bluuebunny/crossref_metadata_2025 huggingface dataset:
Soft‐decision schemes for radar estimation of elevation at low grazing angles
Authors: Meller Michal , Stawiarski Kamil
Published: June 2019

In modern radars, the problem of estimating elevation angle at low grazing angles is typically solved using super‐resolution techniques. These techniques often require one to provide an estimate of the number of waveforms impinging the array, which one can accomplish using model selection techniques. In this study, the authors investigate the performance of an alternative approach, based on the Bayesian‐like model averaging. The Bayesian approach exploits the fact that the parameters of the model related to multipath signals are nuisance ones, which allows one to avoid the estimation of the number of waveforms and improves estimation performance. The method is introduced for the classical conditional maximum‐likelihood estimator and extended to its, recently proposed, robustified version. The authors find, however, that the robustified estimator includes its own soft‐decision mechanism and benefits from the averaging only for low levels of model uncertainty.
Common knowledge, coordination, and strategic mentalizing in human social life
Authors: De Freitas Julian , Thomas Kyle , DeScioli Peter , Pinker Steven
Published: June 2019

Significance

Humans are an unusually cooperative species, and our cooperation is of 2 kinds: altruistic, when actors benefit others at a cost to themselves, and mutualistic, when actors benefit themselves and others simultaneously. One major form of mutualism is coordination, in which actors align their choices for mutual benefit. Formal examples include meetings, division of labor, and legal and technological standards; informal examples include friendships, authority hierarchies, alliances, and exchange partnerships. Successful coordination is enabled by common knowledge: knowledge of others’ knowledge, knowledge of their knowledge of one’s knowledge, ad infinitum. Uncovering how people acquire and represent the common knowledge needed for coordination is thus essential to understanding human sociality, from large-scale institutions to everyday experiences of civility, hypocrisy, outrage, and taboo.
Adjusted macroeconomic indicators to account for ecosystem degradation: an illustrative example
Authors: La Notte Alessandra , Marques Alexandra
Published: June 2019

Adjusting macroeconomic indicators to account for the depletion and degradation of natural capital has long been viewed as a way to show the linkages between nature and the economy and foster more sustainable paths of development. Here, we show how the System of Environmental Economic Accounting (SEEA) Experimental Ecosystem Accounting (EEA) can be used to develop environmentally adjusted macroeconomic indicators. More specifically, we show how an enlargement of the production boundary to include the consideration of ecosystems as institutional units allows the development of a net value added metric that reflects depreciation and degradation of the natural capital assets. This measurement could be useful for policymaking: the linkage of ecosystem services to economic activities allows us to account for loss, repair and substitution of natural capital, and thus helps us to formulate and monitor environmental policies.
What Does it Mean to Be a #PlasticSurgeon? Analyzing Plastic Surgery Hashtag Utilization in Social Media
Authors: Siegel Nicholas , Jenny Hillary , Chopra Karan , Yang Robin
Published: June 2019

Background

The utilization of social media is growing among academic and private practice plastic surgeons.

Objectives

The aim of this study was to determine training backgrounds and board certification of medical professionals through the use of plastic surgery-related hashtags on a single social media platform, Instagram.

Methods

Instagram was queried with 15 plastic surgery–related hashtags. Only the top 50 posts of each hashtag were analyzed at a single time point and international accounts were excluded. Data collected included account owner, degree, medical specialty, board certification, and type of post.

Results

The study sample consisted of 750 posts from an Instagram query in January 2019. Medical professionals accounted for 75% (n = 561) of posts. Board-certified physicians accounted for 56% (n = 420) of posts. Of the physician posters, 51% (n = 230) were trained in plastic surgery, 30% (n = 133) in otolaryngology, and 19% (n = 87) in other specialties. Facial rejuvenation content was more likely to be posted by otolaryngologists rather than plastic surgeons (P ≤ 0.001), whereas body-contouring procedures were more likely to be posted by plastic surgeons. Nonsurgical procedures and injectables were more likely to be posted by nonphysicians (P ≤ 0.001). Physicians without training in plastic surgery or otolaryngology were also more likely to post nonsurgical procedure–related hashtags (P ≤ 0.001).

Conclusions

Medical professionals publish the majority of plastic surgery–related posts on Instagram; however, the utilization of plastic surgery hashtags by other specialties may be confusing or misleading to social media users who are unaware of interdisciplinary training differences.
A Rare Mutation in SPLUNC1 Affects Bacterial Adherence and Invasion in Meningococcal Disease
Authors: Mashbat Bayarchimeg , Bellos Evangelos , Hodeib Stephanie , Bidmos Fadil , Thwaites Ryan S , Lu Yaxuan , Wright Victoria J , Herberg Jethro A , Klobassa Daniela S , Walton William G , Zenz Werner , Hansel Trevor T , Nadel Simon , Langford Paul R , Schlapbach Luregn J , Li Ming-Shi , Redinbo Matthew R , Di Y Peter , Levin Michael , Sancho-Shimizu Vanessa
Published: June 2019

Background

Neisseria meningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD), but the contributions of rare variants other than those in the complement system have not been determined.

