bluuebunny/crossref_metadata_2025 huggingface dataset:
A conserved ATG2-GABARAP interaction is critical for phagophore closure
Authors: Bozic Mihaela , van den Bekerom Luuk , Milne Beth A. , Goodman Nicola , Roberston Lisa , Prescott Alan R. , Macartney Thomas J. , Dawe Nina , McEwan David G.
Published: May 2019

The intracellular trafficking pathway, macroautophagy, acts as a recycling and disposal service that can be upregulated during periods of stress, to maintain cellular homeostasis. An essential transition point in the pathway is the sealing of the immature phagophore to form an autophagosome, isolating unwanted cargo prior to lysosomal degradation. However, little mechanistic detail is known about phagophore closure. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to be key players during phagophore closure. We have identified a highly-conserved motif driving the interaction between human ATG2 and GABARAP proteins that is in close proximity to the ATG2-WIPI4 interaction site. We show that the ATG2-GABARAP interaction mutants are unable to close phagophores resulting in blocked autophagy, similar to ATG2A/ATG2B double knock-out cells. In contrast, the ATG2-WIPI4 interaction mutant fully restored phagophore closure and autophagy flux, similar to wild type ATG2. Taken together, we provide new mechanistic insights to the requirements for ATG2 function at the phagophore and suggest that an ATG2-GABARAP interaction is essential for phagophore closure, whereas ATG2-WIPI4 interaction is dispensable.
General Practitioners’ adherence to prescribing guidelines for statins in the United Kingdoms
Authors: Ricciardi Federico , Nazareth Irwin , Petersen Irene
Published: May 2019

Objective

In this retrospective cohort study we aimed to assess, in 202,247 people who started a statin therapy between 2007-2014, the factors that led to the initiation of the drug. To do this we explored CVD risk factors singularly and in combinations as recorded in electronic health records in the year before they receive their first prescription and we compared the risk scores with that suggested by the NICE guideline at that time.

Methods

We summarised demographic characteristics and proportions of people with a risk score below the threshold. Regression-based analyses are performed to evaluate the association between the missingness of the risk score and relevant risk score components.

Results

45,364 individuals (22.4%) were prescribed statins without a record of a risk score being available in the year prior to the prescription date. When the risk score was available, 68,174 out of 156,883 patients were prescribed statins even with a score below the 20% threshold. Smoking status was the most frequently recorded variable (74.9% of the instances), followed by systolic blood pressure (71.6%) and total cholesterol (70%), while HDL cholesterol was the least recorded (34.1%). Cholesterol levels are positively associated with the missingness of the risk score, while systolic blood pressure shows a negative association.

Conclusions

GPs often start statins on people with no risk score recorded in their clinical records or in those with risk scores below the recommended threshold. Higher cholesterol values may result in a GP starting statin therapy without recording the other relevant components required to calculate a risk score.

STRENGTHS AND LIMITATIONS OF THIS STUDY

Our cohort contains a large number of individuals: the study provide a representative picture of initiation of statins in UK primary care.

We specifically focus on which variables and factors GPs record in electronic databases in the year prior statin treatment initiation: this is the first study to directly tackle the issue of statins prescribing in the absence of all the information required by the NICE guideline

We are not able to verify if GPs actually used the records of the individual health indicators, when these were available, to calculate the risk score.
Neuromuscular and biomechanical functions subserving finger dexterity in musicians
Authors: Kimoto Yudai , Oku Takanori , Furuya Shinichi
Published: May 2019

Exceptional finger dexterity enables skillful motor actions such as those required for musical performance. However, it has been not known whether specialized neuromuscular or biomechanical features subserve the dexterity. We aimed to identify the features firstly differentiating the finger dexterity between trained and untrained individuals and secondly accounting for the individual differences in the dexterity across trained individuals. To this aim, two studies were conducted. The first study (Study 1) compared the finger motor dexterity and several neuromuscular and biomechanical characteristics of the fingers between pianists and musically untrained individuals (non-musicians). The results showed no differences in any biomechanical features between the groups with different musical expertise. However, the pianists exhibited faster individual finger movements and more independent control of movements between the fingers. These observations indicate expertise-dependence of the finger motor skills and neuromuscular control of the fingers. The second study (Study 2) assessed individual differences in the finger dexterity between trained pianists. A penalized regression determined an association of the maximum movement speed of the pianists’ individual fingers with both finger muscular strength and biomechanical characteristics of the hand, but not with independent movement control between the fingers. In addition, none of these features covaried with measures of early and deliberate piano practice. Taken together, these findings indicate that distinct biological factors of finger motor dexterity differentiate between the effects of piano training and individual differences across skilled pianists.
Spatial patterning of tissue volume loss in schizophrenia reflects brain network architecture
Authors: Shafiei Golia , Markello Ross D. , Makowski Carolina , Talpalaru Alexandra , Kirschner Matthias , Devenyi Gabriel A. , Guma Elisa , Hagmann Patric , Cashman Neil R. , Lepage Martin , Chakravarty M. Mallar , Dagher Alain , Mišić Bratislav
Published: May 2019

Background

There is growing recognition that connectome architecture shapes cortical and sub-cortical grey matter atrophy across a spectrum of neurological and psychiatric diseases. Whether connectivity contributes to tissue volume loss in schizophrenia in the same manner remains unknown.

