bluuebunny/crossref_metadata_2025 huggingface dataset:
g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update)
Authors: Raudvere Uku , Kolberg Liis , Kuzmin Ivan , Arak Tambet , Adler Priit , Peterson Hedi , Vilo Jaak
Published: April 2019

Biological data analysis often deals with lists of genes arising from various studies. The g:Profiler toolset is widely used for finding biological categories enriched in gene lists, conversions between gene identifiers and mappings to their orthologs. The mission of g:Profiler is to provide a reliable service based on up-to-date high quality data in a convenient manner across many evidence types, identifier spaces and organisms. g:Profiler relies on Ensembl as a primary data source and follows their quarterly release cycle while updating the other data sources simultaneously. The current update provides a better user experience due to a modern responsive web interface, standardised API and libraries. The results are delivered through an interactive and configurable web design. Results can be downloaded as publication ready visualisations or delimited text files. In the current update we have extended the support to 467 species and strains, including vertebrates, plants, fungi, insects and parasites. By supporting user uploaded custom GMT files, g:Profiler is now capable of analysing data from any organism. All past releases are maintained for reproducibility and transparency. The 2019 update introduces an extensive technical rewrite making the services faster and more flexible. g:Profiler is freely available at https://biit.cs.ut.ee/gprofiler.
Rapid functional activation of a horizontally transferred eukaryotic gene in a bacterial genome in the absence of selection
Authors: Li Zhichao , Bock Ralph
Published: April 2019

Horizontal gene transfer has occurred between organisms of all domains of life and contributed substantially to genome evolution in both prokaryotes and eukaryotes. Phylogenetic evidence suggests that eukaryotic genes horizontally transferred to bacteria provided useful new gene functions that improved metabolic plasticity and facilitated adaptation to new environments. How these eukaryotic genes evolved into functional bacterial genes is not known. Here, we have conducted a genetic screen to identify the mechanisms involved in functional activation of a eukaryotic gene after its transfer into a bacterial genome. We integrated a eukaryotic selectable marker gene cassette driven by expression elements from the red alga Porphyridium purpureum into the genome of Escherichia coli. Following growth under non-selective conditions, gene activation events were indentified by antibiotic selection. We show that gene activation in the bacterial recipient occurs at high frequency and involves two major types of spontaneous mutations: deletion and gene amplification. We further show that both mechanisms result in promoter capture and are frequently triggered by microhomology-mediated recombination. Our data suggest that horizontally transferred genes have a high probability of acquiring functionality, resulting in their maintenance if they confer a selective advantage.
“Public Health, Public Goods, and Market Failure”
Authors: Horne L Chad
Published: April 2019

This discussion revises and extends Jonny Anomaly's ‘public goods’ account of public health ethics in light of recent criticism from Richard Dees. Public goods are goods that are both non-rival and non-excludable. What is significant about such goods is that they are not always provided efficiently by the market. Indeed, the state can sometimes realize efficiency gains either by supplying such goods directly or by compelling private purchase. But public goods are not the only goods that the market may fail to provide efficiently. This point to a way of broadening the public goods account of public health to accommodate Dees' counterexamples, without abandoning its distinctive appeal. On the market failures approach to public health ethics, the role of public health is to correct public health-related market failures of all kinds, so far as possible. The underlying moral commitment is to economic efficiency in the sense of Pareto: if we can re-allocate resources in the economy so as to raise the welfare of some without lowering the welfare of any other, we ought to do so.
Give People a Break: Slips and Moral Responsibility
Authors: Rudy-Hiller Fernando
Published: April 2019

I examine the question of whether people are sometimes morally blameworthy for what I call ‘slips’: wrongful actions or omissions that a good-willed (or at least no ill-willed) agent inadvertently performs due to a non-negligent failure to be aware of relevant considerations. I focus in particular on the capacitarian answer to this question, according to which possession of the requisite capacities to be aware of relevant considerations and respond appropriately explains blameworthiness for slips. I argue, however, that capacitarianism fails to show that agents have responsibility level control over their slips and, consequently, fails to show that it is reasonable to expect agents to avoid this kind of wrongdoing. I conclude that people are typically not blameworthy for their slips, but only regarding the backward-looking, desert-entailing type of blame that has been at issue in this debate. I suggest that ordinary intuitions about blameworthiness for slips can be accommodated by appealing to other types of responsibility and blame.
Take-Up and Targeting: Experimental Evidence from SNAP
Authors: Finkelstein Amy , Notowidigdo Matthew J
Published: April 2019