Methods

We identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-Threatening Infectious Disease Study. Candidate genetic variants were identified by whole-exome sequencing of 2 patients with familial IMD. Candidate variants were further validated by in vitro assays.

Results

Exomes of 2 siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other nonfamilial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defense protein expressed in the nasopharyngeal epithelia; however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 protein inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant recombinant SPLUNC1 (p.G22E) showed reduced antibiofilm activity, increased meningococcal adhesion, and increased invasion of cells, compared with wild-type SPLUNC1.

Conclusions

A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.
Die klingende Ferne; Walter Braunfels’ Opera Die Vögel after Aristophanes’ Birds
Authors: Ewans Michael
Published: June 2019

This article explores the opera Die Vögel (1920) by Walter Braunfels (1882–1954), and its reception of Aristophanes' Birds. The Introduction is substantial, as the work is little known. It is followed by an Overview of each of the two Acts, which discusses in Act I the relationship to Aristophanes (Braunfels discarded the second half of the original Greek comedy and struck out on a completely new path). Then the article analyses the development during Act II of insight into die klingende Ferne (‘the music of far away') by Hopeful, who is the principal human character in Braunfels' adaptation. It is shown that Hopeful's quest for spiritual values almost beyond human understanding is the central theme of the opera; the superiority of the life of birds, which Aristophanes treats humorously in the two parabaseis, is taken seriously in Braunfels' mystical second Act.
Clustered Core- and Pan-Genome Content on Rhodobacteraceae Chromosomes
Authors: Kopejtka Karel , Lin Yan , Jakubovičová Markéta , Koblížek Michal , Tomasch Jürgen
Published: June 2019

In Bacteria, chromosome replication starts at a single origin of replication and proceeds on both replichores. Due to its asymmetric nature, replication influences chromosome structure and gene organization, mutation rate, and expression. To date, little is known about the distribution of highly conserved genes over the bacterial chromosome. Here, we used a set of 101 fully sequenced Rhodobacteraceae representatives to analyze the relationship between conservation of genes within this family and their distance from the origin of replication. Twenty-two of the analyzed species had core genes clustered significantly closer to the origin of replication with representatives of the genus Celeribacter being the most apparent example. Interestingly, there were also eight species with the opposite organization. In particular, Rhodobaca barguzinensis and Loktanella vestfoldensis showed a significant increase of core genes with distance from the origin of replication. The uneven distribution of low-conserved regions is in particular pronounced for genomes in which the halves of one replichore differ in their conserved gene content. Phage integration and horizontal gene transfer partially explain the scattered nature of Rhodobacteraceae genomes. Our findings lay the foundation for a better understanding of bacterial genome evolution and the role of replication therein.
Biological Risk Profiles Among Latino Subgroups in the Health and Retirement Study
Authors: García Catherine , Ailshire Jennifer A
Published: June 2019

Background and Objectives

Latinos residing in the United States exhibit an increased risk for cardiovascular and metabolic diseases compared to non-Latino whites. This elevated risk contributes to a significantly higher prevalence of diabetes and hypertension among Latino adults. Examining biological risk profiles of older Latinos as a “pan-ethnic group” and by Latino subpopulations may help to explain the increased burden of disease in later life among this population. The objective of this study is to document biological risk profiles among a nationally representative sample of older U.S. Latinos by nativity and country of origin.

Research Design and Methods

We use the 2006–2012 Health and Retirement Study to compare cardiovascular, metabolic, inflammatory and cumulative biological risk among U.S.-born Mexicans, foreign-born Mexicans, U.S.-born Puerto Ricans, island-born Puerto Ricans, U.S.-born “other” Latinos, foreign-born “other” Latinos, and non-Latino whites.

Results

Older Latinos exhibit heterogeneous biological risk profiles. U.S.-born Mexicans, foreign-born Mexicans, U.S.-born “other” Latinos, and foreign-born “other” Latinos exhibited a higher rate of cardiovascular risk relative to non-Latino whites. In addition, U.S.-born Mexicans, foreign-born Mexicans, island-born Puerto Ricans, and foreign-born “other” Latinos had a higher rate of metabolic risk than non-Latino whites. Island-born Puerto Ricans were the only group to exhibit higher inflammation than non-Latino whites. The observed differences were largely attenuated by socioeconomic status, indicating that high levels of risk among older Latino subpopulations compared to non-Latino whites are associated with lower socioeconomic status.

