bluuebunny/crossref_metadata_2025_split huggingface dataset:
Raising the stakes: Loss of efflux-pump regulation decreases meropenem susceptibility in Burkholderia pseudomallei
Authors: Sarovich Derek S. , Webb Jessica R. , Pitman Matthew C. , Viberg Linda T. , Mayo Mark , Baird Robert W. , Robson Jennifer M. , Currie Bart J. , Price Erin P. 
Published: October 2017

AbstractBurkholderia pseudomallei, the causative agent of the high-mortality disease melioidosis, is a Gram-negative bacterium that is naturally resistant to many antibiotics. There is no vaccine for melioidosis, and effective eradication is reliant on biphasic and prolonged antibiotic administration. The carbapenem drug, meropenem, is the current gold-standard option for treating severe melioidosis. Intrinsic B. pseudomallei resistance towards meropenem has not yet been documented; however, resistance could conceivably develop over the course of infection, leading to prolonged sepsis and treatment failure. Here, we document 11 melioidosis cases in which B. pseudomallei isolates developed decreased susceptibility towards meropenem during treatment, including two cases not treated with this antibiotic. Meropenem minimum inhibitory concentrations increased over time from 0.5-0.75 to 3-8 μg/mL. Using comparative genomics, we identified multiple mutations affecting multidrug resistance-nodulation-division (RND) efflux pump regulators, leading to over-expression of their corresponding pumps. The most commonly affected pump was AmrAB-OprA, although alterations in the local regulators of BpeEF-OprC or BpeAB-OprB were observed in three cases. This study confirms the role of RND efflux pumps in decreased meropenem susceptibility in B. pseudomallei. Further, we document two concerning examples of severe melioidosis where the reduced treatment efficacy of meropenem was associated with a fatal outcome.Significance StatementThe bacterium Burkholderia pseudomallei, which causes the often-fatal tropical disease melioidosis, is difficult to eradicate. Due to high levels of intrinsic antibiotic resistance, only a handful of antibiotics are effective against this pathogen. One of these, meropenem, is commonly used in the treatment of melioidosis patients who are unresponsive to other treatments or are critically ill. Here, we describe 11 melioidosis cases whereby patients exhibited prolonged or repeated infections that were associated with the development of decreased meropenem susceptibility. We identified the molecular basis for this decreased susceptibility in latter B. pseudomallei isolates obtained from these patients, and functionally confirmed the mechanism conferring this phenotype. Our findings have important ramifications for the diagnosis, treatment and management of life-threatening melioidosis cases.
Pathways-wide genetic risks in Chlamydial infections overlap between tissue tropisms: A genome-wide association scan
Authors: Roberts Chrissy h. , Ouberg Sander , Preston Mark D. , de Vries Henry J.C. , Holland Martin J , Morre Servaas 
Published: October 2017

ABSTRACTChlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection and can lead to tubal factor infertility, a disease characterised by fibrosis of the fallopian tubes. Genetic polymorphisms in molecular pathways involving G protein coupled receptor signalling, the Akt/PI3K cascade, the mitotic cell cycle and immune response have been identified in association with the development of trachomatous scarring, an ocular form of chlamydia-related fibrotic pathology. In this case control study, we performed genome-wide association and pathways based analysis in a sample of 71 Dutch women who attended an STI clinic who were seropositive for Chlamydia trachomatis antibodies and 169 high risk Dutch women who sought similar health services but who were seronegative. We identified two regions of within-gene SNP association with Chlamydia trachomatis serological response and found that GPCR signalling and cell cycle pathways were also associated with the trait. These pathway level associations appear to be common to immunological sequelae of Chlamydial infections in both ocular and urogenital tropisms. These pathways may be central mediators of human refractoriness to chlamydial diseases.
The Polycomb-dependent epigenome controls β-cell dysfunction, dedifferentiation and diabetes
Authors: Lu Tess Tsai-Hsiu , Heyne Steffen , Dror Erez , Casas Eduard , Leonhardt Laura , Boenke Thorina , Yang Chih-Hsiang , Sagar  , Arrigoni Laura , Dalgaard Kevin , Teperino Raffaele , Enders Lennart , Selvaraj Madhan , Ruf Marius , Raja Sunil Jayaramaiah , Xie Huafeng , Boenisch Ulrike , Orkin Stuart H. , Lynn Francis C , Hoffman Brad G. , Grün Dominic , Vavouri Tanya , Lempradl Adelheid , Pospisilik J. Andrew 
Published: October 2017

