bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in the United States Using Antibiotic Prescription Data
Authors: Clancy Cornelius J , Potoski Brian A , Buehrle Deanna , Nguyen M Hong
Published: August 2019

Background

Polymyxins (colistin, polymyxin B) have been first-line antibiotics against carbapenem-resistant Enterobacteriaceae (CRE) infections. New anti-CRE antibiotics (ceftazidime-avibactam, meropenem-vaborbactam, plazomicin) improve outcomes in CRE-infected patients and reduce toxicity compared with polymyxins. It is unclear how widely polymyxins and newer agents are used to treat CRE infections.

Methods

We conducted an online survey of US hospital-based pharmacists to determine antibiotic positioning against CRE infections. Numbers of all infections and CRE infections treated with different antibiotics in the United States were determined using IQVIA prescription data and Driving Re-investment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) estimates of CRE infections.

Results

Ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin were positioned as first-line agents against CRE pneumonia, bacteremia, intra-abdominal infections, and urinary tract infections at 87%, 90%, 83%, and 56% of surveyed US hospitals, respectively. From February 2018 to January 2019, an estimated 9437 and 7941 CRE infections were treated with an intravenous polymyxin or new agent, respectively; these figures represented ~28% (range, 19%–50%) and ~23% (range, 16%–42%) of CRE infections in the United States. Use of ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin exceeded that of intravenous polymyxins against CRE infections as of December 2018. Currently, the new drugs are estimated to treat 35% (23% to 62%) of CRE infections in which they were expected to be first-line agents.

Conclusions

New anti-CRE agents recently surpassed intravenous polymyxins as treatment for CRE infections, but use is less than expected from their positioning at US hospitals. Research on behavioral and economic factors that impact use of new antibiotics is needed, as are financial “pull” incentives that promote an economically viable marketplace.
Ribavirin for Chronic Hepatitis E Virus Infection in Ibrutinib-Exposed Patients
Authors: Protin Caroline , Abravanel Florence , Alric Laurent , Tavitian Suzanne , Obéric Lucie , Izopet Jacques , Martin-Blondel Guillaume , Ysebaert Loic
Published: August 2019

Ibrutinib is an oral first-in-class Bruton’s tyrosine kinase inhibitor approved for the therapy of various B-cell lymphoid malignancies. Among ibrutinib-related infections, viral hepatitis are poorly described. We report our single-center experience with 4 cases of chronic hepatitis E virus infection and their management with ribavirin.
Endothelial and Autonomic Functions in Patients with Migraine
Authors: Dogru Mehmet Tolga , Dilekoz Ergin , Alpua Murat , Eroglu Oguz , Kandemir Hüseyin , Alp Caglar , Bolay Hayrunnisa
Published: August 2019

Objective

It has been shown that patients with migraine have endothelial dysfunction. Migraine patients with aura, especially, have more clinical manifestations of autonomic nervous system dysfunction. We aimed to evaluate the endothelial and autonomic functions in migraine patients during both migraine headache attack and headache-free periods.

Design

This was a cross-sectional, randomized study.

Subjects and Methods

A total of 130 participants (67 male and 63 female patients, minimum age = 19 years, maximum age = 71 years, mean age = 38.8 ± 12.2 years) were enrolled into the study. For the statistical evaluation of data, we classified the participants of the study as follows: group 1: headache (+) aura (+); group 2: headache (+) aura (−); group 3: headache (−) aura (+); group 4: headache (−) aura (−). Noninvasive evaluation of endothelial function was performed by flow-mediated dilation (FMD) and pulse wave analysis methods. Heart rate variability measurements were used for noninvasive evaluation of autonomic functions.

Results

Group 1 had a higher FMD ratio than the control group, group 3, or group 4 (P < 0.001, P < 0.001, and P = 0.003, respectively). Group 4 had lower FMD ratio levels than the other migraine groups and or the control group (P < 0.001). Group 3 had the highest high-frequency (HF) power levels among all migraine groups (P < 0.001). Group 2 had higher low-frequency/HF ratio values than other migraineurs (P < 0.001).

Conclusions

We concluded that endothelial dysfunction and headache are closely related. Additionally, higher parasympathetic tonus might be associated with the presence of aura.
The effects of prebiotics on growth performance and in vitro immune biomarkers in weaned pigs1
Authors: San Andres Joice V , Mastromano Gabriel A , Li Yanshuo , Tran Huyen , Bundy Justin W , Miller Phillip S , Burkey Thomas E
Published: August 2019

