bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathologic Significance of Intestinal-type Molecules’ Expression and Different EGFR Gene Status in Pulmonary Adenocarcinoma
Authors: Feng Chang , Feng Man , Gao Yujun , Zhao Xiaogang , Peng Chuanliang , Yang Xiangshan , Zhang Jing
Published: February 2018

Variant pulmonary adenocarcinoma with intestinal-type molecules shares similar molecular expression with colorectal carcinoma. However, expression of such molecules and their association with survival time with clinicopathologic parameters, such as epidermal growth factor receptor (EGFR) gene status in other types of pulmonary adenocarcinoma, has been rarely demonstrated. Sixty patients with resected pulmonary adenocarcinoma were divided into the enteric differentiation group (I group, n=30) and the usual group (U group, n=30). Immunohistochemical staining was used to assess the expression of carcinoembryonic antigen (CEA), Villin, CK20, and caudal-related homeobox 2 (CDX2). EGFR gene status was examined by Fluorescence Quantitative polymerase chain reaction. Kaplan-Meier survival curve was drawn by GraphPad Prism 5.0 software. The results showed that there was a significant difference between the 2 groups (P<0.05) in the expression of Villin, CK20, and CDX2, whereas the expression of CEA showed no significant difference (P>0.05). Compared with the U group, patients in the I group were mainly female individuals and in clinical stages III to IV, prone to lymph node metastasis (P<0.05). The patients in the I group with CDX2+CK20− phenotype (tumor size>5 cm) had a shorter survival time (P<0.05), and EGFR gene status was not associated with median survival time and the expression of CEA, Villin, CK20, and CDX2 (P>0.05). Thus, our research indicates that patients with enteric differentiation have unique clinical characteristics and different prognosis, which may play important roles in diagnosis and choosing therapeutic strategies for pulmonary adenocarcinoma patients in clinical practice.
Targetable Immune Regulatory Molecule Expression in High-Grade Serous Ovarian Carcinomas in African American Women: A Study of PD-L1 and IDO in 112 Cases From the African American Cancer Epidemiology Study (AACES)
Authors: Mills Anne M. , Peres Lauren C. , Meiss Alice , Ring Kari L. , Modesitt Susan C. , Abbott Sarah E. , Alberg Anthony J. , Bandera Elisa V. , Barnholtz-Sloan Jill , Bondy Melissa L. , Cote Michele L. , Funkhouser Ellen , Moorman Patricia G. , Peters Edward S. , Schwartz Ann G. , Terry Paul D. , Wallace Kristin , Schildkraut Joellen M.
Published: February 2018

African American women with high-grade serous ovarian carcinoma have worse outcomes compared with women of European descent. Although the discrepancy is partially attributed to differences in access to care, the tumor immune microenvironment may also contribute. Expression of targetable immune regulatory molecules such as programmed cell death ligand-1 (PD-L1) and indoleamine 2,3 dioxygenase (IDO) is of particular interest as it may help guide therapy in this population. Using cases from the largest study of African American women with ovarian cancer, the African American Cancer Epidemiology Study, we characterized PD-L1 and IDO expression in 112 high-grade serous ovarian carcinomas. Immunohistochemistry for PD-L1, IDO, CD8, FOX3p, and CD68 was performed. PD-L1 and IDO were scored as the percentage of positive tumor cells and tumor-associated immune cells. CD8 and FOX3p counts were averaged across 10 high-power fields. Cox proportional hazards regression was used to evaluate the association between PD-L1 and IDO expression and survival. Tumor cells were positive for PD-L1 and IDO in 29% and 58% of cases, respectively. The majority showed <10% staining, and no cases exceeded 25% positivity. The majority of PD-L1-positive cases coexpressed IDO. PD-L1 and IDO expression was associated with higher CD8 and FOX3p counts (P<0.05). No association was observed between PD-L1 and IDO and survival. In summary, expression of PD-L1 and IDO is seen in a subset of high-grade serous ovarian carcinoma from African American women and is correlated with elevated lymphocyte infiltration. While PD-L1 and IDO co-expression suggests a role for dual immunotherapy, diffuse expression of PD-L1 and IDO is rare, invoking caution regarding the potential for immunotherapeutic response.
FDG PET/CT Findings of Erdheim–Chester Disease
Authors: Akin Esma A. , Osman Murat , Ellenbogen Amy L.
Published: February 2018

Erdheim–Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with deposition of lipid-laden macrophages in numerous organs. A 74-year-old man with a history of coronary artery disease, hypertension, and hyperlipidemia presented with nonspecific symptoms including back pain, nausea, vomiting, vertigo, and left leg pain. A neutrophil-predominant elevated WBC count and a bone biopsy revealing histiocytic proliferation positive for CD68 and CD163 and negative for S100 was noted. FDG PET/CT, MRA, and CTA images were obtained. We review the radiologic hallmarks of ECD and demonstrate the radiologic manifestations of response to combined BRAF and MEK inhibitor treatment.
How hemorrhage control became common sense
Authors: Hawk Alan James
Published: February 2018

BACKGROUND

Just over 200 years ago, surgeons were puzzled that the use of the tourniquet to control hemorrhage as common sense during surgery was a relatively recent development. Within the last 20 years, much progress has been made to controlling hemorrhage in the prehospital context. Then, as now, it was surprising that progress on something that appeared obvious had occurred only recently, begging the question how controlling blood loss was common sense in a surgical context, but not for emergency treatment.

