bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysosomes in acute myeloid leukemia: potential therapeutic targets?
Authors: Rafiq Sreoshee , McKenna Sharon L. , Muller Sylviane , Tschan Mario P. , Humbert Magali 
Published: August 2021

AbstractLysosomes, since their discovery, have been primarily known for degrading cellular macromolecules. However, in recent studies, they have begun to emerge as crucial regulators of cell homeostasis. They are at the crossroads of catabolic and anabolic pathways and are intricately involved in cellular trafficking, nutrient signaling, energy metabolism, and immune regulation. Their involvement in such essential cellular functions has renewed clinical interest in targeting the lysosome as a novel way to treat disease, particularly cancer. Acute myeloid leukemia (AML) is an aggressive blood cancer with a low survival probability, particularly in older patients. The genomic landscape of AML has been extensively characterized but few targeted therapies (with the exception of differentiation therapy) can achieve a long-term cure. Therefore, there is an unmet need for less intensive and more tolerable therapeutic interventions. In this review, we will give an overview on the myriad of functions performed by lysosomes and their importance in malignant disease. Furthermore, we will discuss their relevance in hematopoietic cells and different ways to potentially target them in AML.
Grey and white matter microstructure is associated with polygenic risk for schizophrenia
Authors: Stauffer Eva-Maria , Bethlehem Richard A. I. , Warrier Varun , Murray Graham K. , Romero-Garcia Rafael , Seidlitz Jakob , Bullmore Edward T. 
Published: August 2021

AbstractRecent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition. We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macrostructural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed-effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures, and 14 white matter tracts. Other microstructural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate, and prefrontal cortical areas, insula, and hippocampus. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia. Risk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical, and white matter microstructure may be linked to the genetic mechanisms of schizophrenia.
The Smac mimetic BV6 cooperates with STING to induce necroptosis in apoptosis-resistant pancreatic carcinoma cells
Authors: Hannes Sabine , Karlowitz Rebekka , van Wijk Sjoerd J. L. 
Published: August 2021

AbstractPancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2′3′-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2′3′-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2′3′-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
Exosomal transfer of tumor-associated macrophage-derived hsa_circ_0001610 reduces radiosensitivity in endometrial cancer
Authors: Gu Xiaobin , Shi Yonggang , Dong Meilian , Jiang Li , Yang Jing , Liu Zheyan 
Published: August 2021

AbstractThe occurrence of radioresistance is a clinical obstacle to endometrial cancer (EC) treatment and induces tumor relapse. In this study, we found that tumor-associated macrophages (TAMs) enriched in EC specimens were determined to present an M2-like phenotype. In vitro, the coculture of M2-polarized macrophages significantly downregulated the radiosensitivity of EC cells by releasing exosomes. Hsa_circ_0001610 was found to be abundant in exosomes derived from M2-polarized macrophages (EXOs), and hsa_circ_0001610 knockdown eliminated the reduction effect of EXOs on the radiosensitivity of EC cells. The following mechanism research revealed that hsa_circ_0001610 functioned as the competing endogenous RNA of miR-139-5p, thereby upregulating cyclin B1 expression, which is a vital pusher of radioresistance in several types of cancer by regulating the cell cycle. Hsa_circ_0001610 overexpression reduced the radiosensitivity of EC cells, which was then reversed by miR-139-5p overexpression. In vivo, the promotion effect of EXOs on xenograft tumor growth in nude mice treated with irradiation was further reinforced after hsa_circ_0001610 overexpression. In conclusion, TAM-derived exosomes transferred hsa_circ_0001610 to EC cells, and the overexpressed hsa_circ_0001610 in EC cells released cyclin B1 expression through adsorbing miR-139-5p, thereby weakening the radiosensitivity of EC cells.
Microbial production of megadalton titin yields fibers with advantageous mechanical properties
Authors: Bowen Christopher H. , Sargent Cameron J. , Wang Ao , Zhu Yaguang , Chang Xinyuan , Li Jingyao , Mu Xinyue , Galazka Jonathan M. , Jun Young-Shin , Keten Sinan , Zhang Fuzhong 
Published: August 2021

