bluuebunny/crossref_metadata_2025_split huggingface dataset:
A human receptor occupancy assay to measure anti‐PD‐1 binding in patients with prior anti‐PD‐1
Authors: Junker Fabian , Gulati Pratiksha , Wessels Uwe , Seeber Stefan , Stubenrauch Kay‐Gunnar , Codarri‐Deak Laura , Markert Christoph , Klein Christian , Camillo Teixeira Priscila , Kao Henry 
Published: March 2021

AbstractReceptor occupancy (RO) assessment by flow cytometry is an important pharmacodynamic (PD) biomarker in the clinical development of large molecules such as monoclonal therapeutic antibodies (mAbs). The total‐drug‐bound RO assay format directly assesses mAb binding to cell surface targets using anti‐drug detection antibodies. Here, we generated a flow cytometry detection antibody specifically binding to mAbs of the IgG1 P329GLALA backbone. Using this reagent, we developed a total‐drug‐bound RO assay format for RG7769, a bi‐specific P329GLALA containing mAb targeting PD‐1 and TIM3 on T cells. In its fit‐for‐purpose validated version, this RO assay has been used in the Phase‐I dose escalation study of RG7769, informing on peripheral T cell RO and RG7769 antibody binding capacity (ABC). We assessed RG7769 RO in checkpoint‐inhibitor (CPI) naïve patients and anti‐PD‐1 CPI experienced patients using our novel assay. Here, we show that in both groups, complete T cell RO can be achieved (~100%). However, we found that the maximum number of T cell binding sites for RG7769 pre‐dosing was roughly twofold lower in patients recently having undergone anti‐PD‐1 treatment. We show that this is due to steric hindrance exerted by competing mAbs masking the available drug binding sites. Our findings highlight the importance of quantitative mAb assessment in addition to relative RO especially in the context of patients who have previously received anti‐PD‐1 treatment.
Nutrient limitation may induce microbial mining for resources from persistent soil organic matter
Authors: Hicks Lettice C. , Lajtha Kate , Rousk Johannes 
Published: March 2021

AbstractFungi and bacteria are the two principal microbial groups in soil, responsible for the breakdown of organic matter (OM). The relative contribution of fungi and bacteria to decomposition is thought to impact biogeochemical cycling at the ecosystem scale, whereby bacterially dominated decomposition supports the fast turnover of easily available substrates, whereas fungal‐dominated decomposition leads to the slower turnover of more complex OM. However, empirical support for this is lacking. We used soils from a detritus input and removal treatment experiment in an old‐growth coniferous forest, where above‐ and belowground litter inputs have been manipulated for 20 yr. These manipulations have generated variation in OM quality, as defined by energetic content and proxied as respiration per g soil organic matter (SOM) and the δ13C signature in respired CO2and microbial PLFAs. Respiration per g SOM reflects the availability and lability of C substrate to microorganisms, and the δ13C signature indicates whether the C used by microorganisms is plant derived and higher quality (more δ13C depleted) or more microbially processed and lower quality (more δ13C enriched). Surprisingly, higher quality C did not disproportionately benefit bacterial decomposers. Both fungal and bacterial growth increased with C quality, with no systematic change in the fungal‐to‐bacterial growth ratio, reflecting the relative contribution of fungi and bacteria to decomposition. There was also no difference in the quality of C targeted by bacterial and fungal decomposers either for catabolism or anabolism. Interestingly, respired CO2was more δ13C enriched than soil C, suggesting preferential use of more microbially processed C, despite its lower quality. Gross N mineralization and consumption were also unaffected by differences in the ratio of fungal‐to‐bacterial growth. However, the ratio of C to gross N mineralization was lower than the average C/N of SOM, meaning that microorganisms specifically targeted N‐rich components of OM, indicative of selective microbial N‐mining. Consistent with the δ13C data, this reinforces evidence for the use of more microbially processed OM with a lower C/N ratio, rather than plant‐derived OM. These results challenge the widely held assumption that microorganisms favor high‐quality C sources and suggest that there is a trade‐off in OM use that may be related to the growth‐limiting factor for microorganisms in the ecosystem.
Synthesis, Structure and Luminescent Properties of Rare‐Earth‐Metal Oxyacridinates
Authors: Balashova Tatyana V. , Polyakova Svetlana K. , Arsenyev Maxim V. , Ilichev Vasily A. , Kukinov Andrey A. , Marugin Alexey V. , Rumyantcev Roman V. , Fukin Georgy K. , Yablonskiy Artem N. , Bochkarev Mikhail N. 
Published: March 2021