METHODS

This article is a historical survey of the evolution of the medical understanding of hemorrhage along with technological response.

RESULTS

The danger of blood loss had historically been consistently underestimated as physicians looked at other explanations for symptoms of how the human body responded to trauma. As the danger from hemorrhage became apparent, even obvious, responsibility for hemorrhage control was delegated down from the surgeon to the paramedic and eventually to individual service members and civilian bystanders with training to “stop the bleed.”

CONCLUSION

Hippocratic medicine assumed that blood diffused centrifugally into periphery through arteries. William Harvey’s observation in 1615 that blood ran through a closed circulatory system gradually transformed conventional wisdom about blood loss, leading to the development of the tourniquet about a century later by Jean-Louis Petit, which made amputation of limbs survivable. However, physicians were cautious about their application during the First World War over concerns over effects on patient recovery. Hemorrhage had generally been seen as symptom to be managed until the patient would be seen by a surgeon who would stop the bleeding. More thorough collection and analysis of data related to case histories of soldiers wounded during the Vietnam Conflict transformed how surgeons understood the importance to hemorrhage leading to development of the doctrine of Tactical Combat Casualty Care in the late 1990s.

LEVEL OF EVIDENCE

Background Information: Economic/decision study.
State-of-the-art and future directions for extinction as a translational model for fear and anxiety
Authors: Craske Michelle G. , Hermans Dirk , Vervliet Bram
Published: February 2018

Through advances in both basic and clinical scientific research, Pavlovian fear conditioning and extinction have become an exemplary translational model for understanding and treating anxiety disorders. Discoveries in associative and neurobiological mechanisms underlying extinction have informed techniques for optimizing exposure therapy that enhance the formation of inhibitory associations and their consolidation and retrieval over time and context. Strategies that enhance formation include maximizing prediction-error correction by violating expectancies, deepened extinction, occasional reinforced extinction, attentional control and removal of safety signals/behaviours. Strategies that enhance consolidation include pharmacological agonists of NMDA (i.e.
d
-cycloserine) and mental rehearsal. Strategies that enhance retrieval include multiple contexts, retrieval cues, and pharmacological blockade of contextual encoding. Stimulus variability and positive affect are posited to influence the formation and the retrieval of inhibitory associations. Inhibitory regulation through affect labelling is considered a complement to extinction. The translational value of extinction will be increased by more investigation of elements central to extinction itself, such as extinction generalization, and interactions with other learning processes, such as instrumental avoidance reward learning, and with other clinically relevant cognitive–emotional processes, such as self-efficacy, threat appraisal and emotion regulation, will add translational value. Moreover, framing fear extinction and related processes within a developmental context will increase their clinical relevance.

This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.
Brain neuroreceptor density and personality traits: towards dimensional biomarkers for psychiatric disorders
Authors: Farde Lars , Plavén-Sigray Pontus , Borg Jacqueline , Cervenka Simon
Published: February 2018

Positron emission tomography has, for 30 years, been used in numerous case-control studies searching for hypothesized differences in the density of neuroreceptor or transporter proteins in psychiatric disorders such as schizophrenia and depression. In most cases, the results have not been conclusive. One reason could be the sizeable interindividual variability in biochemical markers, which in twin studies have shown to emanate from both environmental and genetic factors, leading to low statistical power for the detection of group effects. On the other hand, the same interindividual variability has served as an opportunity for correlative studies on the biological underpinning of behaviour. Using this approach, a series of studies has linked markers for the dopamine and serotonin system to personality traits associated with psychiatric conditions. Based on increasing evidence for the view that many psychopathological states represent extremes of a continuum rather than distinct categories, this research strategy may lead to new biological insights about the vulnerability to and pathophysiology of major psychiatric disorders.

This article is part of the theme issue ‘Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.
Perspectives on two temperamental biases
Authors: Kagan Jerome
Published: February 2018

This paper describes the contribution of two infant temperamental biases to variation in behaviour and biology over the first 18 years in a sample of middle-class Caucasian children. One bias, called high reactive, is defined by frequent display of limb activity and crying in four-month-old infants to unexpected or unfamiliar events. The other, called low reactive, is defined by the opposite pair of behaviours to the same incentives. High reactive infants are likely to display cautious, avoidant responses and signs of an excitable amygdala to unexpected experiences. Low reactives are characterized by a sociable, emotionally spontaneous profile to the same experiences and a minimally excitable amygdala. However, each bias is a better predictor of the future traits that are unlikely to develop than the ones that do. The final pattern of traits is a function of the person's temperaments, life history, and current circumstances.

