bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunogenomic landscape of hematological malignancies
Authors: Dufva Olli , Pölönen Petri , Brück Oscar , Keränen Mikko , Mehtonen Juha , Kumar Ashwini , Heckman Caroline , Siitonen Sanna , Granberg Kirsi , Leivonen Suvi-Katri , Meriranta Leo , Leppä Sirpa , Nykter Matti , Lohi Olli , Heinäniemi Merja , Mustjoki Satu 
Published: April 2019

SUMMARYUnderstanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. Here, we integrated over 8,000 transcriptomes and over 1,000 samples with multilevel genomic data of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival. Infiltration of cytotoxic immune cells was associated with distinct microenvironmental responses and driver alterations in different cancers, such asTP53in acute myeloid leukemia andDTX1in diffuse large B cell lymphoma. Epigenetic modification ofCIITAregulating antigen presentation, cancer type-specific immune checkpoints such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity. Prognostic models highlighted the significance of immunological properties in predicting survival. Our study represents the most comprehensive effort to date to link immunology with cancer subtypes and genomics in hematological malignancies, providing a resource to guide future studies and immunotherapy development.
A curated knowledgebase enabling a network perspective on endocrine disrupting chemicals and their biological systems-level perturbations
Authors: Karthikeyan Bagavathy Shanmugam , Ravichandran Janani , Mohanraj Karthikeyan , Vivek-Ananth R.P. , Samal Areejit 
Published: April 2019

AbstractHuman well-being can be affected by exposure to several chemicals in the environment. One such group is endocrine disrupting chemicals (EDCs) that can perturb the hormonal homeostasis leading to adverse health effects. In this work, we have developed a detailed workflow to identify EDCs with supporting evidence of endocrine disruption in published experiments in humans or rodents. Thereafter, this workflow was used to manually evaluate more than 16000 published research articles and identify 686 potential EDCs with published evidence in humans or rodents. Importantly, we have compiled the observed adverse effects or endocrine-specific perturbations along with the dosage information for the potential EDCs from their supporting published experiments. Subsequently, the potential EDCs were classified based on the type of supporting evidence, their environmental source and their chemical properties. Additional compiled information for potential EDCs include their chemical structure, physicochemical properties, predicted ADMET properties and target genes. In order to enable future research based on this compiled information on potential EDCs, we have built an online knowledgebase, Database of Endocrine Disrupting Chemicals and their Toxicity profiles (DEDuCT), accessible at: https://cb.imsc.res.in/deduct/. After building this comprehensive resource, we employed a network biology approach to study the chemical space of EDCs and its potential link to the biological space of target genes of EDCs. Specifically, we have constructed two networks of EDCs using our resource based on similarity of chemical structures or target genes. Ensuing analysis of these two networks revealed that EDCs can differ both in their chemical structure and set of target genes. Though our detailed results highlight potential challenges in developing predictive models for EDCs, the compiled information in our resource will undoubtedly enable future research in the field, especially, those focussed towards mechanistic understanding of the systems-level perturbations caused by EDCs.
Slow life-history strategies are associated with negligible actuarial senescence in western Palearctic salamanders
Authors: Cayuela Hugo , Olgun Kurtuluş , Angelini Claudio , Üzüm Nazan , Peyronel Olivier , Miaud Claude , Avci Aziz , Lemaitre Jean-François , Schmidt Benedikt R. 
Published: April 2019