AbstractManmade high-performance polymers are typically non-biodegradable and derived from petroleum feedstock through energy intensive processes involving toxic solvents and byproducts. While engineered microbes have been used for renewable production of many small molecules, direct microbial synthesis of high-performance polymeric materials remains a major challenge. Here we engineer microbial production of megadalton muscle titin polymers yielding high-performance fibers that not only recapture highly desirable properties of natural titin (i.e., high damping capacity and mechanical recovery) but also exhibit high strength, toughness, and damping energy — outperforming many synthetic and natural polymers. Structural analyses and molecular modeling suggest these properties derive from unique inter-chain crystallization of folded immunoglobulin-like domains that resists inter-chain slippage while permitting intra-chain unfolding. These fibers have potential applications in areas from biomedicine to textiles, and the developed approach, coupled with the structure-function insights, promises to accelerate further innovation in microbial production of high-performance materials.
Lowering the thermal noise barrier in functional brain mapping with magnetic resonance imaging
Authors: Vizioli Luca , Moeller Steen , Dowdle Logan , Akçakaya Mehmet , De Martino Federico , Yacoub Essa , Uğurbil Kamil 
Published: August 2021

AbstractFunctional magnetic resonance imaging (fMRI) has become an indispensable tool for investigating the human brain. However, the inherently poor signal-to-noise-ratio (SNR) of the fMRI measurement represents a major barrier to expanding its spatiotemporal scale as well as its utility and ultimate impact. Here we introduce a denoising technique that selectively suppresses the thermal noise contribution to the fMRI experiment. Using 7-Tesla, high-resolution human brain data, we demonstrate improvements in key metrics of functional mapping (temporal-SNR, the detection and reproducibility of stimulus-induced signal changes, and accuracy of functional maps) while leaving the amplitude of the stimulus-induced signal changes, spatial precision, and functional point-spread-function unaltered. We demonstrate that the method enables the acquisition of ultrahigh resolution (0.5 mm isotropic) functional maps but is also equally beneficial for a large variety of fMRI applications, including supra-millimeter resolution 3- and 7-Tesla data obtained over different cortical regions with different stimulation/task paradigms and acquisition strategies.
A nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila
Authors: Koyama Takashi , Terhzaz Selim , Naseem Muhammad T. , Nagy Stanislav , Rewitz Kim , Dow Julian A. T. , Davies Shireen A. , Halberg Kenneth V. 
Published: August 2021

AbstractAnimals maintain metabolic homeostasis by modulating the activity of specialized organs that adjust internal metabolism to external conditions. However, the hormonal signals coordinating these functions are incompletely characterized. Here we show that six neurosecretory cells in the Drosophila central nervous system respond to circulating nutrient levels by releasing Capa hormones, homologs of mammalian neuromedin U, which activate the Capa receptor (CapaR) in peripheral tissues to control energy homeostasis. Loss of Capa/CapaR signaling causes intestinal hypomotility and impaired nutrient absorption, which gradually deplete internal nutrient stores and reduce organismal lifespan. Conversely, increased Capa/CapaR activity increases fluid and waste excretion. Furthermore, Capa/CapaR inhibits the release of glucagon-like adipokinetic hormone from the corpora cardiaca, which restricts energy mobilization from adipose tissue to avoid harmful hyperglycemia. Our results suggest that the Capa/CapaR circuit occupies a central node in a homeostatic program that facilitates the digestion and absorption of nutrients and regulates systemic energy balance.
Asymmetric biomimetic transamination of α-keto amides to peptides
Authors: Cai Weiqi , Qiao Xuelong , Zhang Hao , Li Bo , Guo Jianhua , Zhang Liangliang , Chen Wen-Wen , Zhao Baoguo 
Published: August 2021

