bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phylogenetic Permulations: a statistically rigorous approach to measure confidence in associations between phenotypes and genetic elements in a phylogenetic context
Authors: Saputra Elysia , Kowalczyk Amanda , Cusick Luisa , Clark Nathan , Chikina Maria 
Published: October 2020

AbstractThe wealth of high-quality genomes for numerous species has motivated many investigations into the genetic underpinnings of phenotypes. Comparative genomics methods approach this task by identifying convergent shifts at the genetic level that are associated with traits evolving convergently across independent lineages. However, these methods have complex statistical behaviors that are influenced by non-trivial and oftentimes unknown confounding factors. Consequently, using standard statistical analyses in interpreting the outputs of these methods leads to potentially inaccurate conclusions. Here, we introduce phylogenetic permulations, a novel statistical strategy that combines phylogenetic simulations and permutations to calculate accurate, unbiased p-values from phylogenetic methods. Permulations construct the null expectation for p-values from a given phylogenetic method by empirically generating null phenotypes. Subsequently, empirical p-values that capture the true statistical confidence given the correlation structure in the data are directly calculated based on the empirical null expectation. We examine the performance of permulation methods by analyzing both binary and continuous phenotypes, including marine, subterranean, and long-lived large-bodied mammal phenotypes. Our results reveal that permulations improve the statistical power of phylogenetic analyses and correctly calibrate statements of confidence in rejecting complex null distributions while maintaining or improving the enrichment of known functions related to the phenotype. We also find that permulations refine pathway enrichment analyses by correcting for non-independence in gene ranks. Our results demonstrate that permulations are a powerful tool for improving statistical confidence in the conclusions of phylogenetic analysis when the parametric null is unknown.
Climbing up and down binding landscapes: a high-throughput study of mutational effects in homologous protein-protein complexes
Authors: Heyne Michael , Shirian Jason , Cohen Itay , Peleg Yoav , Radisky Evette S. , Papo Niv , Shifman Julia M. 
Published: October 2020

AbstractEach protein-protein interaction (PPI) has evolved to possess binding affinity that is compatible with its cellular function. As such, cognate enzyme/inhibitor interactions frequently exhibit very high binding affinities, while structurally similar non-cognate PPIs possess substantially weaker binding affinities. To understand how slight differences in sequence and structure could lead to drastic changes in PPI binding free energy (ΔΔGbind), we study three homologous PPIs that span nine orders of magnitude in binding affinity and involve a serine protease interacting with an inhibitor BPTI. Using state-of-the-art methodology that combines protein randomization and affinity sorting coupled to next-generation sequencing and data normalization, we report quantitative binding landscapes consisting of ΔΔGbindvalues for the three PPIs, gleaned from tens of thousands of single and double mutations in the BPTI binding interface. We demonstrate that the three homologous PPIs possess drastically different binding landscapes and lie at different points in respect to the landscape maximum. Furthermore, the three PPIs demonstrate distinct patterns of coupling energies between two simultaneous mutations that depend not only on positions involved but also on the nature of the mutation. Interestingly, we find that in all three PPIs positive epistasis is frequently observed at hot-spot positions where mutations lead to loss of high affinity, while conversely negative epistasis is observed at cold-spot positions, where mutations lead to affinity enhancement. The new insights on PPI evolution revealed in this study will be invaluable in understanding evolution of other biological complexes and can greatly facilitate design of novel high-affinity protein inhibitors.SignificanceProtein-protein interactions (PPIs) have evolved to display binding affinities that can support their function. As such, cognate and non-cognate PPIs could be highly similar structurally but exhibit huge differences in binding affinities. To understand this phenomenon, we studied the effect of tens of thousands of single and double mutations on binding affinity of three homologous protease-inhibitor complexes. We show that binding landscapes of the three complexes are strikingly different and depend on the PPI evolutionary optimality. We observe different patterns of couplings between mutations for the three PPIs with negative and positive epistasis appearing most frequently at hot-spot and cold-spot positions, respectively. The evolutionary trends observed here are likely to be universal to all biological complexes in the cell.
Expression analysis of colon adenocarcinoma in the South Indian population reveals novel signals of pathogenesis
Authors: Ariyannur Prasanth S. , Joy Reenu Anne , Menon Veena , Paulose Roopa Rachael , Pavithran Keechilat , Vasudevan Damodaran M. 
Published: October 2020