The objective of the experiment was to investigate the effects of prebiotics in nursery pigs on growth performance and immune biomarkers. Sixty-four weaned pigs (31 ± 1 d; BW 8 ± 0.1 kg) of mixed gender were housed (4 pigs/pen) in an environmentally controlled nursery with ad libitum access to feed and water over a 35-d study. Pigs were randomly assigned to one of four treatments: control (53% corn, 32% SBM, 7% fishmeal, 8% others), control + 2.5% GroBiotic-S (GS), control + 0.05% chicory (CL), or control + 0.5% chicory (CH). Feeders and pigs were weighed weekly. On day 21, blood samples were obtained from three pigs/treatment for collection of peripheral blood mononuclear cells (PBMC). Isolated PBMC were cultured and subsequently challenged with lipopolysaccharide (LPS; 20 ng/mL). Cell culture supernatants were collected for quantification of the pro- and anti-inflammatory cytokines, interleukin (IL)-8 and IL-10, respectively. Dietary treatment had no effect on BW. At days 28 to 35, pigs fed GS (790 ± 15 g), CL (704 ± 15 g), or CH (692 ± 15 g) had greater (P < 0.05) ADG compared with control (643 ± 15 g) pigs. In addition, overall (days 0–35), pigs fed GS (823 ± 18 g), CL (783 ± 18 g), or CH (782 ± 18 g) had greater (P < 0.05) ADFI compared with control, and ADFI for GS-fed pigs was greater (P < 0.05) than either CL or CH. There was no difference in G:F among treatments. In vitro LPS challenge increased (P < 0.05) IL-8 secretion from PBMC isolated from CL (23,731 ± 3,221 pg/mL) pigs compared with control (10,061 ± 3,221 pg/mL) and CH (12,411 ± 3,221 pg/mL) pigs. Secretion of IL-10 from PBMC isolated from CL (63 ± 9 pg/mL) pigs was greater (P < 0.05) compared with control (22 ± 9 pg/mL) pigs and tended (P < 0.1) to be greater compared with CH (34 ± 9 pg/mL) pigs. Results indicate that inclusion of prebiotics in nursery pig diets has positive effects on growth performance and may have immunomodulatory effects (in vitro) on cells isolated from prebiotic-fed pigs.
Supplementation of OmniGen-AF improves the metabolic response to a glucose tolerance test in beef heifers1,2
Authors: Burdick Sanchez Nicole C , Carroll Jeffery A , Broadway Paul R , Schell Tyler H , Puntenney Steve B , McLean Derek J
Published: August 2019

This study determined whether feeding the immunomodulating supplement, OmniGen-AF, to feedlot heifers would alter metabolic profiles to a glucose tolerance test. Heifer calves (n = 32; 217 ± 2 kg) were allocated into two treatment diets: 1) Control, fed a standard receiving ration, and 2) OmniGen, fed the Control diet supplemented with OmniGen at 4.54 g/45 kg BW/d. Heifers were fed for 42 d. On d 42, Heifers were processed through a working facility for placement of indwelling jugular catheters. After these procedures, heifers were moved into individual stanchions in an enclosed barn and all heifers were fed their treatment diets at 1400 h. All orts were removed at 2000 h to allow for a 12-h fast prior to first blood collection. The following day, heifers were administered 0.5 mL/kg BW of a 50% dextrose solution at 0900 h (0 min). Blood samples were collected for serum isolation at −60, −45, −30, −15, 0, 10, 20, 30, 45, 60, 90, 120, and 150 min relative to bolus dextrose infusion. Serum was stored at −80 oC until analyzed for cortisol, glucose, insulin, non-esterified fatty acid (NEFA) and urea N concentrations. There was a treatment × time interaction for post-challenge cortisol (P = 0.004) such that cortisol was greater in OmniGen heifers than Control heifers from 10- to 45- min post-infusion. Glucose concentrations increased post-infusion (P < 0.01) and were reduced in OmniGen compared to Control heifers at 10-, 45-, and 90-min after challenge (treatment × time P < 0.001). Similarly, there was a treatment × time interaction for post-challenge insulin concentrations (P = 0.04) such that insulin was greater in OmniGen-fed heifers than Control heifers from 10 to 30 min. In addition, there was a treatment × time interaction (P = 0.01) for NEFA concentrations such that concentrations were reduced in OmniGen-supplemented heifers from 10 to 30 min following administration of the dextrose bolus. Serum urea N concentrations were greater in Control heifers at 150 min compared to OmniGen-fed heifers (post-challenge treatment × time interaction: P < 0.001). These data suggest that OmniGen-fed heifers were more responsive to changes in glucose, perhaps affecting the storage and/or redistribution of energy deposits and provide further evidence for altered metabolism in OmniGen-supplemented cattle. The differences observed may explain differences observed in the immune response in OmniGen-supplemented calves.
Soybean Fungal Endophytes Alternaria and Diaporthe spp. are Differentially Impacted by Fungicide Application
Authors: Batzer Jean Carlson , Mueller Daren S.
Published: August 2019