Discussion and Implications

Older U.S. Latinos are a demographically diverse population with unique sociocultural characteristics which may contribute to differences in biological risk across the life course that influence disease progression. Examining Latinos by nativity and country of origin may help identify risks specific to individual subpopulations that can lead to culturally appropriate interventions which help prevent and reduce the burden of cardiovascular and metabolic diseases.
In Pursuit of Genuine Chinese Equivalents: The Case of a Nineteenth-Century Dutch-Chinese Dictionary
Authors: Heijns Audrey
Published: June 2019

Despite the consensus among scholars that it is impossible for equivalence to have the same meaning in linguistics as it does in mathematics – it is impossible to have equivalents in translation – there is still merit in investigating bilingual dictionaries as they can help us understand the different gradation and distinct types of equivalence and thus illustrate the problems that compilers faced. As a case study, this paper examines Gustaaf Schlegel’s Dutch–Chinese dictionary, with occasional comparison to other dictionaries from the nineteenth century, in order to reconstruct Schlegel’s aim of ‘genuine Chinese equivalents’. Findings show that, in many instances, Schlegel is skilful in providing cognitive, explanatory or translational equivalents in terms of meaning and function, while providing useful information about the Chinese language and culture. Yet, in some cases, his attempts to find his so-called genuine equivalent fail, because he would not resort to the coining of new words, as other compilers did in that era.
The Texture of Rare and Common Lesions in Soemmerring and Baillie
Authors: Meli Domenico Bertoloni
Published: June 2019

The publications on morbid anatomy by Matthew Baillie and Samuel Thomas Soemmerring put pathological preparations and images center stage. A comparison between their works highlights major shifts from exceptional to more representative cases and significant differences in the art of representation. Initially Baillie provided careful descriptions of internal postmortem lesions (1793). Then Soemmerring’s prompt German translation added a wealth of references to the literature and specifically to pathological images available in print (1794). Soon after a second unillustrated edition incorporating some of Soemmerring’s comments (1797), Baillie issued ten installments with dozens of pathological plates (1799-1803). His plates differed from those referred to by Soemmerring for their broader scope, representing common and rare conditions alike, and specific attention to the fine changes of texture of the affected parts. Their works document the crucial status of pathological preparations and images at the time and highlight the achievement of Baillie’s work at an artistic as well as at an intellectual level.
Comparison between the seventh and eighth edition of the AJCC/UICC staging system for nasopharyngeal cancer integrated with pretreatment plasma Epstein–Barr virus DNA level in a non-Chinese population: secondary analysis from a prospective randomized trial
Authors: Kitpanit Sarin , Jittapiromsak Nutchawan , Sriyook Aniwat , Prayongrat Anussara , Kannarunimit Danita , Chakkabat Chakkapong , Lertbutsayanukul Chawalit
Published: June 2019

The eighth AJCC/UICC staging for nasopharyngeal cancer had higher prognostic values than the previous edition. Pretreatment plasma EBV DNA integrated into the next edition could further improve the outcome prediction.
Laparoscopic management of a late gastric perforation post-fundoplication
Authors: Keilig Robert , Shariff Raza M
Published: June 2019

Nissen fundoplication is a safe and effective procedure for gastroesophageal reflux. Gastric ulceration leading to perforation is an uncommon late complication with a mechanism of action that is poorly understood.

A 40-year-old male presented 3 years following his fundoplication with a perforated ulcer in the upper body of the stomach. The patient admitted ibuprofen use leading up to the perforation. The perforation was successfully repaired via laparoscopy, with good postoperative outcome.

Gastric ulcer perforation post-fundoplication is a rare late outcome. Gastric perforation may have been precipitated by the use of non-steroidal anti-inflammatory drugs (NSAIDs) in concert with the vascular mechanical changes caused by this procedure. A review of the literature reveals only a handful of accounts of gastric ulcers or perforations as a late outcome. Of note, many of these perforations occur in the upper stomach and in tandem with NSAID use.
Co-occurrence graph-based context adaptation: a new unsupervised approach to word sense disambiguation
Authors: Rahmani Saeed , Fakhrahmad Seyed Mostafa , Sadreddini Mohammad Hadi
Published: June 2019

Word sense disambiguation (WSD) is the task of selecting correct sense for an ambiguous word in its context. Since WSD is one of the most challenging tasks in various text processing systems, improving its accuracy can be very beneficial. In this article, we propose a new unsupervised method based on co-occurrence graph created by monolingual corpus without any dependency on the structure and properties of the language itself. In the proposed method, the context of an ambiguous word is represented as a sub-graph extracted from a large word co-occurrence graph built based on a corpus. Most of the words are connected in this graph. To clarify the exact sense of an ambiguous word, its senses and relations are added to the context graph, and various similarity functions are employed based on the senses and context graph. In the disambiguation process, we select senses with highest similarity to the context graph. As opposite to other WSD methods, the proposed method does not use any language-dependent resources (e.g. WordNet) and it just uses a monolingual corpus. Therefore, the proposed method can be employed for other languages. Moreover, by increasing the size of corpus, it is possible to enhance the accuracy of WSD. Experimental results on English and Persian datasets show that the proposed method is competitive with existing supervised and unsupervised WSD approaches.
Electromyographic Activity Evolution of Local Twitch Responses During Dry Needling of Latent Trigger Points in the Gastrocnemius Muscle: A Cross-Sectional Study
Authors: Baraja-Vegas Luis , Martín-Rodríguez Saúl , Piqueras-Sanchiz Francisco , Martín-Ruiz Julio , Yeste Fabregat Mireia , Florencio Lidiane L , Fernández-de-las-Peñas César
Published: June 2019

