bluuebunny/crossref_metadata_2025 huggingface dataset:
oRNAment: a database of putative RNA binding protein target sites in the transcriptomes of model species
Authors: Benoit Bouvrette Louis Philip , Bovaird Samantha , Blanchette Mathieu , Lécuyer Eric
Published: October 2019

Protein–RNA interactions are essential for controlling most aspects of RNA metabolism, including synthesis, processing, trafficking, stability and degradation. In vitro selection methods, such as RNAcompete and RNA Bind-n-Seq, have defined the consensus target motifs of hundreds of RNA-binding proteins (RBPs). However, readily available information about the distribution features of these motifs across full transcriptomes was hitherto lacking. Here, we introduce oRNAment (o RNA motifs enrichment in transcriptomes), a database that catalogues the putative motif instances of 223 RBPs, encompassing 453 motifs, in a transcriptome-wide fashion. The database covers 525 718 complete coding and non-coding RNA species across the transcriptomes of human and four prominent model organisms: Caenorhabditis elegans, Danio rerio, Drosophila melanogaster and Mus musculus. The unique features of oRNAment include: (i) hosting of the most comprehensive mapping of RBP motif instances to date, with 421 133 612 putative binding sites described across five species; (ii) options for the user to filter the data according to a specific threshold; (iii) a user-friendly interface and efficient back-end allowing the rapid querying of the data through multiple angles (i.e. transcript, RBP, or sequence attributes) and (iv) generation of several interactive data visualization charts describing the results of user queries. oRNAment is freely available at http://rnabiology.ircm.qc.ca/oRNAment/.
Introduction: History and Development of Flow Diverter Technology and Evolution
Authors: Kühn Anna Luisa , Gounis Matthew J , Puri Ajit S
Published: October 2019

The introduction of flow diverter technology to the field of neurointervention has revolutionized the treatment of intracranial aneurysms. The therapy approach has shifted from intrasaccular aneurysm treatment to exclusion of the aneurysm from the blood circulation with remodeling of the parent artery. Previously, “difficult”-to-treat aneurysms including fusiform and blister aneurysms, but also aneurysms arising from a diseased vessel segment, can now be safely and permanently treated with flow diverters.

 A little over a decade ago, after extensive bench testing and refinement of the flow diverter concept, the device was eventually available for clinical use and today it has become a standard treatment for intracranial aneurysms. Currently, United States Food and Drug Administration (FDA)-approved flow diverters are the Pipeline Embolization Device (Medtronic) and the Surpass Streamline Flow Diverter (Stryker).

 The devices can either be delivered or deployed via a standard femoral artery approach or a radial artery approach. Other considerations for catheter setup and device deployment strategies depending on aneurysm location or vessel anatomy are described.
Suzaku observation of diffuse X-ray emission from a southwest region of the Carina Nebula
Authors: Ezoe Yuichiro , Hamaguchi Kenji , Fukushima Aoto , Ogawa Tomohiro , Ohashi Takaya
Published: October 2019

A southwest region of the Carina Nebula was observed with the Suzaku observatory for $47\:$ks in 2010 December. This region shows distinctively soft X-ray emission in the Chandra campaign observations. Suzaku clearly detects the diffuse emission above known foreground and background components between 0.4–$5\:$keV at the surface brightness of $3.3\times 10^{-14}\:$erg$\:$s$^{-1}\:$arcmin$^{-2}$. The spectrum requires two plasma emission components with $kT \sim 0.2$ and $0.5\:$keV, which suffer interstellar absorption of $N_{\,\rm H} \sim 1.9 \times 10^{21}\:$cm$^{-2}$. Multiple absorption models assuming two-temperature plasmas at ionization equilibrium or non-equilibrium are tested but there is no significant difference in terms of $\chi ^{2}/$d.o.f. These plasma temperatures are similar to those of the central and eastern parts of the Carina Nebula measured in earlier Suzaku observations, but the surface brightness of the hot component is significantly lower than those of the other regions. This means that these two plasma components are physically separated and have different origins. The elemental abundances of O, Ne, and Mg with respect to Fe favor that the diffuse plasma originates from core-collapsed supernovae or massive stellar winds.
Conquering Space through Internal Improvements: Federal Nation-Building in Nineteenth-Century America
Authors: Clarke Andrew J , Pears Emily
Published: October 2019

Early American political leaders were tasked with sustaining a representative republic on a seemingly impossible scale. Their struggle to stave off political dissolution raises an important question for scholars of federalism. How can democratic governments integrate disparate political communities across a vast—and rapidly expanding—territory? We revisit the solution most often proposed by contemporary political leaders: a nationally directed system of internal improvements. Using a dataset of nineteenth-century appropriations, we find that patterns in internal improvement funding are consistent with a nation-building strategy. Congressional districts at the fringes of the republic received disproportionate support from the federal government, even after accounting for political preferences, positions of legislative authority, and sub-national spending patterns. Our research stands in contrast to existing work on internal improvements, which is primarily interested in testing theories of distributive politics, and contributes to a diverse body of research on federalism, nation-building, congressional politics, and American political development.
The Return to Protectionism*
Authors: Fajgelbaum Pablo D , Goldberg Pinelopi K , Kennedy Patrick J , Khandelwal Amit K
Published: October 2019

