bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma
Authors: Arulananda Surein , O’Brien Megan , Evangelista Marco , Jenkins Laura J. , Poh Ashleigh R. , Walkiewicz Marzena , Leong Trishe , Mariadason John M. , Cebon Jonathan , Balachander Srividya B. , Cidado Justin R. , Lee Erinna F. , John Thomas , Fairlie Walter D. 
Published: May 2021

AbstractMalignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.
hsa_circ_0008234 inhibits the progression of lung adenocarcinoma by sponging miR-574-5p
Authors: Jiang Wei , He Yaozhou , Ma Zijian , Zhang Yu , Zhang Chengpeng , Zheng Nianpeng , Tang Xing 
Published: May 2021

AbstractcircRNAs are a novel type of noncoding RNA (ncRNA) that have been identified as an important regulator of gene expression and play a part in the progression of various diseases. However, the function of circ_0008234 in lung adenocarcinoma (LUAC) remains unknown. Through the GEO (Gene Expression Omnibus) database, circ_0008234 was first found to be downregulated in LUAC tissues. It could inhibit cell growth and accelerate apoptosis in vitro and in vivo. In terms of its possible mechanism, circ_0008234 mainly was present in the cytoplasm and competed with miR-574-5p to regulate RND3 (Rho family GTPase 3). Our results revealed that circ_0008234 inhibited the progression of LUAC through a competing endogenous RNA (ceRNA)-based mechanism and provided potential biomarkers and therapeutic targets for LUAC treatment.
Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart
Authors: Lyu Yankun , Verma Vipin K. , Lee Younjee , Taleb Iosif , Badolia Rachit , Shankar Thirupura S. , Kyriakopoulos Christos P. , Selzman Craig H. , Caine William , Alharethi Rami , Navankasattusas Sutip , Seidel Thomas , Drakos Stavros G. , Sachse Frank B. 
Published: May 2021

AbstractIt is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF. Using left ventricular myocardium from donors and HF patients with ages between 19 and 75 years, we established a library of 3D reconstructions of the t-system as well as ryanodine receptor (RyR) and junctophilin 2 (JPH2) clusters. Aging was characterized by t-system alterations and sarcolemmal dissociation of RyR clusters. This remodeling was less pronounced than in HF and accompanied by major alterations of JPH2 arrangement. Our study indicates that targeting sarcolemmal association of JPH2 might ameliorate age-associated deficiencies of heart function.
FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity
Authors: Timbrell Simon , Aglan Hosam , Cramer Angela , Foden Phil , Weaver David , Pachter Jonathan , Kilgallon Aoife , Clarke Robert B. , Farnie Gillian , Bundred Nigel J. 
Published: May 2021

AbstractCancer stem-like cells (CSC) contribute to therapy resistance and recurrence. Focal adhesion kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies. FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and paclitaxel reduced self-renewal in triple negative cell lines. An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population. Combined FAK and paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative patient derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.
Telomere biology disorders
Authors: Kam Michelle L. W. , Nguyen Trang T. T. , Ngeow Joanne Y. Y. 
Published: May 2021

AbstractTelomere biology disorders (TBD) are a heterogeneous group of diseases arising from germline mutations affecting genes involved in telomere maintenance. Telomeres are DNA-protein structures at chromosome ends that maintain chromosome stability; their length affects cell replicative potential and senescence. A constellation of bone marrow failure, pulmonary fibrosis, liver cirrhosis and premature greying is suggestive, however incomplete penetrance results in highly variable manifestations, with idiopathic pulmonary fibrosis as the most common presentation. Currently, the true extent of TBD burden is unknown as there is no established diagnostic criteria and the disorder often is unrecognised and underdiagnosed. There is no gold standard for measuring telomere length and not all TBD-related mutations have been identified. There is no specific cure and the only treatment is organ transplantation, which has poor outcomes. This review summarises the current literature and discusses gaps in understanding and areas of need in managing TBD.
Notch-Wnt signal crosstalk regulates proliferation and differentiation of osteoprogenitor cells during intramembranous bone healing
Authors: Lee S. , Remark L. H. , Josephson A. M. , Leclerc K. , Lopez E. Muiños , Kirby D. J. , Mehta Devan , Litwa H. P. , Wong M. Z. , Shin S. Y. , Leucht P. 
Published: May 2021