AbstractActuarial senescence (hereafter “senescence”) has been viewed for a long time as an inevitable and uniform process. However, the work on senescence has mainly focused on endotherms (especially mammals) with deterministic growth and low regeneration capacity at adult stages, leading to a strong taxonomic bias in the study of aging. Recent studies have highlighted that senescence could indeed display highly variable trajectory shape that correlates with species life history traits. Slow life histories and indeterminate growth seem to be associated with weak and late senescence. Furthermore, a few studies have suggested that high regenerative abilities could make senescence negligible in several ectotherms (e.g., hydra and salamanders). However, demographic data for species that would allow testing of these hypotheses are scarce and fragmented. Here, we investigated senescence patterns in a group of salamanders (i.e. “true salamanders”) from the Western Palearctic using capture-recapture data and Bayesian modeling. Our results showed that salamanders have slow life histories and that they experience negligible senescence. This pattern was consistent at both intra- and interspecific levels, suggesting that the absence of senescence may be a phylogenetically conserved trait. The regenerative capacities of true salamanders, and urodeles in general, likely explains why these small ectotherms have lifespans similar to that of large endotherms (e.g., ungulates, large birds) and undergo negligible senescence contrary to most amniotes including humans. Our study seriously challenges the idea that senescence is a ubiquitous phenomenon in the living world.
The scaling of genome size and cell size limits maximum rates of photosynthesis with implications for ecological strategies
Authors: Roddy Adam B. , Théroux-Rancourt Guillaume , Abbo Tito , Benedetti Joseph W. , Brodersen Craig R. , Castro Mariana , Castro Silvia , Gilbride Austin B. , Jensen Brook , Jiang Guo-Feng , Perkins John A. , Perkins Sally D. , Loureiro João , Syed Zuhah , Thompson R. Alexander , Kuebbing Sara E. , Simonin Kevin A. 
Published: April 2019

AbstractA central challenge in plant ecology is to define the major axes of plant functional variation with direct consequences for fitness. Central to the three main components of plant fitness (growth, survival, and reproduction) is the rate of metabolic conversion of CO2into carbon that can be allocated to various structures and functions. Here we (1) argue that a primary constraint on the maximum rate of photosynthesis per unit leaf area is the size and packing density of cells and (2) show that variation in genome size is a strong predictor of cell sizes, packing densities, and the maximum rate of photosynthesis across terrestrial vascular plants. Regardless of the genic content associated with variation in genome size, the simple biophysical constraints of encapsulating the genome define the lower limit of cell size and the upper limit of cell packing densities, as well as the range of possible cell sizes and densities. Genome size, therefore, acts as a first-order constraint on carbon gain and is predicted to define the upper limits of allocation to growth, reproduction, and defense. The strong effects of genome size on metabolism, therefore, have broad implications for plant biogeography and for other theories of plant ecology, and suggest that selection on metabolism may have a role in genome size evolution.
Pupil-associated states modulate excitability but not stimulus selectivity in primary auditory cortex
Authors: Schwartz Zachary P. , Buran Brad N. , David Stephen V. 
Published: April 2019