We develop a framework for welfare analysis of interventions designed to increase take-up of social safety net programs in the presence of potential behavioral biases. We calibrate the key parameters using a randomized field experiment in which 30,000 elderly individuals not enrolled in—but likely eligible for—the Supplemental Nutrition Assistance Program (SNAP) are either provided with information that they are likely eligible, provided with this information and offered assistance in applying, or are in a “status quo” control group. Only 6% of the control group enrolls in SNAP over the next nine months, compared to 11% of the Information Only group and 18% of the Information Plus Assistance group. The individuals who apply or enroll in response to either intervention have higher net income and are less sick than the average enrollee in the control group. We present evidence consistent with the existence of optimization frictions that are greater for needier individuals, which suggests that the poor targeting properties of the interventions reduce their welfare benefits.
ChiIV3 Acts as a Novel Target of WRKY40 to Mediate Pepper Immunity Against Ralstonia solanacearum Infection
Authors: Liu Zhiqin , Shi Lanping , Weng Yahong , Zou Huasong , Li Xia , Yang Sheng , Qiu Shanshan , Huang Xueying , Huang Jinfeng , Hussain Ansar , Zhang Kan , Guan Deyi , He Shuilin
Published: April 2019

ChiIV3, a chitinase of pepper (Capsicum annuum), stimulates cell death in pepper plants. However, there are only scarce reports on its role in resistance against bacterial wilt disease such as that caused by Ralstonia solanacearum and their transcriptional regulation. In this study, the silencing of ChiIV3 in pepper plants significantly reduced the resistance to R. solanacearum. The transcript of ChiIV3 was induced by R. solanacearum inoculation (RSI) as well as exogenous application of methyl jasmonate and abscisic acid. The bioinformatics analysis revealed that the ChiIV3 promoter consists of multiple stress-related cis elements, including six W-boxes and one MYB1AT. With the 5′ deletion assay in the ChiIV3 promoter, the W4-box located from −640 to −635 bp was identified as the cis element that is required for the response to RSI. In addition, the W4-box element was shown to be essential for the binding of the ChiIV3 promoter by the WRKY40 transcription factor, which is known to positively regulate the defense response to R. solanacearum. Site-directed mutagenesis in the W4-box sequence impaired the binding of WRKY40 to the ChiIV3 promoter. Subsequently, the transcription of ChiIV3 decreased in WRKY40-silenced pepper plants. These results demonstrated that the expression of the defense gene ChiIV3 is controlled through multiple modes of regulation, and WRKY40 directly binds to the W4-box element of the ChiIV3 promoter region for its transcriptional regulation.
Association of Intracranial Hypertension With Calvarial and Skull Base Thinning
Authors: Rabbani Cyrus C. , Patel Janaki M. , Nag Amit , Schueth Elizabeth , Saltagi Mohamad Z. , Kao Richard , Nelson Rick F.
Published: April 2019

Objective:

Determine if patients with increased opening pressure (OP) on lumbar puncture (LP) have thinner calvaria and skull bases.

Study Design:

Retrospective cohort study.

Setting:

Tertiary referral center.

Patients:

Patients (≥18 yr of age) who had a recorded OP on LP and high-resolution computed tomography imaging of the head. Patient age, sex, body mass index were calculated. Intracranial hypertension (IH) was defined with an OP≥25 cm-H2O and low intracranial pressure with an OP<15 cm-H2O.

Intervention:

Measurement of calvarial, zygoma, and skull base thickness when blinded to OP with three-dimensional slicer and radiologic calipers.

Main Outcome Measures:

Association of calvarial, skull base, and zygoma thickness with OP and age.

Results:

Fifty-eight patients were included with a mean (SD) age of 53.1 (16.2) years and average (SD) body mass index of 30.1 (9.1) kg/m2. Patients with IH had thinner mean (SD) calvaria (3.01 [0.81] versus 2.70 [0.58] mm; p = 0.036) and skull bases (5.17 [1.22] versus 4.60 [1.42] mm; p = 0.043) when compared with patients without IH. The mean (SD) extracranial zygoma thickness was similar between the two groups (5.09 [0.76] versus 5.00 [0.73] mm; p = 0.56). General linear model regression demonstrated advancing age was associated with increasing calvarial thickness in patients without IH and calvarial thinning in patients with IH (p = 0.038).

Conclusion:

IH is independently associated with intracranial bone (calvaria and skull base) thinning and not extracranial (zygoma) thinning. Skull thinning occurs with IH and advancing age. These findings support a possible role of increased ICP in the pathophysiologic development of spontaneous cerebrospinal fluid leaks.
Mastoid Cavity Myiasis: A Case Report and Review of the Literature
Authors: Kahane Jacob , Longworth Caleena , Dickson Crystal , Ng Matthew
Published: April 2019

Objective:

We report a case study of mastoid cavity aural myiasis in an urban developed setting and review the relevant literature.

Data Source:

Retrospective case report and review of the English literature via PubMed.

Data Selection:

English-language articles concerning aural myiasis and mastoid cavity myiasis were included.

Data Extraction:

Two previous case reports of mastoid cavity myiasis were identified and analyzed.

