bluuebunny/crossref_metadata_2025 huggingface dataset:
Proper Education on Spinal Orthotics: A Way to Minimize Associated Complications
Authors: Elia Christopher , Huynh Katie , Dong Fanglong , Miulli Dan
Published: January 2018

Spinal orthotic bracing is a common modality for treating nonoperative spinal fractures with risks. This study aimed to assess the effect of an intervention on critical care nurses to improve their clinical knowledge and comfort level of managing patients. A literature review was conducted regarding common complications associated with spinal orthotics. This information was compiled and used to create a questionnaire and spinal orthotic course for nurses. Pre- and postassessments of nurses' knowledge regarding spinal orthotics were conducted. A total of 197 nurses completed the presentation. The ability to correctly identify thoracolumbosacral orthotics (TLSO), lumbosacral orthotics (LSO) and cervico-thoracic orthotics (CTO) all significantly increased. Regarding the clinical knowledge, the right answer to the question whether or not halo vest needed to be removed for cardiopulmonary resuscitation increased from 45.2% to 100% (p < .0001), and the correct answer to the question whether or not TLSO braces need to be worn at all times in patients with spinal precautions increased from 62.4% to 100% (p < .0001). Nurses reported that their comfort level of taking care of patients with spinal precautions increased from 94.4% before the presentation to 100% after the presentation. The quality improvement project seemed to improve the critical care nurses' ability to correctly identify different type of braces and their comfort level of managing patients with spinal precautions.
Ten-year experience of transjugular intrahepatic portosystemic shunt for noncirrhotic portal hypertension
Authors: Regnault David , d’Alteroche Louis , Nicolas Charlotte , Dujardin Fanny , Ayoub Jean , Perarnau Jean Marc
Published: January 2018

Background

Transjugular intrahepatic portosystemic shunt (TIPS) is considered to be well suited for the treatment of noncirrhotic portal hypertension (NCPHT) because of a usually severe portal hypertension (PHT) and a mild liver failure, but very less data are available.

Patients and methods

Records of patients referred for TIPS between 2004 and 2015 for NCPHT were reviewed. No patient should have clinical or biological or histological features of cirrhosis.

Results

Twenty-five patients with a wide variety of histological lesions (sinusoidal dilatations, granulomatosis, regenerative nodular hyperplasia, obliterative portal venopathy, or subnormal liver) and a wide variety of associated diseases (thrombophilia, sarcoidosis, common variable immunodeficiency, scleroderma, Castleman’s disease, early primitive biliary cirrhosis, congenital liver fibrosis, chemotherapy, purinethol intake, and congenital varices) were included. Two complications occurred during the procedure: one periprosthetic hematoma and the other misposition of a covered stent. During the first month, two other patients had an early thrombosis, another had induced encephalopathy, and one died of early rebleeding. Two of these complications occurred in patients with cavernoma. With a mean follow-up of 39 months, 10 patients experienced at least one episode of spontaneous encephalopathy, with three of these patients requiring a stent reduction. Five patients had a recurrence of their initial symptoms, and one had an asymptomatic hemodynamic dysfunction.

Conclusion

TIPS is effective in NCPHT but can be technically difficult, especially in the case of cavernoma. Good liver function does not prevent the occurrence of long-term encephalopathy.
Integrating High-Reliability Principles to Transform Access and Throughput by Creating a Centralized Operations Center
Authors: Davenport Paul B. , Carter Kimberly F. , Echternach Jeffrey M. , Tuck Christopher R.
Published: January 2018

High-reliability organizations (HROs) demonstrate unique and consistent characteristics, including operational sensitivity and control, situational awareness, hyperacute use of technology and data, and actionable process transformation. System complexity and reliance on information-based processes challenge healthcare organizations to replicate HRO processes. This article describes a healthcare organization’s 3-year journey to achieve key HRO features to deliver high-quality, patient-centric care via an operations center powered by the principles of high-reliability data and software to impact patient throughput and flow.
Mesoporous silica nanoparticle-based intelligent drug delivery system for bienzyme-responsive tumour targeting and controlled release
Authors: Zhang Yang , Xu Juan
Published: January 2018