In field trials in Iowa, we investigated the association of a fungicide applied at early pod set to the diversity and composition of foliar endophytic fungi in presenescent soybeans. The main purpose of our study was to determine whether fungicides affect the microbiome of soybean plants during the pod-fill reproductive stage. In a replicated experiment focused on the impact of a fungicide application including a quinone outside inhibitor (QoI) and a pyrazole-carboxamide spanning two growing seasons, healthy stems and leaves near the tops of soybean were sampled for endophytic fungi. The survey yielded 1,791 isolates belonging to 17 putative species, identified by morphology and sequence analysis of the ribosomal DNA internal transcribed spacer region. Taxa were grouped by genus into operational taxonomic units: Alternaria, Colletotrichum, and Diaporthe were the dominant genera isolated. Plant parts were analyzed separately using a multivariate community analysis of isolate counts per plant. The 14.3% fluxapyroxad and 28.6% pyraclostrobin fungicide spray significantly increased the proportion of Diaporthe isolates over no-spray controls, whereas the inverse occurred for foliar Alternaria isolates. In addition, seed harvested from fields with shorter-season varieties and sprayed with fungicide showed higher percentages of Diaporthe isolates than fields with no fungicide spray. In conclusion, soybean farmers may want to consider that the application of a QoI fungicide in the absence of disease pressure might adversely impact seed quality.
Herring gulls respond to human gaze direction
Authors: Goumas Madeleine , Burns Isabella , Kelley Laura A. , Boogert Neeltje J.
Published: August 2019

Human–wildlife conflict is one of the greatest threats to species populations worldwide. One species facing national declines in the UK is the herring gull (
Larus argentatus
), despite an increase in numbers in urban areas. Gulls in urban areas are often considered a nuisance owing to behaviours such as food-snatching. Whether urban gull feeding behaviour is influenced by human behavioural cues, such as gaze direction, remains unknown. We therefore measured the approach times of herring gulls to a food source placed in close proximity to an experimenter who either looked directly at the gull or looked away. We found that only 26% of targeted gulls would touch the food, suggesting that food-snatching is likely to be conducted by a minority of individuals. When gulls did touch the food, they took significantly longer to approach when the experimenter's gaze was directed towards them compared with directed away. However, inter-individual behaviour varied greatly, with some gulls approaching similarly quickly in both treatments, while others approached much more slowly when the experimenter was looking at them. These results indicate that reducing human–herring gull conflict may be possible through small changes in human behaviour, but will require consideration of behavioural differences between individual gulls.
Optimal foraging and the information theory of gambling
Authors: Baddeley Roland J. , Franks Nigel R. , Hunt Edmund R.
Published: August 2019

At a macroscopic level, part of the ant colony life cycle is simple: a colony collects resources; these resources are converted into more ants, and these ants in turn collect more resources. Because more ants collect more resources, this is a multiplicative process, and the expected logarithm of the amount of resources determines how successful the colony will be in the long run. Over 60 years ago, Kelly showed, using information theoretic techniques, that the rate of growth of resources for such a situation is optimized by a strategy of betting in proportion to the probability of pay-off. Thus, in the case of ants, the fraction of the colony foraging at a given location should be proportional to the probability that resources will be found there, a result widely applied in the mathematics of gambling. This theoretical optimum leads to predictions as to which collective ant movement strategies might have evolved. Here, we show how colony-level optimal foraging behaviour can be achieved by mapping movement to Markov chain Monte Carlo (MCMC) methods, specifically Hamiltonian Monte Carlo (HMC). This can be done by the ants following a (noisy) local measurement of the (logarithm of) resource probability gradient (possibly supplemented with momentum, i.e. a propensity to move in the same direction). This maps the problem of foraging (via the information theory of gambling, stochastic dynamics and techniques employed within Bayesian statistics to efficiently sample from probability distributions) to simple models of ant foraging behaviour. This identification has broad applicability, facilitates the application of information theory approaches to understand movement ecology and unifies insights from existing biomechanical, cognitive, random and optimality movement paradigms. At the cost of requiring ants to obtain (noisy) resource gradient information, we show that this model is both efficient and matches a number of characteristics of real ant exploration.
The effect of step size on straight-line orientation
Authors: Khaldy Lana , Peleg Orit , Tocco Claudia , Mahadevan L. , Byrne Marcus , Dacke Marie
Published: August 2019

Moving along a straight path is a surprisingly difficult task. This is because, with each ensuing step, noise is generated in the motor and sensory systems, causing the animal to deviate from its intended route. When relying solely on internal sensory information to correct for this noise, the directional error generated with each stride accumulates, ultimately leading to a curved path. In contrast, external compass cues effectively allow the animal to correct for errors in its bearing. Here, we studied straight-line orientation in two different sized dung beetles. This allowed us to characterize and model the size of the directional error generated with each step, in the absence of external visual compass cues (motor error) as well as in the presence of these cues (compassandmotor errors). In addition, we model how dung beetles balance the influence of internal and external orientation cues as they orient along straight paths under the open sky. We conclude that the directional error that unavoidably accumulates as the beetle travels is inversely proportional to the step size of the insect, and that both beetle species weigh the two sources of directional information in a similar fashion.
Interlinked GTPase cascades provide a motif for both robust switches and oscillators
Authors: Ehrmann Andreas , Nguyen Basile , Seifert Udo
Published: August 2019