Objective

Trigger points (TrPs) are hypersensitive spots within taut bands of skeletal muscles that elicit referred pain and motor changes. Among the variety of techniques used for treating TrPs, dry needling is one of the most commonly applied interventions. The question of eliciting local twitch responses (LTRs) during TrP dry needling is unclear. Our main aim was to investigate the evolution of the electromyographic (EMG) peak activity of each LTR elicited during dry needling into latent TrPs of the gastrocnemius medialis muscle.

Methods

Twenty asymptomatic subjects with latent TrPs in the gastrocnemius medialis muscle participated in this cross-sectional study. Changes in EMG signal amplitude (root mean square [RMS]) with superficial EMG were assessed five minutes before, during, and five minutes after dry needling. The peak RMS score of each LTR was calculated (every 0.5 sec).

Results

Analysis of variance revealed a significant effect (F = 29.069, P <0.001) showing a significant decrease of RMS peak amplitude after each subsequent LTR. Differences were significant (P <0.001) during the first three LTRs, and stable until the end of the procedure. No changes (P =0.958) were found for mean RMS data at rest before (mean = 65.2 mv, 95% confidence interval [CI] = 47.3–83.1) and after (61.0 mv, 95% CI = 42.3–79.7) dry needling.

Conclusions

We found that, in a series of LTRs elicited during the application of dry needling over latent TrPs in the medial gastrocnemius muscle, the RMS peak amplitude of each subsequent LTR decreased as compared with the initial RMS peak amplitude of previous LTRs. No changes in superficial EMG activity at rest were observed after dry needling of latent TrPs of the gastrocnemius medialis muscle.
Developing Purpose-Oriented Networks: A Process View
Authors: Berthod Olivier , Segato Federica
Published: June 2019

Rejoining other authors’ arguments in favor of less linear and more process-based studies of change in purpose-oriented networks (PONs), we propose conceiving of PONs not as social entities or forms, but as processes constantly in flux. From this perspective, PONs comprise more or less interconnected processes constantly at play, albeit with more or less intensity, depending on the reflexive management and actions of their participants. We contend that a process view sheds light on three major themes categorizing extant research on network development: network development as the product of engineered, planned managerial actions; network evolution as the product of unintended, systemic changes both within and outside of PONs; and the management of network tensions as the central object of managerial attention.
Exposure to environmental level pesticides stimulates and diversifies evolution inEscherichia colitowards greater antibiotic resistance
Authors: Xing Yue , Wu Shuaiqi , Men Yujie
Published: June 2019

Antibiotic resistance is one of the most challenging issues in public health. Antibiotic resistance can be selected by antibiotics at sub-inhibitory concentrations, the concentrations typically occurring in natural and engineered environments. Meanwhile, many other emerging organic contaminants such as pesticides are frequently co-occurring with antibiotics in agriculture-related environments and municipal wastewater treatment plants. To investigate the effects of the co-existing, non-antibiotic pesticides on the development of antibiotic resistance, we conducted long-term exposure experiments using a modelEscherichia colistrain. The results revealed that 1) the exposure to a high level (in mg/L) of pesticides alone led to the emergence of mutants with significantly higher resistance to streptomycin; 2) the exposure to an environmental level (in µg/L) of pesticides together with a sub-inhibitory level (in sub mg/L) of ampicillin synergistically stimulated the selection of ampicillin resistance and the cross-selection of resistance to three other antibiotics (i.e., ciprofloxacin, chloramphenicol, and tetracycline). Resistance levels of mutants selected from co-exposure were significantly higher than those of mutants selected from ampicillin exposure only. The comparative genomic and transcriptomic analyses indicate that distinct and diversified genetic mutations in ampicillin- and ciprofloxacin-resistant mutants were selected from co-exposure, which likely caused holistic transcriptional regulation and the increased antibiotic resistance. Together, the findings provide valuable fundamental insights into the development of antibiotic resistance under environmentally relevant conditions, as well as the underlying molecular mechanisms of the elevated antibiotic resistance induced by the exposure to pesticides.