This paper proposes a novel type of multifunctional envelope-type mesoporous silica nanoparticle (MSN) to achieve cancer cell targeting and drug-controlled release. In this system, MSNs were first modified by active targeting moiety hyaluronic acid (HA) for breast cancer cell targeting and hyaluronidases (Hyal)-induced intracellular drug release. Then gelatin, a proteinaceous biopolymer, was grafted onto the MSNs to form a capping layer via glutaraldehyde-mediated cross-linking. To shield against unspecific uptake of cells and prolong circulation time, the nanoparticles were further decorated with poly(ethylene glycol) polymers (PEG) to obtain MSN@HA-gelatin-PEG (MHGP). Doxorubicin (DOX), as a model drug, was loaded into PEMSN to assess the breast cancer cell targeting and drug release behaviours.
In vitro
study revealed that PEG chains protect the targeting ligand and shield against normal cells. After reaching the breast cancer cells, MMP-2 overpressed by cells hydrolyses gelatin layer to deshield PEG and switch on the function of HA. As a result, DOX-loaded MHGP was selectively trapped by cancer cells through HA receptor-mediated endocytosis and subsequently release DOX due to Hyal-catalysed degradation of HA. This system presents successful bienzyme-responsive targeting drug delivery in an optimal fashion and provides potential applications for targeted cancer therapy.
Modelling science trustworthiness under publish or perish pressure
Authors: Grimes David Robert , Bauch Chris T. , Ioannidis John P. A.
Published: January 2018

Scientific publication is immensely important to the scientific endeavour. There is, however, concern that rewarding scientists chiefly on publication creates a perverse incentive, allowing careless and fraudulent conduct to thrive, compounded by the predisposition of top-tier journals towards novel, positive findings rather than investigations confirming null hypothesis. This potentially compounds a reproducibility crisis in several fields, and risks undermining science and public trust in scientific findings. To date, there has been comparatively little modelling on factors that influence science trustworthiness, despite the importance of quantifying the problem. We present a simple phenomenological model with cohorts of diligent, careless and unethical scientists, with funding allocated by published outputs. This analysis suggests that trustworthiness of published science in a given field is influenced by false positive rate, and pressures for positive results. We find decreasing available funding has negative consequences for resulting trustworthiness, and examine strategies to combat propagation of irreproducible science.
Plasmid stability is enhanced by higher-frequency pulses of positive selection
Authors: Stevenson Cagla , Hall James P. J. , Brockhurst Michael A. , Harrison Ellie
Published: January 2018

Plasmids accelerate bacterial adaptation by sharing ecologically important traits between lineages. However, explaining plasmid stability in bacterial populations is challenging owing to their associated costs. Previous theoretical and experimental studies suggest that pulsed positive selection may explain plasmid stability by favouring gene mobility and promoting compensatory evolution to ameliorate plasmid cost. Here we test how the frequency of pulsed positive selection affected the dynamics of a mercury-resistance plasmid, pQBR103, in experimental populations ofPseudomonas fluorescensSBW25. Plasmid dynamics varied according to the frequency of Hg2+positive selection: in the absence of Hg2+plasmids declined to low frequency, whereas pulses of Hg2+selection allowed plasmids to sweep to high prevalence. Compensatory evolution to ameliorate the cost of plasmid carriage was widespread across the entire range of Hg2+selection regimes, including both constant and pulsed Hg2+selection. Consistent with theoretical predictions, gene mobility via conjugation appeared to play a greater role in promoting plasmid stability under low-frequency pulses of Hg2+selection. However, upon removal of Hg2+selection, plasmids which had evolved under low-frequency pulse selective regimes declined over time. Our findings suggest that temporally variable selection environments, such as those created during antibiotic treatments, may help to explain the stability of mobile plasmid-encoded resistance.
A case report of brain abscess caused by Nocardia cyriacigeorgica in a diabetic patient
Authors: Khorshidi Mehdi , Navid Sepehr , Azadi Davood , Shokri Darioush , Shojaei Hasan
Published: January 2018