Methods

Here we relate tissue volume loss in patients with schizophrenia to patterns of structural and functional connectivity. Grey matter deformation was estimated in a sample ofN= 133 individuals with chronic schizophrenia (48 female, 34.7 ± 12.9 years) andN= 113 controls (64 female, 23.5 ± 8.4 years). Deformation-based morphometry (DBM) was used to estimate cortical and subcortical grey matter deformation from T1-weighted MR images. Structural and functional connectivity patterns were derived from an independent sample ofN= 70 healthy participants using diffusion spectrum imaging and resting-state functional MRI.

Results

We find that regional deformation is correlated with the deformation of structurally- and functionally-connected neighbours. Distributed deformation patterns are circumscribed by specific functional systems (the ventral attention network) and cytoarchitectonic classes (limbic class), with an epicenter in the anterior cingulate cortex.

Conclusions

Altogether, the present study demonstrates that brain tissue volume loss in schizophrenia is conditioned by structural and functional connectivity, accounting for 25-35% of regional variance in deformation.
The Dynamics of Attention Shifts Among Concurrent Speech in a Naturalistic Multi-Speaker Virtual Environment
Authors: Cohen Keren Shavit , Golumbic Elana Zion
Published: May 2019

Focusing attention on one speaker on the background of other irrelevant speech can be a challenging feat. A longstanding question in attention research is whether and how frequently individuals shift their attention towards task-irrelevant speech, arguably leading to occasional detection of words in a so-called unattended message. However, this has been difficult to gauge empirically, particularly when participants attend to continuous natural speech, due to the lack of appropriate metrics for detecting shifts in internal attention. Here we introduce a new experimental platform for studying the dynamic deployment of attention among concurrent speakers, utilizing a unique combination of Virtual Reality and Eye-Tracking technology. We created a Virtual Café in which participants sit across from and attend to the narrative of a target speaker. We manipulate the number and location of distractor speakers, manifest as additional patrons throughout the Virtual Café. By monitoring participant’ eye-gaze dynamics, we studied the patterns of overt shifts of attention among the concurrent speakers as well as the consequences of these shifts on speech comprehension.

Our results reveal important individual differences in the gaze-pattern displayed during selective attention to speech. While some participants stayed fixated on a target speaker throughout the entire experiment, approximately 30% of participants frequently shifted their gaze toward distractor speakers or other locations in the environment, regardless of the severity of audiovisual distraction. Critically, the tendency for frequent gaze-shifts negatively impacted comprehension of the target speaker. We also found that gaze-shifts occurred primarily during gaps in the acoustic input, suggesting they are prompted by momentary unmasking of the competing audio, in line with ‘glimpsing’ theories of processing speech in noise.

These results open a new window into understanding the dynamics of attention as they wax and wane over time, and the different listening patterns employed for dealing with the influx of sensory input in multisensory environments. Moreover, the novel approach developed here for tracking the locus of momentary attention in a naturalistic virtual-reality environment holds high promise for extending the study of human behavior and cognition and bridging the gap between the laboratory and real-life.
Relapse prevention through health technology program reduces hospitalization in schizophrenia
Authors: Homan Philipp , Schooler Nina R. , Brunette Mary F. , Rotondi Armando , Ben-Zeev Dror , Gottlieb Jennifer D. , Mueser Kim T. , Achtyes Eric D. , Gingerich Susan , Marcy Patricia , Meyer-Kalos Piper , Hauser Marta , John Majnu , Robinson Delbert G. , Kane John M.
Published: May 2019

Importance

Psychiatric hospitalization is a major driver of cost in the treatment of schizophrenia. Symptom relapses are a frequent cause of hospitalization and both are primary source of burden to patients and their supporters.

Objective

To determine whether a novel, multicomponent, and technology-enhanced approach to relapse prevention in outpatients following a psychiatric hospitalization could reduce days spent in a hospital after discharge.

Design

The Improving Care and Reducing Cost (ICRC) study was a quasi-experimental clinical trial in outpatients with schizophrenia conducted between February 2013 and April 2015 at 10 different sites in the US. Data were obtained from 89 participants who received usual relapse prevention services, followed by a second cohort of 349 participants who received the technology-enhanced relapse prevention program. Both groups were followed for 6 months.

Setting

Outpatient setting.

Participants

Patients were between 18 and 60 years old; had a diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified; and were currently hospitalized or had been hospitalized within the past 30 days.

Intervention

Patients received usual care or a technology-enhanced relapse prevention program during a 6-month period after discharge.

Main Outcome(s) and Measure(s)

Days spent in a psychiatric hospital during 6 months after discharge.

Results

The study included 438 patients. Control participants (N = 89; 37 females) were enrolled first and received usual care for relapse prevention, and followed by 349 participants (128 females) who received technology-enhanced relapse prevention. Days of hospitalization were reduced by 4 days (Mean days: b = −4.25, 95% CI: −8.29; −0.21, P = 0.039) during follow-up in the intervention condition compared to control.