SUMMARYChromatin is the physical template that stabilizes and specifies transcriptional programs. To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combined deep epigenome mapping with single cell transcriptomics to mine for evidence of chromatin dysregulation in type-2 diabetes. We identify two chromatin-state signatures that track the trajectory of β-cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-domains and a loss of expression at a subclass of highly active domains containing key lineage-defining genes. β-cell specific deletion of Polycomb (Eed/PRC2) triggers parallel transcriptional signatures. Intriguingly, these β-cell Eed-knockouts also exhibit highly penetrant hyperglycemia-independent dedifferentiation indicating that Polycomb dysregulation sensitizes the β-cell for dedifferentiation. These findings provide novel resources for exploring transcriptional and epigenetic control of β-cell (dys)function. They identify PRC2 as necessary for long-term maintenance of β-cell identity. The data suggest a two-hit model for loss of β-cell identity in diabetes and highlight epigenetic therapeutic potential to block dedifferentiation.
HuD is a neural enhancer of global translation acting on mTORC1-responsive genes and sponged by the Y3 small non-coding RNA
Authors: Zuccotti Paola , Tebaldi Toma , Peroni Daniele , Köhn Marcel , Gasperini Lisa , Potrich Valentina , Dudnakova Tatiana , Sanguinetti Guido , Conti Luciano , Macchi Paolo , Tollervey David , Hüttelmaier Stefan , Quattrone Alessandro 
Published: October 2017

SummaryThe RNA-binding protein HuD promotes neurogenesis and favors recovery from peripheral axon injury. HuD interacts with many mRNAs, altering both stability and translation efficiency. UV-crosslinking and analysis of cDNA (CRAC) generated a nucleotide resolution map of the HuD RNA interactome in motor neuron-like cells. HuD target sites were identified in 1304 mRNAs, predominantly in the 3’UTR, with enrichment for genes involved in protein synthesis and axonogenesis. HuD bound many mRNAs encoding mTORC1-responsive ribosomal proteins and translation factors. Altered HuD expression correlated with the translational efficiency of these mRNAs and overall protein synthesis, in a mTORC1-independent fashion. The predominant HuD target was the abundant, small non-coding RNA Y3, which represented 70% of HuD interaction signal. Y3 functions as a molecular sponge for HuD, dynamically limiting its activity. These findings uncover an alternative route to the mTORC1 pathway for translational control in motor neurons that is tunable by a small non-coding RNA.Graphical abstract
Long-Term Leisure-Time Physical Activity and Other Health Habits as Predictors of Objectively Monitored Late-Life Physical Activity – A 40-Year Twin Study
Authors: Waller Katja , Vähä-Ypyä Henri , Törmäkangas Timo , Hautasaari Pekka , Lindgren Noora , Iso-Markku Paula , Heikkilä Kauko , Rinne Juha , Kaprio Jaakko , Sievänen Harri , Kujala Urho M. 
Published: October 2017