Introduction.
Nocardia are Gram-positive partially acid-fast bacilli capable of inducing a wide range of infections in patients with immunodeficiency, AIDS, cancer, lupus erythematous and diabetes. Nocardia cyriacigeorgica was first isolated in 2001 from a patient with chronic bronchitis. Since then, there have been reports on the clinical significance of this organism in patients with bronchitis, brain abscess and lung diseases. We, herein, report a case of brain abscess in an elderly diabetic patient from Iran.

Case presentation. The patient was a 73 year-old woman admitted to hospital due to severe headache and shortness of breath. The patient had lived with diabetes for 20 years and suffered from chronic foot ulcer. She was admitted to hospital with fever, weakness, drowsiness and vomiting. Clinical examination and the head CT scan of the left frontal lobe of the brain revealed a metastatic carcinoma involving skull bone in the tumor that resulted in two surgical operations in the following two years. The brain abscess biopsy revealed an infection with Nocardia cyriacigeorgica confirmed by phenotypic and molecular tests including a PCR-based amplification of a target genetic marker, a 596 bp fragment of 16S rRNA gene, followed by almost full 16S rRNA sequencing.

Conclusion. The rare infections, such as brain abscess with Nocardia, are easily neglected or misdiagnosed due to the fastidious nature of the organism and inadequate microbiological experience of laboratories in the hospitals of developing countries. This case shows that hospitals should consider a better laboratory protocol to deal with the clinical cases in which fastidious organisms, and in particular Nocardia, are involved.
MentaLiST – A fast MLST caller for large MLST schemes
Authors: Feijao Pedro , Yao Hua-Ting , Fornika Dan , Gardy Jennifer , Hsiao William , Chauve Cedric , Chindelevitch Leonid
Published: January 2018

MLST (multi-locus sequence typing) is a classic technique for genotyping bacteria, widely applied for pathogen outbreak surveillance. Traditionally, MLST is based on identifying sequence types from a small number of housekeeping genes. With the increasing availability of whole-genome sequencing data, MLST methods have evolved towards larger typing schemes, based on a few hundred genes [core genome MLST (cgMLST)] to a few thousand genes [whole genome MLST (wgMLST)]. Such large-scale MLST schemes have been shown to provide a finer resolution and are increasingly used in various contexts such as hospital outbreaks or foodborne pathogen outbreaks. This methodological shift raises new computational challenges, especially given the large size of the schemes involved. Very few available MLST callers are currently capable of dealing with large MLST schemes. We introduce MentaLiST, a new MLST caller, based on a k-mer voting algorithm and written in the Julia language, specifically designed and implemented to handle large typing schemes. We test it on real and simulated data to show that MentaLiST is faster than any other available MLST caller while providing the same or better accuracy, and is capable of dealing with MLST schemes with up to thousands of genes while requiring limited computational resources. MentaLiST source code and easy installation instructions using a Conda package are available at https://github.com/WGS-TB/MentaLiST.
Iron oxidation by a fused cytochrome-porin common to diverse iron-oxidizing bacteria
Authors: Keffer Jessica L. , McAllister Sean M. , Garber Arkadiy , Hallahan Beverly J. , Sutherland Molly C. , Rozovsky Sharon , Chan Clara S.
Published: January 2018