This article is part of the theme issue ‘Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.
The functional highly sensitive brain: a review of the brain circuits underlying sensory processing sensitivity and seemingly related disorders
Authors: Acevedo Bianca , Aron Elaine , Pospos Sarah , Jessen Dana
Published: February 2018

During the past decade, research on the biological basis of sensory processing sensitivity (SPS)—a genetically based trait associated with greater sensitivity and responsivity to environmental and social stimuli—has burgeoned. As researchers try to characterize this trait, it is still unclear how SPS is distinct from seemingly related clinical disorders that have overlapping symptoms, such as sensitivity to the environment and hyper-responsiveness to incoming stimuli. Thus, in this review, we compare the neural regions implicated in SPS with those found in fMRI studies of—Autism Spectrum Disorder (ASD), Schizophrenia (SZ) and Post-Traumatic Stress Disorder (PTSD) to elucidate the neural markers and cardinal features of SPS versus these seemingly related clinical disorders. We propose that SPS is a stable trait that is characterized by greater empathy, awareness, responsivity and depth of processing to salient stimuli. We conclude that SPS is distinct from ASD, SZ and PTSD in that in response to social and emotional stimuli, SPS differentially engages brain regions involved in reward processing, memory, physiological homeostasis, self-other processing, empathy and awareness. We suggest that this serves species survival via deep integration and memory for environmental and social information that may subserve well-being and cooperation.

This article is part of the theme issue ‘Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences’.
Functional systems theory and the activity-specific approach in psychological taxonomies
Authors: Rusalov Vladimir
Published: February 2018

This brief opinion contribution reflects on the application of Anokhin's functional systems theory in the development of models of temperament in Russian differential psychophysiology. It points to the benefits of using an activity-specific approach in temperament theory. This approach suggests separating traits related to physical, communicative and mental aspects of behaviour.

This article is part of the theme issue ‘Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.
Culture, morality and individual differences: comparability and incomparability across species
Authors: Saucier Gerard
Published: February 2018

Major routes to identifying individual differences (in diverse species) include studies of behaviour patterns as represented in language and neurophysiology. But results from these approaches appear not to converge on some major dimensions. Identifying dimensions of human variation least applicable to non-human species may help to partition human-specific individual differences of recent evolutionary origin from those shared across species. Human culture includes learned, enforced social-norm systems that are symbolically reinforced and referenced in displays signalling adherence. At a key juncture in human evolution bullying aggression and deception-based cheating apparently became censured in the language of a moral community, enabling mutual observation coordinated in gossip, associated with external sanctions. That still-conserved cultural paradigm moralistically regulates selfish advantage-taking, with shared semantics and explicit rules. Ethics and moral codes remain critical and universal components of human culture and have a stronger imprint in language than most aspects of the currently popular Big-Five taxonomy, a model that sets out five major lines of individual-differences variation in human personality. In other species (e.g. chimpanzees), human observers might see apparent individual differences in morality-relevant traits, but not because the animals have human-analogue sanctioning systems. Removing the moral dimension of personality and other human-specific manifestations (e.g. religion) may aid in identifying those other bases of individual differences more ubiquitous across species.

This article is part of the theme issue ‘Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences’.
Taxonomic models of individual differences: a guide to transdisciplinary approaches
Authors: Uher Jana
Published: February 2018

Models and constructs of individual differences are numerous and diverse. But detecting commonalities, differences and interrelations is hindered by the common abstract terms (e.g. ‘personality’, ‘temperament’, ‘traits’) that do not reveal the particular phenomena denoted. This article applies a transdisciplinary paradigm for research on individuals that builds on complexity theory and epistemological complementarity. Its philosophical, metatheoretical and methodological frameworks provide concepts to differentiate various kinds of phenomena (e.g. physiology, behaviour, psyche, language). They are used to scrutinize the field's basic concepts and to elaborate methodological foundations for taxonomizing individual variations in humans and other species. This guide to developing comprehensive and representative models explores the decisions taxonomists must make about which individual variations to include, which to retain and how to model them. Selection and reduction approaches from various disciplines are classified by their underlying rationales, pinpointing possibilities and limitations. Analyses highlight that individuals' complexity cannot be captured by one universal model. Instead, multiple models phenotypically taxonomizing different kinds of variability in different kinds of phenomena are needed to explore their causal and functional interrelations and ontogenetic development that are then modelled in integrative and explanatory taxonomies. This research agenda requires the expertise of many disciplines and is inherently transdisciplinary.

This article is part of the theme issue ‘Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.
Task errors contribute to implicit remapping in sensorimotor adaptation
Authors: Leow Li-Ann , Marinovic Welber , de Rugy Aymar , Carroll Timothy J
Published: February 2018