After decades of supporting free trade, in 2018 the United States raised import tariffs and major trade partners retaliated. We analyze the short-run impact of this return to protectionism on the U.S. economy. Import and retaliatory tariffs caused large declines in imports and exports. Prices of imports targeted by tariffs did not fall, implying complete pass-through of tariffs to duty-inclusive prices. The resulting losses to U.S. consumers and firms that buy imports was $51 billion, or 0.27% of GDP. We embed the estimated trade elasticities in a general-equilibrium model of the U.S. economy. After accounting for tariff revenue and gains to domestic producers, the aggregate real income loss was $7.2 billion, or 0.04% of GDP. Import tariffs favored sectors concentrated in politically competitive counties, and the model implies that tradeable-sector workers in heavily Republican counties were the most negatively affected due to the retaliatory tariffs. JEL Code: F1.
Combining Life and Health Insurance*
Authors: Koijen Ralph S J , Van Nieuwerburgh Stijn
Published: October 2019

We estimate the benefit of life-extending medical treatments to life insurance companies. Our main insight is that life insurance companies have a direct benefit from such treatments because they lower the insurer’s liabilities by pushing the death benefit further into the future and raising future premium income. We apply this insight to immunotherapy, treatments associated with durable gains in survival rates for a growing number of cancer patients. We estimate that the life insurance sector’s aggregate benefit from FDA-approved immunotherapies is $9.8 billion a year. Such life-extending treatments are often prohibitively expensive for patients and governments alike. Exploiting this value creation, we explore various ways life insurers could improve stress-free access to treatment. We discuss potential barriers to integration and the long-run implications for the industrial organization of life and health insurance markets, as well as the broader implications for medical innovation and long-term care insurance markets.
Initial Coin Offerings: Financing Growth with Cryptocurrency Token Sales
Authors: Howell Sabrina T , Niessner Marina , Yermack David
Published: October 2019

Initial coin offerings (ICOs) have emerged as a new mechanism for entrepreneurial finance, with parallels to initial public offerings, venture capital, and presale crowdfunding. In a sample of more than 1,500 ICOs that collectively raise ${\$}$12.9 billion, we examine which issuer and ICO characteristics predict successful real outcomes (increasing issuer employment and avoiding enterprise failure). Success is associated with disclosure, credible commitment to the project, and quality signals. An instrumental variables analysis finds that ICO token exchange listing causes higher future employment, indicating that access to token liquidity has important real consequences for the enterprise.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Brain Structural Correlates of Metacognition in First-Episode Psychosis
Authors: Alkan Erkan , Davies Geoff , Greenwood Kathryn , Evans Simon L H
Published: October 2019

Metacognition is impaired in schizophrenia and is an important predictor of functional outcome, but the underlying neuropathology is not clear. Studies have implicated frontal regions and there is also some evidence that the hippocampus might play a pivotal role, but findings are inconsistent. We set out to more comprehensively investigate the neural underpinnings of insight in first-episode psychosis (FEP) using 2 metacognitive measures (the Beck Cognitive Insight Scale [BCIS]) and a perceptual metacognitive accuracy task alongside structural magnetic resonance imaging (MRI). We measured cortical thickness in insula and frontal regions, hippocampal (including subfield) volumes, hippocampal microstructure (using neurite orientation dispersion and density imaging [NODDI]), and fractional anisotropy in fornix. Relative to controls, FEP showed poorer metacognitive accuracy, thinner cortex in frontal regions and lower fornix integrity. In healthy controls (but not FEP), metacognitive accuracy correlated with cortical thickness in frontal cortex and insula. Conversely, in FEP (but not controls), metacognitive accuracy correlated with hippocampal volume and microstructural indices. Subicular hippocampal subregions were particularly implicated. No structural correlates of BCIS were found. These findings suggest that the neural bases of metacognition might differ in FEP: hippocampal (rather than frontal) integrity seems to be critical. Further, the use of objectively measured metacognitive indices seems to be a more powerful method for understanding the neurocircuitry of metacognition in FEP, which has the potential to inform therapeutic strategies and improve outcome in these patients.
Tackling MARCKS‐PIP3 circuit attenuates fibroblast activation and fibrosis progression
Authors: Yang David C. , Li Ji‐Min , Xu Jihao , Oldham Justin , Phan Sem H. , Last Jerold A. , Wu Reen , Chen Ching‐Hsien
Published: October 2019