Conclusions and Relevance

The reduction in days spent in the hospital for participants in the technology-informed relapse prevention program compared to those who received usual care, and the previously reported high satisfaction and usability suggest that technology-enhanced relapse prevention is an effective and feasible way to reduce rehospitalization days among patients with schizophrenia.

Key points

Question

Can rehospitalizations in schizophrenia be prevented at reduced cost by innovative mobile technology-delivered interventions?

Findings

In this clinical trial with 438 patients, a technology-enhanced relapse prevention program compared to usual services reduced an average of four days of hospitalization per patient during the first 6 months following an index hospitalization.

Meaning

Relapse prevention through a health technology may improve care while reducing costs associated with hospitalization.
Effects of siRNA silencing on the susceptibility of the fish cell line CHSE-214 toYersinia ruckeri
Authors: Menanteau-Ledouble Simon , Schachner Oskar , Lawrence Mark L. , El-Matbouli Mansour
Published: May 2019

Bacterial pathogens are known to co-opt mechanisms of the host cells’ physiology to gain intracellular entrance. Among the facultative intracellular bacteria isYersinia ruckeri, an enterobacterium mostly known as the causative agent of enteric redmouth disease in salmonid fish. In the present study, we applied RNA inhibition to silence twenty pre-selected genes on the genome of a fish cell line (CHSE-214) followed by a gentamycin assay to quantify the effect of this silencing on the susceptibility of the cells to infection. It was found that silencing of 16 out of 20 genes significantly reduced the number ofY. ruckerirecovered at the end of the gentamycin assay. Among the genes with the strongest impact were Rab1A, actin and Rac1, which is consistent with our previous findings that N-acetylcysteine, a chemical inhibitor of Rac1, completely prevented invasion of cells byY. ruckeri. Conversely, silencing of the Rho GTPase activating protein had no statistically significant effect, possibly becauseY. ruckeri, like some other members of theYersiniagenus is able to activate Rho GTPase directly. Similarly, the effect of silencing E-cadherin was not statistically significant, suggesting that this might not be a target for the adhesion molecules ofY. ruckeri. Taken together, these findings improve our understanding of the infection process byY. ruckeriand of the interactions between this bacterial pathogen and host cells.

Importance

Intracellular invasiveness is a mean for bacterial pathogen to gain shelter from the immune system as well as access nutrients. The enterobacteriumY. ruckeriis well characterised as a facultative intracellular pathogen. However, the mechanisms of invasion scrutiny. Investigations have mostly focused on the bacterial virulence rather than on the host’s mechanisms hicjacked during invasion. The present findings therefore allow us to better understand the interaction between this important potentially zoonotic pathogen of fish and host cells in vitro.
Population receptive field and connectivity properties of the early visual cortex in human albinism
Authors: Ahmadi Khazar , Herbik Anne , Wagner Markus , Kanowski Martin , Thieme Hagen , Hoffmann Michael B.
Published: May 2019

In albinism, the pathological decussation of the temporal retinal afferents at the optic chiasm leads to superimposed representations of opposing hemifields in the visual cortex. Here, we assessed the equivalence of the two representations and the cortico-cortical connectivity of the early visual areas. Applying fMRI-based population receptive field (pRF)-mapping (both hemifield and bilateral mapping) and connective field (CF)-modeling, we investigated the early visual cortex in 6 albinotic participants and 4 controls. In albinism, superimposed retinotopic representations of the contra- and ipsilateral visual hemifield were observed on the hemisphere contralateral to the stimulated eye. This was confirmed by the observation of bilateral pRFs during bilateral mapping. Hemifield mapping revealed similar pRF-sizes for both hemifield representations throughout V1 to V3. The typical increase of V1-sampling extent for V3 compared to V2 was not found for the albinotic participants. The similarity of the pRF-sizes for opposing visual hemifield representations highlights the equivalence of the two maps in the early visual cortex. The altered V1-sampling extent in V3 indicates the adaptation of cortico-cortical connections to the abnormal input of the visual cortex. These findings thus suggest that conservative developmental mechanisms are complemented by alterations of the extrastriate cortico-cortical connectivity.

Highlights

pRF mapping confirms cortical overlay of opposing visual hemifields in albinism.

Equivalent information processing of both hemifields is indicated by similar pRF sizes.

CF modeling indicates changes to the cortico-cortical connections at the level of V3.
Extremely fast and accurate open modification spectral library searching of high-resolution mass spectra using feature hashing and graphics processing units
Authors: Bittremieux Wout , Laukens Kris , Noble William Stafford
Published: May 2019

Open modification searching (OMS) is a powerful search strategy to identify peptides with any type of modification. OMS works by using a very wide precursor mass window to allow modified spectra to match against their unmodified variants, after which the modification types can be inferred from the corresponding precursor mass differences. A disadvantage of this strategy, however, is the large computational cost, because each query spectrum has to be compared against a multitude of candidate peptides.