Perturbations of sensory feedback evoke sensory prediction errors (discrepancies between predicted and actual sensory outcomes of movements), and reward prediction errors (discrepancies between predicted rewards and actual rewards). Sensory prediction errors result in obligatory remapping of the relationship between motor commands and predicted sensory outcomes. The role of reward prediction errors in sensorimotor adaptation is less clear. When moving towards a target, we expect to obtain the reward of hitting the target, and so we experience a reward prediction error if the perturbation causes us to miss it. These discrepancies between desired task outcomes and actual task outcomes, or “task errors”, are thought to drive the use of strategic processes to restore success, although their role is not fully understood. Here, we investigated the role of task errors in sensorimotor adaptation: during target-reaching, we either removed task errors by moving the target mid-movement to align with cursor feedback of hand position, or enforced task error by moving the target away from the cursor feedback of hand position. Removing task errors not only reduced the rate and extent of adaptation during exposure to the perturbation, but also reduced the amount of post-adaptation implicit remapping. Hence, task errors contribute to implicit remapping resulting from sensory prediction errors. This suggests that the system which implicitly acquires new sensorimotor maps via exposure to sensory prediction errors is also sensitive to reward prediction errors.
Circular RNA expression and regulatory network prediction in posterior cingulate astrocytes in elderly subjects
Authors: Sekar Shobana , Cuyugan Lori , Adkins Jonathan , Geiger Philipp , Liang Winnie S.
Published: February 2018

Background

Circular RNAs (circRNAs) are a novel class of endogenous, non-coding RNAs that form covalently closed continuous loops and are both highly conserved and abundant in the mammalian brain. A role for circRNAs in sponging microRNAs (miRNAs) has been proposed, but the circRNA-miRNA-mRNA interaction networks in human brain cells have not been defined. Therefore, we identified circRNAs in RNA sequencing data previously generated from astrocytes microdissected from the posterior cingulate (PC) of Alzheimer’s disease (AD) patients (N=10) and healthy elderly controls (N=10) using four circRNA prediction algorithms - CIRI, CIRCexplorer, find_circ and KNIFE.

Results

Overall, utilizing these four tools, we identified a union of 4,438 unique circRNAs across all samples, of which 70.3% were derived from exonic regions. Notably, the widely reported CDR1as circRNA was detected in all samples across both groups by find_circ. Given the putative miRNA regulatory function of circRNAs, we identified potential miRNA targets of circRNAs, and further, delineated circRNA-miRNA-mRNA networks using in silico methods. Pathway analysis of the genes regulated by these miRNAs identified significantly enriched immune response pathways, which is consistent with the known function of astrocytes as immune sensors in the brain.

Conclusions

In this study, we performed circRNA detection on cell-specific transcriptomic data and identified potential circRNA-miRNA-mRNA regulatory networks in PC astrocytes. Given the known function of astrocytes in cerebral innate immunity and our identification of significantly enriched immune response pathways, the circRNAs we identified may be associated with such key functions. While we did not detect recurrent differentially expressed circRNAs in the context of healthy controls or Alzheimer’s, we report for the first time circRNAs and their potential regulatory impact in a cell-specific and region-specific manner in aged subjects. These predicted regulatory network and pathway analyses may help provide new insights into transcriptional regulation in the brain.
Some lessons and perspectives for applications of stochastic models in biological and cancer research
Authors: Sabino Alan U. , Vasconcelos Miguel F. S. , Sittoni Misaki Y. , Lautenschläger Willian W. , Queiroga Alexandre S. , de Morais Mauro C. C. , Ramos Alexandre F.
Published: February 2018

Randomness is an unavoidable feature of inner cellular environment and its effects propagate to higher levels of living matter organization such as cells, tissues, and organisms. Approaching those systems experimentally to understand their dynamics is a complex task because of the plethora of compounds interacting in a web that combines intra and inter level elements such that a coordinate behavior come up. Such a characteristic points to the necessity of establishing principles that help on the description, categorization, classification, and the prediction of the behavior of biological systems. The theoretical machinery already available, or the ones to be discovered motivated by biological problems, can play an important role on that quest. Here we exemplify the applicability of theoretical tools by discussing some biological problems that we have approached mathematically: fluctuations in gene expression and cell proliferation in the context of loss of contact inhibition. We discuss the methods that we have employed aiming to provide the reader with a phenomenological, biologically motivated, perspective of the use of theoretical methods. Furthermore, we discuss some of our conclusions after employing our approach and some research perspectives that they motivate.
Towards Resolving and Redefining Amphipyrinae (Lepidoptera, Noctuoidea, Noctuidae): a Massively Polyphyletic Taxon
Authors: Keegan Kevin L. , Lafontaine J. Donald , Wahlberg Niklas , Wagner David L.
Published: February 2018

