bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leveraging the p53 signaling pathway as a radio-sensitization strategy in endometrial cancer
Authors: Vargas Roberto , Petty Aaron , Yard Brian , Durmaz Arda , Lin-Rahardja Kristi , Reizes Ofer , Debernardo Robert , Scott Jacob 
Published: September 2022

AbstractEndometrial cancer (EC) is the most common type of gynecologic malignancy in the United States, with over 66, 200 new cases expected in 2023. The number of mortalities per year now approximate that of ovarian cancer. Despite our ability to identify different biologic clusters of EC, we have yet to understand the functional impact of key genomic alterations associated with discrepant prognoses and exploit this knowledge for therapeutic benefit. Given this, we set out to determine how alterations in p53 signaling, as conferred myTP53mutations, impact radiotherapy response in EC. We also explored if manipulation of this signaling pathway could be utilized as a radio-sensitization strategy in EC. Our work demonstrates that p53 signaling plays a significant role in radiotherapy response for EC and that leveraging this genomic data may allow us to exploit this pathway as a viable radiotherapeutic target in a significant number of EC cases.
Genomic analysis reveals HDAC1 regulates clinically relevant transcriptional programs in pancreatic cancer
Authors: Wright Carter A. , Gordon Emily R. , Cooper Sara J. 
Published: September 2022

ABSTRACTNovel strategies are needed to combat multidrug resistance in pancreatic ductal adenocarcinoma (PDAC). We applied genomic approaches to understand mechanisms of resistance in order to better inform treatment and precision medicine. Altered function of chromatin remodeling complexes contribute to chemoresistance. Our study generates and analyzes genomic and biochemical data from PDAC cells overexpressingHDAC1, a histone deacetylase involved in several chromatin remodeling complexes. We characterized the impact of overexpression on drug response, gene expression, HDAC1 binding, and chromatin structure using RNA-sequencing and ChIP-sequencing for HDAC1 and H3K27 acetylation. Integrative genomic analysis shows thatHDAC1overexpression promotes activation of key resistance pathways including epithelial to mesenchymal transition, cell cycle, and apoptosis through global chromatin remodeling. Target genes are similarly altered in patient tissues and show correlation with patient survival. We also demonstrate that direct targets of HDAC1 that also show altered chromatin are enriched near genes associated with altered GTPase activity. HDAC1 target genes identified usingin vitromethods and observed in patient tissues were used to develop a clinically relevant nine-transcript signature associated with patient prognosis. Integration of multiple genomic and biochemical data types enables understanding of multidrug resistance and tumorigenesis in PDAC, a disease in desperate need of novel treatment strategies.
A report card methodology to showcase progress towards threatened species recovery
Authors: Ward Michelle , Rout Tracy , Stewart Romola , Possingham Hugh P. , McDonald-Madden Eve , Clark Thomas G. , Kindler Gareth S. , Valentine Leonie , Macmillan Ellen , Watson James E.M. 
Published: September 2022