AbstractComplexes of Sc, La, Sm, Gd, Tb and Yb with 1,3‐di‐tert‐butyl‐7‐methylacridin‐4‐olate (AcrMe) and 1,3‐di‐tert‐butyl‐7‐bromoacridin‐4‐olate (AcrBr) ligands were obtained by reactions of respective acridinols with cyclopentadienides or tris(trimethylsilyl)amides of rare earth metals or by metathesis of metal chlorides with Na(AcrR). The Sc and La complexes with AcrMe ligands revealed photo‐ and electroluminescence of moderate intensity while the Sm, Gd, and Tb complexes, as well as all complexes with AkrBr ligands, turned out to be luminescent inactive. The La(AkrBr)3 and Yb(AcrBr)3 complexes showed photovoltaic properties. The best results of energy conversion were achieved on three‐layer model devices containing a lanthanum complex as a photoactive material.
CoS2 Nanoparticles Embedded in Two‐Dimensional Sheet‐Shaped N‐Doped Carbon for Sodium Storage
Authors: Zhang Chunyang , Tan Pengfei , Cheng Zhijie , Song Jinbo , Zhao Yuyuan , Chen Lei , Cai Xingwei , Zhang Junhao , Yuan Aihua 
Published: March 2021

AbstractNa‐ion batteries (NIBs) have attracted more and more attention due to the plentiful resources of sodium, excellent ion storage capacity and superior cycle life. However, the implementation of NIBs has been limited by the shortage of electrode materials with outstanding comprehensive properties. Among the discovered anode materials, transition metal sulfides (TMSs) have been widely considered as one of the most competitive and promising ones due to their high theoretical specific capacity. Herein, CoS2 nanoparticles embedded in nitrogen‐doped carbon nanosheets (CoS2/NC) were designed and synthesized by using Co‐based Metal‐organic frame‐work (Co−MOF) as precursor of metal sulfurs, followed by a simple combined carbonization‐sulfurization process. The CoS2/NC compo‐sites were evaluated as binder‐free anode materials for NIBs, delivering a high reversible gravimetric capability of 332 mA h g−1 after 60 cycles as well as great rate capability of 326.6 mA h g−1 at 2000 mA g−1. The improvement of electrochemical behavior is attributed to the synergistic interaction between CoS2 nanoparticles with high electro‐chemical activity and the sheet‐shaped N‐doped carbon with high conductivity. This work provides a greatly attractive strategy for energy conversion and storage.
Regioselective Double Oxidative Addition of Bis‐NHC Precursors
Authors: Böhme Matthias D. , Wilm Lukas F. B. , Hepp Alexander , Hahn F. Ekkehardt 
Published: March 2021

AbstractThe 4,4’‐dimethylenebiphenyl linked symmetric bis‐(2‐chlorobenzimidazole) 1 and the unsymmetric 2‐chlorobenzimidazolium/2‐chlorobenzimidazole 2(BF4) have been reacted with one equivalent [Pd(PPh3)4] in oxidative addition reactions. For the symmetric bis‐NHC precursor 1, double metallation of both 2‐chlorobenzimidazole sites to give the dinuclear bis‐pNHC complex [3](BF4)2 was observed. The unsymmetric compound 2(BF4) was only metallated at the 2‐chlorobenz‐imidazolium site with formation of the mononuclear NHC complex [4](BF4). The remaining 2‐chlorobenzimidazole moiety was subsequently metallated in a second oxidative addition reaction with [M(PPh3)4] (M=Pd, Pt) to give the homobimetallic NHC/pNHC complex [5](BF4)2 (M=Pd) and the heterobimetallic complex [6](BF4)2 demonstrating the unique site‐selective metallation of the bis‐NHC precursor 2(BF4) by two consecutive oxidative additions.
An Experimental DUAL Model of Advanced Liver Damage
Authors: Benedé‐Ubieto Raquel , Estévez‐Vázquez Olga , Guo Feifei , Chen Chaobo , Singh Youvika , Nakaya Helder I. , Gómez del Moral Manuel , Lamas‐Paz Arantza , Morán Laura , López‐Alcántara Nuria , Reissing Johanna , Bruns Tony , Avila Matías A. , Santamaría Eva , Mazariegos Marina S. , Woitok Marius Maximilian , Haas Ute , Zheng Kang , Juárez Ignacio , Martín‐Villa José Manuel , Asensio Iris , Vaquero Javier , Peligros Maria Isabel , Argemi Josepmaria , Bataller Ramón , Ampuero Javier , Romero Gómez Manuel , Trautwein Christian , Liedtke Christian , Bañares Rafael , Cubero Francisco Javier , Nevzorova Yulia A. 
Published: March 2021