We have previously introduced the ANN-SoLo tool for fast and accurate open spectral library searching. ANN-SoLo uses approximate nearest neighbor indexing to speed up OMS by selecting only a limited number of the most relevant library spectra to compare to an unknown query spectrum. Here we demonstrate how this candidate selection procedure can be further optimized using graphics processing units. Additionally, we introduce a feature hashing scheme to convert high-resolution spectra to low-dimensional vectors. Based on these algorithmic advances, along with low-level code optimizations, the new version of ANN-SoLo is up to an order of magnitude faster than its initial version. This makes it possible to efficiently perform open searches on a large scale to gain a deeper understanding about the protein modification landscape. We demonstrate the computational efficiency and identification performance of ANN-SoLo based on a large data set of the draft human proteome.

ANN-SoLo is implemented in Python and C++. It is freely available under the Apache 2.0 license at https://github.com/bittremieux/ANN-SoLo.
The use of a centrifuge-free RABiT-II system for high-throughput micronucleus analysis
Authors: Repin Mikhail , Pampou Sergey , Brenner David J. , Garty Guy
Published: May 2019

The cytokinesis-block micronucleus (CBMN) assay is considered as the most suitable biodosimetry method for automation. Previously, we automated this assay on a commercial robotic biotech high-throughput system (RABiT-II) adopting both a traditional and an accelerated micronucleus protocol, both using centrifugation steps for lymphocyte harvesting and washing, after whole blood culturing. Here we describe further development of our accelerated CBMN assay protocol for using on High Throughput/High Content Screening (HTS/HCS) robotic systems without a centrifuge. This opens the way for implementation of the CBMN assay on a wider range of commercial automated HTS/HCS systems and thus increases the potential capacity of dose estimates following a mass-casualty radiological event.
Encoding Information in Synthetic Metabolomes
Authors: Kennedy Eamonn , Arcadia Christopher E. , Geiser Joseph , Weber Peter M. , Rose Christopher , Rubenstein Brenda M. , Rosenstein Jacob K.
Published: May 2019

Biomolecular information systems offer numerous potential advantages over conventional semiconductor technologies. Downstream from DNA, the metabolome is an information-rich molecular system with diverse chemical dimensions which could be harnessed for information storage and processing. As a proof of principle of postgenomic data storage, here we demonstrate a workflow for representing abstract data in synthetic metabolomes. Our approach leverages robotic liquid handling for writing digital information into chemical mixtures, and mass spectrometry for extracting the data. We present several kilobyte-scale image datasets stored in synthetic metabolomes, which are decoded with accuracy exceeding 98-99% using multi-mass logistic regression. Cumulatively, >100,000 bits of digital image data was written into metabolomes. These early demonstrations provide insight into the benefits and limitations of postgenomic chemical information systems.
Persistent fibrosis and decreased cardiac function following cardiac injury in theCtenopharyngodon idella(grass carp)
Authors: Long Daniel W , Webb Charles H , Wang Yadong
Published: May 2019

Following the discovery of heart regeneration in zebrafish, several more species within the Cyprinidae family have been found to have the same capability, suggesting heart regeneration may be conserved within this family. Although gonad regeneration has been observed in grass carp (Ctenopharyngodon idella), one of the largest cyprinid fish, the species’ response to cardiac injury has not been characterized. Surprisingly, we found cardiomyocytes do not repopulate the injured region following cryoinjury to the ventricle, instead exhibiting unresolved fibrosis and decreased cardiac function that persists for the 8-week duration of this study. Compared to other cyprinid fish studied, infiltration of macrophages is delayed and muted in this model. Additionally, fibroblasts are depleted following injury, a phenomenon not previously described in any cardiac model. This study shows that heart regeneration is not conserved among the Cyprinidae family and suggests the important role of non-fibroblasts in chronic fibrosis. Further study of these phenomenon may reveal the underlying differences between regeneration versus unresolved fibrosis in heart disease.

Summary statement

Grass carp, a member of the Cyprinidae family that includes regenerative zebrafish, do not regenerate functional cardiac tissue after cryoinjury. Instead, healing progresses through collagen deposition and scar formation.
Successive passaging of a plant-associated microbiome reveals robust habitat and host genotype-dependent selection
Authors: Morella Norma M. , Weng Francis Cheng-Hsuan , Joubert Pierre M. , Metcalf C. Jessica E. , Lindow Steven , Koskella Britt
Published: May 2019

There is increasing interest in the plant microbiome as it relates to both plant health and agricultural sustainability. One key unanswered question is whether we can select for a plant microbiome that is robust after colonization of target hosts. We used a successive passaging experiment to address this question by selecting upon the tomato phyllosphere microbiome. Beginning with a diverse microbial community generated from field-grown tomato plants, we inoculated replicate plants across five plant genotypes for four eight-week long passages, sequencing the microbial community at each passage. We observed consistent shifts in both the bacterial (16S amplicon sequencing) and fungal (ITS amplicon sequencing) communities across replicate lines over time, as well as a general loss of diversity over the course of the experiment suggesting that much of the naturally observed microbial community in the phyllosphere is likely transient or poorly adapted. We found that both host genotype and environment shape microbial composition, but the relative importance of genotype declines through time. Furthermore, using a community coalescence experiment, we found that the bacterial community from the end of the experiment was robust to invasion by the starting bacterial community. These results highlight that selecting for a stable microbiome that is well adapted to a particular host environment is indeed possible, emphasizing the great potential of this approach in agriculture and beyond.