AbstractAmong the conservation community, it is well known that Earth’s mass species extinction crisis is getting worse. Yet, an often neglected problem is the need for effectively communicating the species extinction crisis to diverse audiences in ways that catalyse immediate action. Here we generated a streamlined threatened species recovery report card methodology, which combined two input indicators including planning and funding, one output indicator capturing habitat protection, and one outcome indicator which highlights threatened species trajectories, to provide simple scores for all Australian threatened species. We show that just 41 (2.3%) of species achieved an A grade for the input indicator (i.e., recovery plans and federal funding), 240 (13.3%) achieved a C grade, and 1,521 (84.4%) achieved an F. Five hundred and twenty nine (29.3%) species achieved an A for the output indicator (i.e, habitat protection), 130 (7.2%) achieved a B, 158 (8.8%) achieved a C, 189 (10.5%) achieved a D, 212 (11.8%) achieved an E, and 584 (32.4%) achieved a F. While five (0.3%) species achieved an A for the output indicator (i.e., threat status improvement), every other species (99.7%) achieved an F. We provide a method to combine scores to test how individual jurisdictions are tracking and show that Australia is achieving an F for the input and outcome indicators, and a D for the output indicator. While the threatened species recovery report card highlighted a clear failure in many federal environmental legislation responsibilities, it provides a baseline from which different governments can track policy progress and outlines clear direction for immediate improvement including developing adequate recovery plans, funding the actions in the recovery plans, protecting habitat from further destruction, verifying recovery through monitoring and evaluation of species trajectories, and supporting transparency and collaboration on the execution on the plans through an improved data infrastructure. Without an immediate step change in how Australia communicates and faces its species crisis, we will leave a tragic legacy of extinction and fail our obligations to future generations of Australians, and the international community.
High-risk microbial signatures are associated with severe parasitemia in controlledPlasmodiuminfections of both humans and rhesus macaques
Authors: Gustin Andrew T. , Broedlow Courtney A. , Hager Kevin , Coronado Ernesto , Wangari Solomon , Iwayama Naoto , Ahrens Chul Y. , Garrison William D. , Guerriero Kathryn A. , De Paris Kristina , Gale Michael , Klatt Nichole R. , Kublin James G. , Manuzak Jennifer A. 
Published: September 2022

AbstractWhile functions of the gastrointestinal (GI) microbiome include maintenance of immune homeostasis and protection against infectious disease, its role in determining disease severity duringPlasmodiuminfection has been limited to mouse models and observational human cohorts. Here, we performed controlledPlasmodiuminfection in both humans and rhesus macaques (RMs) to experimentally determine the impact of GI microbiome composition on disease progression. Through analysis of serially collected microbiome samples, we identified a high-risk microbial signature that strongly associated with increased risk of developing severe parasitemia in human participants. Importantly, we identified a parallel phenomenon in RMs. The combined weight of this evidence demonstrates that pre-infection GI microbiome composition is highly indicative ofP. falciparumdisease risk. Moreover, our observation thatP. fragile-microbiome dynamics in RMs closely mirrorsP. falciparum-microbiome interactions in humans strongly supports the use of this model in pre-clinical investigations of novel microbiome-targeting approaches to reduce malaria burden.
Quantitative physiology and proteome adaptations of Bifidobacterium breve NRBB57 at near-zero growth rates
Authors: Camargo Angela Rocio Ortiz , van Mastrigt Oscar , Bongers Roger S. , Ben- Amor Kaouther , Knol Jan , Abee Tjakko , Smid Eddy J. 
Published: September 2022

ABSTRACTIn natural environments, nutrients are usually scarce causing microorganisms to grow slow while staying metabolically active. These natural conditions can be simulated using retentostat cultivations. The present study describes the physiological and proteome adaptations of the probiotic Bifidobacterium breve NRBB57 from high (0.4 h−1) to near-zero growth rates. Lactose-limited retentostat cultivations were carried out for 21 days in which the bacterial growth rate progressively reduced to 0.00092 h−1, leading to a 3.4-fold reduction of the maintenance energy requirement. Lactose was mainly converted into acetate, formate and ethanol at high growth rates while in the retentostat lactate production increased. Interestingly, the consumption of several amino acids (serine, aspartic acid and glutamine/arginine) and glycerol increased over time in the retentostat. Morphological changes and viable but non-culturable cells were also observed in the retentostat. Proteomes were compared for all growth rates, revealing a down-regulation of ribosomal proteins at near-zero growth rates and an up-regulation of proteins involved in the catabolism of alternative energy sources. Finally, we observed induction of the stringent response and stress defence systems. Retentostat cultivations were proven useful to study the physiology of B. breve, mimicking the nutrient scarcity of its complex habitat, the human gut.IMPORTANCEIn natural environments, nutrients are usually scarce causing microorganisms to grow slow while staying metabolically active. In this study we used retentostat cultivation to investigate how the probiotic Bifidobacterium breve adapts its physiology and proteome under severe nutrient limitation resulting in near-zero growth rates (<0.001 h−1). We showed that the nutrient limitation induced a multifaceted response including stress defence and stringent response, metabolic shifts and the activation of novel alternative energy producing pathways.
Counting sperm whales and visualising their dive profiles using two-hydrophone recordings and an automated click detector algorithm in a longline depredation context
Authors: Pinson Samuel , Richard Gaëtan 
Published: September 2022