AbstractHigh throughput somatic expression analyses of colon adenocarcinoma conducted so far were mostly in the western population, and no major studies are currently available in the Indian population. We have performed Nanostring PanCancer pathway panel assay in Stage II colon cancer (n = 11) and compared against normal colon tissues (n = 4). Differentially expressed (DE) genes were identified and superimposed on the Cancer Genome Atlas (TCGA) data, from the Genome Expression Profiling Interactive Analysis (GEPIA) and Tumor Immune Estimation Resource (TIMER).83 out of 730 genes were significantly different (p-value < 0.01), 19 of which had a fold-change |FC(log2)| ≥ 2. A comparison of these signals on TCGA COAD data revealed four common (MET, MCM2, ETV4, and MMP7) and15 uncommon genes. On group comparison, ETV4 expression was significantly higher in microsatellite stable (MSS). Significant DE genes, unique in the study, were INHBA, COL1A1, COL11A1, COMP, SFRP4, and SPP1, which were clustered in STRING.db network analysis and correlated with tumor-infiltrating immune cells in TIMER.MMR functions of colon cancer pathogenesis in India may be differentiated by validating the somatic expression of most common genes identified in the study.
How do neuroglial cells respond to ultrasound induced cavitation?
Authors: Wrede Alex H. , Luo Jie , Montazami Reza , Kanthasamy Anumantha , Hashemi Nicole N. 
Published: October 2020

AbstractReactive astrocytes are known to play a vital role in the overall response of the brain during a traumatic brain injury (TBI). Modern studies have speculated the existence of cavitation in the skull during a TBI, which has alarming potential to cause detrimental damages. Previous studies have confirmed the upregulation of various harmful genes in neurodegenerative diseases. Studying the longitudinal presence of these harmful genes in response to cavitation allows for optimized understanding and treatment methods in cavitation exposure. We seek to characterize the longitudinal genetic expression levels that astrocytes exhibit after exposure to cavitation and further elucidate the startling presence of cranial cavitation. Astrocytic expression levels of various common genes that have been documented in TBI research are our target of interest, like, TNFα, IL-1β, and NOS1. Results summarize specific gene trends from 1-48 hours after cavitation. Our data concludes that maximum expression is not consistently exhibited immediately after cavitation exposure, and most genes have individualized genetic trends. IL-1β shows a decreasing expression over 48 hours, and TNFα shows upregulation until the 6 hour time point but then begins to decrease in expression. The upregulation of NOS1 has been documented in neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease. This study has shown a consistent upregulation in NOS1 expression from 0-48 hours. These results postulate a possible linkage between cavitation damage and neurodegenerative diseases. This analysis also provides novelty in optimizing treatments for astrocytic function post-TBI and legitimizing the concern of cranial cavitation existence. These results add motivation for future studies of cavitation elimination or minimization via advanced helmet and airbag engineering.
Chemotherapy response prediction with diffuser elapser network
Authors: Koyuncu Batuhan , Melek Ahmet , Yilmaz Defne , Tuzer Mert , Unlu Mehmet Burcin 
Published: October 2020

AbstractIn solid tumors, elevated fluid pressure and inadequate blood perfusion resulting from unbalanced angiogenesis are the prominent reasons for the ineffective drug delivery inside tumors. To normalize the heterogeneous and tortuous tumor vessel structure, antiangiogenic treatment is an effective approach. Additionally, the combined therapy of antiangiogenic agents and chemotherapy drugs has shown promising effects on enhanced drug delivery. However, the need to find the appropriate scheduling and dosages of the combination therapy is one of the main problems in anticancer therapy. Our study aims to generate a realistic response to the treatment schedule, making it possible for future works to use these patient-specific responses to decide on the optimal starting time and dosages of cytotoxic drug treatment. Our dataset is based on our previous in-silico model with a framework for the tumor microenvironment, consisting of a tumor layer, vasculature network, interstitial fluid pressure, and drug diffusion maps. In this regard, the chemotherapy response prediction problem is discussed in the study, putting forth a proof-of-concept for deep learning models to capture the tumor growth and drug response behaviors simultaneously. The proposed model utilizes multiple convolutional neural network submodels to predict future tumor microenvironment maps considering the effects of ongoing treatment. Since the model has the task of predicting future tumor microenvironment maps, we use two image quality evaluation metrics, which are structural similarity and peak signal-to-noise ratio, to evaluate model performance. We track tumor cell density values of ground truth and predicted tumor microenvironments. The model predicts tumor microenvironment maps seven days ahead with the average structural similarity score of 0.973 and the average peak signal ratio of 35.41 in the test set. It also predicts tumor cell density at the end day of 7 with the mean absolute percentage error of 2.292 ± 1.820.Author summaryThe disorganized structure and leakiness of tumor vessels induce the inadequate blood supply and high fluid pressure within tumors. These features of the tumor microenvironment, identified as delivery barriers, lead to an insufficient amount of drugs to reach the interior parts of tumors. It is observed that the use of anti-vascular drugs makes the structure and function of the tumor vascular system more normal. Moreover, the combination of these drugs with cytotoxic agents provides favorable results with increased treatment response. But, it is also important to adjust the treatment schedule properly. In this regard, we build a deep learning model, designed to examine the tumor response with the ongoing treatment schedule. Our study suggests that deep learning models can be used to predict tumor growth and drug response in the scheduling of cytotoxic drugs.
Characterisation of growth plate dynamics in murine models of osteoarthritis
Authors: Samvelyan Hasmik J. , Madi Kamel , Törnqvist Anna E. , Javaheri Behzad , Staines Katherine A. 
Published: October 2020