Iron (Fe) oxidation is one of Earth’s major biogeochemical processes, key to weathering, soil formation, water quality, and corrosion. However, our understanding of microbial contribution is limited by incomplete knowledge of microbial iron oxidation mechanisms, particularly in neutrophilic iron-oxidizers. The genomes of many, diverse iron-oxidizers encode a homolog to an outer-membrane cytochrome (Cyc2) shown to oxidize iron in two acidophiles. Phylogenetic analyses show Cyc2 sequences from neutrophiles cluster together, suggesting a common function, though this function has not been verified in these organisms. Therefore, we investigated the iron oxidase function of heterologously expressed Cyc2 from a neutrophilic iron-oxidizerMariprofundus ferrooxydansPV-1. Cyc2PV-1 is capable of oxidizing iron, and its redox potential is 208 ± 20 mV, consistent with the ability to accept electrons from Fe2+at neutral pH. These results support the hypothesis that Cyc2 functions as an iron oxidase in neutrophilic iron-oxidizing organisms. Sequence analysis and modeling reveal the entire Cyc2 family share a unique fused cytochrome-porin structure, with a defining consensus motif in the cytochrome region. Based on structural analyses, we predict that the monoheme cytochrome Cyc2 specifically oxidizes dissolved Fe2+, in contrast to multiheme iron oxidases, which may oxidize solid Fe(II). With our results, there is now functional validation for diverse representatives of Cyc2 sequences. We present a comprehensive Cyc2 phylogenetic tree and offer a roadmap for identifyingcyc2/Cyc2 homologs and interpreting their function. The occurrence ofcyc2in many genomes beyond known iron-oxidizers presents the possibility that microbial iron oxidation may be a widespread metabolism.

Importance

Iron is practically ubiquitous across Earth’s environments, central to both life and geochemical processes, which depend heavily on the redox state of iron. Although iron oxidation, or “rusting,” can occur abiotically at near neutral pH, we find neutrophilic iron-oxidizing bacteria (FeOB) are widespread, including in aquifers, sediments, hydrothermal vents, pipes, and water treatment systems. FeOB produce highly reactive Fe(III) oxyhydroxides that bind a variety of nutrients and toxins, thus these microbes are likely a controlling force in iron and other biogeochemical cycles. There has been mounting evidence that Cyc2 functions as an iron oxidase in neutrophiles, but definitive proof of its function has long eluded us. This work provides conclusive biochemical evidence of iron oxidation by Cyc2 from neutrophiles. Cyc2 is common to a wide variety of iron-oxidizers, including acidophilic and phototrophic iron-oxidizers, suggesting that this fused cytochrome-porin structure is especially well-adapted for iron oxidation.
A quantitative map of human Condensins provides new insights into mitotic chromosome architecture
Authors: Walther Nike , Hossain M. Julius , Politi Antonio Z. , Koch Birgit , Kueblbeck Moritz , Ødegård-Fougner Øyvind , Lampe Marko , Ellenberg Jan
Published: January 2018

The two Condensin complexes in human cells are essential for mitotic chromosome structure. We used homozygous genome editing to fluorescently tag Condensin I and II subunits and mapped their absolute abundance, spacing and dynamic localization during mitosis by fluorescence correlation spectroscopy-calibrated live cell imaging and super-resolution microscopy. While ∼35,000 Condensin II complexes are stably bound to chromosomes throughout mitosis, ∼195,000 Condensin I complexes dynamically bind in two steps, in prometaphase and early anaphase. The two Condensins rarely co-localize at the chromatid axis, where Condensin II is centrally confined but Condensin I reaches ∼50% of the chromatid diameter from its center. Based on our comprehensive quantitative data, we propose a three-step hierarchical loop model of mitotic chromosome compaction: Condensin II initially fixes loops of a maximum size of ∼450 kb at the chromatid axis whose size is then reduced by Condensin I binding to ∼90 kb in prometaphase and ∼70 kb in anaphase, achieving maximum chromosome compaction upon sister chromatid segregation.
Identification of the Goliath beetles Fornasinius fornasini Bertoloni and Fornasinius hauseri Kraatz (Scarabaeidae: Cetoniinae)
Authors: De Palma Michele , Takano Hitoshi
Published: January 2018