GTPases regulate a wide range of cellular processes, such as intracellular vesicular transport, signal transduction and protein translation. These hydrolase enzymes operate as biochemical switches by toggling between an active guanosine triphosphate (GTP)-bound state and an inactive guanosine diphosphate (GDP)-bound state. We compare two network motifs, a single-species switch and an interlinked cascade that consists of two species coupled through positive and negative feedback loops. We find that interlinked cascades are closer to the ideal all-or-none switch and are more robust against fluctuating signals. While the single-species switch can only achieve bistability, interlinked cascades can be converted into oscillators by tuning the cofactor concentrations, which catalyse the activity of the cascade. These regimes can only be achieved with sufficient chemical driving provided by GTP hydrolysis. In this study, we present a thermodynamically consistent model that can achieve bistability and oscillations with the same feedback motif.
Adaptive integrate-and-fire model reproduces the dynamics of olfactory receptor neuron responses in a moth
Authors: Levakova Marie , Kostal Lubomir , Monsempès Christelle , Lucas Philippe , Kobayashi Ryota
Published: August 2019

In order to understand how olfactory stimuli are encoded and processed in the brain, it is important to build a computational model for olfactory receptor neurons (ORNs). Here, we present a simple and reliable mathematical model of a moth ORN generating spikes. The model incorporates a simplified description of the chemical kinetics leading to olfactory receptor activation and action potential generation. We show that an adaptive spike threshold regulated by prior spike history is an effective mechanism for reproducing the typical phasic–tonic time course of ORN responses. Our model reproduces the response dynamics of individual neurons to a fluctuating stimulus that approximates odorant fluctuations in nature. The parameters of the spike threshold are essential for reproducing the response heterogeneity in ORNs. The model provides a valuable tool for efficient simulations of olfactory circuits.
Optimization of sand casting performance parameters and missing data prediction
Authors: Xu Qingwei , Xu Kaili , Li Li , Yao Xiwen
Published: August 2019

Due to a wide range of applications, sand casting occupies an important position in modern casting practice. The main purpose of this study was to optimize the performance parameters of sand casting based on grey relational analysis and predict the missing data using back propagation (BP) neural network. First, the influence of human factors was eliminated by adopting the objective entropy weight method, which also saved manpower. The larger variation degree in the evaluation indicators, indicating that the evaluated projects had good discrimination in this regard, the larger weight should be given to these evaluation indicators. Second, the performance parameters of sand casting were optimized based on grey relational analysis, providing a reference for sand milling. The larger the grey relational degree, the closer the evaluated project was to the ideal project. Third, this paper provided a new method for determining the number of hidden neurons in a network according to the mean square error of training samples, and venting quality was predicted based on BP neural network. The relevant theory was deduced before predicting missing data, such that there will be a general understanding regarding the prediction principle of BP neural network. Fourth, to demonstrate the validity of BP neural network adopted in the process of missing data prediction, grey system theory was applied to compare the result of missing data prediction.
Dielectric elastomer actuators based on stretchable and self-healable hydrogel electrodes
Authors: Gao Yang , Fang Xiaoliang , Tran Danhquang , Ju Kuan , Qian Bo , Li Jin
Published: August 2019

Dielectric elastomer actuator (DEA) based on dielectric elastomer holds promising applications in soft robotics. Compliant electrodes with large stretchability and high electrical conductivity are the vital components for the DEAs. In this study, a type of DEA was developed using carbon nanotube/polyvinyl alcohol (CNT/PVA) hydrogel electrodes. The CNT/PVA hydrogel electrodes demonstrate a stretchability up to 200% with a small relative resistance change of approximately 1.2, and a self-healing capability. The areal strain of the DEA based on the CNT/PVA hydrogel electrodes is more than 40%, much higher than the ones based on pure PVA electrodes.
Cranial ontogeny of
Thamnophis radix
(Serpentes: Colubroidea) with a re-evaluation of current paradigms of snake skull evolution
Authors: Strong Catherine R. C. , Simões Tiago R. , Caldwell Michael W. , Doschak Michael R.
Published: August 2019

Accurate knowledge of skeletal ontogeny in extant organisms is crucial in understanding important morpho-functional systems and in enabling inferences of the ontogenetic stage of fossil specimens. However, detailed knowledge of skeletal ontogeny is lacking for most squamates, including snakes. Very few studies have discussed postnatal development in snakes, with none incorporating data from all three major ontogenetic stages—embryonic, juvenile and adult. Here, we provide the first analysis encompassing these three ontogenetic stages for any squamate, using the first complete micro-computed tomography (micro-CT)-based segmentations of any non-adult snake, based on fresh specimens of
Thamnophis radix
. The most significant ontogenetic changes involve the feeding apparatus, with major elongation of the tooth-bearing elements and jaw suspensorium causing a posterior shift in the jaw articulation. This shift enables macrostomy (large-gaped feeding in snakes) and occurs in
T. radix
via a different developmental trajectory than in most other macrostomatans, indicating that the evolution of macrostomy is more complex than previously thought. The braincase of
T. radix
is also evolutionarily unique among derived snakes in lacking a crista circumfenestralis, a phenomenon considered herein to represent paedomorphic retention of the embryonic condition. We thus present numerous important challenges to current paradigms regarding snake cranial evolution.
Consistency of co-occurring actions influences young children’s word learning
Authors: Eiteljoerge Sarah F. V. , Adam Maurits , Elsner Birgit , Mani Nivedita
Published: August 2019

