of species account for a considerable part of the variation in species’ distribution and abundance that is left unexplained by morphological traits alone and ignoring these differences can lead to false mechanistic conclusions. Therefore, our findings highlight the potential of integrating proxies for species’ energy allocation strategies into trait‐based models not only for understanding the physiological mechanisms underlying variation in species’ distribution and abundance, but also for improving predictions of the population dynamics of species.
CD8+CD73+ T cells in the tumor microenvironment of head and neck cancer patients are linked to diminished T cell infiltration and activation in tumor tissue
Authors: Panigrahi Soumya , Bazdar Douglas A. , Albakri Marwah , Ferrari Brian , Antonelli Christopher J. , Freeman Michael L. , Dubyak George , Zender Chad , Sieg Scott F.
Published: June 2020

Recent studies have implicated a role for adenosine‐dependent immunosuppression in head and neck tumor microenvironments. We describe expression of CD73, an enzyme critical to the generation of adenosine from extracellular AMP, in T cells and other cell types within human head and neck tumors. Flow cytometric analyses of tumor‐infiltrating cells indicate that CD3+ cells are the predominant source of CD73 among immune infiltrating cells and that CD73 expression, especially among CD8+ T cells, is inversely related to indices of T cell infiltration and T cell activation in the microenvironment of head and neck tumors. We provide evidence that CD73 expression on peripheral T cells and levels of soluble CD73 in circulation are correlated with CD73 expression on CD8+ T cells in tumors. Moreover, fluorescent microscopy studies reveal that CD8+CD73+ cells are observed in close proximity to tumor cells as well as in surrounding tissue. In vitro studies with peripheral blood T cells indicate that anti‐CD3‐stimulation causes loss of CD73 expression, especially among cells that undergo proliferation and that exogenous AMP can impair T cell proliferation, while sustaining CD73 expression. These data suggest that CD8+CD73+ T cells may be especially important mediators of immunosuppression in human head and neck cancer.
Generalizability of harm and pain expectations after exposure in chronic low back pain patients
Authors: Riecke Jenny , Rief Winfried , Vlaeyen Johan W.S. , Glombiewski Julia A.
Published: June 2020

Background

Exposure treatments are shown to be effective in reducing pain‐related fear and the perceived harmfulness of physical activities. However, due to the fragility of extinction its stability is questionable. We investigated the generalizability of exposure effects in chronic low back pain (CLBP) patients by integrating a behavioral test in the context of an intervention study.

Methods

The study is an additional analysis of a randomized controlled trial investigating the efficacy of exposure in vivo. A total of 67 CLBP patients were randomly assigned to one of the three groups: Exposure‐short (EXP‐S); exposure‐long (EXP‐L) and cognitive behavioral therapy (CBT). Participants rated the expected harmfulness of daily activities (Photograph Series of Daily Activities) before and after therapy. Post‐treatment participants were confronted with an individually tailored, threatening movement in a new context. Harm and pain expectations before the exposure were compared to the actual experience after exposure.

Results

We found that EXP leads to more strongly reduced harm expectations (F(2,50) = 11.37, p < .001, η2 = 0.31) compared to CBT, regardless of the duration of EXP. After therapy, patients expected less harm (F(2,50) = 3.61, p = .034, η2 = 0.13) but not less pain (F(2,50) = 3.61, p = .034, η2 = 0.13) when confronted with a novel movement.

Conclusions

Exposure successfully reduced harm but not pain expectations in patients with CLBP. Further, preliminary results showed that these specific exposure effects were generalized to a novel activity in a different context outside therapy.

Significance

This study investigats the generalizability and stability of exposure effects in patients with CLBP by combining a behavioral test with an intervention study. We found strong and stable effects on harm expectations but not on pain expectations. Results show promising preliminary evidence that reduced harm expectations can be generalized to a novel threatening activity in a new context. Clinical implications of our findings suggest that exposure treatment would benefit from a clear focus on harm expectations.
Process adapted calibration improves fluorometric pH sensor precision in sophisticated fermentation processes
Authors: Newton Joseph , Oeggl Reinhard , Janzen Nils H. , Abad Sandra , Reinisch Daniela
Published: June 2020