AbstractRecent research in mice indicates that luminance-independent fluctuations in pupil size predict variability in spontaneous and evoked activity of single neurons in auditory and visual cortex. These findings suggest that pupil is an indicator of large-scale changes in arousal state that affect sensory processing. However, it is not known whether pupil-related state also influences the selectivity of auditory neurons. We recorded pupil size and single-unit spiking activity in the primary auditory cortex (A1) of non-anesthetized male and female ferrets during presentation of natural vocalizations and tone stimuli that allow measurement of frequency and level tuning. Neurons showed a systematic increase in both spontaneous and sound-evoked activity when pupil was large, as well as desynchronization and a decrease in trial-to-trial variability. Relationships between pupil size and firing rate were non-monotonic in some cells. In most neurons, several measurements of tuning, including acoustic threshold, spectral bandwidth, and best frequency, remained stable across large changes in pupil size. Across the population, however, there was a small but significant decrease in acoustic threshold when pupil was dilated. In some recordings, we observed rapid, saccade-like eye movements during sustained pupil constriction, which may indicate sleep. Including the presence of this state as a separate variable in a regression model of neural variability accounted for some, but not all, of the variability and non-monotonicity associated with changes in pupil size.New & NoteworthyCortical neurons vary in their response to repeated stimuli, and some portion of the variability is due to fluctuations in network state. By simultaneously recording pupil and single-neuron activity in auditory cortex of ferrets, we provide new evidence that network state affects the excitability of auditory neurons, but not sensory selectivity. In addition, we report the occurrence of possible sleep states, adding to evidence that pupil provides an index of both sleep and physiological arousal.
A genetic hazard score to personalize prostate cancer screening, applied to population data
Authors: Huynh-Le Minh-Phuong , Fan Chun Chieh , Karunamuni Roshan , Walsh Eleanor I. , Turner Emma L. , Lane J. Athene , Martin Richard M. , Neal David E. , Donovan Jenny L. , Hamdy Freddie C. , Parsons J. Kellogg , Eeles Rosalind A. , Easton Douglas F. , Kote-Jarai ZSofia , Olama Ali Amin Al , Garcia Sara Benlloch , Muir Kenneth , Gronberg Henrik , Wiklund Fredrik , Aly Markus , Schleutker Johanna , Sipeky Csilla , Tammela Teuvo LJ , Nordestgaard Børge G. , Key Tim J. , Travis Ruth C. , Pharoah Paul , Pashayan Nora , Khaw Kay-Tee , Thibodeau Stephen N. , McDonnell Shannon K. , Schaid Daniel J. , Maier Christiane , Vogel Walther , Luedeke Manuel , Herkommer Kathleen , Kibel Adam S. , Cybulski Cezary , Wokolorczyk Dominika , Kluzniak Wojciech , Cannon-Albright Lisa , Brenner Hermann , Schöttker Ben , Holleczek Bernd , Park Jong Y. , Sellers Thomas A. , Lin Hui-Yi , Slavov Chavdar , Kaneva Radka , Mitev Vanio , Batra Jyotsna , Clements Judith A. , Spurdle Amanda ,   Australian Prostate Cancer BioResource (APCB), Teixeira Manuel R. , Paulo Paula , Maia Sofia , Pandha Hardev , Michael Agnieszka , Kierzek Andrzej , Mills Ian G. , Andreassen Ole A. , Dale Anders M. , Seibert Tyler M. ,   The PRACTICAL Consortium
Published: April 2019

AbstractBackgroundGenetic risk stratification may inform decisions of whether—and when—a man should undergo prostate cancer (PCa) screening. We previously validated a polygenic hazard score (PHS), a weighted sum of 54 single-nucleotide polymorphism genotypes, for accurate prediction of age of onset of aggressive PCa and improved screening performance. We now assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population data were fit to a continuous model of age-specific PCa incidence. Using hazard ratios estimated from ProtecT trial data, age-specific incidence rates were calculated for percentiles of genetic risk. Incidence of higher-grade PCa (Gleason≥7) was estimated from age-specific data from the linked CAP trial. PHS and incidence data were combined to give a risk-equivalent age, when a man with a given PHS percentile will have risk of higher-grade PCa equivalent to that of a typical man at age 50 (50-years standard). Positive predictive value (PPV) of PSA testing was calculated using PHS-adjusted (PCa-risk-equivalent age) groups identified from ProtecT.ResultsExpected age of onset of higher-grade PCa is modulated by 19 years between the 1st and 99th PHS percentiles. A man with PHS in the 99th percentile reaches 50-years-standard risk at age 41; conversely, a man in the 1st percentile reaches this risk at age 60. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS informs PCa screening strategies with individualized estimates of risk-equivalent age for higher-grade PCa. Screening initiation could be adjusted according to a man’s genetic hazard score, improving PPV of PSA screening.
Are the Matrix Metalloproteinases 2 and 9 beeing expressed in the mucosa of the rat small intestine during its intrauterine and postnatal life development ?
Authors: dos Reis Camila Audrey , Gomes José Rosa 
Published: April 2019

ABSTRACTMMP-2 and MMP-9 are proteins with well stablished roles on the remodeling of tissue during morphogenesis. This study aimed to evaluate the activity and expression of the MMP-2 and MMP-9 in the rat small intestine mucosa layer on 15thand 18thdays of intratuterine life (i.u.) and at 3rd, 10th, 17th, 25th, and 32thdays after birth (a.b.). Samples were submitted to zimography, immunohistochemistry methods and Masson trichrome staining. Results showed that MMP-2 and MMP-9 were not expressed in the small intestine epithelium during intrauterine life. MMP-9 was immunolocalized in the villi goblet cells and in the lamina propria in cells identified as being the mast cells (a.b.). We concluded that in the i.u. and a.b. life the MMP-2 and MMP-9 were not expressed in the small intestine epithelium. However, after birth, because MMP-9 was expressed in the mast cels present in the lamina propria it may be involved in the remodeling process of the innate immunity that occurs during the small intestine development.
Integrating patterns of thermal tolerance and phenotypic plasticity with population genetics to improve understanding of vulnerability to warming in a widespread copepod
Authors: Sasaki Matthew C. , Dam Hans G. 
Published: April 2019

