bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative transcriptomics of a monocotyledonous geophyte reveals shared molecular mechanisms of underground storage organ formation
Authors: Tribble Carrie M. , Martínez-Gómez Jesús , Alzate-Guarin Fernando , Rothfels Carl J. , Specht Chelsea D. 
Published: November 2019

AbstractMany species from across the vascular plant tree-of-life have modified standard plant tissues into tubers, bulbs, corms, and other underground storage organs (USOs), unique innovations which allow these plants to retreat underground. Our ability to understand the developmental and evolutionary forces that shape these morphologies is limited by a lack of studies on certain USOs and plant clades. Bomarea multiflora (Alstroemeriaceae) is a monocot with tuberous roots, filling a key gap in our understanding of USO development. We take a comparative transcriptomics approach to characterizing the molecular mechanisms of tuberous root formation in B. multiflora and compare these mechanisms to those identified in other USOs across diverse plant lineages. We sequenced transcriptomes from the growing tip of four tissue types (aerial shoot, rhizome, fibrous root, and root tuber) of three individuals of B. multiflora. We identify differentially expressed isoforms between tuberous and non-tuberous roots and test the expression of a priori candidate genes implicated in underground storage in other taxa. We identify 271 genes that are differentially expressed in root tubers versus non-tuberous roots, including genes implicated in cell wall modification, defense response, and starch biosynthesis. We also identify a phosphatidylethanolamine-binding protein (PEBP), which has been implicated in tuberization signalling in other taxa and, through gene-tree analysis, place this copy in a phylogenytic context. These findings suggest that some similar molecular processes underlie the formation of underground storage structures across flowering plants despite the long evolutionary distances among taxa and non-homologous morphologies (e.g., bulbs versus tubers).
Transposon-mediated telomere destabilization: a driver of genome evolution in the blast fungus
Authors: Rahnama Mostafa , Novikova Olga , Starnes John , Chen Li , Zhang Shouan , Farman Mark 
Published: November 2019

ABSTRACTMagnaporthe oryzaeis a filamentous ascomycete fungus that causes devastating diseases of crops that include rice and wheat, and a variety of turf, forage and wild grasses. Strains from ryegrasses possess highly stable chromosome ends that undergo frequent rearrangements during vegetative growth in culture andin planta. Instability is associated with the presence of two related retrotransposons (MagnaportheoryzaeTelomericRetrotransposons - MoTeRs) inserted within the telomere repeat tracts. The objective of the present study was to determine the mechanisms by which MoTeRs promote telomere instability. Targeted cloning, restriction mapping, and sequencing of both parental and novel telomeric restriction fragments, along with MinION sequencing of DNA from three single-spore cultures, allowed us to document the molecular alterations for 109 newly-formed telomeres. Rearrangement events included truncations of subterminal rDNA sequences; acquisition of MoTeR insertions by “plain” telomeres; insertion of the MAGGY retrotransposons into MoTeR arrays; expansion and contraction of subtelomeric tandem repeats; MoTeR truncations; duplication and terminalization of internal sequences; and breakage at long, interstitial telomeres generated during MoTeR insertion. Together, our data show that when MoTeRs invade the telomeres, they can dramatically perturb the integrity of chromosome ends, leading to the generation of unprotected DNA termini whose repair has the potential to generate chromosome alterations that extend well into the genome interior.
Endocrine autoimmune disease as a fragility of immune-surveillance against hypersecreting mutants
Authors: Kohanim Yael Korem , Tendler Avichai , Mayo Avi , Friedman Nir , Alon Uri 
Published: November 2019

SummaryMany endocrine organs show prevalent autoimmune diseases (AID) such as type-1-diabetes and Hashimoto’s-thyroiditis. The fundamental origins of these diseases is unclear. Here we address AID from the viewpoint of feedback control. Endocrine tissues maintain their mass by feedback-loops that balance cell proliferation and removal according to input signals related to the hormone function. Such feedback is unstable to mutant cells that mis-sense the signal, and therefore hyper-proliferate and hyper-secrete the hormone. We hypothesize that in order to prevent these mutants from expanding, each organ has a dedicated ‘autoimmune surveillance of hyper-secreting mutants’ (ASHM), in which hyper-secreting cells are preferentially eliminated, at the cost of a fragility to AID. ASHM correctly predicts the identity of the self-antigens and the presence of T-cells against these self-antigens in healthy individuals. It offers a predictive theory for which tissues get frequent AID, and which do not and instead show frequent mutant-expansion disease (e.g. hyperparathyroidism).
The immunogenic potential of recurrent cancer drug resistance mutations: anin silicostudy
Authors: Punta Marco , Jennings Victoria , Melcher Alan , Lise Stefano 
Published: November 2019