AbstractIMPORTANCEModerate-to-vigorous physical activity (MVPA) in old age is an important indicator of good health and functional capacity enabling independent living.OBJECTIVETo investigate whether physical activity and other health habits at ages 31-48 years predict objectively measured MVPA decades later.DESIGN, SETTING, AND PARTICIPANTSThis prospective twin cohort study in Finland comprised 616 individuals (197 complete twin pairs, including 91 monozygotic pairs, born 1940-1944), who responded to baseline questionnaires in 1975, 1981, and 1990, and participated in accelerometer monitoring at follow-up (mean age, 73 years).EXPOSURESPrimary exposure was long-term leisure-time physical activity, 1975-1990 (LT-mMET index). Covariates were body mass index (BMI), work-related physical activity, smoking, heavy alcohol use and health status in 1990, and socioeconomic status.MAIN OUTCOMES AND MEASURESPhysical activity was measured with a waist-worn triaxial accelerometer (at least 10 hours per day for at least 4 days) to obtain daily mean MVPA values.RESULTSHigh baseline LT-mMET index predicted higher amounts of MVPA (increase in R2 of 6.9% after age and sex adjustment, P<.001) at follow-up. After addition of BMI to the regression model, the R2 value of the whole multivariate model was 17.2%, and with further addition of baseline smoking, socioeconomic status, and health status, the R2 increased to 20.3%. In pairwise analyses, differences in MVPA amount were seen only among twin pairs who were discordant at baseline for smoking (n=40 pairs, median follow-up MVPA 25 vs. 35 min, P=.037) or for health status (n=69 pairs, 30 vs. 44 min, P=.014). For smoking, the difference in MVPA also was seen for monozygotic pairs, but for health status, it was seen only for dizygotic pairs. Mediation analysis showed that shared genetic factors explained 82% of the correlation between LT-mMET and MVPA.CONCLUSIONS AND RELEVANCELow leisure-time physical activity at younger age, overweight, smoking, low socioeconomic status, and health problems predicted low MVPA in old age in individual-based analyses. However, based on the pairwise analyses and quantitative trait modeling, genetic factors and smoking seem to be important determinants of later-life MVPA.
Normative Brain Size Variation and the Remodeling of Brain Shape in Humans
Authors: Reardon P. K. , Vandekar Simon N. , Liu Siyuan , Patel Raihaan , Park Min Tae M. , Alexander-Bloch Aaron , Seidlitz Jakob , Clasen Liv S. , Blumenthal Jonathan D. , Giedd Jay N. , Gur Ruben C. , Gur Raquel E. , Lerch Jason P. , Chakravarty M. Mallar , Satterthwaite Theodore D. , Shinohara Russel T. , Raznahan Armin 
Published: October 2017

AbstractEvolutionary and developmental increases in primate brain size have been accompanied by systematic shifts in the proportionality of different primate brain systems. However, it remains unknown if and how brain patterning varies across the more than 2-fold inter-individual variation in brain size that occurs amongst typically-developing humans. Using in vivo neuroimaging data from 2 independent cohorts totaling nearly 3000 individuals, we find that larger-brained humans show preferential areal expansion within specific fronto-parietal cortical networks (default mode, dorsal attentional) and related subcortical regions, at the expense of primary sensory/motor systems. This targeted areal expansion recapitulates cortical remodeling across evolution, manifests by early childhood and is linked to molecular signatures of heightened metabolic cost. Our results define a new organizing principle in human brain patterning which governs the highly-coordinated remodeling of human brain shape as a function of naturally-occurring variations in brain size.One Sentence SummaryA hodologically and metabolically expensive brain network is preferentially expanded in larger-brained humans.
Demographic fluctuation of community-acquired antibiotic-resistant Staphylococcus aureus lineages: potential role of flimsy antibiotic exposure
Authors: Gustave Claude-Alexandre , Tristan Anne , Martins-Simoes Patricia , Stegger Marc , Benito Yvonne , Andersen Paal Skytt , Bes Michèle , Glaser Philippe , Laurent Frédéric , Wirth Thierry , Vandenesch François 
Published: October 2017

AbstractCommunity-acquired (CA) -as opposed to hospital acquired- methicillin-resistant Staphylococcus aureus (MRSA) lineages arose worldwide during the 1990s. To determine which factors, including selective antibiotic pressure, govern the expansion of two major lineages of CA-MRSA, namely “USA300” in Northern America and the “European ST80” in North Africa, Europe and the Middle East, we explored virulence factor expression, and fitness levels with or without antibiotics. The sampled strains were collected in a temporal window representing various steps of the epidemics, reflecting predicted effective population size as inferred from whole genome analysis. In addition to slight variations in virulence factor expression and biofilm production that might influence the ecological niches of theses lineages, competitive fitness experiments revealed that the biological cost of resistance to methicillin, fusidic-acid and fluoroquinolone is totally reversed in the presence of trace amount of antibiotics. Our results suggest that low-level antibiotics exposure in human and animal environments contributed to the expansion of both European-ST80 and USA300 lineages in community setting. This surge was likely driven by antibiotic (ab)use promoting the accumulation of antibiotics as environmental pollutants. The current results provide a novel link between effective population size increase of a pathogen and a selective advantage conferred by antibiotic resistance.
Memory consolidation is linked to spindle-mediated information processing during sleep
Authors: Cairney S.A. , Guttesen A. , El Marj N. , Staresina B.P. 
Published: October 2017