Significance Statement

There is great interest in selecting for host-associated microbiomes that confer particular functions to their host, and yet it remains unknown whether selection for a robust and stable microbiome is possible. Here, we use a microbiome passaging approach to measure the impact of host-mediated selection on the tomato phyllosphere (above ground) microbiome. We find robust community selection across replicate lines that is shaped by plant host genotype in early passages, but changes in a genotype-independent manner in later passages. Work such as ours is crucial to understanding the general principles governing microbiome assembly and adaptation, and is widely applicable to both sustainable agriculture and microbiome-related medicine.
The reliability of the isotropic fractionator method for counting total cells and neurons
Authors: Neves Kleber , Menezes Daniel , Rayêe Danielle , Valério-Gomes Bruna , Iack Pamela Meneses , Lent Roberto , Mota Bruno
Published: May 2019

Background

The Isotropic Fractionator (IF) is a method used to determine the cellular composition of nervous tissue. It has been mostly applied to assess variation across species, where differences are expected to be large enough not to be masked by methodological error. However, understanding the sources of variation in the method is important if the goal is to detect smaller differences, for example, in same-species comparisons. Comparisons between different mice strains suggest that the IF is consistent enough to detected these differences. Nevertheless, the internal validity of the method has not yet been examined directly.

Method

In this study, we evaluate the reliability of the IF method for the determination of cellular and neuronal numbers. We performed repeated cell counts of the same material by different experimenters to quantify different sources of variation.

Results

In total cell counts, we observed that for the cerebral cortex most of the variance was at the counter level. For the cerebellum, most of the variance is attributed to the sample itself. As for neurons, random error along with the immunological staining correspond to most of the variation, both in the cerebral cortex and in the cerebellum. Test-retest reliability coefficients were relatively high, especially for cell counts.

Conclusions

Although biases between counters and random variation in staining could be problematic when aggregating data from different sources, we offer practical suggestions to improve the reliability of the method. While small, this study is a most needed step towards more precise measurement of the brain’s cellular composition.

Highlights

Most variance in cell counts was between counters (η = 0.58) for cerebral cortices.

For cerebella, most of the variance was attributed to the samples (η = 0.49).

Variance in immunocytochemical counts was mostly residual/random (η > 0.8).

Test-retest reliability was high (same counter, same sample).

Practical suggestions are offered to improve the reliability of the method.
Modeling cell infection via virus-producing cells rather than free infectious virus significantly improves fits ofin vitroviral kinetic data
Authors: Bernhauerová Veronika , Rezelj Veronica V. , Levi Laura I. , Vignuzzi Marco
Published: May 2019

Chikungunya and Zika viruses are arthropod-borne viruses that pose significant threat to public health. Experimental data show that duringin vitroinfection both viruses exhibit qualitatively distinct replication cycle kinetics. Chikungunya viral load rapidly accumulates within the first several hours post infection whereas Zika virus begins to increase at much later times. We sought to characterize these qualitatively distinctin vitrokinetics of chikungunya and Zika viruses by fitting a family of mathematical models to time course viral load datasets. We demonstrate that the standard viral kinetic model, which considers that new infections result only from free virus penetrating susceptible cells, does not fit experimental data as well as a model in which the number of virus-infected cells is the primary determinant of infection rate. We provide biologically meaningful quantifications of the main viral kinetic parameters and show that our results support cell-to-cell or localized transmission as a significant contributor to viral infection with chikungunya and Zika viruses.

Importance

Mathematical modeling has become a useful tool to tease out information about virus-host interactions and thus complements experimental work in characterizing and quantifying processes within viral replication cycle. Importantly, mathematical models can fill in incomplete data sets and identify key parameters of infection, provided the appropriate model is used. Thein vitrotime course dynamics of mosquito transmitted viruses, such as chikungunya and Zika, have not been studied by mathematical modeling and thus limits our knowledge about quantitative description of the individual determinants of viral replication cycle. This study employs dynamical modeling framework to show that the rate at which cells become virus-infected is proportional to the number or virus-infected cells rather than free extracellular virus in the milieu, a widely accepted assumption in models of viral infections. Using the refined mathematical model in combination with viral load data, we provide quantification of the main drivers of chikungunya and Zikain vitrokinetics. Together, our results bring quantitative understanding of the basic components of chikungunya and Zika virus dynamics.
Unexpected activity of oral fosfomycin against resistant strains ofEscherichia coliin murine pyelonephritis
Authors: Pourbaix Annabelle , Guérin François , Burdet Charles , Massias Laurent , Chau Françoise , Cattoir Vincent , Fantin Bruno
Published: May 2019