ABSTRACTCancer somatic mutations have been identified as a source of antigens that can be targeted by cancer immunotherapy. In this work, expanding on previous studies, we analyse the immunogenic properties of mutations that are known to drive resistance to cancer targeted-therapies. We survey a large dataset of mutations that confer resistance to different drugs and occur in numerous genes and tumour types. We show that a significant number of these mutations are predictedin silicoto have immunogenic potential across a large proportion of the human population. Two of these mutations had previously been experimentally validated and it was confirmed that some of their associated neopeptides elicit T-cell responsesin vitro. The identification of potent cancer-specific antigens can be instrumental for developing more effective immunotherapies. Resistance mutations, several of which are known to recur in different patients, could be of particular interest in the context of off-the-shelf precision immunotherapies such as therapeutic cancer vaccines.
Genetic buffering and potentiation in metabolism
Authors: Poyatos Juan F. 
Published: November 2019

AbstractCells adjust their metabolism in response to mutations, but how this reprogramming depends on the genetic context is not well known. Specifically, the absence of individual enzymes can affect reprogramming and thus the impact of mutations in cell growth. Here, we examine this issue with an in silico model of Saccharomyces cerevisiae’s metabolism. By quantifying the variability in the growth rate of 10000 different mutant metabolisms that accumulated changes in their reaction fluxes, in the presence, or absence, of a specific enzyme, we distinguish a subset of modifier genes serving as buffers or potentiators of variability. We notice that the most potent modifiers refer to the glycolysis pathway and that, more broadly, they show strong pleiotropy and epistasis. Moreover, the evidence that this subset depends on the specific growing condition strengthens its systemic underpinning, a feature only observed before in a simple model of a gene-regulatory network. Some of these enzymes also modulate the effect that biochemical noise and environmental fluctuations produce in growth. Thus, the reorganization of metabolism triggered by mutations has not only direct physiological implications but also changes the influence that other mutations have on growth. This is a general result with implications in the development of cancer therapies based on metabolic inhibitors.
Mutation of kvrA causes OmpK35/36 porin downregulation and reduced meropenem/vaborbactam susceptibility in KPC-producing Klebsiella pneumoniae
Authors: Dulyayangkul Punyawee , Ismah Wan Ahmad Kamil Wan Nur , Douglas Edward J. A. , Avison Matthew B. 
Published: November 2019

AbstractMeropenem/vaborbactam resistance in Klebsiella pneumoniae is associated with loss of function mutations in the OmpK36 porin. Here we identify two previously unknown loss of function mutations that confer cefuroxime resistance in K. pneumoniae. The proteins lost were NlpD and KvrA; the latter is a transcriptional repressor that controls capsule production. We demonstrate that KvrA loss reduces OmpK35 and OmpK36 porin production, which confers reduced susceptibility to meropenem/vaborbactam in a KPC-3 producing K. pneumoniae clinical isolate.
Alternative polyadenylation mediates genetic regulation of gene expression
Authors: Mittleman Briana , Pott Sebastian , Warland Shane , Zeng Tony , Kaur Mayher , Gilad Yoav , Li Yang I 
Published: November 2019

AbstractWith the exception of mRNA splicing, little is known about co-transcriptional or post-transcriptional regulatory mechanisms that link noncoding variation to variation in organismal traits. To begin addressing this gap, we used 3’ Seq to characterize alternative polyadenylation (APA) in the nuclear and total RNA fractions of 52 HapMap Yoruba lymphoblastoid cell lines, which we have studied extensively in the past. We identified thousands of polyadenylation sites that are differentially detected in nuclear mRNA and whole cell mRNA, and found that APA is an important mediator of genetic effects on gene regulation and complex traits. Specifically, we mapped 602 apaQTLs at 10% FDR, of which 152 were found only in the nuclear fraction. Nuclear-specific apaQTLs are highly enriched in introns and are also often associated with changes in steady-state expression levels, suggesting a widespread mechanism whereby genetic variants decrease mRNA expression levels by increasing usage of intronic PAS. We identified 24 apaQTLs associated with protein expression levels, but not mRNA expression, and found that eQTLs that are not associated with chromatin QTLs are enriched in apaQTLs. These findings support multiple independent pathways through which genetic effects on APA can impact gene regulation. Finally, we found that 19% of apaQTLs were also previously associated with disease. Thus, our work demonstrates that APA links genetic variation to variation in gene expression levels, protein expression levels, and disease risk, and reveals uncharted modes of genetic regulation.
Multi-differentiation potential is necessary for optimal tenogenesis of tendon stem cells
Authors: Rajpar Ibtesam , Barrett Jennifer G. 
Published: November 2019