Miniaturization and automation have become increasingly popular in bioprocess development in recent years, enabling rapid high‐throughput screening and optimization of process conditions. In addition, advances in the bioprocessing industry have led to increasingly complex process designs, such as pH and temperature shifts, in microbial fed‐batch fermentations for optimal soluble protein expression in a range of hosts. However, in order to develop an accurate scale‐down model for bioprocess screening and optimization, small‐scale bioreactors must be able to accurately reproduce these complex process designs. Monitoring methods, such as fluorometric‐based pH sensors, provide elegant solutions for the miniaturization of bioreactors, however, previous research suggests that the intrinsic fluorescence of biomass alters the sigmoidal calibration curve of fluorometric pH sensors, leading to inaccurate pH control. In this article, we present results investigating the impact of biomass on the accuracy of a commercially available fluorometric pH sensor. Subsequently, we present our calibration methodology for more precise online measurement and provide recommendations for improved pH control in sophisticated fermentation processes.
Strength‐reduction factors for the design of light nonstructural elements in buildings
Authors: Kazantzi Athanasia K. , Miranda Eduardo , Vamvatsikos Dimitrios
Published: June 2020

Strength‐reduction factors that reduce ordinates of floor spectra acceleration due to nonlinearity in the secondary system are investigated. In exchange for permitting some inelastic deformation to occur in the secondary system or its supports, these strength reduction factors allow to design the nonstructural elements or their supports for lateral forces that are smaller than those that would be required to maintain them elastically during earthquakes. This paper presents the results of a statistical analysis on component strength‐reduction factors that were computed considering floor motions recorded on instrumented buildings in California during various earthquakes. The effect of yielding in the component or its anchorage/bracing in offering protection against excessive component acceleration demands is investigated. It is shown that strength‐reduction factors computed from floor motions are significantly different from those computed from ground motions recorded on rock or on firm soils. In particular, they exhibit much larger reductions for periods tuned or nearly tuned to the dominant modal periods of the building response. This is due to the large differences in frequency content of ground motions and floor motions, with the former typically characterized by wide‐band spectra whereas the latter are characterized by narrow‐band spectra near periods of dominant modes in the response of the building. Finally, the study provides approximate equations to estimate component strength‐reduction factors computed through nonlinear regression analyses.
Regionally encoded functional heterogeneity of astrocytes in health and disease: A perspective
Authors: Clarke Benjamin E. , Taha Doaa M. , Tyzack Giulia E. , Patani Rickie
Published: June 2020

Increasing evidence has suggested that astrocytes demonstrate striking regionally allocated functional heterogeneity. Here, we discuss how this spatiotemporally encoded diversity determines the astrocytic phenotype along a finely grained spectrum from neuroprotective to deleterious states. With increasing recognition of their diverse and evolving roles in the central neuraxis, astrocytes now represent a tractable cellular target for therapies aiming to restore neural circuit integrity in a broad range of neurodegenerative disorders. Understanding the determinants of astrocyte physiology along with the true extent of heterogeneity in their regional and subregional functions will ultimately inform therapeutic strategy in neurodegenerative diseases.
Diagnostic and Prognostic Significance of Complement in Patients With Alcohol‐Associated Hepatitis
Authors: Fan Xiude , McCullough Rebecca L. , Huang Emily , Bellar Annette , Kim Adam , Poulsen Kyle L. , McClain Craig J. , Mitchell Mack , McCullough Arthur J. , Radaeva Svetlana , Barton Bruce , Szabo Gyongyi , Dasarathy Srinivasan , Rotroff Daniel M. , Nagy Laura E.
Published: June 2020

Background and Aims

Given the lack of effective therapies and high mortality in acute alcohol‐associated hepatitis (AH), it is important to develop rationally designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here, we investigated whether a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90‐day mortality.

Approach and Results

Plasma samples collected at time of diagnosis from 254 patients with moderate and severe AH recruited from four medical centers and 31 healthy persons were used to quantify complement proteins by enzyme‐linked immunosorbent assay and Luminex arrays. Components of the classical and lectin pathways, including complement factors C2, C4b, and C4d, as well as complement factor I (CFI) and C5, were reduced in AH patients compared to healthy persons. In contrast, components of the alternative pathway, including complement factor Ba (CFBa) and factor D (CFD), were increased. Markers of complement activation were also differentially evident, with C5a increased and the soluble terminal complement complex (sC5b9) decreased in AH. Mannose‐binding lectin, C4b, CFI, C5, and sC5b9 were negatively correlated with Model for End‐Stage Liver Disease score, whereas CFBa and CFD were positively associated with disease severity. Lower CFI and sC5b9 were associated with increased 90‐day mortality in AH.

Conclusions

Taken together, these data indicate that AH is associated with a profound disruption of complement. Inclusion of complement, especially CFI and sC5b9, along with other laboratory indicators, could improve diagnostic and prognostic indications of disease severity and risk of mortality for AH patients.