Conclusion:

Neglected mastoid cavity care, low socioeconomic status, poor personal hygiene, homelessness, and chronic suppurative otitis media are likely contributing factors to this uncommon presentation occurring in an urban setting.
Code Team Structure and Training in the Pediatric Resuscitation Quality International Collaborative
Authors: Pfeiffer Stephen , Lauridsen Kasper Glerup , Wenger Jesse , Hunt Elizabeth A. , Haskell Sarah , Atkins Dianne L. , Duval-Arnould Jordan M. , Knight Lynda J. , Cheng Adam , Gilfoyle Elaine , Su Felice , Balikai Shilpa , Skellett Sophie , Hui Mok Yee , Niles Dana E. , Roberts Joan S. , Nadkarni Vinay M. , Tegtmeyer Ken , Dewan Maya ,   for the Pediatric Resuscitation Quality Collaborative Investigators
Published: April 2019

Objectives

Code team structure and training for pediatric in-hospital cardiac arrest are variable. There are no data on the optimal structure of a resuscitation team. The objective of this study is to characterize the structure and training of pediatric code teams in sites participating in the Pediatric Resuscitation Quality Collaborative.

Methods

From May to July 2017, an anonymous voluntary survey was distributed to 18 sites in the international Pediatric Resuscitation Quality Collaborative. The survey content was developed by the study investigators and iteratively adapted by consensus. Descriptive statistics were calculated.

Results

All sites have a designated code team and hospital-wide code team activation system. Code team composition varies greatly across sites, with teams consisting of 3 to 17 members. Preassigned roles for code team members before the event occur at 78% of sites. A step stool and backboard are used during resuscitations in 89% of surveyed sites. Cardiopulmonary resuscitation (CPR) feedback is used by 72% of the sites. Of those sites that use CPR feedback, all use an audiovisual feedback device incorporated into the defibrillator and 54% use a CPR coach. Multidisciplinary and simulation-based code team training is conducted by 67% of institutions.

Conclusions

Code team structure, equipment, and training vary widely in a survey of international children's hospitals. The variations in team composition, role assignments, equipment, and training described in this article will be used to facilitate future studies regarding the impact of structure and training of code teams on team performance and patient outcomes.
Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor
Authors: Asundi Archana , Robles Yvonne , Starr Tyler , Landay Alan , Kinslow Jennifer , Ladner Joshua , White Laura , Plank Rebeca M. , Melbourne Kathleen , Weisholtz Daniel , Bennett Monica , Pan Hong , Stern Emily , Lin Alexander , Kuritzkes Daniel R. , Lin Nina H.
Published: April 2019

Background:

The biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV.

Setting:

Two single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017.

Methods:

Twenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses.

Results:

NP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4+ and CD8+ HLA−DR−/CD38+ subsets both increased (P = 0.05, 0.02).

Conclusions:

Even asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.
Brief Report: HIV Antibodies Decline During Antiretroviral Therapy but Remain Correlated With HIV DNA and HIV-Specific T-Cell Responses
Authors: Keating Sheila M. , Jones Richard Brad , Lalama Christina M. , Bosch Ronald J. , McMahon Deborah , Hampton Dylan , Cyktor Joshua , Eron Joseph J. , Mellors John W. , Busch Michael P. , Gandhi Rajesh T. ,   the ACTG 5321 Team
Published: April 2019

Background:

In people with HIV on antiretroviral therapy (ART), the relationship between HIV-specific immune responses and measures of HIV persistence is uncertain.

Methods:

We evaluated 101 individuals on suppressive ART in the AIDS Clinical Trials Group A5321 cohort. Cell-associated (CA) HIV DNA and RNA levels and HIV antibody concentrations and avidity to Env/p24 were measured longitudinally at years 1, 4, and 6–15 after ART initiation. Plasma HIV RNA by single copy assay and T-cell responses (IFN-γ ELISPOT) against multiple HIV antigens were measured at the last time point.

Results:

HIV antibody levels declined significantly with increasing time on ART (19%/year between year 1 and 4). HIV antibody levels correlated with T-cell responses to HIV Pol (r = 0.28, P = 0.014) and to Nef/Tat/Rev (r = 0.34; P = 0.002). HIV antibody and T-cell responses were positively associated with HIV DNA levels; for example, at the last time point (median 7 years on ART), r = 0.35 for antibody levels and HIV DNA (P < 0.001); r = 0.23 for Nef/Tat/Rev-specific T-cell responses and HIV DNA (P = 0.03). Neither antibody nor T-cell responses correlated with cell-associated HIV RNA or plasma RNA by single copy assay.

Conclusions:

In individuals on long-term ART, HIV-specific antibody and T-cell responses correlate with each other and with HIV DNA levels. The positive correlation between HIV immune responses and HIV DNA implies that the immune system is sensing, but not clearing, infected cells, perhaps because of immune dysfunction. Measuring immune responses to HIV antigens may provide insight into the impact of reservoir-reducing strategies.
Caribbean multi-centre study of Klebsiella pneumoniae: whole-genome sequencing, antimicrobial resistance and virulence factors
Authors: Heinz Eva , Brindle Richard , Morgan-McCalla Andrina , Peters Keisha , Thomson Nicholas R.
Published: April 2019