AbstractHow are brief encounters transformed into lasting memories? Previous research has established the role of non-rapid eye movement (NREM) sleep, along with its electrophysiological signatures of slow oscillations (SOs) and spindles, for memory consolidation. More recently, experimental manipulations have demonstrated that NREM sleep provides a window of opportunity to selectively strengthen particular memory traces via the delivery of sensory cues. It has remained unclear, however, whether experimental memory cueing triggers the brain’s endogenous consolidation mechanisms (linked to SOs and/or spindles) and whether those mechanisms in turn mediate effective processing of the cue information. Here we devised a novel paradigm in which associative memories (adjective-object and adjective-scene pairs) were selectively cued during a post-learning nap, successfully stabilising next-day retention relative to non-cued memories. First, we found that compared to novel control adjectives, memory cues were accompanied by an increase in fast spindles coupled to SO up states. Critically, EEG pattern decodability of the associated memory category (object vs. scene) was temporally linked to cue-induced spindles and predicted next-day retrieval performance across participants. These results provide highly controlled empirical evidence for an information processing role of sleep spindles in service of memory consolidation.
Verbal paired associates and the hippocampus: The role of scenes
Authors: Clark Ian A. , Kim Misun , Maguire Eleanor A. 
Published: October 2017

ABSTRACTIt is widely agreed that patients with bilateral hippocampal damage are impaired at binding pairs of words together. Consequently, the verbal paired associates (VPA) task has become emblematic of hippocampal function. This VPA deficit is not well understood, and is particularly difficult for hippocampal theories with a visuospatial bias to explain (e.g., cognitive map and scene construction theories). Resolving the tension among hippocampal theories concerning the VPA could be important for leveraging a fuller understanding of hippocampal function. Notably, VPA tasks typically use high imagery concrete words and so conflate imagery and binding. To determine why VPA engages the hippocampus, we devised an fMRI encoding task involving closely matched pairs of scene words, pairs of object words and pairs of very low imagery abstract words. We found that the anterior hippocampus was engaged during processing of both scene and object word pairs in comparison to abstract word pairs, despite binding occurring in all conditions. This was also the case when just subsequently remembered stimuli were considered. Moreover, for object word pairs, fMRI activity patterns in anterior hippocampus were more similar to those for scene imagery than object imagery. This was especially evident in participants who were high imagery users, and not in mid and low imagery users. Overall, our results show that hippocampal engagement during VPA, even when object word pairs are involved, seems to be evoked by scene imagery rather than binding. This may help to resolve the issue that visuospatial hippocampal theories have in accounting for verbal memory.
Roosting in exposed microsites by a nocturnal bird, the rufous-cheeked nightjar: implications for water balance under current and future climate conditions
Authors: O’Connor Ryan S. , Brigham R. Mark , McKechnie Andrew E. 
Published: October 2017

