bluuebunny/crossref_metadata_2025_split huggingface dataset:
Petagraph: A large-scale unifying knowledge graph framework for integrating biomolecular and biomedical data
Authors: Stear Benjamin J. , Ahooyi Taha Mohseni , Vasisht Shubha , Simmons Alan , Beigel Katherine , Callahan Tiffany J. , Silverstein Jonathan C. , Taylor Deanne M. 
Published: February 2023

AbstractThe use of biomedical knowledge graphs (BMKG) for knowledge representation and data integration has increased drastically in the past several years due to the size, diversity, and complexity of biomedical datasets and databases. Data extraction from a single dataset or database is usually not particularly challenging. However, if a scientific question must rely on integrative analysis across multiple databases or datasets, it can often take many hours to correctly and reproducibly extract and integrate data towards effective analysis. To overcome this issue, we created Petagraph, a large-scale BMKG that integrates biomolecular data into a schema incorporating the Unified Medical Language System (UMLS). Petagraph is instantiated on the Neo4j graph platform, and to date, has fifteen integrated biomolecular datasets. The majority of the data consists of entities or relationships related to genes, animal models, human phenotypes, drugs, and chemicals. Quantitative data sets containing values from gene expression analyses, chromatin organization, and genetic analyses have also been included. By incorporating models of biomolecular data types, the datasets can be traversed with hundreds of ontologies and controlled vocabularies native to the UMLS, effectively bringing the data to the ontologies. Petagraph allows users to analyze relationships between complex multi-omics data quickly and efficiently.
Aberrant accumulation of age- and disease-associated factors following neural probe implantation in a mouse model of Alzheimer’s disease
Authors: Wellman Steven M. , Coyne Olivia A. , Douglas Madeline M. , Kozai Takashi D.Y. 
Published: February 2023

1.0.ABSTRACTElectrical stimulation has had a profound impact on our current understanding of nervous system physiology and provided viable clinical options for addressing neurological dysfunction within the brain. Unfortunately, the brain’s immune suppression of indwelling microelectrodes currently presents a major roadblock in the long-term application of neural recording and stimulating devices. In some ways, brain trauma induced by penetrating microelectrodes produces similar neuropathology as debilitating brain diseases, such as Alzheimer’s disease (AD), while also suffering from end-stage neuron loss and tissue degeneration. To understand whether there may be any parallel mechanisms at play between brain injury from chronic microelectrode implantation and those of neurodegenerative disorder, we used two-photon microscopy to visualize the accumulation, if any, of age- and disease-associated factors around chronically implanted electrodes in both young and aged mouse models of AD. With this approach, we determined that electrode injury leads to aberrant accumulation of lipofuscin, an age-related pigment, in wild-type and AD mice alike. Furthermore, we reveal that chronic microelectrode implantation reduces the growth of pre-existing amyloid plaques while simultaneously elevating amyloid burden at the electrode-tissue interface. Lastly, we uncover novel spatial and temporal patterns of glial reactivity, axonal and myelin pathology, and neurodegeneration related to neurodegenerative disease around chronically implanted microelectrodes. This study offers multiple novel perspectives on the possible neurodegenerative mechanisms afflicting chronic brain implants, spurring new potential avenues of neuroscience investigation and design of more targeted therapies for improving neural device biocompatibility and treatment of degenerative brain disease.
The Small GTPase Rab7 Regulates Release of Mitochondria in Extracellular Vesicles in Response to Lysosomal Dysfunction
Authors: Liang Wenjing , Diao Rachel Y. , Quiles Justin M. , Najor Rita H. , Chi Liguo , Woodall Benjamin P. , Leon Leonardo J. , Duran Jason , Cauvi David M. , De Maio Antonio , Adler Eric D. , Gustafsson Åsa B. 
Published: February 2023

AbstractMitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.
Simple in-vitro single stranded linear and circular DNA preparation and validation via SELEX using phosphor-derived modifications
Authors: Hamidi Seyed Vahid , Perreault Jonathan 
Published: February 2023