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol‐associated and metabolic‐associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol‐associated liver disease plus metabolic‐associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA‐sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.
Navigating the health system in responding to health workforce challenges of the COVID‐19 pandemic: the case of Maldives (short case)
Authors: Usman Sofoora Kawsar , Moosa Sheena , Abdullah Aminath Shaina 
Published: March 2021

AbstractBeing a small island and low‐middle income country (LMIC) heavily dependent on global markets for sustaining its basic needs and health system, Maldives faced specific challenges during the COVID‐19 pandemic. This was reinforced through tensions between the heavily centralized healthcare delivery and a partially decentralized public health system. Using the pillars of pandemic response proposed by the World Health Organisation, this article explores the planning assumptions, resource estimations and strategies adopted to equip the health system with resources for the pandemic response. The resource need estimates based on projections for COVID‐19 identified a shortfall of medical professionals to care for patients while maintaining 55% of the workforce for regular healthcare across the atolls. The findings show that while the policy of lockdown bought time to increase hospital beds and devices, the country was unable to increase the healthcare workforce. Furthermore, as the lockdown eased, the exponential increase of cases took Maldives to the global one per capita incidence. Despite this, with cautious planning and use of resources, the country has so far managed to maintain low mortality from COVID‐19. The lessons from this experience are paramount in future pandemic response planning, not only for Maldives, but other small island LMICs.
Effects of various calcium transporters on mitochondrial Ca2+ changes and oocyte maturation
Authors: Wang Feng , Fan Li‐Hua , Li Ang , Dong Feng , Hou Yi , Schatten Heide , Sun Qing‐Yuan , Ou Xiang‐Hong 
Published: March 2021

AbstractCa2+ participates in many important cellular processes, but the underlying mechanisms are still poorly understood, especially during oocyte maturation. First, we confirmed that calcium in the culture medium was essential for oocyte maturation. Next, various inhibitors of Ca2+ channels were applied to investigate their roles in mitochondrial Ca2+ changes and oocyte maturation. Our results showed that Trmp7, Orai, T‐type Ca2+ channels and Na+/Ca2+ exchanger complex (NCLX) were important for oocyte maturation. Trmp7 inhibition delayed germinal vesicle breakdown. Orai and NCLX inhibition significantly weakened the distribution of mitochondrial Ca2+ around the nucleus compared to the Ctrl group. Interestingly, even T‐type Ca2+ channels‐specific inhibitor Mibefradil blocked germinal vesicle breakdown; mitochondrial Ca2+ surrounding the nucleus still was maintained at a high level without spindle formation. Two calcium transporter inhibitors, Thapsigargin and Ruthenium Red, which have been confirmed to inhibit oocyte activation, did not significantly affect oocyte maturation. Increasing the knowledge of calcium transport may provide a basis to build on for improving oocyte in vitro maturation in human assisted reproduction clinics.
Transition metals and metal complexes in autophagy and diseases
Authors: Luo Yuping , Fu Yuanyuan , Huang Zhiying , Li Min 
Published: March 2021