AbstractNocturnally active birds roosting in exposed diurnal microsites with intense solar radiation can experience operative temperatures (Te) that markedly differ from air temperature (Ta). Quantifying Tethus becomes important for accurately modeling energy and water balance. We measured Teat roost and nest sites used by Rufous-cheeked Nightjars (Caprimulgus rufigena) with three-dimensionally printed biophysical models covered with the integument and plumage of a bird. Additionally, we estimated site-specific diurnal water requirements for evaporative cooling by integrating Teand Taprofiles with evaporative water loss (EWL) data for Rufous-cheeked Nightjars. Between 12:00 and 15:00 hrs, average Teat roost sites varied from 33.1 to 49.9 °C, whereas at the single nest site Teaveraged 51.4 °C. Average diurnal EWL, estimated using Te, was as high as 10.5 and 11.3 g at roost and nest sites, respectively, estimates 3.8- and 4.0-fold greater, respectively, than when calculated with Taprofiles. These data illustrate that under current climatic conditions, Rufous-cheeked Nightjars can experience EWL potentially approaching their limits of dehydration tolerance. In the absence of microsite changes, climate change during the 21stcentury could perhaps create thermal conditions under which Rufous-cheeked Nightjars exceed dehydration tolerance limits before the onset of their nocturnal active phase.
Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin
Authors: Lee Chul-Hwan , Yu Jia-Ray , Kumar Sunil , Jin Ying , Kaneko Syuzo , Hamilton Andrew D. , Reinberg Danny 
Published: October 2017

SUMMARYPRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here, we report a step-wise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifest little activity in vivo but, unexpectedly, exhibited similar chromatin association as wild-type PRC2, indicating an uncoupling of PRC2 activity and recruitment. With genetic and chemical tools, we further demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2Y646X oncogenic mutations. These results revealed critical implications to the regulation and biology of PRC2 and a novel vulnerability in tackling PRC2-addicted cancers.
An intermittent control model predicts the triphasic muscles activity during hand reaching
Authors: Leib Raz , d’Avella Andrea , Nisky Ilana 
Published: October 2017

AbstractThere are numerous ways to reach for an apple hanging from a tree. Yet, our motor system uses a specific muscle activity pattern to generate reaching movements that have similar characteristics. For many decades, we know that this pattern features activity bursts and silent periods. We suggest that these bursts are a strong evidence against the common view that the brain continuously controls the commands to the muscles. Instead, we suggest a model that changes these commands in a discrete way. We use unsupervised machine learning to identify transitions in the state of the muscles, and show that fitting a discrete model to the kinematics of movement using only one parameter predicts the transitions in the state of the muscles. Such discrete controller suggests that the brain reduces the complexity of the motor control problem as well as the wear-and-tear of the muscles by sending commands to the muscles at sparse times. Identifying this discrete controller can be applied in the control of prostheses and physical human-robot interaction systems such as exoskeletons and assistive devices.
Exploring the single-cell RNA-seq analysis landscape with the scRNA-tools database
Authors: Zappia Luke , Phipson Belinda , Oshlack Alicia 
Published: October 2017

AbstractAs single-cell RNA-sequencing (scRNA-seq) datasets have become more widespread the number of tools designed to analyse these data has dramatically increased. Navigating the vast sea of tools now available is becoming increasingly challenging for researchers. In order to better facilitate selection of appropriate analysis tools we have created the scRNA-tools database (www.scRNA-tools.org) to catalogue and curate analysis tools as they become available. Our database collects a range of information on each scRNA-seq analysis tool and categorises them according to the analysis tasks they perform. Exploration of this database gives insights into the areas of rapid development of analysis methods for scRNA-seq data. We see that many tools perform tasks specific to scRNA-seq analysis, particularly clustering and ordering of cells. We also find that the scRNA-seq community embraces an open-source approach, with most tools available under open-source licenses and preprints being extensively used as a means to describe methods. The scRNA-tools database provides a valuable resource for researchers embarking on scRNA-seq analysis and records of the growth of the field over time.Author summaryIn recent years single-cell RNA-sequeing technologies have emerged that allow scientists to measure the activity of genes in thousands of individual cells simultaneously. This means we can start to look at what each cell in a sample is doing instead of considering an average across all cells in a sample, as was the case with older technologies. However, while access to this kind of data presents a wealth of opportunities it comes with a new set of challenges. Researchers across the world have developed new methods and software tools to make the most of these datasets but the field is moving at such a rapid pace it is difficult to keep up with what is currently available. To make this easier we have developed the scRNA-tools database and website (www.scRNA-tools.org). Our database catalogues analysis tools, recording the tasks they can be used for, where they can be downloaded from and the publications that describe how they work. By looking at this database we can see that developers have focued on methods specific to single-cell data and that they embrace an open-source approach with permissive licensing, sharing of code and preprint publications.