Significance statement

Antibiotic resistance is a major threat to public health globally. Besides clinically relevant environments, the emergence and spread of resistant bacteria in non-clinical environments can also potentially pose risks of therapy failures. This study showed that the long-term, environment-level exposure to pesticides with and without antibiotics significantly stimulated the development of greater antibiotic resistance. The resistant strains selected from the exposure to pesticides are genetically and metabolically distinct from the ones selected by the antibiotic only. Although it is still being debated regarding whether or not a large use of antibiotics in plant agriculture is harmful, our findings provide the first fundamental evidence that greater concerns of antibiotic resistance may result if antibiotics are applied together with non-antibiotic pesticides.
Transcranial magnetic stimulation during British Sign Language production reveals monitoring of discrete linguistic units in left superior parietal lobule
Authors: Vinson David , Fox Neil , Devlin Joseph T. , Emmorey Karen , Vigliocco Gabriella
Published: June 2019

Successful human hand and arm movements are typically carried out by combining visual, motoric, and proprioceptive information in planning, initiation, prediction, and control. The superior parietal lobule (SPL) has been argued to play a key role in integrating visual and motoric information particularly during grasping of objects and other such tasks which prioritise visual information. However, sign language production also engages SPL even though fluent signers do not visually track their hands or fixate on target locations. Does sign language production simply rely on the motoric/ proprioceptive processes engaged in visually guided action, or do the unique characteristics of signed languages change these processes? Fifteen fluent British Sign Language users named pictures while we administered transcranial magnetic stimulation (TMS) to left SPL, a control site, or no TMS. TMS to SPL had very specific effects: an increased rate of (sign-based) phonological substitution errors for complex two-handed signs (those requiring hand contact), but TMS did not slow or otherwise impair performance. Thus, TMS decreased the likelihood of detecting or correcting phonological errors during otherwise successful bimanual coordination, but it did not noticeably alter fine movement control. These findings confirm that for fluent signers SPL has adapted to monitor motor plans for discrete hand configurations retrieved from memory as well as more fine-grained aspects of visually guided actions.
Quantifying phenotypic variability and fitness in finite microbial populations
Authors: Levien Ethan , Kondev Jane , Amir Ariel
Published: June 2019

In isogenic microbial populations, phenotypic variability is generated by a combination of intrinsic factors, specified by cell physiology, and environmental factors. Here we address the question: how does phenotypic variability of a microbial population affect its fitness? While this question has previously been studied for exponentially growing populations, the situation when the population size is kept fixed has received much less attention. We show that in competition experiments with multiple microbial species, the fitness of the population can be determined from the distribution of phenotypes, provided all variability is due to intrinsic factors. We then explore how robust the relationship between fitness and phenotypic variability is to environmental fluctuations. We find that this relationship breaks down in the presence of environmental fluctuations, and derive a simple formula relating the average fitness of a population to the phenotype distribution and fluctuations in the instantaneous population growth rate. Using published experimental data we demonstrate how our formulas can be used to discriminate between intrinsic and environmental contributions to phenotypic diversity.
Nicotinamide riboside augments the human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial
Authors: Elhassan Yasir S , Kluckova Katarina , Fletcher Rachel S , Schmidt Mark , Garten Antje , Doig Craig L , Cartwright David M , Oakey Lucy , Burley Claire V , Jenkinson Ned , Wilson Martin , Lucas Samuel J E , Akerman Ildem , Seabright Alex , Lai Yu-Chiang , Tennant Daniel A , Nightingale Peter , Wallis Gareth A , Manolopoulos Konstantinos N , Brenner Charles , Philp Andrew , Lavery Gareth G
Published: June 2019

NAD+ is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD+ metabolome, and questioned if tissue NAD+ levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain.
Distinct Basket Nucleoporins roles in Nuclear Pore Function and Gene Expression: Tpr is an integral component of the TREX-2 mRNA export pathway
Authors: Aksenova Vasilisa , Lee Hang Noh , Smith Alexandra , Chen Shane , Bhat Prasanna , Iben James , Echeverria Carlos , Fontoura Beatriz , Arnaoutov Alexei , Dasso Mary
Published: June 2019

Nuclear pore complexes (NPCs) are important for many processes beyond nucleocytoplasmic trafficking, including protein modification, chromatin remodeling, transcription, mRNA processing and mRNA export. The multi-faceted nature of NPCs and the slow turnover of their components has made it difficult to understand the role of basket nucleoporins (Nup153, Nup50 and Tpr) in these diverse processes. To address this question, we used anAuxin-InducedDegron (AID) system to distinguish roles of basket nucleoporins: Loss of individual nucleoporins caused distinct alteration in patterns of nucleocytoplasmic trafficking and gene expression. Importantly, Tpr elimination caused rapid and pronounced changes in transcriptomic profiles within two hours of auxin addition. These changes were dissimilar to shifts observed after loss of Nup153 or Nup50, but closely related to changes after depletion of mRNA export receptor NXF1 or the GANP subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex. Moreover, GANP association to NPCs was specifically disrupted upon TPR depletion. Together, our findings demonstrate a unique and pivotal role of Tpr in regulating gene expression through GANP- and/or NXF1-dependent mRNA nuclear export.
Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder
Authors: Alberry Bonnie LJ , Castellani Christina A , Singh Shiva M
Published: June 2019

Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the United States and Canada. Children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood. We have modeled FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We report an association between adult hippocampal gene expression and prenatal ethanol exposure followed by postnatal separation stress that is related to behavioral changes. Clustering of expression profiles through weighted gene co-expression network analysis (WGCNA) identifies a set of transcripts, module 19, associated with anxiety-like behavior (r = 0.79, p = 0.002) as well as treatment group (r = 0.68, p = 0.015). Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation (q = 2e-12, p = 0.004, respectively). Together, transcriptional control in the hippocampus is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.