AbstractAdult bone regeneration is orchestrated by the precise actions of osteoprogenitor cells (OPCs). However, the mechanisms by which OPC proliferation and differentiation are linked and thereby regulated are yet to be defined. Here, we present evidence that during intramembranous bone formation OPC proliferation is controlled by Notch signaling, while differentiation is initiated by activation of canonical Wnt signaling. The temporospatial separation of Notch and Wnt signal activation during the early stages of bone regeneration suggests crosstalk between the two pathways. In vitro and in vivo manipulation of the two essential pathways demonstrate that Wnt activation leads to initiation of osteogenic differentiation and at the same time inhibits Notch signaling, which results in termination of the proliferative phase. Here, we establish canonical Wnt signaling as a key regulator that facilitates the crosstalk between OPC proliferation and differentiation during intramembranous, primary bone healing.
Dispositional empathy predicts primary somatosensory cortex activity while receiving touch by a hand
Authors: Schaefer Michael , Kühnel Anja , Rumpel Franziska , Gärtner Matti 
Published: May 2021

AbstractPrevious research revealed an active network of brain areas such as insula and anterior cingulate cortex when witnessing somebody else in pain and feeling empathy. But numerous studies also suggested a role of the somatosensory cortices for state and trait empathy. While recent studies highlight the role of the observer’s primary somatosensory cortex when seeing painful or nonpainful touch, the interaction of somatosensory cortex activity with empathy when receiving touch on the own body is unknown. The current study examines the relationship of touch related somatosensory cortex activity with dispositional empathy by employing an fMRI approach. Participants were touched on the palm of the hand either by the hand of an experimenter or by a rubber hand. We found that the BOLD responses in the primary somatosensory cortex were associated with empathy personality traits personal distress and perspective taking. This relationship was observed when participants were touched both with the experimenter’s real hand or a rubber hand. What is the reason for this link between touch perception and trait empathy? We argue that more empathic individuals may express stronger attention both to other’s human perceptions as well as to the own sensations. In this way, higher dispositional empathy levels might enhance tactile processing by top-down processes. We discuss possible implications of these findings.
Are heavy metals in urban garden soils linked to vulnerable populations? A case study from Guelph, Canada
Authors: Montaño-López Fernando , Biswas Asim 
Published: May 2021

AbstractWith increasing population, there is growing concern for food security in urban areas. Though, urban gardening has gained popularity, several studies have found higher concentrations of contaminants in urban soils, especially heavy metals, often at toxic levels, which pose a potential risk for human health. Moreover, heavy metal polluted sites have been strongly associated with areas populated by low-income families, newcomers and racial minorities. In this study, heavy metals in the soils of community gardens in the city of Guelph, ON were examined as a case study and their relationship with vulnerable populations. We analyzed soil samples at two depths for a range of heavy metals and characterized their spatial patterns to see if they were related to disadvantaged communities. We estimated the pollution levels using two index-based approaches and assessed their potential risk for human health, although concentrations of most heavy metals were below the limits established by Canadian regulations, metals like Cd, Pb, Se and Zn exhibited a mild degree of pollution, whereas As exhibited a severe degree. Their association with vulnerable populations were weak, but hotspots were mainly located in low-income areas. This case study provides scientific evidence that could help to expand our understanding around the interconnection between pollution and poverty/racial inequality. Also the importance of generating strategies for the protection of human health and sustainable soil management practices in urban areas where food for human consumption is grown.
Rapid evolution of mammalian APLP1 as a synaptic adhesion molecule
Authors: Onodera Wataru , Asahi Toru , Sawamura Naoya 
Published: May 2021

AbstractAmyloid precursor protein (APP) family members are involved in essential neuronal development including neurite outgrowth, neuronal migration and maturation of synapse and neuromuscular junction. Among the APP gene family members, amyloid precursor-like protein 1 (APLP1) is selectively expressed in neurons and has specialized functions during synaptogenesis. Although a potential role for APLP1 in neuronal evolution has been indicated, its precise evolutionary and functional contributions are unknown. This study shows the molecular evolution of the vertebrate APP family based on phylogenetic analysis, while contrasting the evolutionary differences within the APP family. Phylogenetic analysis showed 15 times higher substitution rate that is driven by positive selection at the stem branch of the mammalian APLP1, resulting in dissimilar protein sequences compared to APP/APLP2. Docking simulation identified one positively selected site in APLP1 that alters the heparin-binding site, which could affect its function, and dimerization rate. Furthermore, the evolutionary rate covariation between the mammalian APP family and synaptic adhesion molecules (SAMs) was confirmed, indicating that only APLP1 has evolved to gain synaptic adhesion property. Overall, our results suggest that the enhanced synaptogenesis property of APLP1 as one of the SAMs may have played a role in mammalian brain evolution.
The distributional properties of exemplars affect category learning and generalization
Authors: Carvalho Paulo F. , Chen Chi-hsin , Yu Chen 
Published: May 2021