ABSTRACTOdontocetes depredating fish caught on longlines is a serious socio-economic and conservation issue. A good understanding of the depredation behaviour by odontocetes is therefore required. Within this purpose, a method is described to follow diving behaviour of sperm whales, considered as proxy of their foraging activity. The study case took place around Kerguelen Islands from the Patagonian toothfish fishery. The method uses the coherence between direct-path sperm whale clicks, recorded by two synchronized hydrophones, to distinguish them from decoherent clicks that are reflected by the water surface or seefloor (due to surface roughness). Its low computational cost permits to process large dataset and bring new insights on sperm whales behaviour. Detection of sperm whale clicks permits to estimate the number of sperm whales and to assess their diving behaviour. Three diving behaviour were identified as “Water Column” (individual goes down and up), “Water Wander” (individual seems to go up and down multiple times in the water column), and “Seafloor” (individual spend time on the seabed). Results suggest that sperm whales have different diving behaviours with specific dives as they are either “interacting” or “not-interacting” with a hauling vessel.
Cumulative multisensory discrepancies shape the ventriloquism aftereffect but not the ventriloquism bias
Authors: Kayser Christoph , Park Hame , Heuer Herbert 
Published: September 2022

AbstractMultisensory integration and recalibration are two processes by which perception deals with discrepant signals. Both are often studied in the spatial ventriloquism paradigm. There, integration is probed by the presentation of discrepant audio-visual stimuli, while recalibration manifests as an aftereffect in subsequent unisensory judgements. Both biases are typically quantified against the degree of audio-visual discrepancy, reflecting the possibility that both may arise from common underlying multisensory principles. We tested a specific prediction of this: that both processes should also scale similarly with the history of multisensory discrepancies experienced in previous trials. Analysing data from ten experiments we confirmed the expected dependency of each bias on the immediately presented discrepancy. And in line with the aftereffect being a cumulative process, this scaled with the discrepancies presented in multiple preceding audio-visual trials. However, the ventriloquism bias did not depend on the history of multisensory discrepancies and also did not depend on the aftereffect biases in previous trials - making these two multisensory processes experimentally dissociable. These findings support the notion that the ventriloquism bias and the aftereffect reflect distinct functions, with integration maintaining a stable percept by reducing immediate sensory discrepancies and recalibration maintaining an accurate percept by accounting for consistent discrepancies.
Predicting bioactivity of antibiotic metabolites by molecular docking and dynamics
Authors: Chio Hokin , Guest Ellen E , Hobman Jon L , Dottorini Tania , Hirst Jonathan D , Stekel Dov J 
Published: September 2022

AbstractAntibiotics enter the environment through waste streams, where they can exert selective pressure for antimicrobial resistance in bacteria. However, many antibiotics are excreted as partly metabolized forms, or can be subject to partial breakdown in wastewater treatment, soil, or through natural processes in the environment. If a metabolite is bioactive, even at sub-lethal levels, and also stable in the environment, then it could provide selection pressure for resistance. (5S)-penicilloic acid of piperacillin has previously been found complexed to the binding pocket of penicillin binding protein 3 (PBP3) of Pseudomonas aeruginosa. Here, we predicted the affinities of all potentially relevant antibiotic metabolites of ten different penicillins to that target protein, using molecular docking and molecular dynamics simulations. Docking predicts that, in addition to penicilloic acid, pseudopenicillin derivatives of these penicillins, as well as 6-aminopenicillanic acid (6APA), could also bind to this target. Molecular dynamics simulations further confirmed that (5R)-pseudopenicillin and 6APA bind the target protein, in addition to (5S)-penicilloic acid. Thus, it is possible that these metabolites are bioactive, and, if stable in the environment, could be contaminants selective for antibiotic resistance. This could have considerable significance for environmental surveillance for antibiotics as a means to reduce antimicrobial resistance, because targeted mass spectrometry could be required for relevant metabolites as well as the native antibiotics.
Msh2-Msh3 interferes with DNA metabolismin vivo
Authors: Medina-Rivera Melisa , Phelps Samantha , Sridharan Madhumita , Becker Jordan , Lamb Natalie A. , Kumar Charanya , Sutton Mark D. , Bielinsky Anja , Balakrishnan Lata , Surtees Jennifer A. 
Published: September 2022