Fosfomycin-tromethamine activity is well established for oral treatment of uncomplicated lower urinary tract infections but little is known about its potential efficacy in pyelonephritis. Ascending pyelonephritis was induced in mice infected with 6 strains ofEscherichia coli(fosfomycin MICs: 1 μg/ml to 256 μg/ml). Urine pH was 4.5 before infection and 5.5-6.0 during infection. Animals were treated for 24h with fosfomycin (100 mg/kg subcutaneously every 4 hours) and CFU were enumerated in kidneys 24h after the last fosfomycin injection. Peak (20.5 μg/ml at 1h) and trough (3.5 μg/ml at 4h) levels in plasma were comparable to those obtained in human after an oral dose of 3 grams. Fosfomycin treatment significantly reduced bacterial loads in kidneys (3.65 log10CFU/g [min-max=1.83-7.03] and 1.88 log10CFU/g [1.78-5.74] in start-of-treatment control mice and treated mice, respectively,P< 10-6). However, this effect was not found to differ across the 6 study strains (P = 0.71) and between the 3 susceptible and the 3 resistant strains (P=0.09). Three phenomena may contribute to explain this unexpectedin vivoactivity: i) in mice, fosfomycin kidney/plasma concentrations ratio increased from 1 to 7.8 (95% CI, 5.2; 10.4) within 24 hours;in vitro, when pH decreased to 5: (ii) fosfomycin MICs for the 3 resistant strains (64-256 μg/ml) decreased into the susceptible range (16-32 μg/ml) and: iii) maximal growth rates significantly decreased for all strains and were the lowest in urine. These results suggest that local fosfomycin concentrations and physiological conditions may favour fosfomycin activity in pyelonephritis, even against resistant strains.
Carbon monoxide dehydrogenases enhance bacterial survival by oxidising atmospheric CO
Authors: Cordero Paul R.F. , Bayly Katherine , Leung Pok Man , Huang Cheng , Islam Zahra F. , Schittenhelm Ralf B. , King Gary M. , Greening Chris
Published: May 2019

Carbon monoxide (CO) is a ubiquitous atmospheric trace gas produced by natural and anthropogenic sources. Some aerobic bacteria can oxidize atmospheric CO and, collectively, they account for the net loss of ~250 teragrams of CO from the atmosphere each year. However, the physiological role, genetic basis, and ecological distribution of this process remain incompletely resolved. In this work, we addressed these knowledge gaps through culture-based and culture-independent work. We confirmed through shotgun proteomic and transcriptional analysis that the genetically tractable aerobic soil actinobacteriumMycobacterium smegmatisupregulates expression of a carbon monoxide dehydrogenase by 50-fold when exhausted for organic carbon substrates. Whole-cell biochemical assays in wild-type and mutant backgrounds confirmed that this organism aerobically respires CO, including at sub-atmospheric concentrations, using the enzyme. Contrary to current paradigms on CO oxidation, the enzyme did not support chemolithoautotrophic growth and was dispensable for CO detoxification. However, it significantly enhanced long-term survival, suggesting that atmospheric CO serves a supplemental energy source during organic carbon starvation. Phylogenetic analysis indicated that atmospheric CO oxidation is widespread and an ancestral trait of CO dehydrogenases. Homologous enzymes are encoded by 685 sequenced species of bacteria and archaea, including from seven dominant soil phyla, and we confirmed genes encoding this enzyme are abundant and expressed in terrestrial and marine environments. On this basis, we propose a new survival-centric model for the evolution of CO oxidation and conclude that, like atmospheric H2, atmospheric CO is a major energy source supporting persistence of aerobic heterotrophic bacteria in deprived or changeable environments.
The Solanum tuberosum GBSSI gene: a target for assessing gene and base editing in tetraploid potato
Authors: Veillet Florian , Chauvin Laura , Kermarrec Marie-Paule , Sevestre François , Merrer Mathilde , Terret Zoé , Szydlowski Nicolas , Devaux Pierre , Gallois Jean-Luc , Chauvin Jean-Eric
Published: May 2019

Genome editing has recently become a method of choice for basic research and functional genomics, and holds great potential for molecular plant breeding applications. The powerful CRISPR-Cas9 system that typically produces double-strand DNA breaks is mainly used to generate knockout mutants. Recently, the development of base editors has broadened the scope of genome editing, allowing precise and efficient nucleotide substitutions. In this study, we produced mutants in two cultivated elite cultivars of the tetraploid potato (Solanum tuberosum) using stable or transient expression of the CRISPR-Cas9 components to knockout the amylose-producing StGBSSI gene. We set up a rapid, highly sensitive and cost-effective screening strategy based on high-resolution melting analysis followed by direct Sanger sequencing and trace chromatogram analysis. Most mutations consisted of small indels, but unwanted insertions of plasmid DNA were also observed. We successfully created tetra-allelic mutants with impaired amylose biosynthesis, confirming the loss-of-function of the StGBSSI protein. The second main objective of this work was to demonstrate the proof of concept of CRISPR-Cas9 base editing in the tetraploid potato by targeting two loci encoding catalytic motifs of the StGBSSI enzyme. Using a cytidine base editor (CBE), we efficiently and precisely induced DNA substitutions in the KTGGL-encoding locus, leading to discrete variation in the amino acid sequence and generating a loss-of-function allele. The successful application of base editing in the tetraploid potato opens up new avenues for genome engineering in this species.