Amphipyrinae have long been a catchall taxon for Noctuidae, with most members lacking discernible morphological synapomorphies that would allow their assignment to one of the many readily diagnosable noctuid subfamilies. Here data from seven gene regions (>5,500 base pairs) for more than 120 noctuid genera are used to infer a phylogeny for Amphipyrinae and related subfamilies. Sequence data for 57 amphipyrine genera—most represented by the type species of the genus—are examined. Presented here are: the first large-scale molecular phylogenetic study of Amphipyrinae and largest molecular phylogeny of Noctuidae to date; several proposed nomenclatural changes for well supported results; and the identification of areas of noctuid phylogeny where greater taxon sampling and/or genomic-scale data are needed. Adult and larval morphology, along with life history traits, for taxonomic groupings most relevant to the results are discussed. Amphipyrinae are significantly redefined; many former amphipyrines, excluded as a result of these analyses, are reassigned to other noctuid subfamily-level taxa. Four genera,ChamaecleaGrote,HeminocloaBarnes & Benjamin,HemioslariaBarnes & Benjamin, andThurberiphagaDyar are transferred to the tribe Chamaecleini Keegan & WagnerNew Tribein Acontiinae. Stiriina is elevated to StiriinaeRevised Status, Grotellina is elevated to GrotellinaeRevised Status, and Annaphilina is elevated to AnnaphiliniRevised Status.AcopaHarvey is transferred to Bryophilinae,AleptinaDyar is transferred to Condicinae,LeucocnemisHampson andOxycnemis gracillinea(Grote) are transferred to Oncocnemidinae,NacopaBarnes & Benjamin is transferred to Noctuinae, andNarthecophoraSmith is transferred to Stiriinae.AzeniaGrote (and its subtribe Azeniina),CropiaWalker,MetaponpneumataMöschler,SexserrataBarnes & Benjamin, andTristylaSmith are transferred to Noctuidaeincertae sedis.HemigrotellaBarnes & McDunnough (formerly in subtribe Grotellina) is retained in Amphipyrinae.

This published work has been registered in ZooBank,http://zoobank.org/urn:lsid:zoobank.org:pub:4A140782-31BA-445A-B7BA-6EAB98ED43FA
Differential expression of an alternative splice variant of IL-12Rβ1 impacts early dissemination in the mouse and associates with disease outcome in both mouse and humans exposed to tuberculosis
Authors: Das Mrinal K. , Ray Aurelie A. , Cai Yi , Singhania Akul , Graham Christine M. , Liao Mingfeng , Fountain Jeffrey J. , Pearl John E. , Pareek Manish , Haldar Pranab , O’Garra Anne , Chen Xinchun , Cooper Andrea M.
Published: February 2018

Experimental mouse models of TB suggest that early events in the lung impact immunity. Early events in the human lung in response to TB are difficult to probe and their impact on disease outcome is unknown. We have shown in mouse that a secreted alternatively-spliced variant of IL-12Rβ1, lacking the transmembrane domain and termed ΔTM-IL-12Rβ1, promotes dendritic cell migration to the draining lymph node, augments T cell activation and limits dissemination ofM. tuberculosis(Mtb). We show here that CBA/J and C3H/HeJ mice (both highly susceptible to Mtb) express higher levels of ΔTM-IL-12Rβ1 than resistant C57BL6 mice and limit early dissemination of Mtb from the lungs. Both CD11c+ cells and T cells express ΔTM-IL-12Rβ1 in humans, and mice unable to make ΔTM-IL-12Rβ1 in either CD4 or CD11c expressing cells permit early dissemination from the lung. Analysis of publically available blood transcriptomes indicates that pulmonary TB is associated with high ΔTM-IL-12Rβ1 expression and that of all IL-12 related signals, the ΔTM-IL-12Rβ1 signal best predicts active disease. ΔTM-IL-12Rβ1 expression reflects the heterogeneity of latent TB infection and has the capacity to discriminate between latent and active disease. In a new Chinese TB patient cohort, ΔTM-IL-12Rβ1 effectively differentiates TB from latent TB, healthy controls and pneumonia patients. Finally, ΔTM-IL-12Rβ1 expression drops in drug-treated individuals in the UK and China where infection pressure is low. We propose that ΔTM-IL-12Rβ1 regulates early dissemination from the lung and that it has diagnostic potential and provides mechanistic insights into human TB.
A Methodological Assessment and Characterization of Genetically-Driven Variation in Three Human Phosphoproteomes
Authors: Engelmann Brett W. , Hsiao Chiaowen Joyce , Blischak John D. , Fourne Yannick , Ford Michael , Gilad Yoav
Published: February 2018

Phosphorylation of proteins on serine, threonine, and tyrosine residues is a ubiquitous post-translational modification that plays a key part of essentially every cell signaling process. It is reasonable to assume that inter-individual variation in protein phosphorylation may underlie phenotypic differences, as has been observed for practically any other molecular regulatory phenotype. However, we do not know much about the extent of inter-individual variation in phosphorylation because it is quite challenging to perform a quantitative high throughput study to assess inter-individual variation in any post-translational modification. To test our ability to address this challenge with current technology, we quantified phosphorylation levels for three genotyped human cell lines within a nested experimental framework, and found that genetic background is the primary determinant of phosphoproteome variation. We uncovered multiple functional, biophysical, and genetic associations with germline driven phosphopeptide variation. Variants affecting protein levels or structure were among these associations, with the latter presenting, on average, a stronger effect. Interestingly, we found evidence that is consistent with a phosphopeptide variability buffering effect endowed from properties enriched within longer proteins. Because the small sample size in this ‘pilot’ study may limit the applicability of our genetic observations, we also undertook a thorough technical assessment of our experimental workflow to aid further efforts. Taken together, these results provide the foundation for future work to characterize inter-individual variation in post-translational modification levels and reveal novel insights into the nature of inter-individual variation in phosphorylation.
Aspartyl Protease 5 matures virulence factors found at the host-parasite interface in Toxoplasma gondii
Authors: Coffey Michael J , Dagley Laura F , Kapp Eugene A , Infusini Giuseppe , Boddey Justin A , Webb Andrew I , Tonkin Christopher J
Published: February 2018