Communication with young children is often multimodal in nature, involving, for example, language and actions. The simultaneous presentation of information from both domains may boost language learning by highlighting the connection between an object and a word, owing to temporal overlap in the presentation of multimodal input. However, the overlap is not merely temporal but can also covary in the extent to which particular actions co-occur with particular words and objects, e.g. carers typically produce a hopping action when talking about rabbits and a snapping action for crocodiles. The frequency with which actions and words co-occurs in the presence of the referents of these words may also impact young children’s word learning. We, therefore, examined the extent to which consistency in the co-occurrence of particular actions and words impacted children’s learning of novel word–object associations. Children (18 months, 30 months and 36–48 months) and adults were presented with two novel objects and heard their novel labels while different actions were performed on these objects, such that the particular actions and word–object pairings always co-occurred (Consistentgroup) or varied across trials (Inconsistentgroup). At test, participants saw both objects and heard one of the labels to examine whether participants recognized the target object upon hearing its label. Growth curve models revealed that 18-month-olds did not learn words for objects in either condition, and 30-month-old and 36- to 48-month-old children learned words for objects only in the Consistent condition, in contrast to adults who learned words for objects independent of the actions presented. Thus, consistency in the multimodal input influenced word learning in early childhood but not in adulthood. In terms of a dynamic systems account of word learning, our study shows how multimodal learning settings interact with the child’s perceptual abilities to shape the learning experience.
Synthesis and photoluminescence properties of silica-modified SiO
2
@ANA-Si-Tb@SiO
2
, SiO
2
@ANA-Si-Tb-L@SiO
2
core–shell–shell nanostructured composites
Authors: Feng Lina , Li Wenxian , Bao Jinrong , Zheng Yushan , Li Yilian , Ma Yangyang , Yang Kuisuo , Qiao Yan , Wu Anping
Published: August 2019

Three novel core–shell nanostructured composites SiO
2
@ANA-Si-Tb, SiO
2
@ANA-Si-Tb-L (L = second ligand) with SiO
2
as the core and terbium organic complex as the shell were successfully synthesized. The core and shell were connected together by covalent bonds. The terbium ion was coordinated with organic ligand-forming terbium organic complex in the shell layer. The organosilane (HOOCC
5
H
4
NN(CONH(CH
2
)
3
Si(OCH
2
CH
3
)
3
)
2
(abbreviated as ANA-Si) was used as the first ligand and 1,10-phenanthroline (phen) or 2-thenoyltrifluoroacetone (TTA) was used as the second ligand. Furthermore, silica-modified SiO
2
@ANA-Si-Tb@SiO
2
, SiO
2
@ANA-Si-Tb-L@SiO
2
core–shell–shell nanostructured composites were also synthesized by sol–gel chemical route, which involved the hydrolysis and polycondensation processes of tetraethoxysilane (TEOS) using cetyltrimethyl ammonium bromide (CTAB) as a surface-active agent. An amorphous silica shell was coated around the SiO
2
@ANA-Si-Tb, SiO
2
@ANA-Si-Tb-L core–shell nanostructured composites. The core–shell and core–shell–shell nanostructured composites exhibited excellent luminescence in the solid state. Meanwhile, an improved luminescent stability property of the core–shell–shell nanostructured composites was observed for the aqueous solution. This type of core–shell–shell nanostructured composites exhibited bright luminescence, high stability and good solubility, which may present potential applications in the fields of optoelectronic devices, bio-imaging, medical diagnosis and study on the structure of function composite materials.
Theoretical study of the structures of bimetallic Ag–Au and Cu–Au clusters up to 108 atoms
Authors: Du Rongbin , Tang Sai , Wu Xia , Xu Yiqing , Chen Run , Liu Tao
Published: August 2019

The stable structures of Ag–Au and Cu–Au clusters with 1 : 1, 1 : 3 and 3 : 1 compositions with up to 108 atoms are obtained using a modified adaptive immune optimization algorithm with Gupta potential. The dominant motifs of Ag–Au and Cu–Au clusters are decahedron and icosahedron, respectively. However, in Ag-rich Ag–Au clusters, more icosahedra are found, and in Cu-rich Cu–Au clusters, there exist several decahedral motifs. Four Leary tetrahedral motifs are predicted. Cu
core
Au
shell
configurations are predicted in Cu–Au clusters. In Ag–Au clusters, most Ag atoms are on the surface, but partial ones are located in the inner shell, while Au atoms are interconnected in the middle shell.
Specialization of small non-conjugative plasmids in Escherichia coli according to their family types
Authors: Branger Catherine , Ledda Alice , Billard-Pomares Typhaine , Doublet Benoît , Barbe Valérie , Roche David , Médigue Claudine , Arlet Guillaume , Denamur Erick
Published: August 2019