AbstractInterest in preparation of single stranded circular DNA library has been increasing recently, therefore developing a simple and efficient method for circular DNA generation will be very useful for all procedures and techniques that are dependent on single stranded circular DNA preparation. In this study a new simple method for in vitro preparation of circular single stranded DNA is proposed. We hypothesized that using a phosphorylated-phosphorothioated primer would not affect the efficiency of PCR reactions, but, more importantly, would suppress the activity of Lambda Exonuclease enzyme even if it is phosphorylated. The produced phosphorylated single stranded DNA is ready to be circularized via a ligation reaction using a bridging oligonucleotide. Several optimizations and enhancements have been conducted in the ligation reaction, notably by embedding an extra thymine nucleotide at the ligation site to compensate for the additional adenosine nucleotide added by Taq during the PCR reaction. In addition, the performance of the proposed method has been validated by selecting linear and circular aptamers against MERS-CoV spike protein during 15 successive cycles of SELEX. Because this new method is simple and user-friendly, it has a potential to be automated for high-throughput purposes and may further stir growing interests in preparation of single stranded circular DNA and its applications.
Reduction of oligomer size modulates the competition between cluster formation and phase separation of the tumor suppressor SPOP
Authors: Sabri Nafiseh , Cuneo Matthew J. , Marzahn Melissa R. , Lee Jihun , Bouchard Jill J. , Vaithiyalingam Sivaraja , Borgia Madeleine B. , Schmit Jeremy , Mittag Tanja 
Published: February 2023

AbstractPhase separation is a ubiquitous process that compartmentalizes many cellular pathways. Given that the same interactions that drive phase separation mediate the formation of complexes below the saturation concentration, the contribution of condensates vs complexes to function is not always clear. Here, we characterized several new cancer-associated mutations of the tumor suppressor Speckle-type POZ protein (SPOP), a substrate recognition subunit of the Cullin3-RING ubiquitin ligase (CRL3), which pointed to a strategy for generating separation-of-function mutations. SPOP self-associates into linear oligomers and interacts with multivalent substrates, and this mediates the formation of condensates. These condensates bear the hallmarks of enzymatic ubiquitination activity. We characterized the effect of mutations in the dimerization domains of SPOP on its linear oligomerization, binding to the substrate DAXX, and phase separation with DAXX. We showed that the mutations reduce SPOP oligomerization and shift the size distribution of SPOP oligomers to smaller sizes. The mutations therefore reduce the binding affinity to DAXX, but enhance the poly-ubiquitination activity of SPOP towards DAXX. This unexpectedly enhanced activity may be explained by enhanced phase separation of DAXX with the SPOP mutants. Our results provide a comparative assessment of the functional role of clusters versus condensates and support a model in which phase separation is an important factor in SPOP function. Our findings also suggest that tuning of linear SPOP self-association could be used by the cell to modulate its activity, and provide insights into the mechanisms underlying hypermorphic SPOP mutations. The characteristics of these cancer-associated SPOP mutations suggest a route for designing separation-of-function mutations in other phase-separating systems.
Seasonal variation exists in B-Cell Precursor Childhood Acute Lymphoblastic Leukemia diagnosis, but not in Acute Myeloid Leukemia, Brain Tumors or Solid Tumors – a Swedish population-based study
Authors: Bychkov Gleb , Bang Benedicte , Engsner Niklas , Heyman Mats Marshall , Nordenvall Anna Skarin , Tettamanti Giorgio , Herold Nikolas , Taylan Fulya , Pontén Emeli , Albert Jan , Jörnsten Rebecka , Strannegård Claes , Nordgren Ann 
Published: February 2023