The surveillance of antimicrobial-resistant isolates has proven to be one of the most valuable tools to understand the global rise of multidrug-resistant bacterial pathogens. We report the first insights into the current situation in the Caribbean, where a pilot project to monitor antimicrobial resistance (AMR) through phenotypic resistance measurements combined with whole-genome sequencing was set up in collaboration with the Caribbean Public Health Agency (CARPHA). Our first study focused on

Klebsiella pneumoniae

, a highly relevant organism amongst the Gram-negative opportunistic pathogens worldwide causing hospital- and community-acquired infections. Our results show that not only carbapenem resistance, but also hypervirulent strains, are circulating in patients in the Caribbean. Our current data does not allow us to infer their prevalence in the population. We argue for the urgent need to further support AMR surveillance and stewardship in this almost uncharted territory, which can make a significant impact on the reduction of antimicrobial usage. This article contains data hosted by Microreact (https://microreact.org).
Interactions of pharmaceutical companies with world countries, cancers and rare diseases from Wikipedia network analysis
Authors: Rollin Guillaume , Lages José , Serebriyskaya Tatiana S. , Shepelyansky Dima L.
Published: April 2019

Using the English Wikipedia network of more than 5 million articles we analyze interactions and interlinks between the 34 largest pharmaceutical companies, 195 world countries, 47 rare renal diseases and 37 types of cancer. The recently developed algorithm using a reduced Google matrix (REGOMAX) allows us to take account both of direct Markov transitions between these articles and also of indirect transitions generated by the pathways between them via the global Wikipedia network. This approach therefore provides a compact description of interactions between these articles that allows us to determine the friendship networks between them, as well as the PageRank sensitivity of countries to pharmaceutical companies and rare renal diseases. We also show that the top pharmaceutical companies in terms of their Wikipedia PageRank are not those with the highest market capitalization.
tRNAscan-SE 2.0: Improved Detection and Functional Classification of Transfer RNA Genes
Authors: Chan Patricia P. , Lin Brian Y. , Mak Allysia J. , Lowe Todd M.
Published: April 2019

tRNAscan-SE has been widely used for transfer RNA (tRNA) gene prediction for over twenty years, developed just as the first genomes were decoded. With the massive increase in quantity and phylogenetic diversity of genomes, the accurate detection and functional prediction of tRNAs has become more challenging. Utilizing a vastly larger training set, we created nearly one hundred specialized isotype-and clade-specific models, greatly improving tRNAscan-SE’s ability to identify and classify both typical and atypical tRNAs. We employ a new comparative multi-model strategy where predicted tRNAs are scored against a full set of isotype-specific covariance models, allowing functional prediction based on both the anticodon and the highest-scoring isotype model. Comparative model scoring has also enhanced the program’s ability to detect tRNA-derived SINEs and other likely pseudogenes. For the first time, tRNAscan-SE also includes fast and highly accurate detection of mitochondrial tRNAs using newly developed models. Overall, tRNA detection sensitivity and specificity is improved for all isotypes, particularly those utilizing specialized models for selenocysteine and the three subtypes of tRNA genes encoding a CAU anticodon. These enhancements will provide researchers with more accurate and detailed tRNA annotation for a wider variety of tRNAs, and may direct attention to tRNAs with novel traits.
Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality
Authors: Arsenault Benoit J. , Pelletier William , Kaiser Yannick , Perrot Nicolas , Couture Christian , Khaw Kay-Tee , Wareham Nicholas J. , Bossé Yohan , Pibarot Philippe , Stroes Erik S.G. , Mathieu Patrick , Thériault Sébastien , Boekholdt S. Matthijs
Published: April 2019

Background

Elevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether genetically-determined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality.

Methods

We determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or father’s age of death ≥90 or mother still alive and older than 93 or mother’s age of death ≥93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study.

Results

In the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7×10−8). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels <50 mg/dL, those with Lp(a) levels ≥50 mg/dL had an increased hazard ratio (HR) for all-cause (HR=1.17, 95% CI=1.08-1.27) and cardiovascular (HR=1.54, 95% CI=1.37-1.72) mortality. Compared to individuals with Lp(a) levels below the 50th percentile of the Lp(a) distribution (in whom event rates were 29.8% and 11.3%, respectively for all-cause and cardiovascular mortality), those with Lp(a) levels equal or above the 95th percentile of the population distribution (≥70 mg/dL) had HRs of 1.22 (95% CI=1.09-1.37, event rate 37.5%) and 1.71 (95% CI=1.46-2.00, event rate 20.0%), for all-cause mortality and cardiovascular mortality, respectively.