ABSTRACTBackgroundTendon injury is a significant clinical problem, and regenerative treatments are limited by our understanding of endogenous tendon stem cells. Recent evidence suggests that tendon stem cells are diverse in phenotypic character, and may in fact exist on a spectrum of differentiation capacities. However, the functional significance of each differentiation phenotype is poorly understood. Toward this end, we performed a comprehensive assessment of differentiation capacity toward four connective tissue lineages (adipose, bone, cartilage and tendon) with clonal tendon stem cell lines to: 1) evaluate the differences, if any, in tenogenic potential, and 2) identify the relationships in differentiation phenotype and proliferation capacity.MethodsTendon stem cells were derived from whole equine flexor tendons for this study (N=3). Clonal tendon stem lines were generated by low-density cell plating, and subjected to standard assays of tri-lineage differentiation and population doublings. For tenogenesis, a previously engineered three-dimensional hydrogel construct was incorporated. Differentiation was quantified by the relative gene expression of lineage-specific markers, and confirmed with lineage-specific cell staining. Tenogenesis was further analyzed by hydrogel contraction and histomorphometry. Statistical significance was determined using analysis of variance and post-hoc Tukey’s tests.ResultsThree distinct tendon stem cell phenotypes were identified, namely differentiation toward: 1) adipose, bone, cartilage and tendon, 2) bone, cartilage and tendon, or 3) adipose, cartilage and tendon. Further, a positive correlation was found in the ability to differentiate toward all four lineages and the generation of a robust, composite tendon-like construct upon tenogenesis, manifested by the strongest expressions of scleraxis and mohawk, and parallel alignment of tenocyte-like cells with elongated cell morphologies. Significantly increased numbers of cumulative cell population doublings were seen in the absence of adipogenic potential in clonal tendon stem cell lines.ConclusionsOur study strengthens reports on the heterogeneous character of tendon stem cells and identifies key differences in their differentiation and proliferative potentials. Isolation of potent tendon stem cell populations from tendon stromal fractions may yield improved therapeutic benefits in clinical models of repair and promote a native, regenerative phenotype in engineered tendons. Future studies may be targeted to understanding the functional contributions of each tendon stem cell phenotypein vivo, and identifying additional cell phenotypes.
Structure of the human BBSome core complex in the open conformation
Authors: Klink Björn U. , Gatsogiannis Christos , Hofnagel Oliver , Wittinghofer Alfred , Raunser Stefan 
Published: November 2019

AbstractThe BBSome is a heterooctameric protein complex that plays a central role in primary cilia homeostasis. Its malfunction causes the severe ciliopathy Bardet-Biedl syndrome (BBS). The complex acts as a cargo adapter that recognizes signaling proteins such as GPCRs and links them to the intraflagellar transport machinery. The underlying mechanism is poorly understood. Here we present a high-resolution cryo-EM structure of a human heterohexameric core subcomplex of the BBSome. The structure reveals the architecture of the complex in atomic detail. It explains how the subunits interact with each other and how disease-causing mutations hamper this interaction. The complex adopts a conformation that is open for binding to membrane-associated GTPase Arl6 and a large positively charged patch likely strengthens the interaction with the membrane. A prominent negatively charged cleft at the center of the complex is likely involved in binding of positively charged signaling sequences of cargo proteins.
Different mechanisms for modulation of the initiation and steady-state of smooth pursuit eye movements
Authors: Behling Stuart , Lisberger Stephen G. 
Published: November 2019

AbstractSmooth pursuit eye movements are used by primates to track moving objects. They are initiated by sensory estimates of target speed represented in the middle temporal (MT) area of extrastriate visual cortex and then supported by motor feedback to maintain steady-state eye speed at target speed. Here, we show that reducing the coherence in a patch of dots for a tracking target degrades the eye speed both at the initiation of pursuit and during steady-state tracking, when eye speed reaches an asymptote well below target speed. The deficits are quantitatively different between the motor-supported steady-state of pursuit and the sensory-driven initiation of pursuit, suggesting separate mechanisms. The deficit in visually-guided pursuit initiation could not explain the deficit in steady-state tracking. Pulses of target speed during steady-state tracking revealed lower sensitivities to image motion across the retina for lower values of dot coherence. However, sensitivity was not zero, implying that visual motion should still be driving eye velocity towards target velocity. When we changed dot coherence from 100% to lower values during accurate steady-state pursuit, we observed larger eye decelerations for lower coherences, as expected if motor feedback was reduced in gain. A simple pursuit model accounts for our data based on separate modulation of the strength of visual-motor transmission and motor feedback. We suggest that reduced dot coherence creates less reliable target motion that impacts pursuit initiation by changing the gain of visual-motor transmission and perturbs steady-state tracking by modulation of the motor corollary discharges that comprise eye velocity memory.
Quantification of the Resilience and Vulnerability of HIV-1 Native Glycan Shield at Atomistic Detail
Authors: Chakraborty Srirupa , Berndsen Zachary T. , Hengartner Nicolas W. , Korber Bette T. , Ward Andrew B. , Gnanakaran S. 
Published: November 2019