Key Message

The StGBSSI gene was successfully and precisely edited in the tetraploid potato using gene and base editing strategies, leading to plants with impaired amylose biosynthesis.
Induced illusory body ownership in Borderline Personality Disorder
Authors: Neustadter Eli S. , Fineberg Sarah K. , Leavitt Jacob , Carr Meagan M. , Corlett Philip R.
Published: May 2019

Background

One aspect of selfhood that may have relevance for Borderline Personality Disorder (BPD) is variation in sense of body ownership. We employed the rubber hand illusion (RHI) to manipulate sense of body ownership in BPD. We extended previous research on illusory body ownership in BPD by testing: 1) two illusion conditions: asynchronous & synchronous stimulation, 2) relationship between Illusion experience and BPD symptoms, and 3) relationship between illusion experience and maladaptive personality traits.

Methods

We measured illusion strength (questionnaire responses), proprioceptive drift (perceived shift in physical hand position), BPD symptoms (DIB-R score), and maladaptive personality traits (PID-5) in 24 BPD and 21 control participants.

Results

For subjective illusion strength, we found a main effect of group (BPD > HC, F = 11.94 p = 0.001), and condition (synchronous > asynchronous, F(1,43) = 22.80, p < 0.001). There was a group x condition interaction for proprioceptive drift (F(1,43) = 6.48, p = 0.015) such that people with BPD maintained illusion susceptibility in the asynchronous condition. Borderline symptom severity correlated with illusion strength within the BPD group, and this effect was specific to affective symptoms (r = 0.48, p < 0.01). Across all participants, trait psychoticism correlated with illusion strength (r = 0.44, p < 0.01).

Conclusion

People with BPD are more susceptible to illusory body ownership than controls. This is consistent with the clinical literature describing aberrant physical and emotional experience of self in BPD. A predictive-coding framework holds promise to develop testable mechanistic hypotheses for disrupted bodily self in BPD.

Highlights

The rubber hand illusion (RHI) allows measurement of self-disturbance.

People with BPD had greater illusion susceptibility and this correlated with affective symptoms.

Interoception stabilizes representations of body ownership, and is impaired in BPD.

Illusion strength correlates with psychotic traits across levels of psychopathology.

Predictive coding frameworks can probe mechanisms of impaired body ownership in psychopathology.
The structure of the yeast Ctf3 complex
Authors: Hinshaw Stephen M. , Dates Andrew N. , Harrison Stephen C.
Published: May 2019

Kinetochores are the chromosomal attachment points for spindle microtubules. They are also signaling hubs that control major cell cycle transitions and coordinate chromosome folding. Most well-studied eukaryotes rely on a conserved set of factors, which are divided among two loosely-defined groups, for these functions. Outer kinetochore proteins contact microtubules or regulate this contact directly. Inner kinetochore proteins designate the kinetochore assembly site by recognizing a specialized nucleosome containing the H3 variant Cse4/CENP-A. We previously determined the structure, resolved by cryo-electron microscopy (cryo-EM), of the yeast Ctf19 complex (Ctf19c, homologous to the vertebrate CCAN), providing a high-resolution view of inner kinetochore architecture. We now extend these observations by reporting a near-atomic model of the Ctf3 complex, the outermost Ctf19c sub-assembly seen in our original cryo-EM density. The model is sufficiently well-determined by the new data to enable molecular interpretation of Ctf3 recruitment and function.
The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators
Authors: Gobin Christina , Schwendt Marek
Published: May 2019

Rationale

Cocaine use disorder (CUD) remains difficult to treat with no FDA-approved medications to reduce relapse. Antagonism of metabotropic glutamate receptor 5 (mGlu5) has been demonstrated to decrease cocaine seeking but may also further compromise cognitive function in long-term cocaine users.

Objectives

Here we assessed the effect of repeated administration of negative or positive allosteric modulators (NAM or PAM) of mGlu5 on both cognitive performance and (context+cue)-primed cocaine seeking after prolonged abstinence.

Methods

Adult male Sprague-Dawley rats underwent 6 days of short-access (1 h/day) and 12 days of long-access (6 h/day) cocaine self-administration. Rats were then trained and tested in a delayed-match-to-sample (DMS) task to establish baseline working memory performance over a five-day block of testing. Next, rats received daily systemic administration of the mGlu5 NAM MTEP (3 mg/kg), mGlu5 PAM CDPPB (30 mg/kg) or vehicle prior to DMS testing during a block of five days, followed by a 5-day washout DMS testing block.

Results

MTEP and CDPPB decreased drug seeking in response to cocaine-associated cues after prolonged abstinence. However, repeated treatment with MTEP impaired working memory, while CDPPB had no effects on performance.