Targeting activated fibroblasts, including myofibroblast differentiation, has emerged as a key therapeutic strategy in patients with idiopathic pulmonary fibrosis (IPF). However, there is no available therapy capable of selectively eradicating myofibroblasts or limiting their genesis. Through an integrative analysis of the regulator genes that are responsible for the activation of IPF fibroblasts, we noticed the phosphatidylinositol 4,5‐bisphosphate (PIP2)‐binding protein, myristoylated alanine‐rich C‐kinase substrate (MARCKS), as a potential target molecule for IPF. Herein, we have employed a 25‐mer novel peptide, MARCKS phosphorylation site domain sequence (MPS), to determine if MARCKS inhibition reduces pulmonary fibrosis through the inactivation of PI3K/protein kinase B (AKT) signaling in fibroblast cells. We first observed that higher levels of MARCKS phosphorylation and the myofibroblast marker α‐smooth muscle actin (α‐SMA) were notably overexpressed in all tested IPF lung tissues and fibroblast cells. Treatment with the MPS peptide suppressed levels of MARCKS phosphorylation in primary IPF fibroblasts. A kinetic assay confirmed that this peptide binds to phospholipids, particularly PIP2, with a dissociation constant of 17.64 nM. As expected, a decrease of phosphatidylinositol (3,4,5)‐trisphosphate pools and AKT activity occurred in MPS‐treated IPF fibroblast cells. MPS peptide was demonstrated to impair cell proliferation, invasion, and migration in multiple IPF fibroblast cells in vitro as well as to reduce pulmonary fibrosis in bleomycin‐treated mice in vivo. Surprisingly, we found that MPS peptide decreases α‐SMA expression and synergistically interacts with nintedanib treatment in IPF fibroblasts. Our data suggest MARCKS as a druggable target in pulmonary fibrosis and also provide a promising antifibrotic agent that may lead to effective IPF treatments.—Yang, D. C., Li, J.‐M., Xu, J., Oldham, J., Phan, S. H., Last, J. A., Wu, R., Chen, C.‐H. Tackling MARCKS‐PIP3 circuit attenuates fibroblast activation and fibrosis progression. FASEB J. 33, 14354‐14369 (2019). www.fasebj.org
Lithium targeting of AMPK protects against cisplatin‐induced acute kidney injury by enhancing autophagy in renal proximal tubular epithelial cells
Authors: Bao Hui , Zhang Qianyun , Liu Xinying , Song Yaxiang , Li Xinhua , Wang Zhen , Li Changbin , Peng Ai , Gong Rujun
Published: October 2019

Autophagy has been demonstrated to be vital for kidney homeostasis and is centrally implicated in the pathogenesis of cisplatin‐induced acute kidney injury (AKI). Lithium is a potent autophagy inducer in a number of cell types. However, it remains uncertain whether its autophagic activity is associated with a beneficial effect on renal tubular cells in AKI. This study aimed to examine the effect of lithium on renal autophagy in cisplatin‐induced AKI. Mice or renal proximal tubular epithelial cells in culture were exposed to cisplatin‐induced acute injury in the presence or absence of lithium treatment. AKI or tubular cell injury was evaluated, and cell signaling associated with autophagy was examined. Lithium pretreatment prominently ameliorated acute renal tubular damage in mice exposed to cisplatin insult, associated with enhanced autophagy in renal tubules, as assessed by measuring microtubule‐associated protein 1A/1B‐light chain 3 (LC3) BII/I expression and autophagosome formation. Consistently, in cisplatin‐injured renal tubular cells in vitro, lithium enhanced autophagic activities, improved cell viability, and attenuated cell death. Mechanistically, lithium triggered AMPK‐α phosphorylation and activation, which in turn positively correlated with the induced expression of autophagy‐related molecules, like mammalian target of rapamycin and LC3BII/I. AMPK‐α activation is likely required for lithium‐induced tubular cell autophagy and protection in cisplatin‐induced AKI because blockade of AMPK‐α phosphorylation by compound C markedly abrogated lithium‐induced autophagosome formation and mitigated the protective effect of lithium on AKI. Our findings suggest that lithium represents a promising therapeutic strategy for protecting renal tubular cells against cisplatin‐induced AKI by enhancing autophagy via AMPK‐α activation.—Bao, H., Zhang, Q., Liu, X., Song, Y., Li, X., Wang, Z., Li, C., Peng, A., Gong, R. Lithium targeting of AMPK protects against cisplatin‐induced acute kidney injury by enhancing autophagy in renal proximal tubular epithelial cells. FASEB J. 33, 14370‐14381 (2019). www.fasebj.org
Time trends in socio-economic inequalities in HIV testing: insights from population-based surveys in 16 sub-Saharan African countries
Authors: Ante-Testard Pearl Anne , Benmarhnia Tarik , Bekelynck Anne , Baggaley Rachel , Ouattara Eric , Temime Laura , Jean Kévin
Published: October 2019

Background

Overall increase in the uptake of HIV testing in the past decades may hide discrepancies across socio-economic groups. We used population-based surveys conducted in sub-Saharan Africa to quantify socio-economic inequalities in recent HIV testing uptake, together with their trends over the two past decades.

Methods

We analyzed the data from Demographic and Health Surveys in sub-Saharan African countries where at least one survey was conducted before and after 2008. Country- and gender-specific proportions of recent (<12 month) HIV testing were assessed across wealth and education groups, and inequalities were quantified using the relative and slope indices of inequalities. Time trends in inequalities were assessed and results were pooled across countries using random-effect meta-analyses.