Toxoplasma gondii infects approximately 30% of the world’s population, causing disease primarily during pregnancy and in individuals with weakened immune systems. Toxoplasma secretes and exports effector proteins that modulate the host during infection and several of these proteins are processed by the Golgi-associated Aspartyl Protease 5 (ASP5). Here, we identify ASP5 substrates by selectively enriching N-terminally-derived peptides from wildtype and Δasp5 parasites. We reveal over two thousand unique Toxoplasma N-terminal peptides, mapping to both natural N-termini and protease cleavage sites. Several of these peptides mapped directly downstream of the characterised ASP5-cleavage site, arginine-arginine-leucine (RRL). We validate candidates as true ASP5 substrates, revealing they are not processed in parasites lacking ASP5, nor in wild type parasites following mutation of the motif from RRL⟶ARL. All new ASP5 substrates are dense granule proteins, and interestingly none appear to be exported, thus differing from the analogous system in related Plasmodium spp., instead revealing that the majority of substrates reside within the parasitophorous vacuole (PV), and its membrane (the PVM), including two kinases and one phosphatase. Furthermore, we show that several of these ASP5-substrates are virulence factors, with their removal leading to attenuation in a mouse model, suggesting that phosphorylation at the host-parasite interface is important for virulence. Collectively, these data constitute the first in-depth analyses of the total list of ASP5 substrates, and shed new light on the role of ASP5 as a maturase of dense granule proteins during the Toxoplasma lytic cycle.
Rules for PP2A-controlled phosphosignalling and drug responses
Authors: Kauko Otto , Imanishi Susumu Y. , Kulesskiy Evgeny , Laajala Teemu Daniel , Yetukuri Laxman , Laine Anni , Jumppanen Mikael , Haapaniemi Pekka , Ruan Luyao , Yadav Bhagwan , Suni Veronika , Varila Taru , Corthals Garry , Reimand Jüri , Wennerberg Krister , Aittokallio Tero , Westermarck Jukka
Published: February 2018

Systemic understanding of protein phosphatase 2A (PP2A)-regulated cellular processes is still at infancy. Here, we present mass-spectrometry analysis of phospho-targets (dephosphorylome) regulated by PP2A modulation. In addition to PP2A-regulated processes and targets, the data reveal important general concepts and rules related to PP2A-mediated phosphoregulation. These include the unidirectionality paradigm of regulation of phosphorylation, and differential spatial distribution of kinase-and phosphatase-dominated phosphotargets. Data also present first systemic analysis of targets of PP2A-modulating oncoproteins, CIP2A, PME-1, and SET; including targets via which PP2A may coordinately regulate activities of cancer drivers and tumor suppressors such as MYC or TP53. To validate functional utility of this dataset, PP2A dephosphorylome activity was correlated with cancer cell responses to over 300 drugs. Notably, we find that cancer therapy responses can be broadly classified based on PP2A dephosphorylome activity, both in quantitative and qualitative manner. In summary, our data characterize rules by which PP2A coordinate cancer cell phosphosignaling and drug responses. The results also may also direct the use of emerging pharmacological approaches for PP2A activity modulation in human diseases.
Human primary astrocytes increase basal fatty acid oxidation following recurrent low glucose to maintain intracellular nucleotide levels
Authors: Weightman Potter Paul G , Walker Julia M. Vlachaki , Robb Josephine L , Chilton John K. , Williamson Ritchie , Randall Andrew , Ellacott Kate L.J. , Beall Craig
Published: February 2018

Hypoglycemia is a major barrier to good glucose control in type 1 diabetes and frequent exposure to hypoglycemia can impair awareness to subsequent bouts of hypoglycemia. The neural changes that occur to reduce a person’s awareness of hypoglycemia are poorly defined. Moreover, the molecular mechanisms by which glial cells contribute to hypoglycemia sensing and glucose counterregulation require further investigation. To test whether glia, specifically astrocytes, could detect changes in glucose, we utilized human primary astrocytes (HPA) and U373 astrocytoma cells and exposed them to recurrent low glucose (RLG) in vitro. This allowed measurement, with high specificity and sensitivity, of changes in cellular metabolism following RLG. We report that the AMP-activated protein kinase (AMPK) is activated over a pathophysiologically-relevant glucose concentration range. We observed an increased dependency on fatty acid oxidation for basal mitochondrial metabolism and hallmarks of mitochondrial stress including increased proton leak and reduced coupling efficiency. Relative to glucose availability, lactate release increased during low glucose but this was not modified by RLG, nor were glucose uptake or glycogen levels. Taken together, these data indicate that astrocyte mitochondria are dysfunctional following recurrent low glucose exposure, which could have implications for hypoglycemia glucose counterregulation and/or hypoglycemia awareness.
Specific enrichment of hyperthermophilic electroactive Archaea from deep-sea hydrothermal vent on electrically conductive support
Authors: Pillot Guillaume , Frouin Eléonore , Pasero Emilie , Godfroy Anne , Combet-Blanc Yannick , Davidson Sylvain , Liebgott Pierre-Pol
Published: February 2018