SummaryDense surface glycosylation on the HIV-1 envelope (Env) protein acts as a shield from the adaptive immune system. However, the molecular complexity and flexibility of glycans make experimental studies a challenge. Here we have integrated high-throughput atomistic modeling of fully glycosylated HIV-1 Env with graph theory to capture immunologically important features of the shield topology. This is the first complete all-atom model of HIV-1 Env SOSIP glycan shield that includes both oligomannose and complex glycans, providing results which are physiologically more relevant than the previous models with uniform glycosylation. This integrated approach including quantitative comparison with cryo-electron microscopy data provides hitherto unexplored details of the native shield architecture and its difference from the high-mannose glycoform. We have also derived a measure to quantify the shielding effect over the antigenic protein surface that defines regions of relative vulnerability and resilience of the shield and can be harnessed for rational immunogen design.
The Mitochondrial Iron Regulated (MIR) gene is Oryza genus-specific and evolved before the speciation of major AA-genome lineages
Authors: de Oliveira Ben-Hur Neves , Wairich Andriele , Turchetto-Zolet Andreia Carina , Fett Janette Palma , Ricachenevsky Felipe Klein 
Published: November 2019

AbstractRice (Oryza sativa L.) is both a model species and an economically relevant crop. The Oryza genus comprises 25 species, which constitute a genetic reservoir for cultivated rice breeding. Genomic data is available for several Oryza species, making it a good model for genetics and evolution within closely related species. The Mitochondrial Iron Regulated (MIR) gene was previously implicated in O. sativa Fe deficiency response, and was considered an orphan gene present only in rice. Here we show that MIR is also found in other Oryza species that belong to the AA genome group. We characterized the evolutionary pattern of MIR genes within the Oryza genus. Our data suggest that MIR originated de novo from non-coding sequences present only in AA genome species, but these sequences in turn are derived from an exon fragment of Raffinose Synthase genes, present in several groups of monocots. We also show that all species that have a putative functional MIR conserve their regulation by Fe deficiency, with the exception of Oryza barthii. In O. barthii, the MIR coding sequence was translocated to a different chromosomal position and separated from its regulatory region, which led to a lack of Fe deficiency responsiveness. Moreover, we show that MIR co-expression subnetwork cluster in O. sativa is responsive to Fe deficiency, evidencing the importance of the newly originated gene in Fe uptake. This work establishes that MIR is not an orphan gene as previously proposed, but a de novo originated gene within the Oryza genus. We also showed that MIR is undergoing genomic changes in at least one species (O. barthii), which can impact its role in Fe deficiency.
Propagation of THz irradiation energy through aqueous layers: Demolition of actin filaments in living cells
Authors: Yamazaki Shota , Harata Masahiko , Ueno Yuya , Tsubouchi Masaaki , Konagaya Keiji , Ogawa Yuichi , Isoyama Goro , Otani Chiko , Hoshina Hiromichi 
Published: November 2019

AbstractThe effect of terahertz (THz) radiation on deep tissues of human body has been considered negligible due to strong absorption by water molecules. However, we observed that the energy of THz pulses transmits a millimeter thick in the aqueous solution, possibly as a shockwave, and demolishes actin filaments. Collapse of actin filament induced by THz irradiation was also observed in the living cells under an aqueous medium. We also confirmed that the viability of the cell was not affected under the exposure of THz pulses. The potential of THz waves as an invasive method to alter protein structure in the living cells is demonstrated.One sentence summaryThe energy of the THz wave propagates several millimeters into an aqueous medium and demolishes actin filaments via shockwaves.
Structural insights into filament recognition by cellular actin markers
Authors: Kumari Archana , Kesarwani Shubham , Javoor Manjunath G , Vinothkumar Kutti R. , Sirajuddin Minhajuddin 
Published: November 2019

AbstractCellular studies of filamentous actin (F-actin) processes commonly utilize fluorescent versions of toxins, peptides and proteins that bind actin. While the choice of these markers has been largely based on availability and ease, there is a severe dearth of structural data for an informed judgment in employing suitable F-actin markers for a particular requirement. Here we describe the electron cryomicroscopy structures of phalloidin, lifeAct and utrophin bound to F-actin, providing the first high-resolution structures and comparison of widely used actin markers and their influence towards F-actin. Our results show that phalloidin binding does not induce conformations and lifeAct specifically recognizes ADP-actin state, which can be used as a sensor for distinguishing different nucleotide states of F-actin. The utrophin structural model aided designing minimal utrophin, which can be utilized as F-actin marker. Together, our study provides a structural perspective, where the binding sites of utrophin and lifeAct overlap with majority of actin binding proteins. Further offering an invaluable resource for researchers in choosing appropriate actin markers and generating new marker variants.