Findings

We analyzed data from 32 surveys conducted between 2003 and 2016 in 16 countries among 537,784 participants. In pre-2008 surveys, women reported higher HIV testing uptake than men in 8 out of 16 countries, and in 15 out of 16 countries in post-2008 surveys. After 2008, the wealthiest women were on average 2.77 (95% CI 1.42-5.40) times more likely to report recent testing than the poorest; and 3.55 (1.85-6.81) times in men. The averaged absolute difference in recent testing between the richest and poorest was 11.1 (4.6-17.5) percentage points in women and 15.1 (9.6-20.6) in men. Over time, relative inequalities in recent HIV testing decreased in both genders, while absolute inequalities plateaued in women and increased in men.

Interpretations

The overall increase in HIV testing uptake that was stimulated by the impetus to scale up HIV treatment in sub-Saharan Africa led to a decrease in relative inequalities, while absolute inequalities persisted. Within most countries, large inequalities still remained, both in absolute and relative scales, especially in West and Central Africa. A greater focus should be put on equity in monitoring HIV testing programs.

A French version of this article is available in the Appendices [Une version française de cet article est disponible en appendice].

Funding

INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), grant number ANRS-12377.
Short-term mental health sequelae of bereavement predict long-term physical health decline in older adults: US Health and Retirement Study Analysis
Authors: Domingue Benjamin W. , Duncan Laramie , Harrati Amal , Belsky Daniel W.
Published: October 2019

Objective

Death of a spouse is a common late-life event with mental- and physical-health sequelae. Whereas mental-health sequelae of spousal death tend to be transient, physical-health sequelae may persist, leading to disability and mortality. Growing evidence linking poor mental health to aging-related disease suggests the hypothesis that transient poor mental health following death of a spouse could be a harbinger of physical health decline. If so, identification of bereavement-related mental health symptoms could provide an opportunity for prevention.

Methods

We analyzed data from N=35,103 individuals followed from 1994-2014 in the US Health and Retirement Study (HRS) and identified N=4,629 who were widowed during follow-up. We tested change in mental and physical health from pre-bereavement through the 5-year period following spousal death.

Results

Bereaved spouses experienced an immediate increase in depressive symptoms following their spouses’ deaths but the depressive shock attenuated within one year. Bereaved spouses also experienced increases in disability, chronic-disease morbidity, and hospitalization, which grew in magnitude with time since spousal death, especially among older HRS participants. Bereaved spouses were at increased risk of death compared to HRS participants who were not bereaved. The magnitude of depressive symptoms in the immediate aftermath of spousal death predicted physical-health decline and mortality risk over 5 years of follow-up.

Conclusions

Bereavement-related depressive symptoms provide an indicator of risk for physical health decline and death in older adults. Screening for depressive symptoms in bereaved older adults may represent an opportunity for intervention to preserve healthy lifespan.

Plain Language Summary

The clinical significance of depressive symptoms during bereavement for long-term health is not well understood. We analyzed longitudinal data tracking mental and physical health of more than 4,000 older adults who were widowed during follow-up. Widows and widowers who experienced more severe depressive symptoms immediately following their spouse’s death were at increased risk for incident disability, chronic disease, hospitalization, and mortality over the five years following their spouse’s death. Transient depressive symptoms related to bereavement may provide a clinical indicator of risk for long-term physical health decline in older adults. Findings motivate increased integration of psychiatric assessment in geriatric care.
Awareness and knowledge of interventional radiology among medical students at an Indian institution
Authors: Agrawal Deepsha , Renfrew Michael Alan , Singhal Sulove , Bhansali Yash
Published: October 2019

Purpose

Interventional radiology (IR) is a novel and evolving sub-specialty that encompasses image guided diagnostic and therapeutic procedures. With the advent of new imaging techniques and an increasing demand of minimally invasive procedures IR continues to grow as a core component in medical and surgical therapeutics. Radiology teaching is a part of medical undergraduate curriculum, however, the medical undergraduate cohort lacks exposure to IR principles, methods and techniques.

The purpose of this study is to determine the knowledge and awareness of IR among medical students in a single university in India.

Materials and Methods

Anonymous electronic surveys were sent to 350 medical students of Pt. JNM Medical College, Raipur, India. Each survey comprised of questions assessing knowledge and exposure to IR. A total of 70 students (20%) responded.

Results

85.7% of respondents believed that radiologists have a role in diagnostic as well as therapeutic interventions, however, 60% of students cited a very poor/poor knowledge of IR. A larger part, 91.5%, stated that they would be interested in IR based teaching delivered as a part of their undergraduate teaching program. Those who knew at least one interventional radiology technique were 1.51 (95% CI: 1.02 - 2.22; p < 0.05) times more likely to consider it as a career.

Conclusion

Medical Students demonstrate a poor knowledge of IR. This corresponds to a limited and inconsistent exposure to IR in medical schools. The study suggests that there is a need to deliver an IR based curriculum in medical undergraduate teaching in India.
The Impact of Scaling up Dolutegravir on Antiretroviral Resistance in South Africa
Authors: Hauser Anthony , Kusejko Katharina , Johnson Leigh F. , Günthard Huldrych F. , Riou Julien , Wandeler Gilles , Egger Matthias , Kouyos Roger D.
Published: October 2019

Background

Rising resistance of HIV-1 to non-nucleoside reverse transcriptase inhibitors (NNRTIs) threatens the success of the global scale-up of antiretroviral therapy (ART). The switch to WHO-recommended dolutegravir (DTG)-based regimens could reduce this threat due to DTG’s high genetic barrier to resistance. We used mathematical modelling to examine the impact of the scale-up of DTG-based ART on NNRTI pre-treatment drug resistance (PDR) in South Africa, 2019-2040.