ABSTRACTMismatch repair (MMR) is a highly conserved DNA repair pathway that safeguards the genome from errors in DNA replication. InSaccharomyces cerevisiae, two MutS homolog (Msh) complexes, Msh2-Msh3 or Msh2-Msh6, initiate MMR. Msh2-Msh3, the focus of this study, recognizes and directs repair of insertion/deletion loops (IDLs) up to ~17 nucleotides. Msh2-Msh3 also recognizes and binds distinct looped and branched DNA structures with varying affinities, thereby contributing to genome stability outside post-replicative MMR through homologous recombination, double-strand break repair (DSBR), and the DNA damage response. Msh2-Msh3 also promotes genome instability through trinucleotide repeat (TNR) expansions. This non-canonical activity is likely an unfortunate consequence of Msh2-Msh3’s intrinsic ability to bind a wide range of DNA structures, including those formed with single-stranded (ss) TNR sequences. We previously demonstrated that Msh2-Msh3 binding to 5’ ssDNA flap structures interfered with thein vitrobinding and cleavage activities of the flap endonuclease Rad27 (Fen1 in mammals), which promotes 5’ ssDNA flap processing during Okazaki fragment maturation (OFM) and long-patch base excision repair (LP-BER). Here we demonstrate that elevated Msh2-Msh3 levels interfere with DNA replication and LP-BERin vivo, consistent with the hypothesis that protein abundance and Msh3 ATPase activities are key drivers of Msh2-Msh3-mediated genomic instability.
lncRNA-WAL Promotes Aggressiveness of Triple-Negative Breast Cancer via inducing β-Catenin nuclear translocation
Authors: Huang Hongyan , Jin Haiyun , Lei Rong , He Zhanghai , He Shishi , Chen Jiewen , Saw Phei Er , Qiu Zhu , Ren Guosheng , Nie Yan 
Published: September 2022

AbstractBecause of its insensitive to existing radiotherapy, chemotherapy and targeted treatments, Triple-negative breast cancer (TNBC) remains a great challenge to overcome. More and more evidence has indicated abnormal wnt/β-catenin pathway activation in TNBC but not luminal or her2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between Activated and inactivated Wnt/β-catenin pathway of TNBC tissues, lnc-WAL (Wnt/β-catenin associated lncRNA; WAL) was selected as the top up-regulated lncRNA in Wnt/β-catenin pathway activation compared with the inactivation group. RIP-seq was analyzed between β-catenin and IgG groups of, where lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in the TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted the EMT, the ability of breast cancer stem cells (BCSC), proliferation, migration and invasion of TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, β-catenin was accumulated in nuclear and activated the target genes. Importantly, Wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL maybe as potential therapeutic target against TNBC.
Genome assembly with variable order de Bruijn graphs
Authors: Díaz-Domínguez Diego , Onodera Taku , Puglisi Simon J. , Salmela Leena 
Published: September 2022