Conclusions

Results of this study suggest a potentially causal effect of Lp(a) on human longevity, support the use of parental lifespan as a tool to study the genetic determinants of human longevity, and provide a rationale for a trial of Lp(a)-lowering therapy in individuals with high Lp(a) levels.
Predicting the time of entry of nanoparticles in cellular membranes
Authors: Liu Changjiang , Elvati Paolo , Majumder Sagardip , Wang Yichun , Liu Allen , Violi Angela
Published: April 2019

The understanding of the molecular interactions between nanoparticles (NPs) and biological systems is crucial for the systematic advance in many high-impact fields, such as biomedicine and nanotechnology. A key aspect to understand and predict the biological effect of NPs, e.g., cytotoxicity, bioavailability, is their interaction with membranes, specifically the mechanisms that regulate passive transport, which controls the permeation of most small molecules. In this paper, we introduce a new streamlined theoretical model that is able to predict the interactions between NPs and biological membranes (average permeation time), by separating the NPs’ characteristics (i.e., size, shape, solubility) from the membrane properties (density distribution). This factorization allows the inclusion of data obtained from both experimental and computational sources, as well as rapid estimation of large sets of permutation in new membranes. We validated our approach, by comparing our prediction for the interactions between different carbonaceous NPs and lipid bilayers with both experiments of measuring graphene quantum dot leakage encapsulated in lipid vesicles and time of entry from MD simulations.
Modification of an atypical clathrin-independent AP-2 adaptin complex of Plasmodium falciparum reduces susceptibility to artemisinin
Authors: Henrici Ryan C. , Edwards Rachel L. , Zoltner Martin , van Schalkwyk Donelly A. , Hart Melissa N. , Mohring Franziska , Moon Robert W. , Nofal Stephanie D. , Patel Avnish , Flueck Christian , Baker David A. , John Audrey Odom , Field Mark C. , Sutherland Colin J.
Published: April 2019

The efficacy of current antimalarial drugs is threatened by reduced susceptibility of Plasmodium falciparum to artemisinin. In the Mekong region this is associated with mutations in the kelch propeller-encoding domain of pfkelch13, but variants of other parasite proteins are also thought to modulate the response to drug. Evidence from human and rodent studies suggests that the μ-subunit of the AP-2 adaptin trafficking complex is one such protein of interest. We generated transgenic Plasmodium falciparum parasites encoding the I592T variant of pfap2μ, orthologous to the I568T mutation associated with in vivo artemisinin resistance in P. chabaudi. When exposed to a four-hour pulse of dihydroartemisin in the ring-stage survival assay, two P. falciparum clones expressing AP-2μ I592T displayed significant and reproducible survival of 8.0% and 10.3%, respectively, compared to <2% for the 3D7 parental line (P = 0.0011 for each clone). In immunoprecipitation and localisation studies of HA-tagged AP-2μ, we identified interacting partners including AP-2α, AP-1/2β, AP-2σ and a kelch-domain protein encoded on chromosome 10 of P. falciparum, K10. Conditional knockout indicates that the AP-2 trafficking complex in P. falciparum is essential for the fidelity of merozoite biogenesis and membrane organisation in the mature schizont. We also show that while other heterotetrameric AP-complexes and secretory factors interact with clathrin, AP-2 complex subunits do not. Thus, the AP-2 complex may be diverted from a clathrin-dependent endocytic role seen in most eukaryotes into a Plasmodium-specific function. These findings represent striking divergences from eukaryotic dogma and support a role for intracellular traffic in determining artemisinin sensitivity in vitro, confirming the existence of multiple functional routes to reduced ring-stage artemisinin susceptibility. Therefore, the utility of pfkelch13 variants as resistance markers is unlikely to be universal, and phenotypic surveillance of parasite susceptibility in vivo may be needed to identify threats to our current combination therapies.
Reevaluation of the RNA binding properties of the Tetrahymena thermophila telomerase reverse transcriptase N-terminal domain
Authors: Palka Christina , Deshpande Aishwarya P. , Stone Michael D. , Collins Kathleen
Published: April 2019

Telomerase restores chromosome-capping telomeric repeats lost with each round of genome replication by DNA-templated DNA polymerases. The telomerase reverse transcriptase (TERT) N-terminal (TEN) domain is a peripheral, telomerase-specific, processivity-stimulatory addition to more conserved domains that encircle the active site cavity. Reports of ciliate, yeast, and mammalian telomerase TEN domain associations with the telomerase RNA subunit (TR) describe low affinity interactions of uncertain specificity. Unfortunately two cryo-EM structures of synthesis-paused telomerase holoenzymes lack sufficient resolution to discriminate molecular specificity of possible TR contact(s) with the TEN domain, and there is no assigned density for the TEN domain termini implicated in RNA binding. Furthermore, studies have revealed alternative secondary structures for TR regions that could interact with TERT prior to TR folding into active conformation. Informed by recent advances in knowledge of telomerase structure, we returned to the investigation of Tetrahymena thermophila TERT TEN domain interaction with TR. Instead of finding specificity for a particular TR sequence or structure, we discovered that the tagged TEN domain used in previous characterizations has trace contamination with a bacterial RNA-interacting protein not detectable by SDS-PAGE. By resolving this interference, we show that the TEN domain binds RNAs dependent on RNA length rather than sequence.
Proinflammatory and autoimmunogenic gut microbiome in systemic lupus erythematosus
Authors: Chen Bei-di , Jia Xin-miao , Xu Jia-yue , Zhao Li-dan , Ji Jun-yi , Wu Bing-xuan , Fei Yun-yun , Yang Hua-xia , Chen Hua , Zuo Xiao-xia , Li Hui , Pan Wen-you , Wang Xiao-han , Ye Shuang , Guo Dong-geng , Wang Li , Li Jing , Peng Lin-yi , Zheng Wen-jie , Zhang Wen , Zhang Feng-chun , Zhang Jian-min , He Wei , Cao Xue-tao , Liu De-pei , Wang Jun , Zhang Xuan
Published: April 2019