Methods and results

We adapted the MARISA (Modelling Antiretroviral drug Resistance In South Africa) model, an epidemiological model of the transmission of NNRTI resistance in South Africa. We modelled the introduction of DTG in 2019 under two scenarios: DTG as first-line regimen for ART-initiators, or DTG for all patients, including patients on suppressive NNRTI-based ART. Due to safety concerns related to DTG during pregnancy, we assessed the impact of prescribing DTG to all men and in addition to i) women beyond reproductive age, ii) women beyond reproductive age or using contraception, and iii) all women. The model projections show that, compared to the continuation of NNRTI-based ART, introducing DTG would lead to a reduction in NNRTI resistance in all scenarios if both ART initiators are started on a DTG-based regimens and those on NNRTI-based regimens are rapidly switched to DTG. NNRTI resistance would continue to increase if DTG-based ART was restricted to men. When given to all men and women, DTG-based ART could reduce the level of NNRTI resistance from 58.5% (without DTG) to 14.8% (with universal DTG) in 2040. If all men and women beyond reproductive age or on contraception are started on or switched to DTG-based ART, NNRTI resistance would reach 35.1% in 2040.

Conclusions

Our model shows the potential benefit of scaling up DTG-based regimens for halting the rise of NNRTI resistance. Starting or switching all men and women to DTG would lead to a sustained decline in resistance levels whereas using DTG-based ART in all men, or in men and women beyond childbearing age, would slow down the increase in levels of NNRTI resistance.
Cohort profile: The International epidemiology Databases to Evaluate AIDS (IeDEA) in sub-Saharan Africa, 2012-2019
Authors: Chammartin Frédérique , Dao Ostinelli Cam Ha , Anastos Kathryn , Jaquet Antoine , Brazier Ellen , Brown Steven , Dabis François , Davies Mary-Ann , Duda Stephany N , Malateste Karen , Nash Denis , Wools-Kaloustian Kara K , von Groote Per M , Egger Matthias
Published: October 2019

Purpose

The objectives of the International epidemiology Databases to Evaluate AIDS (IeDEA) are to (i) evaluate the delivery of combination antiretroviral therapy (ART) in children, adolescents and adults in sub-Saharan Africa, (ii) to describe ART regimen effectiveness, durability and tolerability, (iii) to examine HIV-related comorbidities and co-infections, and (iv) to examine the pregnancy- and HIV-related outcomes of women on ART and their infants exposed to HIV or antiretroviral therapy in utero or via breastmilk.

Participants

IeDEA is organized in four regions (Central, East, Southern and West Africa), with 240 treatment and care sites, six data centres at African, European and US universities, and almost 1.4 million children, adolescents and adult people living with HIV (PLWHIV) enrolled.

Findings to date

The data include socio-demographic characteristics, clinical outcomes, opportunistic events, treatment regimens, clinic visits and laboratory measurements. They have been used to analyse outcomes in people living with HIV-1 or HIV-2 who initiate ART, including determinants of mortality, of switching to second-line and third-line ART, drug resistance, loss to follow-up and the immunological and virological response to different ART regimens. Programme-level estimates of mortality have been corrected for loss to follow-up. We examined the impact of co-infection with hepatitis B and C, and the epidemiology of different cancers and of (multi-drug resistant) tuberculosis, renal disease and of mental illness. The adoption of “Treat All”, making ART available to all PLWHIV regardless of CD4+ cell count or clinical stage was another important research topic.

Future plans

IeDEA has formulated several research priorities for the “Treat All” era in sub-Saharan Africa. It recently obtained funding to set up sentinel sites where additional data are prospectively collected on cardiometabolic risks factors as well as mental health and liver diseases, and is planning to create a drug resistance database.
The Pan-Cancer Landscape of Prognostic Germline Variants in 10,582 Patients
Authors: Chatrath Ajay , Przanowska Roza , Kiran Shashi , Su Zhangli , Saha Shekhar , Wilson Briana , Tsunematsu Takaaki , Ahn Ji-Hye , Lee Kyung Yong , Paulsen Teressa , Sobierajska Ewelina , Kiran Manjari , Tang Xiwei , Li Tianxi , Kumar Pankaj , Ratan Aakrosh , Dutta Anindya
Published: October 2019

While clinical data provides physicians with information about patient prognosis, genomic data can further improve these predictions. We analyzed sequencing data from over 10,000 cancer patients and identified hundreds of prognostic germline variants using multivariate Cox regression models. These variants provide information about patient outcomes beyond clinical information currently in use and may augment clinical decisions based on expected tumor aggressiveness. Molecularly, at least twelve of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences. About half of these germline variants are in previously reported tumor suppressors or oncogenes, with the other half pointing to loci of previously unstudied genes in the literature that should be further investigated for roles in cancers. Our results suggest that germline variation contributes to tumor progression across most cancers and contains patient outcome information not captured by clinical factors.
Defective Nucleotide Catabolism Defines a Subset of Cancers Sensitive to Purine Nucleoside Phosphorylase Inhibition
Authors: Abt Evan R. , Lok Vincent , Le Thuc M. , Poddar Soumya , Kim Woosuk , Capri Joseph R. , Abril-Rodriguez Gabriel , Czernin Johannes , Donahue Timothy R. , Mehrling Thomas , Ribas Antoni , Radu Caius G.
Published: October 2019