While more and more investigations are done to isolate hyperthermophilic exoelectrogenic communities from environments, none have been performed yet on deep-sea hydrothermal vent. Samples of black smoker chimney from Rainbow site on the Atlantic mid-oceanic ridge have been harvested for enriching exoelectrogens in microbial electrolysis cells under hyperthermophilic (80°C) condition. Two enrichments have been performed: one from direct inoculation of crushed chimney and the other one from inoculation of a pre-cultivation on iron (III) oxide. In both experiments, a current production was observed from 2.4 A/m2 to 5.8 A/m2 with a set anode potential of +0.05 vs SHE. Taxonomic affiliation of the exoelectrogen communities obtained exhibited a specific enrichment of Archaea from Thermococcales and Archeoglobales orders on the electrode, even when both inocula were dominated by Bacteria.
Genomic prediction informed by biological processes expands our understanding of the genetic architecture underlying free amino acid traits in dryArabidopsisseeds
Authors: Turner-Hissong Sarah D. , Bird Kevin A. , Lipka Alexander E. , King Elizabeth G. , Beissinger Timothy M. , Angelovici Ruthie
Published: February 2018

Plant growth, development, and nutritional quality depends upon amino acid homeostasis, especially in seeds. However, our understanding of the underlying genetics influencing amino acid content and composition remains limited, with only a few candidate genes and quantitative trait loci identified to date. Improved knowledge of the genetics and biological processes that determine amino acid levels will enable researchers to use this information for plant breeding and biological discovery. Towards this goal, we used genomic prediction to identify biological processes that are associated with, and therefore potentially influence, free amino acid (FAA) composition in seeds of the model plantArabidopsis thaliana. Markers were split into categories based on metabolic pathway annotations and fit using a genomic partitioning model to evaluate the influence of each pathway on heritability explained, model fit, and predictive ability. Selected pathways included processes known to influence FAA composition, albeit to an unknown degree, and spanned four categories: amino acid, core, specialized, and protein metabolism. Using this approach, we identified associations for pathways containing known variants for FAA traits, in addition to finding new trait-pathway associations. Markers related to amino acid metabolism, which are directly involved in the FAA regulation, improved predictive ability for branched chain amino acids and histidine. The use of genomic partitioning also revealed patterns across biochemical families, in which serine-derived FAAs were associated with protein related annotations and aromatic FAAs were associated with specialized metabolic pathways. Taken together, these findings provide evidence that genomic partitioning is a viable strategy to uncover the relative contributions of biological processes to FAA traits in seeds, offering a promising framework to guide hypothesis testing and narrow the search space for candidate genes.
A novel environmental DNA (eDNA) sampling method for aye-ayes from their feeding traces
Authors: Aylward Megan L. , Sullivan Alexis P. , Perry George H. , Johnson Steig E. , Louis Edward E.
Published: February 2018

Non-invasive sampling is an important development in population genetic monitoring of wild animals. Particularly, the collection of environmental DNA (eDNA) which can be collected without needing to encounter the target animal, facilitates the genetic analysis of cryptic and threatened species. One method that has been applied to these types of sample is target capture and enrichment which overcomes the issue of high proportions of exogenous (non-host) DNA from these lower quality samples. We tested whether target capture of mitochondrial DNA from sampled feeding traces of wild aye-ayes would yield mitochondrial DNA sequences for population genetic monitoring. We sampled gnawed wood from feeding traces where aye-ayes excavate wood-boring insect larvae from trees. We designed RNA probes complementary to the aye-aye’s mitochondrial genome and used these to isolate aye-aye DNA from other non-target DNA in these samples. We successfully retrieved six near-complete mitochondrial genomes from two sites within the aye-aye’s geographic range that had not been sampled previously. This method can likely be applied to alternative foraged remains to sample species other than aye-ayes. Our method demonstrates the application to next-generation molecular techniques to species of conservation concern.
GenFam: A web application and database for gene family-based classification and functional enrichment analysis
Authors: Bedre Renesh , Mandadi Kranthi
Published: February 2018

Genome-scale studies using high-throughput sequencing (HTS) technologies generate substantial lists of differentially expressed genes under different experimental conditions. These gene lists need to be further mined to narrow down biologically relevant genes and associated functions in order to guide downstream functional genetic analyses. A popular approach is to determine statistically overrepresented genes in a user-defined list through enrichment analysis tools, which rely on functional annotations of genes based on Gene Ontology (GO) terms. Here, we propose a new approach, GenFam, which allows classification and enrichment of genes based on their gene family, thus simplifying identification of candidate gene families and associated genes that may be relevant to the query. GenFam and its integrated database comprises of three-hundred and eighty-four unique gene families and supports gene family classification and enrichment analyses for sixty plant genomes. Four comparative case studies with plant species belonging to different clades and families were performed using GenFam which demonstrated its robustness and comprehensiveness over preexisting functional enrichment tools. To make it readily accessible for plant biologists, GenFam is available as a web-based application where users can input gene IDs and export enrichment results in both tabular and graphical formats. Users can also customize analysis parameters by choosing from the various statistical enrichment tests and multiple testing correction methods. Additionally, the web-based application, source code and database are freely available to use and download. Website:http://mandadilab.webfactional.com/home/. Source code and database:http://mandadilab.webfactional.com/home/dload/.
Most regulatory interactions are not in linkage disequilibrium
Authors: Whalen Sean , Pollard Katherine S.
Published: February 2018