AbstractWhat we learn about the world is affected by the input we receive. Many extant category learning studies use uniform distributions as input in which each exemplar in a category is presented the same number of times. Another common assumption on input used in previous studies is that exemplars from the same category form a roughly normal distribution. However, recent corpus studies suggest that real-world category input tends to be organized around skewed distributions. We conducted three experiments to examine the distributional properties of the input on category learning and generalization. Across all studies, skewed input distributions resulted in broader generalization than normal input distributions. Uniform distributions also resulted in broader generalization than normal input distributions. Our results not only suggest that current category learning theories may underestimate category generalization but also challenge current theories to explain category learning in the real world with skewed, instead of the normal or uniform distributions often used in experimental studies.
Aging affects artemisinin synthesis in Artemisia annua
Authors: Li Jiao , Chu Xiao-Hui , Wang Xiao-Yu , Feng Bao-Min , Yu Zong-Xia 
Published: May 2021

AbstractArtemisinin (ART) is the most effective component in malaria treatment, however, the extremely low content restricts its clinical application. Therefore, it is urgent to increase the yield of ART. ART gradually accumulates with aging, small RNA (sRNA) and transcriptome analysis were applied on the leaves of 2-week-old (2 w) and 3-month-old (3 m) A. annua respectively. Among all the annotated sRNAs, 125 were upregulated and 128 downregulated in the 3 m sample compared to the 2 w one. Whereas 2183 genes were upregulated and 2156 downregulated. Notably, the level of miR156 and several annotated miRNAs gradually decreased while SPLs increased. In addition, the genes on ART biosynthesis pathway were significantly upregulated including ADS, CYP71AV1, ADH1, DBR2 and ALDH1, and so were the positive transcription factors like AaERF1, AaORA and AaWRKY1 indicating that age influences the ART biosynthesis by activating the expression of the synthesizing genes as well as positive transcription factors. This study contributes to reveal the regulatory effects of age on ART biosynthesis both in sRNA and transcription levels.
Synthesis, structure, and properties of carbon/carbon composites artificial rib for chest wall reconstruction
Authors: Tan Zhoujian , Zhang Xiang , Ruan Jianming , Liao Jiqiao , Yu Fenglei , Xia Lihong , Wang Bin , Liang Chaoping 
Published: May 2021

AbstractIn this work, braided carbon fiber reinforced carbon matrix composites (3D-C/C composites) are prepared by chemical vapor infiltration process. Their composite structure, mechanical properties, biocompatibility, and in vivo experiments are investigated and compared with those of traditional 2.5D-C/C composites and titanium alloys TC4. The results show that 3D-C/C composites are composed of reinforced braided carbon fiber bundles and pyrolytic carbon matrix and provide 51% open pores with a size larger than 100 μm for tissue adhesion and growth. The Young’s modulus of 3D-C/C composites is about 5 GPa, much smaller than those of 2.5D-C/C composites and TC4, while close to the autogenous bone. 3D-C/C composites have a higher tensile strength (167 MPa) and larger elongation (5.0%) than 2.5D-C/C composites (81 MPa and 0.7%), and do not show obvious degradation after 1 × 106 cyclic tensile loading. The 3D-C/C composites display good biocompatibility and have almost no artifacts on CT imaging. The in vivo experiment reveals that 3D-C/C composites artificial ribs implanted in dogs do not show displacement or fracture in 1 year, and there are no obvious proliferation and inflammation in the soft tissues around 3D-C/C composites implant. Our findings demonstrate that 3D-C/C composites are suitable for chest wall reconstruction and present great potentials in artificial bones.
A photoacoustic Zn2+ sensor based on a merocyanine/xanthene-6-ol hybrid chromophore and its ratiometric imaging in mice
Authors: Fang Hongbao , Wang Chengjun , Chen Yuncong , Chen Zhongyan , Yao Shankun , Yang Shiping , Dong Lei , Guo Zijian , He Weijiang 
Published: May 2021

HD-Zn was constructed for reversible ratiometric PA Zn2+ imaging in vivo. Zn2+ titration experiments together with a theoretical study suggests that Zn2+ chelation-induced ICT alteration in HD-Zn is responsible for its ratiometric PA sensing ability.
Synthesis of 3-spirooxindole 3H-indoles through Rh(iii)-catalyzed [4 + 1] redox-neutral spirocyclization of N-aryl amidines with diazo oxindoles
Authors: Zhou Qianting , Song Xia , Zhang Xinying , Fan Xuesen 
Published: May 2021

Presented herein is a novel synthesis of 3-spirooxindole 3H-indoles via the coupling and spirocyclization of N-aryl amidines with diazo oxindoles.
Flexible power control strategy for elliptical trajectory based dynamic voltage restorer during voltage sags
Authors: Li Peng , Wang Yi , Wang Can , Pan Xuewei , Lu Jinghang , Li Xue , Blaabjerg Frede 
Published: May 2021