AbstractDifferences in population vulnerability to warming are defined by spatial patterns in thermal adaptation. These patterns may be driven by natural selection over spatial environmental gradients, but can also be shaped by gene flow, especially in marine taxa with high dispersal potential. Understanding and predicting organismal responses to warming requires disentangling the opposing effects of selection and gene flow. We begin by documenting genetic divergence of thermal tolerance and developmental phenotypic plasticity. Ten populations of the widespread copepodAcartia tonsawere collected from sites across a large thermal gradient, ranging from the Florida Keys to Northern New Brunswick, Canada (spanning over 20 degrees latitude). Thermal performance curves from common garden experiments revealed local adaptation at the sampling range extremes, with thermal tolerance increasing at low latitudes and decreasing at high latitudes. The opposite pattern was observed in phenotypic plasticity, which was strongest at high latitudes. Over a large portion of the sampled range, however, we observed a remarkable lack of differentiation of thermal performance curves. To examine whether this lack of divergence is the result of selection for a generalist performance curve or constraint by gene flow, we analyzed cytochrome oxidase I mtDNA sequences, which revealed abundant genetic diversity and widely-distributed haplotypes. Strong divergence in thermal performance within genetic clades, however, suggests that the pace of thermal adaptation can be relatively rapid. The combined insight from the laboratory physiological experiments and genetic data indicate that gene flow constrains differentiation of thermal performance curves. This balance between gene flow and selection has implications for patterns of vulnerability to warming. Taking both genetic differentiation and phenotypic plasticity into account, our results suggest that local adaptation does not increase vulnerability to warming, and that low latitude populations in general may be more vulnerable to predicted temperature change over the next century.
Liquid-liquid phase separation and liquid-to-solid transition mediate α-synuclein amyloid fibril containing hydrogel formation
Authors: Ray Soumik , Singh Nitu , Pandey Satyaprakash , Kumar Rakesh , Gadhe Laxmikant , Datta Debalina , Patel Komal , Mahato Jaladhar , Navalkar Ambuja , Panigrahi Rajlaxmi , Chatterjee Debdeep , Maiti Siddhartha , Bhatia Sandhya , Mehra Surabhi , Singh Ajay , Gerez Juan , Chowdhury Arindam , Kumar Ashutosh , Padinhateeri Ranjith , Riek Roland , Krishnamoorthy G , Maji Samir K 
Published: April 2019

SUMMARYα-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson’s disease (PD) pathogenesis. However, the early events involved in this process remain unclear. Here, using in vitro reconstitution and cellular model, we show that liquid-liquid phase separation (LLPS) of α-Syn precedes its aggregation. In particular, in vitro generated α-Syn liquid-like droplets eventually undergo a liquid-to-solid transition and form amyloid-hydrogel containing oligomers and fibrillar species. Factors known to aggravate α-Syn aggregation such as low pH, phosphomimic substitution, and familial PD mutation also promote α-Syn LLPS and its subsequent maturation. We further demonstrate α-Syn liquid droplet formation in cells, under oxidative stress. These cellular α-Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. The present work provides detailed insights into the phase separation behavior of natively unstructured α-Syn and its conversion to a disease-associated aggregated state, which is highly relevant in PD pathogenesis.
Simultaneous ribosome profiling of human host cells infected with Toxoplasma gondii
Authors: Holmes Michael J. , Shah Premal , Wek Ronald C. , Sullivan William J. 
Published: April 2019