The Goliath beetles (subtribe Goliathina) are large Cetoniinae comprising a few highly related genera broadly distributed in sub-Saharan Africa. The genus Fornasinius Bertoloni was established in 1853 by Giuseppe Bertoloni to receive a taxon that was sufficiently distinct from the known representatives of the genus Goliathus Lamarck to merit a different placement. In spite of their large size and showy appearance, the members of the genus Fornasinius are poorly known. Here, the type species of the genus, F. fornasini Bertoloni, 1853 (type locality: Mozambique), is identified and re-described. It has emerged that F. fornasini Bertoloni has been misidentified after its original description and that only a few specimens are known of this species. F. fornasini sensu auct. (nec Bertoloni) is instead referable to another taxon, F. hauseri Kraatz, 1896 sp. bon., of which three subspecies can be distinguished: F. hauseri s. str., from south-central Kenya and possibly Cameroon; F. hauseri ssp. hirthi Preiss, 1904 stat. rev., from the Lake Victoria region and northern Tanzania; and a new subspecies to be described from south-east Democratic Republic of the Congo.
Multiple Linear Regression: Bayesian Inference for Distributed and Big Data in the Medical Informatics Platform of the Human Brain Project
Authors: Melie-Garcia Lester , Draganski Bogdan , Ashburner John , Kherif Ferath
Published: January 2018

We propose a Multiple Linear Regression (MLR) methodology for the analysis of distributed and Big Data in the framework of the Medical Informatics Platform (MIP) of the Human Brain Project (HBP). MLR is a very versatile model, and is considered one of the workhorses for estimating dependences between clinical, neuropsychological and neurophysiological variables in the field of neuroimaging. One of the main concepts behind MIP is to federate data, which is stored locally in geographically distributed sites (hospitals, customized databases, etc.) around the world. We restrain from using a unique federation node for two main reasons: first the maintenance of data privacy, and second the efficiency in management of big volumes of data in terms of latency and storage resources needed in the federation node. Considering these conditions and the distributed nature of data, MLR cannot be estimated in the classical way, which raises the necessity of modifications of the standard algorithms. We use the Bayesian formalism that provides the armamentarium necessary to implement the MLR methodology for distributed Big Data. It allows us to account for the heterogeneity of the possible mechanisms that explain data sets across sites expressed through different models of explanatory variables. This approach enables the integration of highly heterogeneous data coming from different subjects and hospitals across the globe. Additionally, it offers general and sophisticated ways, which are extendable to other statistical models, to suit high-dimensional and distributed multimodal data. This work forms part of a series of papers related to the methodological developments embedded in the MIP.
Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans
Authors: Charlesworth Carsten T. , Deshpande Priyanka S. , Dever Daniel P. , Dejene Beruh , Gomez-Ospina Natalia , Mantri Sruthi , Pavel-Dinu Mara , Camarena Joab , Weinberg Kenneth I. , Porteus Matthew H.
Published: January 2018

The CRISPR-Cas9 system has proven to be a powerful tool for genome editing, allowing for the precise modification of specific DNA sequences within a cell. Many efforts are currently underway to use the CRISPR-Cas9 system for the therapeutic correction of human genetic diseases. The most widely used homologs of the Cas9 protein are derived from the bacteriaStaphylococcus aureus(S. aureus) andStreptococcus pyogenes(S. pyogenes). Based on the fact that these two bacterial species cause infections in the human population at high frequencies, we looked for the presence of pre-existing adaptive immune responses to their respective Cas9 homologs, SaCas9 (S. aureushomolog of Cas9) and SpCas9 (S. pyogeneshomolog of Cas9). To determine the presence of anti-Cas9 antibodies, we probed for the two homologs using human serum and were able to detect antibodies against both, with 79% of donors staining against SaCas9 and 65% of donors staining against SpCas9. Upon investigating the presence of antigen-specific T-cells against the two homologs in human peripheral blood, we found anti-SaCas9 T-cells in 46% of donors. Upon isolating, expanding, and conducting antigen re-stimulation experiments on several of these donors’ anti-SaCas9 T-cells, we observed an SaCas9-specific response confirming that these T-cells were antigen-specific. We were unable to detect antigen-specific T-cells against SpCas9, although the sensitivity of the assay precludes us from concluding that such T-cells do not exist. Together, this data demonstrates that there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials.
Influence of switching rule on motor learning
Authors: Takiyama Ken , Ishii Koutaro , Hayshi Takuji
Published: January 2018