SUMMARY STATEMENT

Mouse hippocampal gene expression alterations following prenatal alcohol exposure and maternal separation are associated with behavioral deficits. Transcriptomic analysis implicates systems defect involving RNA processing, specifically including downregulation of Polr2a.
Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria
Authors: Labana Puneet , Dornan Mark H. , Lafrenière Matthew , Czarny Tomasz L. , Brown Eric D. , Pezacki John P. , Boddy Christopher N.
Published: June 2019

Multi-drug resistant bacteria present an urgent threat to modern medicine, creating a desperate need for the discovery of antibiotics with new modes of action. Natural products whose unique highly diverse structures have been shaped by evolution to possess biologically relevant activity are an ideal discovery ground for new antibiotics with new mechanisms of action. In this study we elucidate the mechanism of action of the Gram-positive antibiotic armeniaspirol, a compound for which resistant bacteria could not be selected for. We show that armeniaspirol inhibits the ATP-dependent proteases ClpXP and ClpYQ in biochemical assays and in the Gram-positive bacteria Bacillus subtilis. We then show that this activity dysregulates key proteins involved in the divisome and elongasome including FtsZ, DivIVA, and MreB all of which are known to inhibit cell division when upregulated. Inhibition of ClpXP and ClpYQ leading to dysregulation of the divisome and elongasome represents a new mechanism of action and armeniaspirol is the first known natural product inhibitor of the coveted anti-virulence target ClpP. Thus armeniaspirol is the lead compound for a promising new class of antibiotics with a unique pharmacology and a novel mechanism for combating antimicrobial resistance, making it a highly promising candidate for further development.
Classic and introgressed selective sweeps shape mimicry loci across a butterfly adaptive radiation
Authors: Moest Markus , Van Belleghem Steven M. , James Jennifer E. , Salazar Camilo , Martin Simon H. , Barker Sarah L. , Moreira Gilson R. P. , Mérot Claire , Joron Mathieu , Nadeau Nicola J. , Steiner Florian M. , Jiggins Chris D.
Published: June 2019

Natural selection leaves distinct signatures in the genome that can reveal the targets and history of adaptive evolution. By analysing high-coverage genome sequence data from four major colour pattern loci sampled from nearly 600 individuals in 53 populations, we show pervasive selection on wing patterns across theHeliconiusadaptive radiation. The strongest signatures correspond to loci with the greatest phenotypic effects, consistent with visual selection by predators, and are found in colour patterns with geographically restricted distributions. These recent sweeps are similar between co-mimics and indicate colour pattern turn-over events despite strong stabilizing selection. Using simulations we compare sweep signatures expected under classic hard sweeps with those resulting from adaptive introgression, an important aspect of mimicry evolution inHeliconius. Simulated recipient populations show a distinct ‘volcano’ pattern with peaks of increased genetic diversity around the selected target, consistent with patterns found in some populations. Our genomic data provide unprecedented insights into the recent history of selection across theHeliconiusadaptive radiation.
Ecophysiology ofpotentilla gracilisdouglas ex hook (rosaceae): effects of night temperature and water stress on photosynthetic gas exchange
Authors: Nepal Madhav P. , Berg Virginia S.
Published: June 2019

Plants in stressful environments have evolved strategies to cope with fluctuating environmental conditions.Potentilla gracilis, also known as Alpine Cinquefoil, grows in alpine meadows of the Rocky Mountains (USA), and is subjected to wide ranges of temperature, light intensity and water availability on a time scale of minutes to days during the growing season. Leaves often freeze to a brittle state at night, are exposed to high radiation while still frosty, dehydrate to wilting during the following light period, and then repeat the cycle the following day. The main objective of this research was to determine the effect of night temperature on subsequent photosynthetic gas exchange inP. gracilis. We used a photosynthetic gas exchange system to compare assimilation and stomatal conductance from light response curves of cold-acclimatedP. gracilisfollowing warm and chilling nights, and for plants at different water potentials. From the light response curves, dark respiration, light compensation point, maximum assimilation, light saturation point, and inhibition of photosynthesis were determined and were compared among the same plants under varying conditions. Assimilation and stomatal conductance decreased with the fall in measurement temperature, following chilling nights, and with the severity of water stress. Low night temperature and high photon flux density during the daytime, which are very common during the growing season in the field, cause a reduction in photosynthesis of the plant. The probable underlying damage during inhibition is likely repairable indicating protection rather than damage. The cold nocturnal temperature, with its less efficient biochemical repair capabilities, may partly be responsible for the reduction in assimilation of the following day.P. gracilisspecies exhibited persistent acquired freezing tolerance; substantial photosynthetic productivity over a wide range of light intensity and temperature; and significant tolerance of, and rapid recovery from, severe drought; making a maximum use of often challenging resources.
Small molecule inhibition of PIKFYVE kinase rescues gain- and loss-of-functionC9ORF72ALS/FTD disease processesin vivo
Authors: Staats K. A. , Seah C. , Sahimi A. , Wang Y. , Koutsodendris N. , Lin S. , Kim D. , Chang W-H. , Gray K. A. , Shi Y. , Li Y. , Chateau M. , Vangoor V. R. , Senthilkumar K. , Pasterkamp R. J. , Cannon P. , Zlokovic B.V. , Ichida J. K.
Published: June 2019