Conclusions

These results emphasize the relevance of evaluating cognitive function within the context of investigating pharmacotherapies to treat CUD. Further research is needed to determine how two mechanistically different pharmacological compounds can exert the same behavioral effects to reduce cocaine seeking.
Validation and delineation of a locus conferring Fusarium crown rot resistance on 1HL in barley by analysing transcriptomes from multiple pairs of near isogenic lines
Authors: Gao Shang , Zheng Zhi , Powell Jonathan , Habib Ahsan , Stiller Jiri , Zhou Meixue , Liu Chunji
Published: May 2019

Background

Fusariumcrown rot (FCR) is a chronic and severe disease in cereal production in semi-arid regions worldwide. One of the putative quantitative trait locus (QTL) designated asQcrs.cpi-1Hhas been previously mapped on chromosome arm 1HL in barley.

Results

In this study, five pairs of near-isogenic lines (NILs) targeting the 1HL locus were developed. Analysing the NILs found that the resistant allele atQcrs.cpi-1Hsignificantly reduced FCR severity. Transcriptomic analysis was then conducted against three of the NIL pairs, which placed theQcrs.cpi-1Hlocus in an interval spanning about 11 Mbp. A total of 56 expressed genes bearing SNPs were detected in this interval, which would facilitate detailed mapping as well as cloning gene(s) underlying the resistance locus. Also, five differentially expressed genes (DEGs) bearing non-synonymous SNPs were identified in the interval. Differences in DEGs regulated byQcrs.cpi-1Hthose byQcrs.cpi-4H(another known locus conferring FCR resistance) indicate that different mechanisms could be involved in their resistance.

Conclusion

NILs developed in this study and the transcriptomic sequences obtained from them did not only allow the validation of the resistance locusQcrs.cpi-1Hand the identification of candidate genes underlying its resistance, they also allowed the delineation of the resistance locus and the development of SNPs markers which formed a solid base for detailed mapping as well as cloning gene(s) underlying the locus.
Dual Value System and its assessment scheme for understanding and valuing ecosystem services
Authors: Yang Haile , Chen Jiakuan
Published: May 2019

Valuing ecosystem services (ES) is helpful for effective ES management. However, there are many limitations in traditional ES valuation approaches, including theoretical challenges and practical difficulties. To overcome these limitations, we proposed a dual value system (DVS). And then, we presented a case study of valuing the water provision in Zhujiang River Basin (Pearl River Basin) based on DVS. DVS follows the axioms that (1) human life would end if we lose any of vital ES which is indispensable to human being’s survival (such as oxygen, freshwater) and (2) ES cannot provide any value to people without human activities. Correspondingly, DVS includes two types of value: the output support value (OSV) of a vital ES refers to the total value produced by human being’s economic and social activities (TVPH) supported by the ES consumption; the optional capacity value (OCV) of a vital ES refers to the optional capacity of supporting TVPH provided by total ES volume. The OCV provided by a vital ES is calculated by using the product of multiplying the OSV (TVPH) by the freedom of choosing the consumption from the total volume of this ES, valued in non-monetary units. Based on DVS, the OSV and OCV of water provision in Zhujiang River Basin were analyzed in river basin scale and sub-basin scale, and the values variation of water provision from 2006 to 2015 was analyzed in sub-basin scale. And then, based on this case study, we discussed the new insights into ES provided by DVS. Results proved that DVS and its assessment scheme overcame the limitations on current ES valuation approaches and provided an innovative quantitative framework to understand and value ES which will help to make good decisions in ES management.
Individual variation of the dark-background-contingent upshift of gaze: effect of past habituation
Authors: Spivak Oleg , Thier Peter , Barash Shabtai
Published: May 2019

We studied the shift of gaze direction induced by dark background in monkeys. Faced with large inter-individual variability, we asked how common the upshift is, and how the upshift size is distributed. Furthermore, we sought to reckon processes influencing the variability. Approaching these questions necessitates a large sample. Here we report data from 10 rhesus monkeys recorded in Tübingen, together with reported data from 4 cynomolgus monkeys studied in Rehovot. In all 14 monkeys, dark background induced upshift – but no systematic horizontal shift. The upshift might be thought of as a simple sensorimotor response; nevertheless, surprisingly, the monkeys’ previous experience appeared to have a decisive role in influencing the upshift’s size. All the monkeys were previously trained in tasks that involved vision and eye movements; by their previous training, the monkeys were naturally divided into two groups. Monkeys of the first, ‘bright-habituated’ group, previously trained in photopic, bright ambient-light conditions; monkeys of the second, ‘dark-habituated’ group previously trained mostly with isolated dots of light appearing in dim ambient lighting or in full darkness. The dark-habituated monkeys had a larger upshift than the bright-habituated: the groups were separated by a border-value such that 6/7 of the dark-habituated monkeys had upshift larger than the border, and 5/7 of the bright-habituated monkeys had upshift smaller than the border. Thus, the size of the dark-background-induced upshift largely reflects the extent to which a monkey is habituated to work in the dark. Though the upshift is reflex-like sensorimotor behavior, its amplitude largely reflects cumulative experience.