We undertook a comprehensive comparative analysis of a collection of 30 small (<25 kb) non-conjugative

Escherichia coli

plasmids previously classified by the gene sharing approach into 10 families, as well as plasmids found in the National Center for Biotechnology Information (NCBI) nucleotide database sharing similar genomic sequences. In total, 302 mobilizable (belonging to 2 MOBrep and 5 MOBRNA families) and 106 non-transferable/relaxase-negative (belonging to three ReLRNA families) plasmids were explored. The most striking feature was the specialization of the plasmid family types that was not related to their transmission mode and replication system. We observed a range of host strain specificity, from narrow

E. coli

host specificity to broad host range specificity, including a wide spectrum of

Enterobacteriaceae

. We found a wide variety of toxin/antitoxin systems and colicin operons in the plasmids, whose numbers and types varied according to the plasmid family type. The plasmids carried genes conferring resistance spanning almost all of the antibiotic classes, from those to which resistance developed early, such as sulphonamides, to those for which resistance has only developed recently, such as colistin. However, the prevalence of the resistance genes varied greatly according to the family type, ranging from 0 to 100 %. The evolutionary history of the plasmids based on the family type core genes showed variability within family nucleotide divergences in the range of

E. coli

chromosomal housekeeping genes, indicating long-term co-evolution between plasmids and host strains. In rare cases, a low evolutionary divergence suggested the massive spread of an epidemic plasmid. Overall, the importance of these small non-conjugative plasmids in bacterial adaptation varied greatly according to the type of family they belonged to, with each plasmid family having specific hosts and genetic traits.
A highly processive actinobacterial topoisomerase I – thoughts on Streptomyces’ demand for an enzyme with a unique C-terminal domain
Authors: Szafran Marcin J. , Strzałka Agnieszka , Jakimowicz Dagmara
Published: August 2019

Topoisomerase I (TopA) is an essential enzyme that is required to remove excess negative supercoils from chromosomal DNA. Actinobacteria encode unusual TopA homologues with a unique C-terminal domain that contains lysine repeats and confers high enzyme processivity. Interestingly, the longest stretch of lysine repeats was identified in TopA from

Streptomyces

, environmental bacteria that undergo complex differentiation and produce a plethora of secondary metabolites. In this review, we aim to discuss potential advantages of the lysine repeats in

Streptomyces

TopA. We speculate that the chromosome organization, transcriptional regulation and lifestyle of these species demand a highly processive but also fine-tuneable relaxase. We hypothesize that the unique TopA provides flexible control of chromosomal topology and globally regulates gene expression.
Metabolic Profiling of Aortic Stenosis and Hypertrophic Cardiomyopathy Identifies Mechanistic Contrasts in Substrate Utilisation
Authors: Pal Nikhil , Acharjee Animesh , Ament Zsuzsanna , Dent Tim , Yavari Arash , Mahmod Masliza , Ariga Rina , West James , Steeples Violetta , Cassar Mark , Howell Neil J. , Lockstone Helen , Elliott Kate , Yavari Parisa , Briggs William , Frenneaux Michael , Prendergast Bernard , Dwight Jeremy S , Kharbanda Rajesh , Watkins Hugh , Ashrafian Houman , Griffin Julian L
Published: August 2019

Background

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are highly distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated.

Method

We undertook a detailed invasive (aortic root and coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison to non-LVH controls, to investigate cardiac fuel selection and metabolic remodelling. These patients were assessed under different physiological states (at rest and during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts.

Results

We identified a highly discriminant metabolomic signature in severe AS characterised by striking accumulation of long-chain acylcarnitines, intermediates of long-chain transport and fatty acid metabolism, and validated this in a separate cohort. Mechanistically, we identify a down-regulation in the PPAR-α transcriptional network, including expression of genes regulating FAO.

Conclusions

We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate fundamental distinctions in substrate preference between AS and HCM, highlighting insufficient long-chain FAO, and the PPAR-α signalling network as a specific metabolic therapeutic target in AS.
Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus
Authors: Yagi Shunya , Splinter Jared E.J. , Tai Daria , Wong Sarah , Wen Yanhua , Galea Liisa A.M.
Published: August 2019

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis.