Systemic lupus erythematosus (SLE), characterized by chronic inflammation and multi-organ damage, has been suggested to associate with gut dysbiosis, but knowledge is limited from small sample size and 16s rRNA-based studies. To shed new light on the role of microbiota in SLE development, we analyzed the fecal metagenome of 117 treatment-naïve SLE patients and 115 sex- and age-matched healthy controls (HC) by deep-sequencing; in addition, 52 of the aforementioned patients have post-treatment fecal metagenome for comparison. We found significant differences in microbial composition and function between SLE and HC, revealing multiple plausible contributing bacterial species and metabolic pathways in SLE. In-depth SNP-based analysis revealed an oral-microbiome origin for two marker species, strengthening the importance of bacterial translocation in disease development. Lastly, we confirmed experimentally that peptides of SLE-enriched species mimicking autoantigens such as Sm and Fas could trigger autoimmune responses, suggesting a potential causal role of gut microbiota in SLE.
Light environment drives the shallow to mesophotic coral community transition
Authors: Tamir Raz , Eyal Gal , Kramer Netanel , Laverick Jack H. , Loya Yossi
Published: April 2019

Abstract

Light quality is a crucial physical factor driving coral distribution along depth gradients. Currently, a 30 m depth limit, based on SCUBA regulations, separates shallow and deep mesophotic coral ecosystems (MCEs). This definition, however, fails to explicitly accommodate environmental variation. Here, we posit a novel definition for a regional or reef-to-reef outlook of MCEs based on the light vs. coral community-structure relationship. A combination of physical and ecological methods enabled us to clarify the ambiguity in relation to that issue. To characterize coral community structure with respect to the light environment, we conducted wide-scale spatial studies at five sites along shallow and MCEs of the Gulf of Eilat/Aqaba (0-100 m depth). Surveys were conducted by Tech-diving and drop-cameras, in addition to one year of light spectral measurements. We quantify two distinct coral assemblages: shallow (<40 m), and MCEs (40-100 m), exhibiting markedly different relationships with light. The depth ranges and morphology of 47 coral genera, was better explained by light than depth, mainly, due to the Photosynthetically Active Radiation (PAR) and Ultra Violet Radiation (1% at 76 m and 36 m, respectively). Branching coral species were found mainly at shallower depths i.e., down to 36 m. Among the abundant upper mesophotic specialist-corals,Leptoseris glabra,Euphyllia paradivisaandAlveoporaspp., were found strictly between 36-76 m depth. The only lower mesophotic-specialist,Leptoseris fragilis, was found deeper than 80 m. We suggest that shallow coral genera are light-limited below a level of 1.25% surface PAR and that the optimal PAR for mesophotic communities is at 7.5%. This study contributes to moving MCEs ecology from a descriptive-phase into identifying key ecological and physiological processes structuring MCE coral communities. Moreover, it may serve as a model enabling the description of a coral zonation world-wide on the basis of light quality data.
Cortical ensemble activity discriminates auditory attentional states
Authors: Yao Pan-tong , Shen Jia , Chen Liang , Ge Shaoyu , Xiong Qiaojie
Published: April 2019

Selective attention modulates sensory cortical activity. It remains unclear how auditory cortical activity represents stimuli that differ behaviorally. We designed a cross-modality task in which mice made decisions to obtain rewards based on attended visual or auditory stimuli. We recorded auditory cortical activity in behaving mice attending to, ignoring, or passively hearing auditory stimuli. Engaging in the task bidirectionally modulates neuronal responses to the auditory stimuli in both the attended and ignored conditions compared to passive hearing. Neuronal ensemble activity in response to stimuli under attended, ignored and passive conditions are readily distinguishable. Furthermore, ensemble activity under attended and ignored conditions are in closer states compared to passive condition, and they share a component of attentional modulation which drives them to the same direction in the population activity space. Our findings suggest that task engagement changes sensory cortical representations across modalities in the same directions, and cross-modality attention may differentially modulates attended and ignored modalities.
Competence ofCorynebacterium glutamicumas a host for the production of type I polyketides
Authors: Kallscheuer Nicolai , Kage Hirokazu , Milke Lars , Nett Markus , Marienhagen Jan
Published: April 2019