AbstractPeptides are important compounds with broad applications in many areas. Asymmetric transamination of α-keto amides can provide an efficient strategy to synthesize peptides, however, the process has not been well developed yet and still remains a great challenge in both enzymatic and catalytic chemistry. For biological transamination, the high activity is attributed to manifold structural and electronic factors of transaminases. Based on the concept of multiple imitation of transaminases, here we report N-quaternized axially chiral pyridoxamines1for enantioselective transamination of α-keto amides, to produce various peptides in good yields with excellent enantio- and diastereoselectivities. The reaction is especially attractive for the synthesis of peptides made of unnatural amino acids since it doesn’t need great efforts to make chiral unnatural amino acids before amide bond formation.
The bowfin genome illuminates the developmental evolution of ray-finned fishes
Authors: Thompson Andrew W. , Hawkins M. Brent , Parey Elise , Wcisel Dustin J. , Ota Tatsuya , Kawasaki Kazuhiko , Funk Emily , Losilla Mauricio , Fitch Olivia E. , Pan Qiaowei , Feron Romain , Louis Alexandra , Montfort Jérôme , Milhes Marine , Racicot Brett L. , Childs Kevin L. , Fontenot Quenton , Ferrara Allyse , David Solomon R. , McCune Amy R. , Dornburg Alex , Yoder Jeffrey A. , Guiguen Yann , Roest Crollius Hugues , Berthelot Camille , Harris Matthew P. , Braasch Ingo 
Published: August 2021

AbstractThe bowfin (Amia calva) is a ray-finned fish that possesses a unique suite of ancestral and derived phenotypes, which are key to understanding vertebrate evolution. The phylogenetic position of bowfin as a representative of neopterygian fishes, its archetypical body plan and its unduplicated and slowly evolving genome make bowfin a central species for the genomic exploration of ray-finned fishes. Here we present a chromosome-level genome assembly for bowfin that enables gene-order analyses, settling long-debated neopterygian phylogenetic relationships. We examine chromatin accessibility and gene expression through bowfin development to investigate the evolution of immune, scale, respiratory and fin skeletal systems and identify hundreds of gene-regulatory loci conserved across vertebrates. These resources connect developmental evolution among bony fishes, further highlighting the bowfin’s importance for illuminating vertebrate biology and diversity in the genomic era.
Herbaceous perennial ornamental plants can support complex pollinator communities
Authors: Erickson E. , Patch H. M. , Grozinger C. M. 
Published: August 2021

AbstractHuman-designed landscapes can host diverse pollinator communities, and the availability of floral resources is central to supporting insect biodiversity in highly modified environments. However, some urban landscapes have relatively few pollinator-attractive plant species and management in urban environments rarely considers the function of these plants in generating and supporting a stable ecological community. Evaluations of 25 cultivars within five commercially popular herbaceous perennial ornamental plant genera (Agastache, Echinacea, Nepeta, Rudbeckia, and Salvia) revealed variation in the total and proportional abundance of visitors attracted. These varieties supported multiple pollinator functional groups, however bees were the primary visitors to in this system. Cultivars were assessed according to their function within a plant–pollinator network. Comparisons of artificial networks created with the six most attractive and six least attractive cultivars demonstrated that a planting scheme using the most attractive cultivars would attract nearly four times as many bee species, including several specialists and rare species. Plant diversity in the landscape was correlated with abundance and diversity of pollinator visitors, demonstrating that community context shapes a plant’s relative attractiveness to pollinators. We conclude that herbaceous perennial cultivars can support an abundance and diversity of pollinator visitors, however, planting schemes should take into consideration the effects of cultivar, landscape plant diversity, floral phenology, floral area, and contribution to a stable ecological community.
Homeostatic model of human thermoregulation with bi-stability
Authors: Hajnová Veronika , Zlámal Filip , Lenárt Peter , Bienertova-Vasku Julie 
Published: August 2021

AbstractAll homoiothermic organisms are capable of maintaining a stable body temperature using various negative feedback mechanisms. However, current models cannot satisfactorily describe the thermal adaptation of homoiothermic living systems in a physiologically meaningful way. Previously, we introduced stress entropic load, a novel variable designed to quantify adaptation costs, i.e. the stress of the organism, using a thermodynamic approach. In this study, we use stress entropic load as a starting point for the construction of a novel dynamical model of human thermoregulation. This model exhibits bi-stable mechanisms, a physiologically plausible features which has thus far not been demonstrated using a mathematical model. This finding allows us to predict critical points at which a living system, in this case a human body, may proceed towards two stabilities, only one of which is compatible with being alive. In the future, this may allow us to quantify not only the direction but rather the extent of therapeutic intervention in critical care patients.
Myocarditis occurrence with cancer immunotherapy across indications in clinical trial and post-marketing data
Authors: Makunts Tigran , Saunders Ila M. , Cohen Isaac V. , Li Mengxing , Moumedjian Talar , Issa Masara A. , Burkhart Keith , Lee Peter , Patel Sandip Pravin , Abagyan Ruben 
Published: August 2021

AbstractAntibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient’s own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.
Validating species distribution models to illuminate coastal fireflies in the South Pacific (Coleoptera: Lampyridae)
Authors: Sutherland Laura N. , Powell Gareth S. , Bybee Seth M. 
Published: August 2021

AbstractThe coastal areas of Vanuatu are under a multitude of threats stemming from commercialization, human development, and climate change. Atyphella Olliff is a genus of firefly that includes species endemic to these coastal areas and will need protection. The research that has already been conducted was affected by accessibility due to the remote nature of the islands which left numerous knowledge gaps caused by a lack of distributional data (e.g., Wallacean shortfall). Species distribution models (SDM) are a powerful tool that allow for the modeling of the broader distribution of a taxon, even with limited distributional data available. SDMs assist in filling the knowledge gap by predicting potential areas that could contain the species of interest, making targeted collecting and conservation efforts more feasible when time, resources, and accessibility are major limiting factors. Here a MaxEnt prediction was used to direct field collecting and we now provide an updated predictive distribution for this endemic firefly genus. The original model was validated with additional fieldwork, ultimately expanding the known range with additional locations first identified using MaxEnt. A bias analysis was also conducted, providing insight into the effect that developments such as roads and settlements have on collecting and therefore the SDM, ultimately allowing for a more critical assessment of the overall model. After demonstrating the accuracy of the original model, this new updated SDM can be used to identify specific areas that will need to be the target of future conservation efforts by local government officials.
Current-induced crystallisation in Heusler alloy films for memory potentiation in neuromorphic computation
Authors: Frost William , Elphick Kelvin , Samiepour Marjan , Hirohata Atsufumi 
Published: August 2021

AbstractThe current information technology has been developed based on von Neumann type computation. In order to sustain the rate of development, it is essential to investigate alternative technologies. In a next-generation computation, an important feature is memory potentiation, which has been overlooked to date. In this study, potentiation functionality is demonstrated in a giant magnetoresistive (GMR) junction consisting of a half-metallic Heusler alloy which can be a candidate of an artificial synapse while still achieving a low resistance-area product for low power consumption. Here the Heusler alloy films are grown on a (110) surface to promote layer-by-layer growth to reduce their crystallisation energy, which is comparable with Joule heating induced by a controlled current introduction. The current-induced crystallisation leads to the reduction in the corresponding resistivity, which acts as memory potentiation for an artificial GMR synaptic junction.
Whole genome sequencing reveals possible host species adaptation of Streptococcus dysgalactiae
Authors: Porcellato Davide , Smistad Marit , Skeie Siv Borghild , Jørgensen Hannah Joan , Austbø Lars , Oppegaard Oddvar 
Published: August 2021

AbstractStreptococcusdysgalactiae (SD) is an emerging pathogen in human and veterinary medicine, and is associated with several host species, disease phenotypes and virulence mechanisms. SD has traditionally been divided into the subspecies dysgalactiae (SDSD) and subsp.equisimilis (SDSE), but recent molecular studies have indicated that the phylogenetic relationships are more complex. Moreover, the genetic basis for the niche versatility of SD has not been extensively investigated. To expand the knowledge about virulence factors, phylogenetic relationships and host-adaptation strategies of SD, we analyzed 78 SDSD genomes from cows and sheep, and 78 SDSE genomes from other host species. Sixty SDSD and 40 SDSE genomes were newly sequenced in this study. Phylogenetic analysis supported SDSD as a distinct taxonomic entity, presenting a mean value of the average nucleotide identity of 99%. Bovine and ovine associated SDSD isolates clustered separately on pangenome analysis, but no single gene or genetic region was uniquely associated with host species. In contrast, SDSE isolates were more heterogenous and could be delineated in accordance with host. Although phylogenetic clustering suggestive of cross species transmission was observed, we predominantly detected a host restricted distribution of the SD-lineages. Furthermore, lineage specific virulence factors were detected, several of them located in proximity to hotspots for integration of mobile genetic elements. Our study indicates that SD has evolved to adapt to several different host species and infers a potential role of horizontal genetic transfer in niche specialization.