AbstractTransition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal‐based compounds have become a prospective source for drug development, particularly in cancer treatment. In recent years, extensive studies have shown that numerous transition metal‐based compounds could modulate autophagy, promising a new therapeutic strategy for metal‐related diseases and the design of metal‐based agents. Copper, zinc, and manganese, which are common components in physiological pathways, play important roles in the progression of cancer, neurodegenerative diseases, and cardiovascular diseases. Furthermore, enrichment of copper, zinc, or manganese can regulate autophagy. Thus, we summarized the current advances in elucidating the mechanisms of some metals/metal‐based compounds and their functions in autophagy regulation, which is conducive to explore the intricate roles of autophagy and exploit novel therapeutic drugs for human diseases.
(Theta, triangle)‐free and (even hole, K4)‐free graphs—Part 1: Layered wheels
Authors: Sintiari Ni Luh Dewi , Trotignon Nicolas 
Published: March 2021

AbstractWe present a construction called layered wheel. Layered wheels are graphs of arbitrarily large treewidth and girth. They might be an outcome for a possible theorem characterizing graphs with large treewidth in terms of their induced subgraphs (while such a characterization is well‐understood in terms of minors). They also provide examples of graphs of large treewidth and large rankwidth in well‐studied classes, such as (theta, triangle)‐free graphs and even‐hole‐free graphs with no (where a hole is a chordless cycle of length at least four, a theta is a graph made of three internally vertex disjoint paths of length at least two linking two vertices, and is the complete graph on four vertices).
Reduced Field‐of‐View Diffusion‐Weighted Magnetic Resonance Imaging of the Pancreas With Tilted Excitation Plane: A Preliminary Study
Authors: Tanabe Masahiro , Higashi Mayumi , Benkert Thomas , Imai Hiroshi , Miyoshi Keisuke , Kameda Fumi , Ariyoshi Shoko , Ihara Kenichiro , Ito Katsuyoshi 
Published: March 2021

BackgroundReduced field‐of‐view diffusion‐weighted imaging (rDWI) with tilted two‐dimensional radiofrequency (RF) excitation planes has not yet been applied to the imaging of the pancreas although the utility of this technique which allows the acquisition of high‐quality images without aliasing artifacts in the phase‐encoding direction has been evaluated for brain and spinal cord imaging.PurposeTo evaluate the visual image quality of the pancreas by tilting the excitation plane (tilted rDWI) in comparison to conventional DWI (cDWI) and rDWI without using the tilted excitation plane.Study typeRetrospective.PopulationThirty‐two patients evaluated for suspected pancreatobiliary diseases.Field Strength/SequenceEcho‐planar imaging DWI (cDWI, rDWI, and tilted rDWI) acquired at 3 T.AssessmentImages from each DWI sequence were analyzed by five radiologists to compare image quality (conspicuity of pancreatic edges, interslice signal homogeneity, overall image quality, and conspicuity of focal pancreatic lesions) and artifacts (presence of blurring or ghosting artifacts, susceptibility artifacts, and aliasing artifact).Statistical TestsShapiro–Wilk test was performed to assess whether data were normally distributed. Friedman test followed by Bonferroni‐adjusted Wilcoxon signed‐rank test for post hoc analysis was performed to compare image quality and artifact scores.ResultsThe mean scores for conspicuity of pancreatic edges (3.36 vs. 2.37), interslice signal homogeneity (3.14 vs. 2.81), presence of ghosting artifacts (3.32 vs. 2.66), susceptibility artifacts (3.06 vs. 2.30), and aliasing artifacts (3.90 vs. 2.34), and overall image quality (3.49 vs. 2.36) were significantly higher in the tilted rDWI than in the rDWI (P < 0.017 for all parameters). The conspicuity score for focal pancreatic lesions tended to be higher in tilted rDWI than in rDWI (2.44 vs. 2.00, P = 0.07).Data ConclusionTilted rDWI had better image quality and reduced artifacts relative to cDWI and rDWI techniques in the pancreas.Level of Evidence4Technical EfficacyStage 2
Diversity of human sapovirus genotypes detected in Japanese pediatric patients with acute gastroenteritis, 2014–2017
Authors: Okitsu Shoko , Khamrin Pattara , Thongprachum Aksara , Hikita Toshiyuki , Kumthip Kattareeya , Pham Ngan Thi Kim , Takanashi Sayaka , Hayakawa Satoshi , Maneekarn Niwat , Ushijima Hiroshi 
Published: March 2021