Small molecule inhibitors of purine nucleoside phosphorylase (PNP) have been explored as a treatment strategy for leukemia and lymphoma, however, the determinants of response to this class of drugs are incompletely understood. PNP inhibitors impair cell proliferation by preventing catabolism of the nucleoside deoxyguanosine (dG) which induces toxic imbalances amongst intracellular deoxyribonucleotide triphosphate (dNTP) pools following its phosphorylation and trapping by nucleoside kinases. We hypothesized that differential nucleoside uptake or catabolism defines cancer cell lines as either sensitive or resistant to PNP inhibition. Among cancer cell lines we found that T-cell acute lymphoblastic leukemia (T-ALL) cells are uniquely and acutely sensitive to PNP inhibition whereas the B-cell leukemia and solid tumor models are completely resistant. We determined that although the nucleoside scavenging kinase deoxycytidine kinase (dCK) was active in all cells tested, PNP inhibitors only induced dGTP pool increases in sensitive models. By evaluating the expression of key genes involved in nucleotide scavenging, biosynthesis, and phosphohydrolysis in a panel of sensitive and resistant cell lines we found that the dNTP phosphohydrolase SAM histidine aspartate containing protein 1 (SAMHD1) was exclusively expressed in resistant models. Using CRISPR/Cas9 SAMHD1 knockout cell lines, we verified that PNP inhibitor sensitivity is a function of SAMHD1 expression and determined that the pharmacological inhibition of dCK or genetic restoration of SAMHD1 conferred resistance to PNP inhibition. Importantly, we determined that low expression of SAMHD1 is not limited to T-ALL as subset of established and primary solid tumors models are SAMHD1-deficient. These solid tumor models were consistently acutely sensitive to PNP inhibitors which indicates that the utility of PNP inhibitors extends beyond hematological malignancies. Additionally, we found that deoxycytidine (dC) can limit the anti-proliferative effects of PNP inhibitors by competing with dG for phosphorylation by dCK but this effect can be overcome by expression of dC-catabolizing gene cytidine deaminase (CDA). Collectively, these results indicate that SAMHD1, dCK and CDA are critical biomarkers that must be used to stratify patients in clinical trials evaluating pharmacological PNP inhibition.
Representation of Visual Landmarks in Retrosplenial Cortex
Authors: Fischer Lukas F. , Soto-Albors Raul Mojica , Buck Friederike , Harnett Mark T.
Published: October 2019

The process by which visual information is incorporated into the brain’s spatial framework to represent landmarks is poorly understood. Studies in humans and rodents suggest that retrosplenial cortex (RSC) plays a key role in these computations. We developed an RSC-dependent behavioral task in which head-fixed mice learned the spatial relationship between visual landmark cues and hidden reward locations. Two-photon imaging revealed that these cues served as dominant reference points for most task-active neurons and anchored the spatial code in RSC. Presenting the same environment but decoupled from mouse behavior degraded encoding fidelity. Analyzing visual and motor responses showed that landmark codes were the result of supralinear integration. Surprisingly, V1 axons recorded in RSC showed similar receptive fields. However, they were less modulated by task engagement, indicating that landmark representations in RSC are the result of local computations. Our data provide cellular- and network-level insight into how RSC represents landmarks.
N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae
Authors: Croft Trevor , Venkatakrishnan Padmaja , James Theoga Raj Christol , Groth Benjamin , Cater Timothy , Lin Su-Ju
Published: October 2019

NAD+is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+biosynthesis pathways are not completely understood. We previously identified the N-terminal (Nt) protein acetyltransferase complex NatB as a NAD+homeostasis factor. Cells lacking NatB show an approximate 50% reduction in the NAD+level and aberrant metabolism of NAD+precursors, which are associated with a decrease of nicotinamide mononucleotide adenylyltransferases (Nmnat) protein levels. Here we show this decrease in NAD+and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins, and not other NatB substrates. Nt-acetylation is a critical regulator of protein degradation by the N-end rule pathways, indicating absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t1/2) of non-Nt-acetylated Nmnats does not significantly differ from Nt-acetylated Nmnats, suggesting reduced Nmnat levels in NmatB mutants are not due to increased post-translational degradation of non-Nt-acetylated Nmnats. In line with these observations, deletion or depletion of N-rule pathway ubiquitin E3 ligases in NatB mutants is not sufficient to restore NAD+levels. Moreover, the status of Nt-acetylation does not alter the rate of translation initiation of Nmnats. Collectively our studies suggest absence of Nt-acetylation may increase co-translational degradation of nascent Nmnat polypeptides, which results in reduced Nmnat levels in NatB mutants. Nmnat activities are essential for all routes of NAD+biosynthesis. Understanding the regulation of Nmnat protein homeostasis will facilitate our understanding of the molecular basis and regulation of NAD+metabolism.
Novel regulation from novel interactions: Identification of an RNA sponge that controls the levels, processing and efficacy of the RoxS riboregulator of central metabolism inBacillus subtilis
Authors: Durand Sylvain , Callan-Sidat Adam , McKeown Josie , Li Stephen , Kostova Gergana , Hernandez-Fernaud Juan R. , Alam Mohammad Tauqeer , Millard Andrew , Constantinidou Chrystala , Condon Ciarán , Denham Emma L.
Published: October 2019