Significance Statement

Previously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimer’s disease and depression.
Comparative analysis of MOBQ4plasmids demonstrates that MOBQis acis-acting-enriched relaxase protein family
Authors: Garcillán-Barcia M. Pilar , Cuartas-Lanza Raquel , Cuevas Ana , de la Cruz Fernando
Published: August 2019

A group of small mobilizable plasmids is increasingly being reported in epidemiology surveys of enterobacteria. Some of them encode colicins, while others are cryptic. All of them encode a relaxase belonging to a previously non-described group of the MOBQclass, MOBQ4. While highly similar in their mobilization module, two families with unrelated replicons can be distinguished, MOBQ41and MOBQ42. Members of both groups were compatible between them and stably maintained inE. coli. MOBQ4plasmids were mobilized by conjugation. They contain two transfer genes,mobAcoding for the MOBQ4relaxase andmobC, which was non-essential but enhanced the plasmid mobilization frequency. The origin of transfer was located between these two divergently transcribedmobgenes. MPFIconjugative plasmids were the most efficient helpers for MOBQ4conjugative transmission. No interference in mobilization was observed when both MOBQ41and MOBQ42were present in the same donor cell. Remarkably, MOBQ4relaxases exhibited acis-acting preference for theiroriTs, a feature already observed in other MOBQplasmids. These findings indicate that MOBQ4plasmids can efficiently spread among enterobacteria aided by coresident IncI1, IncK and IncL/M plasmids, while ensuring their self-dissemination over highly-related elements.

IMPORTANCE

Plasmids are key vehicles of horizontal gene transfer and contribute greatly to bacterial genome plasticity. A group of plasmids, called mobilizable, is able to disseminate aided by helper conjugative plasmids. Here, we studied a group of phylogenetically-related mobilizable plasmids, MOBQ4, commonly found in clinically-relevant enterobacteria, uncovering the helper plasmids responsible for their dissemination. We found that the two plasmid species encompassed in the MOBQ4group can coexist and transfer orthogonally, despite origin-of-transfer cross-recognition by their relaxases. Specific discrimination among their highly similaroriTsequences is guaranteed by the preferentialcisactivity of the MOBQ4relaxases. Such strategy would be biologically relevant in a scenario of co-residence of non-divergent elements to favor self-dissemination.
Three dimensional nanoscopy of whole cells and tissues within situpoint spread function retrieval
Authors: Xu Fan , Ma Donghan , MacPherson Kathryn P. , Liu Sheng , Bu Ye , Wang Yu , Bi Cheng , Kwok Tim , Yin Peng , Calve Sarah , Landreth Gary E. , Huang Fang
Published: August 2019

Single-molecule localization microscopy is a powerful tool in visualizing organelle structures, interactions, and protein functions in biological research. However, whole-cell and tissue specimens challenge the achievable resolution and depth of nanoscopy methods. As imaging depth increases, photons emitted by fluorescent probes, the sole source of molecular positions, were scattered and aberrated, resulting in image artifacts and rapidly deteriorating resolution. We propose a method to allow constructing the in situ 3D response of single emitters directly from single-molecule dataset and therefore allow pin-pointing single-molecule locations with limit-achieving precision and uncompromised fidelity through whole cells and tissues. This advancement expands the routine applicability of super-resolution imaging from selected cellular targets near coverslips to intra- and extra-cellular targets deep inside tissues. We demonstrate this across a range of cellular-tissue architectures from mitochondrial networks, microtubules, and nuclear pores in 2D and 3D cultures, amyloid-β plaques in mouse brains to developing cartilage in mouse forelimbs.
A ClyA nanopore tweezer for analysis of functional states of protein-ligand interactions
Authors: Li Xin , Lee Kuohao , Chen Jianhan , Chen Min
Published: August 2019

Conformational changes of proteins are essential to their functions. Yet it remains challenging to measure the amplitudes and timescales of protein motions. Here we show that the ClyA nanopore can be used as a molecular tweezer to trap a single maltose-binding protein (MBP) within its lumen, which allows conformation changes to be monitored as electrical current fluctuations in real time. The current measurements revealed three distinct ligand-bound states for MBP in the presence of reducing saccharides. Our biochemical and kinetic analysis reveal that these three states represented MBP bound to different isomers of reducing sugars. These findings shed light on the mechanism of substrate recognition by MBP and illustrate that the nanopore tweezer is a powerful, label-free, single-molecule approach for studying protein conformational dynamics under functional conditions.
Mapping RNA splicing variations in clinically-accessible and non-accessible tissues to facilitate Mendelian disease diagnosis using RNA-seq
Authors: Aicher Joseph K , Jewell Paul , Vaquero-Garcia Jorge , Barash Yoseph , Bhoj Elizabeth J
Published: August 2019

Purpose

RNA-seq is a promising approach to improve diagnoses by detecting pathogenic aberrations in RNA splicing that are missed by DNA sequencing. RNA-seq is typically performed on clinically-accessible tissues (CATs) from blood and skin. RNA tissue-specificity makes it difficult to identify aberrations in relevant but non-accessible tissues (non-CATs). We determined how RNA-seq from CATs represent splicing in and across genes and non-CATs.