AbstractSapovirus (SaV) is one of the pathogens related to acute gastroenteritis (AGE) in adults and children worldwide. This study reported the diversity of SaV genotypes in children with AGE in Japan from July 2014 to June 2017. Of a total of 2259 stool samples tested by using reverse transcription‐PCR method and further analyzed by nucleotide sequencing, 114 (5.0%) were positive for SaV and GI.1 (83.3%) was the most predominant genotype, followed by GII.1, GIV.1, GI.2, GI.3, and GII.3 genotypes. Monthly distribution analysis demonstrated two epidemic peaks from July to December 2015 and February to May 2017. However, no detection peak was observed in 2014 and 2016. Phylogenetic analysis of the complete VP1 nucleotide sequences of these GI.1 strains revealed two major clusters of GI.1 and each of which contained GI.1 strains of both 2015 and 2017. This study suggests that the continuous surveillance of SaV is needed to monitor high genetic diversity in Japanese children with AGE.
Evidence of Epstein‐Barr virus heterogeneous gene expression in adult lung transplant recipients with posttransplant lymphoproliferative disorder
Authors: Zaffiri Lorenzo , Frankel Courtney , Bush Erika J. , Neely Megan L. , Pavlisko Elizabeth N. , Mokrova Irina L. , Luftig Micah A. , Palmer Scott M. 
Published: March 2021

AbstractEpstein‐Barr virus (EBV)‐driven posttransplant lymphoproliferative disorder (PTLD) is a serious complication following lung transplant. The extent to which the presence of EBV in PTLD tissue is associated with survival is uncertain. Moreover, whether the heterogeneity in expression of EBV latency programs is related to the timing of PTLD onset remains unexplored. We retrospectively performed a comprehensive histological evaluation of EBV markers at the tissue level in 34 adult lung transplant recipients with early‐ and late‐onset PTLD. Early‐onset PTLD, occurring within the first 12 months posttransplant, had higher odds to express EBV markers. The presence of EBV in PTLD was not associated with a difference in survival relative to EBV‐negative tumors. However, we found evidence of heterogeneous expression of EBV latency programs, including type III, IIb, IIa, and 0/I. Our study suggests that the heterogeneous expression of EBV latency programs may represent a mechanism for immune evasion in patients with PLTD after lung transplants. The recognition of multiple EBV latency programs can be used in personalized medicine in patients who are nonresponsive to traditional types of chemotherapy and can be potentially evaluated in other types of solid organ transplants.
Effect of local anesthetics on platelet physiology and function
Authors: Dregalla Ryan C. , Uribe Yvette , Bodor Marko 
Published: March 2021

AbstractLocal anesthetics are often used at the site of injury or mixed with platelet‐rich plasma to reduce pain when treating orthopedic and sports‐related injuries. Local anesthetics have been shown to have deleterious effects on stromal cells, but their impact on platelets has not been investigated. In this study, we aimed to assess the effects of lidocaine, bupivacaine, and ropivacaine on platelet health. Based on the deleterious effects of local anesthetics on nucleated cells, we hypothesized that these compounds would affect platelet viability, intracellular physiology, and function. Platelet preparations were derived from randomly selected donors and exposed to lidocaine 1%, bupivacaine 0.75%, ropivacaine 0.5%, and saline at 1:1 and 1:3 ratios. Platelet morphology, viability, intracellular calcium, production of radical oxygen species (ROS), apoptosis, and adhesion were assessed via fluorescent microscopy and flow cytometry. Bupivacaine resulted in increased ROS production, calcium dysregulation, apoptosis, and reduced platelet adhesion. By contrast, ropivacaine and lidocaine were similar to saline in most assays, except for a low degree of mitochondrial stress as evidenced by increased ROS production. Ultimately, bupivacaine 0.75% was harmful to platelets as evidenced by reduced platelet viability, adhesion, and increased apoptosis, whereas lidocaine 1% and ropivacaine 0.5% were relatively safe at the 1:1 and 1:3 dilutions.Clinical significance: Lidocaine 1% and ropivacaine 0.5% can be used at up to a 1:1 ratio with platelet preparations to reduce the pain and discomfort of PRP procedures while maintaining platelet therapeutic potential.