AbstractBackgroundB-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy in children and adolescents. A combination of genetic predisposition, exposures to diverse microbiota, infections, and an immature immune system have been associated with BCP-ALL development. Genetic aberrations causing the progression of preleukemic cells to overt BCP-ALL have been identified, but drivers behind these aberrations remain largely unknown.MethodsWe analyzed seasonal variation in 1,380 BCP-ALLs, 385 acute myeloid leukemias (AML), 3,052 solid tumors and 1,945 brain tumors retrieved from the population-based Swedish Childhood Cancer Registry (SCCR), aged 0-18 years at diagnosis and diagnosed between 1995-2017. Cases were first aggregated into three types of quarters (3-month periods) based on the time of BCP-ALL diagnosis. Then, data was analyzed using a Bayesian Generalized Auto Regressive Integrated Moving Average with external variables (GARIMAX) model, adapted for count data via a negative binomial distribution.ResultsAn informative seasonal variation in BCP-ALL with peak quarters in Jul-Sep and Jun-Aug was identified. Manual inspection revealed that the largest number of BCP-ALL cases (138 (10%)) was observed in August. No seasonal variation was detected in the comparison groups of childhood AML, brain tumors, or solid tumors.ConclusionsDiagnosis of childhood BCP-ALL in Sweden displays seasonal variation with a peak during the summer months, in contrast to other tumor types. We present putative explanation models for this incidence peak that build on the hypothesis of infectious exposure/-s triggering the final progression to BCP-ALL diagnosis in at-risk individuals. Further studies using GARIMAX in larger populations with genetically confirmed BCP-ALL subtypes are warranted.
A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis inKRAS-driven lung cancer
Authors: Zhao Liang , Deng Haibin , Zhang Jingyi , Zamboni Nicola , Geest Gerrit Adriaan , Yang Haitang , Yang Zhang , Gao Yanyun , Xu Duo , Zhong Haiqing , Bruggmann Remy , Zhou Qinghua , Schmid Ralph A. , Marti Thomas M. , Dorn Patrick , Peng Ren-Wang 
Published: February 2023

ABSTRACTFerroptosis, a form of non-apoptotic cell death program driven by excessive lipid peroxidation and an important mechanism of tumor suppression, is frequently dysregulated in cancer. However, the mechanisms underlying impaired ferroptosis in oncogene-specific tumors remain poorly understood. Here we report a non- canonical role of lactate dehydrogenase B (LDHB), whose main activity is the conversion of lactate to pyruvate, in protecting KRAS-mutated lung cancer from ferroptosis. Silencing of LDHB impairs intracellular glutathione (GSH) metabolism and drives the hypersensitivity ofKRAS-mutant cells to ferroptosis inducers by inhibiting the SLC7A11/GSH/GPX4 axis, a central antioxidant system against lipid peroxidation and ferroptosis by catalyzing GSH synthesis and utilization. Mechanistically, LDHB promotes SLC7A11 expression and GSH biosynthesis, and inhibition of LDHB confers metabolic synthetic lethality with ferroptosis inducers due to increased glutaminolysis and production of reactive oxygen species (ROS) in mitochondria, ultimately triggering ferroptosis ofKRAS-driven lung cancer cells. Consequently, combined inhibition of LDHB and SLC7A11 synergistically suppresses tumor growth in multipleKRAS-mutant lung cancer implants and in an autochthonous model ofKras-induced lung adenocarcinoma. Taken together, our results reveal a hitherto unrecognized mechanism of ferroptosis defense by glycolytic LDHB and suggest a new strategy for the treatment ofKRAS-dependent lung cancer.
Gene-signatures for early detection of cancers
Authors: Prakash Om , Khan Feroz 
Published: February 2023

ABSTRACTBackgroundGene signatures represents set of molecular modulations in disease genomes or in cells at specific conditions, and are frequently used to classify samples into different groups for better research or clinical treatment. Multiple methods and applications are available in the literature, but powerful ones that can account for early detection of cancer are still lacking.MethodIn this article, gene-signatures identified through new in-house algorithm (NCT method) by processing transcriptome data (DEGs extracted from RNA-seq dataset) from population. NCT-Method utilized for processing population dataset, from 28 different human cancer from TCGA & GTEx databases, as empirical background. NCT-score used for optimal clustering of gene-set. The identified gene clusters evaluated through survival analysis. Gene-sets with disease-vs-normal survival plot with logPvalue < 0.05 represented as reliable gene signatures.ResultsWe applied NCT algorithm to the 28 different cancers, and identified novel gene-signatures as well as inter-relation between different cancers in reference of identified signatures.ConclusionsThe algorithm uses population data, and provides validated gene signatures with reliable capacity to discriminate the cancer and normal samples with higher classification performance. The algorithm will be useful to find signature for any RNA-seq data.
Self-assembly of nanofilaments in cyanobacteria for protein co-localization
Authors: Zedler Julie A. Z. , Schirmacher Alexandra M. , Russo David A. , Hodgson Lorna , Gundersen Emil , Matthes Annemarie , Frank Stefanie , Verkade Paul , Jensen Poul Erik 
Published: February 2023