The most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion (HRE) inC9ORF72that contributes to neurodegeneration by both loss-of-function (decreased C9ORF72 protein levels) and gain-of-function (e.g. dipeptide repeat protein production) mechanisms. Although therapeutics targeting the gain-of-function mechanisms are in clinical development, it is unclear if these will be efficacious given the contribution of C9ORF72 loss-of-function processes to neurodegeneration. Moreover, there is a lack of therapeutic strategies forC9ORF72ALS/FTD with demonstrated efficacyin vivo. Here, we show that small molecule inhibition of PIKFYVE kinase rescues both loss- and gain-of-function C9ORF72 disease mechanismsin vivo. We find that the reduction of C9ORF72 in mouse motor neurons leads to a decrease in early endosomes. In contrast, treatment with the PIKFYVE inhibitor apilimod increases the number of endosomes and lysosomes. We show that reduced C9ORF72 levels increases glutamate receptor levels in hippocampal neurons in mice, and that apilimod treatment rescues this excitotoxicity-related phenotypein vivo. Finally, we show that apilimod also alleviates the gain-of-function pathology induced by theC9ORF72HRE by decreasing levels of dipeptide repeat proteins derived from both sense and antisenseC9ORF72transcripts in hippocampal neuronsin vivo. Our data demonstrate the neuroprotective effect of PIKFYVE kinase inhibition in both gain- and loss-of-function murine models ofC9ORF72ALS/FTD.
Functional clusters of neurons in layer 6 of macaque V1
Authors: Hawken Michael J , Shapley Robert M , Disney Anita A , Garcia-Marin Virginia , Henrie JA , Henry Christopher A , Johnson Elizabeth M , Joshi Siddartha , Kelly Jenna G , Ringach Dario L , Xing Dajun
Published: June 2019

Abstrac

Layer 6 appears to perform a very important role in the function of macaque primary visual cortex, V1, but not enough is understood about the functional characteristics of neurons in the layer 6 population. It is unclear to what extent the population is homogeneous with respect to their visual properties or if one can identify distinct sub-populations. Here we performed a cluster analysis based on measurements of the responses of single neurons in layer 6 of primary visual cortex to achromatic grating stimuli that varied in orientation, direction of motion, spatial and temporal frequency, and contrast. The visual stimuli were presented in a stimulus window that was also varied in size. Using the responses to parametric variation in these stimulus variables we extracted a number of tuning response measures and used them in the cluster analysis. Six main clusters emerged along with some smaller clusters. Additionally we asked whether parameter distributions from each of the clusters were statistically different. There were clear separations of parameters between some of the clusters, particularly for f1/f0 ratio, direction selectivity, and temporal frequency bandwidth but other dimensions also showed differences between clusters. Our data suggest that in layer 6, across the spatial extent of a single cortical hypercolumn, there are multiple parallel circuits that provide information about different aspects of the visual stimulus.
Expansion of apical extracellular matrix underlies the morphogenesis of a recently evolved structure
Authors: Smith Sarah Jacquelyn , Davidson Lance A. , Rebeiz Mark
Published: June 2019

One of the fundamental gaps in our knowledge of the evolution of novel structures is understanding how the morphogenetic processes that form these structures arise. Here, we traced the cellular development of a morphological novelty, the posterior lobe ofD. melanogaster. We found that this genital outgrowth forms through an extreme increase in cell height. By examining the apical extracellular matrix (aECM), we uncovered a vast network associated with the developing genitalia of lobed and non-lobed species. We observed that cells which will form the posterior lobe show expanded expression of the aECM protein Dumpy which connects them to the ancestral aECM network. Further analysis demonstrated a required role for Dumpy in cell height increase during development. We propose that the aECM presents a rich reservoir for generating morphological novelty, in addition to highlighting a yet unseen role for aECM in regulating extreme cell height.
Functional conservation of lncRNAJPXdespite sequence and structural divergence
Authors: Karner Heather M. , Webb Chiu-Ho , Carmona Sarah , Liu Yu , Lin Benjamin , Erhard Micaela , Chan Dalen , Baldi Pierre , Spitale Robert C. , Sun Sha
Published: June 2019