AbstractBackgroundThe purpose of this study was to investigate growth plate dynamics in surgical and loading murine models of osteoarthritis, to understand whether abnormalities in these dynamics predict osteoarthritis vulnerability.Methods8-week-old C57BL/6 male mice underwent destabilisation of medial meniscus (DMM) (n =8) surgery in right knee joints. Contralateral left knee joints had no intervention (controls). In 16-week-old C57BL/6 male mice (n= 6), osteoarthritis was induced using non-invasive mechanical loading of right knee joints with peak force of 11N. Non-loaded left knee joints were internal controls. Chondrocyte transiency in tibial articular cartilage and growth plate was confirmed by histology and immunohistochemistry. Tibial subchondral bone parameters were measured using microCT and correlated to 3D GP bridging analysis.ResultsHigher expression of chondrocyte hypertrophy markers; Col10a1 and MMP13 were observed in tibial articular cartilage chondrocytes of DMM and loaded mice. In tibial growth plate, Col10a1 and MMP13 expressions were widely dispersed in a significantly enlarged zones of proliferative and hypertrophic chondrocytes in DMM (p=0.002 andp<0.0001, respectively) and loaded (bothp<0.0001) tibiae of mice compared to their controls. 3D quantification revealed enriched growth plate bridging and higher bridge densities in medial compared to lateral tibiae of DMM and loaded knee joints of the mice. Growth plate dynamics were associated with higher subchondral bone volume fraction (BV/TV; %) in medial tibiae of DMM and loaded knee joints and epiphyseal trabecular bone volume fraction in medial tibiae of loaded knee joints.ConclusionsThe results confirm articular cartilage chondrocyte transiency in a surgical and loaded murine model of osteoarthritis. Herein, we reveal for the first time spatial variation of growth plate bridging in surgical and loaded osteoarthritis models and how these may contribute to anatomical variation in vulnerability of osteoarthritis development.
Ancient DNA from Guam and the Peopling of the Pacific
Authors: Pugach Irina , Hübner Alexander , Hung Hsiao-chun , Meyer Matthias , Carson Mike T. , Stoneking Mark 
Published: October 2020

AbstractHumans reached the Mariana Islands in the western Pacific by ~3500 years ago, contemporaneous with or even earlier than the initial peopling of Polynesia. They crossed more than 2000 km of open ocean to get there, whereas voyages of similar length did not occur anywhere else until more than 2000 years later. Yet, the settlement of Polynesia has received far more attention than the settlement of the Marianas. There is uncertainty over both the origin of the first colonizers of the Marianas (with different lines of evidence suggesting variously the Philippines, Indonesia, New Guinea, or the Bismarck Archipelago) as well as what, if any, relationship they might have had with the first colonizers of Polynesia. To address these questions, we obtained ancient DNA data from two skeletons from the Ritidian Beach Cave site in northern Guam, dating to ~2200 years ago. Analyses of complete mtDNA genome sequences and genome-wide SNP data strongly support ancestry from the Philippines, in agreement with some interpretations of the linguistic and archaeological evidence, but in contradiction to results based on computer simulations of sea voyaging. We also find a close link between the ancient Guam skeletons and early Lapita individuals from Vanuatu and Tonga, suggesting that the Marianas and Polynesia were colonized from the same source population, and raising the possibility that the Marianas played a role in the eventual settlement of Polynesia.Significance StatementWe know far more about the settlement of Polynesia than we do about the settlement of the Mariana Islands in the western Pacific. There is debate over where people came from to get to the Marianas, with various lines of evidence pointing to the Philippines, Indonesia, New Guinea, or the Bismarck Archipelago, as well as uncertainty over how the ancestors of the present Mariana Islanders, the Chamorro, might be related to Polynesians. We analyzed ancient DNA from Guam, from two skeletons dating to ~2200 years ago, and found that their ancestry is linked to the Philippines. Moreover, they are closely-related to ancient Polynesians from Vanuatu and Tonga, suggesting that the early Mariana Islanders may have been involved in the colonization of Polynesia.
Structural characterization of HIV-1 matrix mutants implicated in envelope incorporation
Authors: Eastep Gunnar N. , Ghanam Ruba H. , Green Todd J. , Saad Jamil S. 
Published: October 2020