Methods

We quantified RNA splicing in 801 RNA-seq samples from 56 different adult and fetal tissues from GTEx and ArrayExpress. We identified genes and splicing events in each non-CAT and determined when RNA-seq in each CAT would inadequately represent them. We developed an online resource, MAJIQ-CAT, for exploring our analysis for specific genes and tissues.

Results

In non-CATs, 39.7% of genes have splicing that is inadequately represented by at least one CAT. 6.2% of genes have splicing inadequately represented by all CATs. A majority (52.8%) of inadequately represented genes are lowly expressed in CATs (TPM < 1), but 6.2% are inadequately represented despite being well expressed (TPM > 10).

Conclusion

Many splicing events in non-CATs are inadequately evaluated using RNA-seq from CATs. MAJIQ-CAT allows users to explore which accessible tissues, if any, best represent splicing in genes and tissues of interest.
Globally Harmonized Carbon Storage Data
Authors: Johnson Justin Andrew
Published: August 2019

This paper presents methods and results that combine multiple carbon storage and above-ground biomass datasets using a simple decision tree approach. The resulting dataset combines the positive attributes of the multiple input datasets in order to have global, high-resolution extent while utilizing the best statistical methods where possible. Visual inspection shows very different spatial configurations of carbon storage between the results and the input data, suggesting that combination of methods can improve estimates. The summation of the decision tree result was 336.55 petagrams while the summation of a dataset based on the IPCC Tier 1 method was 502.38 petagrams (49.27% higher than the results from the decision tree).
WikiMedMap: Expanding the Phenotyping Mapping Toolbox Using Wikipedia
Authors: Sulieman Lina , Wu Patrick , Denny Joshua C. , Bastarache Lisa
Published: August 2019

Researchers utilizing phenotypic data from diverse sources require matching of phenotypes to standard clinical vocabularies. Mapping phenotypes to vocabulary can be difficult, as existing tools are often incomplete, can be difficult to access, and can be cumbersome to use, especially for non-experts. We created WikiMedMap as a simple tool that leverages Wikipedia and maps phenotype strings to standard clinical vocabularies. We assessed WikiMedMap by mapping phenotype strings from questionnaires in the UK Biobank and from Mendelian diseases in Online Mendelian Inheritance in Man (OMIM) database to eight vocabularies: International Classification of Diseases, Ninth Revision (ICD-9), ICD-10, ICD-O, Medical Subject Headings (MeSH), OMIM, Disease Database, and MedlinePlus. WikiMedMap outperformed conventional mapping tools in finding potential matches for phenotype strings. We envision WikiMedMap as a technique that complements existing and established tools to map strings to clinical vocabularies that usually do not coexist in one source.
A Literature-Based Knowledge Graph Embedding Method for Identifying Drug Repurposing Opportunities in Rare Diseases
Authors: Sosa Daniel N. , Derry Alexander , Guo Margaret , Wei Eric , Brinton Connor , Altman Russ B.
Published: August 2019

One in ten people are affected by rare diseases, and three out of ten children with rare diseases will not live past age five. However, the small market size of individual rare diseases, combined with the time and capital requirements of pharmaceutical R&D, have hindered the development of new drugs for these cases. A promising alternative is drug repurposing, whereby existing FDA-approved drugs might be used to treat diseases different from their original indications. In order to generate drug repurposing hypotheses in a systematic and comprehensive fashion, it is essential to integrate information from across the literature of pharmacology, genetics, and pathology. To this end, we leverage a newly developed knowledge graph, the Global Network of Biomedical Relationships (GNBR). GNBR is a large, heterogeneous knowledge graph comprising drug, disease, and gene (or protein) entities linked by a small set of semantic themes derived from the abstracts of biomedical literature. We apply a knowledge graph embedding method that explicitly models the uncertainty associated with literature-derived relationships and uses link prediction to generate drug repurposing hypotheses. This approach achieves high performance on a gold-standard test set of known drug indications (AUROC = 0.89) and is capable of generating novel repurposing hypotheses, which we independently validate using external literature sources and protein interaction networks. Finally, we demonstrate the ability of our model to produce explanations of its predictions.
TheUrfold: Structural Similarity Just above the Superfold Level?
Authors: Mura Cameron , Veretnik Stella , Bourne Philip E.
Published: August 2019

Overview

We suspect that there is a level of granularity of protein structure intermediate between the classical levels of ‘architecture’ and ‘topology’, as reflected in such phenomena as extensive 3D structural similarity above the level of (super)folds. Here, we examine this notion of architectural identity despite topological variability, starting with a concept that we call the ‘Urfold’. We believe that this model could offer a new conceptual approach for protein structural analysis and classification: indeed, the Urfold concept may help reconcile various phenomena that have been frequently recognized or debated for years, such as the precise meaning of ‘significant’ structural overlap and the degree of continuity of fold space. More broadly, the role of structural similarity in sequence/structure/function evolution has been studied via many models over the years; the Urfold may help synthesize these models into a generalized, consistent framework, by addressing a conceptual gap that we believe exists between the architecture and topology levels of structural classification schemes.