Long noncoding RNAs (lncRNAs) have been identified in all eukaryotes and are most abundant in the human genome. However, the functional importance and mechanisms of action for human lncRNAs are largely unknown. Using comparative sequence, structural, and functional analyses, we characterize the evolution and molecular function of human lncRNAJPX. We find that humanJPXand its mouse homolog, lncRNAJpx, have deep divergence in their nucleotide sequences and RNA secondary structures. Despite such differences, both lncRNAs demonstrate robust binding to CTCF, a protein that is central toJpx’s role in X chromosome inactivation. In addition, our functional rescue experiment usingJpx-deletion mutant cells, shows that humanJPXcan functionally complement the loss ofJpxin mouse embryonic stem cells. Our findings support a model for functional conservation of lncRNAs independent from sequence and structural changes. The study provides mechanistic insight into the evolution of lncRNA function.
Loci specific epigenetic drug sensitivity
Authors: Zhang Thanutra , Pilko Anna , Wollman Roy
Published: June 2019

Therapeutic targeting of epigenetic modulators offers a novel approach to the treatment of several diseases including cancer, heart diseases and AIDS. The cellular consequences of chemical compounds that target epigenetic regulators (epi-drugs) are complex. Epi-drugs affect global cellular phenotypes and cause local changes to gene expression due to alteration of a gene chromatin environment. Despite increasing use in the clinic, the mechanisms responsible for cellular changes are unclear. Specifically, to what degree the effects are a result of cell-wide changes or disease related locus specific effects is unknown. Here we developed a platform to systematically and simultaneously investigate the sensitivity of epi-drugs at hundreds of genomic locations by combining DNA barcoding, unique split-pool encoding and single cell expression measurements. Internal controls are used to isolate locus specific effects separately from any global consequences these drugs have. Using this platform we discovered wide-spread loci specific sensitivities to epi-drugs for three distinct epi-drugs that target histone deacetylase, DNA methylation and bromodomain proteins. By leveraging ENCODE data on chromatin modification, we identified features of chromatin environments that are most likely to be affected by epi-drugs. The measurements of loci specific epi-drugs sensitivities will pave the way to the development of targeted therapy for personalized medicine.
Microstructural Abnormalities of Substantia Nigra in Parkinson’s disease: A Neuromelanin Sensitive MRI Atlas Based Study
Authors: Safai Apoorva , Prasad Shweta , Saini Jitender , Pal Pramod Kumar , Ingalhalikar Madhura
Published: June 2019

Microstructural changes associated with degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson’s disease (PD) have been studied using Diffusion Tensor Imaging (DTI). However, these studies show inconsistent results, mainly due to methodological variations in delineation of SNc. To mitigate this, our work aims to construct a probabilistic atlas of SNc based on a Neuromelanin sensitive MRI (NMS-MRI) sequence and demonstrate its applicability to investigate microstructural changes on a large dataset of PD. Using manual segmentation and deformable registrations, we create a novel SNc atlas in the MNI space using NMS-MRI sequences of 27 healthy controls (HC). We employ this atlas to evaluate the diffusivity and anisotropy measures, derived from diffusion MRI in the SNc of 135 patients with PD and 99 HCs. Our observations of significantly increased diffusivity measures provide evidence of microstructural abnormalities in PD. However, no changes in the anisotropy were observed. Moreover, the asymmetry in abnormalities is prominent as the left SNc showed significant increase in diffusivity, and a reduction in FA when compared to the right SNc. Further the diffusivity and FA values also demonstrated a trend when correlated with the PD severity scores. Overall, from this work we establish a normative baseline for the SNc region of interest using NMS-MRI while the application on PD data emphasizes on the contribution of diffusivity measures rather than anisotropy of white matter in PD.
Draft genome assemblies using sequencing reads from Oxford Nanopore Technology and Illumina platforms for four species of North American killifish from the Fundulus genus
Authors: Johnson Lisa K. , Sahasrabudhe Ruta , Gill Tony , Roach Jennifer , Froenicke Lutz , Brown C. Titus , Whitehead Andrew
Published: June 2019

Draft de novo reference genome assemblies were obtained from four North American killifish species (Fundulus xenicus, Fundulus catenatus, Fundulus nottii, and Fundulus olivaceus) using sequence reads from Illumina and Oxford Nanopore Technologies’ PromethION platforms. For each species, the PromethION platform was used to generate 30-45x sequence coverage, and the Illumina platform was used to generate 50-160x sequence coverage. Contig N50 values ranged from 0.4 Mb to 2.7 Mb, and BUSCO scores were consistently above 90% complete using the Eukaryota database. Draft assemblies and raw sequencing data are available for public use. We encourage use and re-use of these data for assembly benchmarking and external analyses.