AbstractCyanobacteria offer great potential as alternative biotechnological hosts due to their photoautotrophic capacities. However, in comparison to established heterotrophic hosts, several key aspects, such as product titers, are still lagging behind. Nanobiotechnology is an emerging field with great potential to improve existing hosts but, so far, it has barely been explored in microbial photosynthetic systems. Here, we report the establishment of large proteinaceous nanofilaments in the unicellular model cyanobacteriumSynechocystissp. PCC 6803 and the fast-growing cyanobacterial strainSynechococcus elongatusUTEX 2973. Transmission electron microscopy and electron tomography demonstrated that overexpression of a modified bacterial microcompartment shell protein, PduA*, led to the generation of bundles of longitudinally aligned nanofilaments inS. elongatusUTEX 2973 and shorter filamentous structures inSynechocystissp. PCC 6803. Comparative proteomics showed that PduA* was at least 50 times more abundant than the second most abundant protein in the cell and that nanofilament assembly only had a minor impact on cellular metabolism. Finally, we targeted the fluorescent reporter mCitrine to the nanofilaments using an encapsulation peptide that natively interacts with PduA. To our knowledge, this is the first study to apply bacterial microcompartment based nanotechnology in cyanobacteria. The establishment of nanofilaments in cyanobacterial cells is an important step towards cellular organization of heterologous pathways and the establishment of cyanobacteria as next generation hosts.
The effect of glucagon-like peptide-1 receptor agonist (GLP1RA) on hypertensive-induced heart failure with preserved ejection fraction and hypertensive cardiomyopathy
Authors: Zhang Zhe Yu , Liao Song-Yan , Zhen Zhe , Sun Sijia , Lai Wing-Hon , Tsang Anita , Hai Jo Jo Siu-Han 
Published: February 2023

ABSTRACTEmerging preclinical data suggest that glucagon-like peptide-1 receptor agonist (GLP1RA) possesses cardioprotective properties against the pathophysiology of hypertension (HT). We sought to unravel the potential therapeutic application of GLP1RA in a clinically relevant large animal model of hypertensive cardiomyopathy (hCMP). A combination of angiotensin II (Ang II) and deoxycorticosterone acetate (DOCA) pellets were used to induce sustained HT status and establish hCMP in porcine model. Changes in cardiac echocardiography, invasive hemodynamic parameters, neurohumoral biomarkers and inflammation-related cytokines were investigated in 23 adult pigs, among which 6 were serving as control, 9 were induced with HT, and the remaining 8 were HT-induced with GLP1RA treatment. Eight weeks after the study initiated, HT pigs have developed sustained high blood pressure (BP) at both systole and diastole. Phenotype of hCMP has also become significant as impairment in systolic/diastolic function, left ventricular remodeling and cardiac hypertrophy was determined by echocardiogram and invasive hemodynamics. Additionally, blood norepinephrine (NE) content, venoarterial NE gradient and pro-inflammatory cytokines in HT pigs were increased. GLP1RA treatment halted the elevation in BP, left ventricular remodeling and cardiac hypertrophy development; preserved the left ventricular systolic/diastolic function; reduced the venoarterial NE gradient as well as the pro-inflammatory cytokines at 18 weeks in pigs with hCMP. Our results demonstrate that GLP1RA treatment has a remarkable effect on BP decrease, inflammation suppression and left ventricular function improvement. Thus, we provide novel insight into the therapeutic potential of GLP1RA in HT-induced heart failure in a large animal model of hCMP.
The dominance of coinfecting parasites’ indirect effects on host traits
Authors: Bolnick Daniel I. , Arruda Sophia , Polania Christian , Simonse Lauren , Padhiar Arshad , Roth Andrea , Rodgers Maria L. 
Published: February 2023