Type I polyketide synthases (PKSs) are large multi-domain proteins converting simple acyl-CoA thioesters such as acetyl-CoA and malonyl-CoA to a large diversity of biotechnologically interesting molecules. Such multi-step reaction cascades are of particular interest for applications in engineered microbial cell factories, as the introduction of a single protein with many enzymatic activities does not require balancing of several individual enzymatic activities. However, functional introduction of type I PKSs into heterologous hosts is very challenging as the large polypeptide chains often do not fold properly. In addition, PKS usually require post-translational activation by dedicated 4’-phosphopantetheinyl transferases (PPTases). Here, we introduce an engineeredCorynebacterium glutamicumstrain as a novel microbial cell factory for type I PKS-derived products. Suitability ofC. glutamicumfor polyketide synthesis could be demonstrated by the functional introduction of the 6-methylsalicylic acid synthase ChlB1 fromStreptomyces antibioticus. Challenges related to protein folding could be overcome by translation fusion of ChlB1Sato the C-terminus of the maltose-binding protein MalE fromEscherichia coli. Surprisingly, ChlB1Sawas also active in absence of a heterologous PPTase, which finally led to the discovery that the endogenous PPTase PptACgofC. glutamicumcan also activate ChlB1Sa. The best strain, engineered to provide increased levels of acetyl-CoA and malonyl-CoA, accumulated up to 41 mg/L (0.27 mM) 6-methylsalicylic acid within 48 h of cultivation. Further experiments showed that PptACgofC. glutamicumcan also activate nonribosomal peptide synthetases (NRPSs), renderingC. glutamicuma promising microbial cell factory for the production of several fine chemicals and medicinal drugs.
Targeting RET Kinase in Neuroendocrine Prostate Cancer
Authors: VanDeusen Halena , Ramroop Johnny R. , Morel Katherine L. , Sheahan Anjali V , Sychev Zoi , Lau Nathan A. , Cheng Larry C. , Tan Victor , Li Zhen , Petersen Ashley , Lee John K. , Park Jung Wook , Yang Rendong , Coleman Ilsa , Witte Owen , Morrissey Colm , Corey Eva , Nelson Peter S. , Ellis Leigh , Drake Justin M.
Published: April 2019

Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression and may be a novel treatment option.

Statement of Significance

There are limited treatment options for patients with metastatic aggressive variant prostate cancer and none are curative. Here we identified aberrantly activated RET kinase signaling in multiple models of NEPC. Inhibiting RET restricted tumor growth, providing a novel approach for treating NEPC.
Cyclosporine A Directly Affects Human and Mouse B cell Migration in vitro by Disrupting a HIF-1α Dependent, O2 Sensing, Molecular Switch
Authors: Hilchey Shannon P , Palshikar Mukta G , Li Dongmei , Garigen Jessica , Cipolla Valantina , Thakar Juilee , Zand Martin S
Published: April 2019

Background

Hypoxia is a potent molecular signal for cellular metabolism, mitochondrial function, and migration. Conditions of low oxygen tension trigger regulatory cascades mediated via the highly conserved HIF-1α post-translational modification system. In the adaptive immune response, B cells (Bc) are activated and differentiate under hypoxic conditions within lymph node germinal centers, and subsequently migrate to other compartments. During migration, they traverse through changing oxygen levels, ranging from 1-5% in the lymph node to 5-13% in the peripheral blood. Interestingly, the calcineurin inhibitor cyclosporine A is known to stimulate prolyl hydroxylase activity, resulting in HIF-1α destabilization and may alter Bc responses directly. Over 60% of patients taking calcineurin immunosuppressant medications have hypo-gammaglobulinemia and poor vaccine responses, putting them at high risk of infection with significantly increased morbidity and mortality.

Results

We demonstrate that O2 tension is a previously unrecognized Bc regulatory switch, altering CXCR4 chemokine receptor signaling in activated Bc through HIF-1α expression and controlling critical aspects of Bc migration. Our data demonstrate that calcineurin inhibition hinders this O2 regulatory switch in primary human Bc.

Conclusion

This previously unrecognized effect of calcineurin inhibition directly on human Bc has significant and direct clinical implications.
Efficacy of the MEK1/2 inhibitor trametinib in combination with clinically-investigated γ-secretase inhibitors in rhabdomyosarcoma
Authors: Cleary Megan M. , Hawkins Douglas S. , Keller Charles
Published: April 2019

The childhood muscle cancer rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. In the last 40 years, outcomes for low and intermediate risk patients have improved; however, high risk patients with metastatic disease still have poor overall survival. Differentiation therapy for RMS has been considered a potential clinical approach to halting tumor progression by inducing the terminal myogenic differentiation program, and thus reducing the need for cytotoxic chemotherapy. Both the NOTCH and MEK pathway have been shown to play varying roles in inducing differentiation in RMS cells. Here, we tested several different RMS cell lines harboring varying genetic abnormalities with the MEK inhibitor trametinib alone, and in combination with γ-secretase inhibitors and found no significant effect on cell viability when used together.
The fungal sesquiterpenoid pyrenophoric acid B uses the plant ABA biosynthetic pathway to inhibit seed germination
Authors: Lozano-Juste Jorge , Masi Marco , Cimmino Alessio , Clement Suzette , Fernández Maria A. , Antoni Regina , Meyer Susan , Rodriguez Pedro L. , Evidente Antonio
Published: April 2019

Highlight

The fungusPyrenophora semeniperdaproduces pyrenophoric acid B, a small molecule that exploits the plant ABA biosynthetic pathway to reduce seed germination, increasing its reproductive success.