Small RNAs (sRNAs) are a taxonomically-restricted but transcriptomically-abundant class of post-transcriptional regulators. While potentially of importance, we know the function of few. This is in no small part because we lack global-scale methodology enabling target identification, this being especially acute in species without known RNA meeting point proteins (e.g. Hfq). We apply a combination of psoralen RNA cross-linking and Illumina-sequencing to identify RNA-RNA interacting pairsin vivoinBacillus subtilis, resolving previously well-described interactants. Although sRNA-sRNA pairings are rare (compared with sRNA/mRNA), we identify a robust example involving the unusually conserved sRNA (RoxS/RsaE) and an unstudied sRNA that we term Regulator of small RNA A (RosA). This interaction is found in independent samples across multiple conditions. Given the possibility of a novel associated regulatory mechanism, and the rarity of well-characterised bacterial sRNA-sRNA interactions, we mechanistically dissect RosA and its interactants. RosA we show to be a sponge RNA, the first to be described in a Gram-positive bacterium. RosA interacts with at least two sRNAs, RoxS and FsrA. Unexpectedly, it acts differently on each. As expected of a sponge RNA, FsrA is sequestered by RosA. The RosA/RoxS interaction is more complex affecting not only the level of RoxS but also its processing and efficacy. Importantly, RosA provides the condition-dependent intermediary between CcpA, the key regulator of carbon metabolism, and RoxS. This not only provides evidence for a novel, and functionally important, regulatory mechanism, but in addition, provides the missing link between transcriptional and post-transcriptional regulation of central metabolism.
Timing matters: The temporal representation of experience in subjective mood reports
Authors: Keren Hanna , Zheng Charles , Jangraw David C. , Chang Katharine , Vitale Aria , Nielson Dylan , Rutledge Robb B. , Pereira Francisco , Stringaris Argyris
Published: October 2019

Humans refer to their own mood state regularly in day-to-day as well as in clinical interactions. Theoretical accounts suggest that when reporting on our mood we integrate over the history of our experiences; yet, the temporal structure of this integration remains unexamined. Here we use a computational approach to quantitatively answer this question and show that early events exert a stronger influence on the reported mood compared to recent events. We show that a Primacy model accounts better for mood reports compared to a range of alternative temporal representations, and replicate this result across random, consistent or dynamic structures of reward environments, age groups and both healthy and depressed participants. Moreover, we find evidence for neural encoding of the Primacy, but not the Recency, model in frontal brain regions related to mood regulation. These findings hold implications for the timing of events in experimental or clinical settings and suggest new directions for individualized mood interventions.

Significance

How we rate our own mood at any given moment is shaped by our experiences; but are the most recent experiences the most influential, as assumed by current theories? Using several sources of experimental data and mathematical modeling, we show that earlier experiences within a context are more influential than recent events, and replicate this finding across task environments, age groups, and in healthy and depressed participants. Additionally, we present neural evidence supporting this primacy model. Our findings show that delineating a temporal structure is crucial in modeling mood and this has key implications for its measurement and definition in both clinical and everyday settings.
Pre- and post-target cortical processes predict speech-in-noise performance
Authors: Kim Subong , Schwalje Adam T. , Liu Andrew S. , Gander Phillip E. , McMurray Bob , Griffiths Timothy D. , Choi Inyong
Published: October 2019

Understanding speech in noise (SiN) is a complex task that recruits multiple cortical subsystems. There is a variance in individuals’ ability to understand SiN that cannot be explained by simple hearing profiles, which suggests that central factors may underlie the variance in SiN ability. Here, we elucidated a few cortical functions involved during a SiN task and their contributions to individual variance using both within- and across-subject approaches. Through our within-subject analysis of source-localized electroencephalography, we investigated how acoustic signal-to-noise ratio (SNR) alters cortical evoked responses to a target word across the speech recognition areas, finding stronger responses in left supramarginal gyrus (SMG, BA40 thedorsal lexiconarea) with quieter noise. Through an individual differences approach, we found that listeners show different neural sensitivity to the background noise and target speech, reflected in the amplitude ratio of earlier auditory-cortical responses to speech and noise, named as aninternal SNR. Listeners with betterinternal SNRshowed better SiN performance. Further, we found that the post-speech time SMG activity explains a further amount of variance in SiN performance that is not accounted for byinternal SNR. This result demonstrates that at least two cortical processes contribute to SiN performance independently: pre-target time processing to attenuate neural representation of background noise and post-target time processing to extract information from speech sounds.
Transcriptomic responses associated with carbon and energy flows under high salinity stress suggest the overflow of acetyl-CoA from glycolysis and NADPH co-factor induces high lipid accumulation and halotolerance inChlorellasp. HS2
Authors: Yun Jin-Ho , Pierrelée Michaël , Cho Dae-Hyun , Kim Urim , Heo Jina , Choi Dong-Yun , Lee Yong Jae , Lee Bongsoo , Kim HyeRan , Habermann Bianca , Chang Yong Keun , Kim Hee-Sik
Published: October 2019