AbstractToxoplasma gondii is a ubiquitous obligate intracellular parasite that infects the nucleated cells of warm-blooded animals. From within the parasitophorous vacuole in which they reside, Toxoplasma tachyzoites secrete an arsenal of effector proteins that can reprogram host gene expression to facilitate parasite survival and replication. Gaining a better understanding of how host gene expression is altered upon infection is central for understanding parasite strategies for host invasion and for developing new parasite therapies. Here, we applied ribosome profiling coupled with mRNA measurements to concurrently study gene expression in the parasite and in host human foreskin fibroblasts. By examining the parasite transcriptome and translatome, we identified potential upstream open reading frames that may permit the stress-induced preferential translation of parasite mRNAs. We also determined that tachyzoites reduce host death-associated pathways and increase survival, proliferation, and motility in both quiescent and proliferative host cell models of infection. Additionally, proliferative cells alter their gene expression in ways consistent with massive transcriptional rewiring while quiescent cells were best characterized by re-entry into the cell cycle. We also identified a translational control regimen consistent with mTOR activation in quiescent cells, and to a lesser degree in proliferative cells. This study illustrates the utility of the method for dissection of gene expression programs simultaneously in parasite and host.ImportanceToxoplasma gondii is a single-celled parasite that has infected up to one-third of the world’s population. Significant overhauls in gene expression in both the parasite and the host cell accompany parasite invasion, and a better understanding of these changes may lead to the development of new therapeutic agents. In this study, we employed ribosome profiling to determine the changes that occur at the levels of transcription and translation in both the parasite and the infected host cell at the same time. We discovered features of Toxoplasma mRNAs that suggest a means for controlling parasite gene expression under stressful conditions. We also show that differences in host gene expression occur depending on whether they are confluent or not. Our findings demonstrate the feasibility of using ribosomal profiling to interrogate the host-parasite dynamic under a variety of conditions.
Rotavirus NSP1 localizes in the nucleus to disrupt PML nuclear bodies during infection
Authors: Murphy Samantha K. , Arnold Michelle M. 
Published: April 2019

ABSTRACTThe rotavirus nonstructural protein 1 (NSP1) antagonizes interferon (IFN) induction in infected host cells. The primary function of NSP1 is thought to be degradation of interferon regulatory factors (IRFs) and beta-transducin repeat-containing protein (β-TrCP) in the cytoplasm to inhibit IFN induction. Here, we report that NSP1 localizes to the cytoplasm and nucleus and disrupts promyelocytic (PML) nuclear bodies (NB) in the nucleus during infection. Nuclear localization of NSP1 did not require an intact C terminus, suggesting NSP1 has a novel function in the nucleus independent of degradation of IRFs or β-TrCP. NSP1 expression either led to a reduction in PML NB number or a change in PML NB morphology from sphere-shaped foci to oblong-shaped structures, depending on the virus strain. Additionally, infection was not affected when cells lack PML NB, suggesting that rotavirus does not require PML for replication in highly permissive cell types. PML was not essential for nuclear localization of NSP1, but PML was required for NSP1 nuclear focus formation. PML NBs play an important role in many cellular functions that include IFN induction and host stress responses. This is the first report that rotavirus, a cytoplasmically replicating virus, encodes a viral protein that localizes to the nucleus during infection, and may suggest a new function of NSP1 in the nucleus.IMPORTANCERotavirus causes severe gastroenteritis in young children and leads to over 200,000 deaths per year. Rotavirus is a cytoplasmically replicating virus, and must find ways to avoid or actively inhibit host antiviral responses to efficiently replicate. The nonstructural protein NSP1 is known to inhibit IFN induction by promoting degradation of host proteins in the cytoplasm of infected cells. Here, we demonstrate that NSP1 also localizes to the nucleus of infected cells, specifically to PML NB. NSP1 causes a disruption of PML NB, which may serve as an additional mechanism of IFN inhibition or interfere with other nuclear processes to promote viral replication. A detailed exploration of the manipulation of nuclear processes in cells infected with cytoplasmically replicating viruses will lead to new insights into viral evasion of host responses.