AbstractIndirect genetic effects (IGEs) exist when there is heritable variation in one species’ ability to alter a second species’ traits. For example, parasites can evolve disparate strategies to manipulate host immune response, whether by evading detection or suppressing immunity. A complication arises during coinfection, when two or more parasite genotypes may try to impose distinct IGEs on the same host trait: which parasite’s IGE will be dominant? Here, we apply the notion of dominance to IGEs during coinfection. Using a mathematical model we show that the dominance of IGEs can alter the evolutionary dynamics of parasites. We consider a resident parasite population receiving rare immigrants with a different immune manipulation trait. These immigrants’ relative fitness depends on resident prevalence (e.g., the probability immigrants are alone in a host, or coinfecting with a native), and the dominance of the immigrant’s IGE on host immunity. Next, we show experimentally that the cestodeSchistocephalus solidusexerts an IGE on a host immune trait: parasite antigens from different populations produced different intensities of fibrosis. We then evaluated IGE dominance, finding evidence for overdominance (coinjected antigens induced an even stronger host immune response) which would be detrimental to immigrants when resident prevalence is high. This combination of experimental and modeling results shows that parasites do exhibit IGEs on host traits, and that the dominance of these IGEs during coinfection can substantially alter parasite evolution.
Viral but not bacterial community succession is characterized by extreme turnover shortly after rewetting dry soils
Authors: Santos-Medellín Christian , Blazewicz Steven J. , Pett-Ridge Jennifer , Emerson Joanne B. 
Published: February 2023

AbstractAs central members of soil trophic networks, viruses have the potential to drive substantial microbial mortality and nutrient turnover. Pinpointing viral contributions to terrestrial ecosystem processes remains a challenge, as temporal dynamics are difficult to unravel in the spatially and physicochemically heterogeneous soil environment. In Mediterranean grasslands, the first rainfall after seasonal drought provides an ecosystem reset, triggering microbial activity during a tractable window for capturing short-term dynamics. Here, we simulated precipitation in microcosms from four distinct, dry grassland soils and generated 144 viromes and 84 metagenomes to characterize viral, prokaryotic, and relic DNA dynamics over 10 days. Vastly different viral communities in each soil followed remarkably similar successional trajectories. Wet-up triggered a significant increase in viral abundance and richness, followed by extensive compositional turnover. While temporal turnover in prokaryotic communities was much less pronounced, differences in the relative abundances of Actinobacteria (enriched in dry soils) and Proteobacteria (enriched in wetted soils) matched those of their predicted phages, indicating viral predation of dominant bacterial taxa. Rewetting also rapidly depleted relic DNA, which subsequently re-accumulated, indicating substantial new microbial mortality in the days after wet-up, particularly of the taxa putatively under phage predation. Production of abundant, diverse viral particles via microbial host cell lysis appears to be a conserved feature of the early response to soil rewetting, and results suggest the potential for ‘Cull-the-Winner’ dynamics, whereby viruses infect and cull but do not decimate dominant host populations.
Selection on many loci drove the origin and spread of a key innovation
Authors: Stankowski Sean , Zagrodzka Zuzanna B. , Garlovsky Martin D. , Pal Arka , Shipilina Daria , Castillo Diego Garcia , Le Moan Alan , Leder Erica , Reeve James , Johannesson Kerstin , Westram Anja M. , Butlin Roger K. 
Published: February 2023

AbstractKey innovations are fundamental to biological diversification, but their genetic architecture is poorly understood. A recent transition from egg-laying to live-bearing inLittorinasnails provides the opportunity to study the architecture of an innovation that has evolved repeatedly in animals. Samples do not cluster by reproductive mode in a genome-wide phylogeny, but local genealogical analysis revealed numerous genomic regions where all live-bearers carry the same core haplotype. Associated regions show evidence for live-bearer-specific positive selection, and are enriched for genes that are differentially expressed between egg-laying and live-bearing reproductive systems. Ages of selective sweeps suggest live-bearing alleles accumulated gradually, involving selection at different times in the past. Our results suggest that innovation can have a polygenic basis, and that novel functions can evolve gradually, rather than in a single step.