AbstractDynamic voltage restorer (DVR) plays an essential role in achieving high‐quality voltage restoration in the distribution system. This paper presents an elliptical‐trajectory‐based approach to guarantee continuous power delivery by considering the active and reactive power limits during voltage sags. Besides, two parameters are proposed in the accurate mathematical analysis of current references. Thus, the control objective can be fulfilled by the flexible current injection strategy that combines a precise balance between the positive and negative sequences. The proposed control method can determine the required power injections by selecting the two proper values to support that the converter output current is smaller than the maximum rated value. Under the presented control, the maximum power limit and flexible power dispatch are combined together to develop four operation schemes. The main advantage is the smooth transition process during changes in the operation schemes and the disappearance of active and reactive power oscillations. Also, these four control states are applied to reveal the flexibility of the proposed designs. Finally, the hardware tests in a laboratory prototype are implemented to validate the feasibility of the proposed method.
Heat-efficient ceramic products based on modified rice straw
Authors: Kodzoev Mukhamad-Basir , Isachenko Sergey , Rasulov Olimjon , Kaddo Maria 
Published: May 2021

The current state of the building ceramics production is based on the following facts. Firstly, as a result of market conditions, the number of operating ceramics factories has significantly decreased. Secondly, considering the increase in the house construction rate due to the shift to new financing mechanisms, there has been an increase in the ceramic brick production by 2-3% since 2019. Growth opportunities are associated with higher thermal efficiency of ceramic products and masonry based thereon.
The research objective in this article was the development of compositions for wall heat-efficient ceramics based on loess low-grade loams with the use of rice straw as a burnout additive and, in particular, the determination of the optimal processed rice straw consumption. The scientific novelty of the research consisted in the development of a method for selecting the ceramic mixtures composition, optimizing the composition and substantiating the rice straw and rice straw ash influence on the ceramic mixtures and products properties.
Rice straw is introduced into clay masses at the preparation stage in an amount of 5-15% (by mass) of fluff rice straw, which burns out with burning temperature of 200-300°C and makes the mass porous, preventing shrinkage and forming ash containing up to 20% of amorphous silica. Carbonates in clay dissociate during firing, interacting with amorphous silica and forming various calcium silicates that strengthen the shard structure.
Control modules in the “Intelligent building” system
Authors: Alyoshintsev Andrey , Mokrova Natalia , Sak Alexander 
Published: May 2021

The relevance of the article consists on the use of telemetry control modules to organize the uninterrupted operation for dispatching service, including remote work. Thanks to telemetric means of dispatching control and management of the conditions of water supply facilities, the process is reaching a new qualitative level. The functionality of the water intake unit has been significantly improved as a result of the introduction of a telemetry and telecontrol system in the form of separate technological modules. The developed modules provide additional functions for water quality control, including residual chlorine, accounting for a number of random pollution factors in addition to the route technology of the dispatching system; remote control of executive mechanisms with the possibility of automatic control; self- diagnostics of the software and hardware complex, as well as planning of preventive and repair work of engineering systems.
The results of water quality on-line monitoring by using a telemetry module in the chlorination room automatically providing the optimal ratio of chlorine added to the water are presented.
Nichtsteroidale Antirheumatika (NSAR) und Niere
Authors: Bonmann Tobias 
Published: May 2021

ZUSAMMENFASSUNGNichtsteroidale Antirheumatika (NSAR) haben über verschiedene pathophysiologische Mechanismen Einfluss auf die Nierenfunktion und können, v. a. beim Vorliegen weiterer Risikofaktoren, ernste und möglicherweise auch bleibende Schäden verursachen. Der Einsatz und die Indikationsstellung zur Einnahme von NSAR sollte daher regelmäßig kritisch hinterfragt werden, um Patienten vor vermeidbaren Komplikationen zu bewahren.
Antibiotikainduzierte Nierenschädigung
Authors: Schricker Severin , Ketteler Markus 
Published: May 2021

ZUSAMMENFASSUNGMedikamentenbedingte Nephrotoxizität ist nach wie vor eine der häufigsten Ursachen für eine akute Nierenschädigung bei hospitalisierten Patienten. Innerhalb der umfangreichen Gruppe von Medikamenten, die mit dem akuten Nierenversagen in Verbindung gebracht werden, sind Antibiotika und andere antimikrobielle Stoffe häufige Auslöser für strukturelle und funktionelle Nierenschäden. Die klinischen Manifestationen reichen von vorübergehenden Formen tubulärer Funktionseinschränkungen bis hin zu einer signifikanten Verschlechterung der Nierenfunktion, die eine akute Nierenersatztherapie erfordert. Dieser Artikel gibt einen Überblick über die Substanzen, Mechanismen und prädisponierten Risikofaktoren für eine antibiotikainduzierte Nierenschädigung sowie einen Überblick über präventive Maßnahmen zur Verringerung von Komplikationen.