ABSTRACTDuring the late phase of HIV-1 infection, viral Gag polyproteins are targeted to the plasma membrane (PM) for assembly. Gag localization at the PM is a prerequisite for the incorporation of the envelope protein (Env) into budding particles. Gag assembly and Env incorporation are mediated by the N-terminal myristoylated matrix (MA) domain of Gag. Nonconservative mutations in the trimer interface of MA (A45E, T70R, and L75G) were found to impair Env incorporation and infectivity, leading to the hypothesis that MA trimerization is an obligatory step for Env incorporation. Conversely, Env incorporation can be rescued by a compensatory mutation in the MA trimer interface (Q63R). The impact of these MA mutations on the structure and trimerization properties of MA is not known. In this study, we employed NMR spectroscopy, x-ray crystallography, and sedimentation techniques to characterize the structure and trimerization properties of HIV-1 MA A45E, Q63R, T70R, and L75G mutant proteins. NMR data revealed that these point mutations did not alter the overall structure and folding of MA but caused minor structural perturbations in the trimer interface. Analytical ultracentrifugation data indicated that mutations had a minimal effect on the MA monomer–trimer equilibrium. The high-resolution x-ray structure of the unmyristoylated MA Q63R protein revealed hydrogen bonding between the side chains of Arg-63 and Ser-67 located in the center of the trimer interface, providing the first structural evidence for a stabilization of the trimer form. These findings advance our knowledge of the interplay of MA trimerization and Env incorporation into HIV-1 particles.
The oncogenic function of PLAGL2 is mediated via specific target genes through a Wnt-independent mechanism in colorectal cancer
Authors: Fischer Anthony D. , Veronese Paniagua Daniel A. , Swaminathan Shriya , Kashima Hajime , Rubin Deborah C. , Madison Blair B. 
Published: October 2020

ABSTRACTColorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressorAPC, whose loss triggers the deregulation of TCF4/β-Catenin activity. CRC tumorigenesis is also driven by multiple epi-mutational modifiers, such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and non-transformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genesIGF2,a fetal growth factor, andASCL2, an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling.
Massive intron gain in the most intron-rich eukaryotes is driven by introner-like transposable elements of unprecedented diversity and flexibility
Authors: Roy Scott William , Gozashti Landen , Bowser Bradley A. , Weinstein Brooke N. , Larue Graham E. 
Published: October 2020

SummarySpliceosomal introns, which interrupt nuclear genes and are removed from RNA transcripts by machinery termed spliceosomes, are ubiquitous features of eukaryotic nuclear genes [1]. Patterns of spliceosomal intron evolution are complex, with some lineages exhibiting virtually no intron creation while others experience thousands of intron gains [2–5]. One possibility is that this punctate phylogenetic distribution is explained by intron creation by Introner-Like Elements (ILEs), transposable elements capable of creating introns, with only those lineages harboring ILEs undergoing massive intron gain [6–10]. However, ILEs have been reported in only four lineages. Here we study intron evolution in dinoflagellates. The remarkable fragmentation of nuclear genes by spliceosomal introns reaches its apex in dinoflagellates, which have some twenty introns per gene [11,12]. Despite this, almost nothing is known about the molecular and evolutionary mechanisms governing dinoflagellate intron evolution. We reconstructed intron evolution in five dinoflagellate genomes, revealing a dynamic history of intron loss and gain. ILEs are found in 4/5 studied species. In one species,Polarella glacialis, we find an unprecedented diversity of ILEs, with ILE insertion leading to creation of some 12,253 introns, and with 15 separate families of ILEs accounting for at least 100 introns each. These ILE families range in mobilization mechanism, mechanism of intron creation, and flexibility of mechanism of intron creation. Comparison within and between ILE families provides evidence that biases in so-called intron phase, the distribution of introns relative to codon periodicity, are driven by ILE insertion site requirements [9,13,14]. Finally, we find evidence for multiple additional transformations of the spliceosomal system in dinoflagellates, including widespread loss of ancestral introns, and alterations in required, tolerated and favored splice motifs. These results reveal unappreciated intron creating elements diversity and spliceosomal evolutionary capacity, and suggest complex evolutionary dependencies shaping genome structures.