Previously, we isolatedChlorellasp. HS2 (referred hereupon HS2) from a local tidal rock pool and demonstrated its halotolerance and relatively high biomass productivity under different salinity conditions. To further understand acclimation responses of this alga against high salinity stress, we performed transcriptome analysis of triplicated culture samples grown in freshwater and marine conditions at both exponential and stationary growth phases.De novoassembly followed by differential expression analysis identified 5907 and 6783 differentially expressed genes (DEGs) respectively at exponential and stationary phases from a total of 52770 transcripts, and the functional enrichment of DEGs with KEGG database resulted in 1445 KEGG Orthology (KO) groups with a defined differential expression. Specifically, the transcripts involved in photosynthesis, TCA and Calvin cycles were downregulated, whereas the upregulation of DNA repair mechanisms and an ABCB subfamily of eukaryotic type ABC transporter was observed at high salinity condition. In addition, while key enzymes associated with glycolysis pathway and triacylglycerol (TAG) synthesis were determined to be upregulated from early growth phase, salinity stress seemed to reduce the carbohydrate content of harvested biomass from 45.6 dw% to 14.7 dw% and nearly triple the total lipid content from 26.0 dw% to 62.0 dw%. These results suggest that the reallocation of storage carbon toward lipids played a significant role in conferring the viability of this alga under high salinity stress, most notably by remediating high level of cellular stress partially caused by ROS generated in oxygen-evolving thylakoids.

Summary Statement

Redirection of storage carbon towards the synthesis of lipids played a critical role in conferring the halotolerance of aChlorellaisolate by remediating excess oxidative stress experienced in photosystems.
Multi-region exome sequencing of ovarian teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components
Authors: Heskett Michael B. , Sanborn John Z. , Boniface Christopher , Goode Benjamin , Chapman Jocelyn , Garg Karuna , Rabban Joseph T. , Zaloudek Charles , Benz Stephen C. , Spellman Paul T. , Solomon David A. , Cho Raymond J.
Published: October 2019

Immature teratoma is a subtype of malignant germ cell tumor of the ovary that occurs most commonly in the first three decades of life, frequently with bilateral ovarian disease. Despite being the second most common malignant germ cell tumor of the ovary, little is known about its genetic underpinnings. Here we performed multi-region whole exome sequencing to interrogate the genetic zygosity, clonal relationship, DNA copy number, and mutational status of 52 pathologically distinct tumor components from 10 females with ovarian immature teratomas, with bilateral tumors present in 5 cases and peritoneal dissemination in 7 cases. We found that ovarian immature teratomas are genetically characterized by 2N near-diploid genomes with extensive loss of heterozygosity and an absence of genes harboring recurrent somatic mutations or known oncogenic variants. All components within a single ovarian tumor (immature teratoma, mature teratoma with different histologic patterns of differentiation, and yolk sac tumor) were found to harbor an identical pattern of loss of heterozygosity across the genome, indicating a shared clonal origin. In contrast, the 4 analyzed bilateral teratomas showed distinct patterns of zygosity changes in the right versus left sided tumors, indicating independent clonal origins. All disseminated teratoma components within the peritoneum (including gliomatosis peritonei) shared a clonal pattern of loss of heterozygosity with either the right or left primary ovarian tumor. The observed genomic loss of heterozygosity patterns indicate that diverse meiotic errors contribute to the formation of ovarian immature teratomas, with 11 out of the 15 genetically distinct clones determined to result from the failure of meiosis I or II. Overall, these findings suggest that copy-neutral loss of heterozygosity resulting from meiotic abnormalities may be sufficient to generate ovarian immature teratomas from germ cells.
Disruption of Redox Balance Enhances the Effects of BRAF-inhibition in Melanoma Cells
Authors: Paudel B. Bishal , Lewis Joshua E. , Hardeman Keisha N. , Hayford Corey E. , Robbins Charles J. , Codreanu Simona G. , Sherrod Stacy D. , McLean John A. , Kemp Melissa L. , Quaranta Vito
Published: October 2019

Melanomas harboringBRAFmutations can be treated with BRAF inhibitors (BRAFi), but responses are varied and tumor recurrence is inevitable. Here, using an integrative approach of experimentation and mathematical flux balance analyses inBRAF-mutated melanoma cells, we report that elevated antioxidant capacity is linked to BRAFi sensitivity in melanoma cells. High levels of antioxidant metabolites in cells with reduced BRAFi sensitivity confirm this conclusion. By extending our analyses to other melanoma subtypes in TCGA, we predict that elevated redox capacity is a general feature of melanomas, not previously observed. We propose that redox vulnerabilities could be exploited for therapeutic benefits and identify unsuspected combination targets to enhance the effects of BRAFi in any melanoma, regardless of mutational status.