AbstractThe nodes of a de Bruijn graph (DBG) of order k correspond to the set of k-mers occurring in a set of reads and an edge is added between two nodes if there is a k − 1 length overlap between them. When using a DBG for genome assembly, the choice of k is a delicate issue: if k is too small, the DBG is tangled, making graph traversal ambiguous, whereas choosing k too large makes the DBG disconnected, resulting in more and shorter contigs. The variable order de Bruijn graph (voDBG) has been proposed as a way to avoid fixing a single value of k. A voDBG represents DBGs of all orders in a single data structure and (conceptually) adds edges between the DBGs of different orders to allow increasing and decreasing the order. Whereas for a fixed order DBG unitigs are well defined, no properly defined notion of contig or unitig exists for voDBGs. In this paper we give the first rigorous definition of contigs for voDBGs. We show that voDBG nodes, whose frequency in the input read set is in interval [ℓ, h] for some h and ℓ > h/2, represent an unambiguous set of linear sequences, which we call the set of (ℓ, h)-tigs. By establishing connections between the voDBG and the suffix trie of the input reads, we give an efficient algorithm for enumerating (ℓ, h)-tigs in a voDBG using compressed suffix trees. Our experiments on real and simulated HiFi data show a prototype implementation of our approach has a better or comparable contiguity and accuracy as compared to other DBG based assemblers.
Coronary artery established through amniote evolution
Authors: Mizukami Kaoru , Higashiyama Hiroki , Arima Yuichiro , Ando Koji , Fukuhara Shigetomo , Miyagawa-Tomita Sachiko , Kurihara Hiroki 
Published: September 2022

AbstractCoronary arteries are part of the vascular system that nourishes the heart; they are generally considered a synapomorphy of jawed vertebrates. However, the so-called coronary arteries originated from different body parts in amniotes and other groups, and the evolution of these arteries remains unclear. Here we propose that the amniote coronary arteries were newly obtained, overriding the ancestral arterial systems. In mouse (Mus musculus) and quail (Coturnix japonica) embryos, the amniote-type coronary arteries are established by the reconstitution of the transient vascular plexus (aortic subepicardial vessels; ASVs) on the outflow tract and the primitive coronary plexus during the development. In contrast, amphibians (Xenopus laevis, Hyla japonica, Lithobates catesbeianus, and Cynops pyrrhogaster) retain the ASV-like vasculature as extrinsic cardiac arteries throughout their lives and have no primitive coronary plexus. A comparison of zebrafish (Danio rerio) and chondrichthyans (Lamna sp., Narke japonica, and Deania calcea) suggested that their hypobranchial arteries correspond morphologically to the ASVs and also serve as heart-feeding arteries throughout their lives. Thus, the coronary artery of adult amniotes is an evolutionary novelty that has acquired new anatomical connections through the addition of a new developmental process to the ancestral pattern. This change is probably related to the modification of branchial arteries, highlights the drastic morphological changes underlying the physiological transition in amniote evolution.
Effective use of genetically-encoded optical biosensors for profiling signalling signatures in iPSC-CMs derived from idiopathic dilated cardiomyopathy patients
Authors: Bourque Kyla , Derish Ida , Hawey Cara , Jones-Tabah Jace , Khan Kashif , Alim Karima , Jiang Alyson , Sadighian Hooman , Zwaig Jeremy , Gendron Natalie , Cecere Renzo , Giannetti Nadia , Hébert Terence E. 
Published: September 2022

AbstractDilated cardiomyopathy (DCM) is a cardiovascular condition that develops when the left ventricle of the heart enlarges, compromising its function and diminishing its capacity to pump oxygenated blood throughout the body. After patients are diagnosed with DCM, disease progression can lead to heart failure and the need for a heart transplantation. DCM is a complex disease where underlying causes can be idiopathic, genetic, or environmental. An incomplete molecular understanding of disease progression poses challenges for drug discovery efforts as effective therapeutics strategies remain elusive. Decades of research using primary cells or animal models have increased our understanding of DCM but has been hampered due to the inaccessibility of human cardiomyocytes, to model cardiac disease, in vitro, in a dish. Here, our goal is to leverage patient-derived hiPSC-CMs and to combine them with biosensors to understand how cellular signalling is altered in DCM. With high sensitivity and versatility, optical biosensors represent the ideal tools to dissect the molecular determinants of cardiovascular disease, in an unbiased manner and in real-time at the level of single cells. By characterizing the pathobiology of dilated cardiomyopathy in a patient-specific manner using high content biosensor-based assays, we aim to uncover personalized mechanisms for the occurrence and development of DCM and as a pathway to development of personalized therapeutics.