Linkage disequilibrium (LD) and genomic proximity are commonly used to map non-coding variants to genes, despite increasing examples of causal variants outside the LD block of the gene they regulate. We compared chromatin contacts in 22 cell types to LD across billions of pairs of loci in the human genome and found no concordance, even at genomic distances below 25 kilobases where both tend to be high. Gene expression and ontology data suggest that chromatin contacts identify regulatory variants more reliably than do LD and genomic proximity. We conclude that the genomic architectures of genetic and physical interactions are independent, with important implications for gene regulatory evolution and precision medicine.
α-proteobacterial RNA degradosomes assemble liquid-liquid phase separated RNP bodies
Authors: Al-Husini Nadra , Tomares Dylan T. , Childers W. Seth , Schrader Jared M.
Published: February 2018

Ribonucleoprotein (RNP) granules play an important role in organizing eukaryotic mRNA metabolism via liquid-liquid phase separation (LLPS) of mRNA decay factors into membrane-less “droplet” organelles in the cytoplasm. Here we show that the bacterium Caulobacter crescentus Ribonuclease (RNase) E assembles RNP LLPS droplets that we term bacterial RNP-bodies (BR-bodies) similar to eukaryotic P-bodies and stress granules. RNase E requires RNA to assemble a BR-body, and disassembly requires RNA cleavage, suggesting BR-bodies provide localized sites of RNA degradation. The unstructured C-terminal domain of RNase E is both necessary and sufficient to assemble the core of the BR-body, is functionally conserved in related α-proteobacteria, and influences mRNA degradation. BR-bodies are rapidly induced under cellular stresses and provide enhanced cell growth under stress. To our knowledge, Caulobacter RNase E is the first bacterial protein identified that forms LLPS droplets, providing an effective strategy for subcellular organization in cells lacking membrane bound compartments.
A prize-collecting Steiner tree application for signature selection to stratify diffuse large B-cell lymphoma subtypes
Authors: Akhmedov Murodzhon , Galbusera Luca , Montemanni Roberto , Bertoni Francesco , Kwee Ivo
Published: February 2018

Background:

With the explosion of high-throughput data available in biology, the bottleneck is shifted to effective data interpretation. By taking advantage of the available data, it is possible to identify the biomarkers and signatures to distinguish subtypes of a specific cancer in the context of clinical trials. This requires sophisticated methods to retrieve the information out of the data, and various algorithms have been recently devised.

Results:

Here, we applied the prize-collecting Steiner tree (PCST) approach to obtain a gene expression signature for the classification of diffuse large B-cell lymphoma (DLBCL). The PCST is a network-based approach to capture new insights about genomic data by incorporating an interaction network landscape. Moreover, we adopted the ElasticNet incorporating PCA as a classification method. We used seven public gene expression profiling datasets (three for training, and four for testing) available in the literature, and obtained 10 genes as signature. We tested these genes by employing ElasticNet, and compared the performance with the DAC algorithm as current golden standard. The performance of the PCST signature with ElasticNet outperformed the DAC in distinguishing the subtypes. In addition, the gene expression signature was able to accurately stratify DLBCL patients on survival data.

Conclusions:

We developed a network-based optimization technique that performs unbiased signature selection by integrating genomic data with biological networks. Our classifier trained with the obtained signature outperformed the state-of-the-art method in subtype distinction and survival data stratification in DLBCL. The proposed method is a general approach that can be applied on other classification problems.
MYC Dysregulates Mitotic Spindle Function Creating a Dependency on TPX2
Authors: Rohrberg Julia , Corella Alexandra , Taileb Moufida , Kilinc Seda , Jokisch Marie-Lena , Camarda Roman , Zhou Alicia , Balakrishnan Sanjeev , Chang Aaron N. , Goga Andrei
Published: February 2018

The MYC oncogene promotes tumorigenesis in part by facilitating cell cycle entry thus driving cellular proliferation. Tumors that overexpress MYC frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. While the role of MYC in overcoming the G1/S checkpoint is well established, it remains poorly understood whether MYC induces chromosomal instability (CIN). Here, we identify a direct influence of MYC on mitotic progression. MYC overexpression induces defects in microtubule nucleation and spindle assembly promoting chromosome segregation defects, micronuclei and CIN. We examined which mitotic regulators are required for the survival of MYC-overexpressing cells and found a reliance on high TPX2 expression. TPX2, a master microtubule regulator, is overexpressed together with MYC in multiple cell lines, in mouse tumor models and in aggressive human breast cancers. High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with deregulated MYC, whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Importantly, attenuation of MYC expression reverses the mitotic defects observed, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of a CIN phenotype in tumors. Here, we implicate the MYC oncogene as a regulator of spindle assembly and dynamics and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.