Pyrenophoric acid (P-Acid), P-Acid B and P-Acid C are three phytotoxic sesquiterpenoids produced by the ascomycete seed pathogenPyrenophora semeniperda,a fungus proposed as a mycoherbicide for biocontrol of cheatgrass, an extremely invasive weed. When tested in cheatgrass bioassays these metabolites were able to delay seed germination, with P-Acid B being the most active compound. Here, we have investigated the cross-kingdom activity of P-Acid B and its mode of action and found that it activates the ABA signaling pathway in order to inhibit seedling establishment. P-Acid B inhibits seedling establishment in wild-typeArabidopsis thalianawhile several mutants affected in the early perception as well as in downstream ABA signaling components were insensitive to the fungal compound. However, in spite of structural similarities between ABA and P-Acid B, the latter is not able to activate the PYR/PYL family of ABA receptors. Instead, we have found that P-Acid B uses the ABA biosynthesis pathway at the level of alcohol dehydrogenase ABA2 to reduce seedling establishment. We propose that the fungusPyrenophora semeniperdamanipulates plant ABA biosynthesis as a strategy to reduce seed germination, increasing its ability to cause seed mortality and thereby increase its fitness through higher reproductive success.
Previously reward-associated stimuli capture spatial attention in the absence of changes in the corresponding sensory representations as measured with MEG
Authors: Tankelevitch L , Spaak E , Rushworth MFS , Stokes MG
Published: April 2019

Studies of selective attention typically consider the role of task goals or physical salience, but recent work has shown that attention can also be captured by previously reward-associated stimuli, even if they are currently task-irrelevant. One theory underlying this value-driven attentional capture (VDAC) is that reward-associated stimulus representations may undergo plasticity in sensory cortex, thereby automatically capturing attention during early processing. To test this, we used magnetoencephalography to probe whether stimulus location and identity representations in sensory cortex are modulated by reward learning. We furthermore investigated the time-course of these neural effects, and their relationship to behavioural VDAC. Male and female human participants first learned stimulus-reward associations. Next, we measured VDAC in a separate task by presenting these stimuli in the absence of reward contingency, and probing their effects on the processing of separate target stimuli presented at different time lags. Using time-resolved multivariate pattern analysis, we found that learned value modulated the spatial selection of previously rewarded stimuli in posterior visual and parietal cortex from ∼260ms after stimulus onset. This value modulation was related to the strength of participants’ behavioural VDAC effect and persisted into subsequent target processing. Furthermore, we found a spatially invariant value signal from ∼340ms. Importantly, learned value did not influence cortical signatures of early processing (i.e., earlier than ∼200ms), nor did it influence the decodability of the identity of previously rewarded stimuli. Our results suggest that VDAC is underpinned by learned value signals which modulate spatial selection throughout posterior visual and parietal cortex. We further suggest that VDAC can occur in the absence of changes in early visual processing in cortex.

Significance statement

Attention is our ability to focus on relevant information at the expense of irrelevant information. It can be affected by previously learned but currently irrelevant stimulus-reward associations, a phenomenon termed “value-driven attentional capture” (VDAC). The neural mechanisms underlying VDAC remain unclear. It has been speculated that reward learning induces visual cortical plasticity which modulates early visual processing to capture attention. Although we find that learned value modulates spatial signals in visual cortical areas, an effect which correlates with VDAC, we find no relevant signatures of changes in early visual processing in cortex.
Dedicated setup for the photoconversion of fluorescent dyes for functional electron microscopy
Authors: Dobson Katharine L. , Howe Carmel L. , Nishimura Yuri , Marra Vincenzo
Published: April 2019

Here, we describe a cost-effective setup for targeted photoconversion of fluorescent signals into electron dense ones. This approach has offered invaluable insights in the morphology and function of fine neuronal structures. The technique relies on the localized oxidation of diaminobenzidine (DAB) mediated by excited fluorophores. This paper includes a detailed description of how to build a simple photoconversion setup that can increase reliability and throughput of this well-established technique. The system described here, is particularly well-suited for thick neuronal tissue, where light penetration and oxygen diffusion may be limiting DAB oxidation. To demonstrate the system, we use Correlative Light and Electron Microscopy (CLEM) to visualize functionally-labelled individual synaptic vesicles released onto an identified layer 5 neuron in an acute cortical slice. The setup significantly simplifies the photoconversion workflow, increasing the depth of photoillumination, improving the targeting of the region of interest and reducing the time required to process each individual samples. We have tested this setup extensively for the photoconversion of FM 1-43FX and Lucifer Yellow both excited at 473 nm. In principle, the system can be adapted to any dye or nanoparticle able to oxidize DAB when excited by a specific light wavelength.