Humans and animals can flexibly switch rules to generate appropriate motor commands; for example, actions can be flexibly produced toward a sensory stimulus (e.g., pro-saccade or pro-reaching) or away from a sensory stimulus (e.g., anti-saccade or anti-reaching). Distinct neural activities are related to pro- and anti-movement actions; however, the effects of switching rules on motor learning are unclear. Here, we study the effect of switching rules on motor learning using pro- and anti-arm-reaching movements and a visuomotor rotation task. Although previous results support the perfect availability of learning effects under the same required movements, we show that the learning effects trained in pro-reaching movements are partially rather than perfectly available in anti-reaching movements even under the same required movement direction between those two conditions. The partial transfer is independent of the difference in the visual cue, the cognitive demand, and the actual movement direction between the pro- and anti-reaching movements. We further demonstrate that the availability of learning effects trained with pro-reaching movements is partial not only in anti-reaching movements but in reaching movements with other rules and the availability of learning effects trained with anti-reaching movements is also partial in pro-reaching movements. We thus conclude that the switching rule causes the availability of learning effects to be partial rather than perfect even under same planned movements.

New & Noteworthy

Most motor learning experiments supported the involvement of planned movement directions in motor learning; the learning effects trained in a movement direction can be available at movement directions close to the trained one. Here, we show that the availability of motor learning effects is partial rather than perfect even under the same planned movements when rule is switched, which indicates that sports training and rehabilitation should include various situations under the same required motions.
The brown algaSaccharina japonicafeatures distinct vanadium-dependent bromoperoxidases and iodoperoxidases
Authors: Chi Shan , Liu Tao , Yin Hongxin , Xu Xin , Zhu Weiming , Wang Yi , Wang Cong , Lv Hui
Published: January 2018

Marine algae have an extraordinary ability to absorb halogens which provide algae with an inorganic antioxidant impacting atmospheric chemistry. Although brown algal Laminariales species are the most efficient iodine accumulators among all living systems, andSaccharina japonicais the primary material used for iodine extraction, the functions and regulatory mechanisms of these species have not been fully documented. In this study, a functional genomics analysis of the algal vanadium-dependent haloperoxidase (vHPO) gene family was conducted; there genes can introduce halogen atoms into organic compounds. The comprehensive analyses regarding the bioinformatics and phylogenetics of novel genomic and transcriptomic sequencing data of 21 Rhodophyta and 19 Ochrophyta marine algal species revealed that brown algalvHPOshave two gene types, vanadium-dependent bromoperoxidase (vBPO) and vanadium-dependent iodoperoxidase (vIPO), with secondary endosymbiotic host origin. The enzyme activity ofS. japonicavBPO and vIPO were verified for the first time and were quite stable in a wide range of temperature and pH values. However, the specific activity and optimal conditions were considerably different between vBPO and vIPO. The transcript expression analysis in differentS. japonicatissues (including rhizoids), generations (sporophytes and gametophytes), sexes (male and female), and stress conditions (hyposaline and hyperthermia) also showed great differences betweenvBPOsandvIPOs. Most of thevBPOswere constitutively expressed with higher expression dose, which may be responsible for basal halogen metabolism. On the contrary,vIPOsmainly showed specific expression, which may be involved in tissue differentiation, generation differentiation, sex differentiation, and stress regulation. Comprehensive analysis of gene family evolution, enzyme biochemical characteristics, and complex transcriptional mechanisms were conducive to the environmental adaptation and sophisticated system evolution of Laminariales. The successful bromination of small-molecule compound substrate by SjavBPO provided high activity and efficient enzymatic tools for artificial synthesis of halogenated compounds.
Spatial gradient in activity within the insula reflects dissociable neural mechanisms underlying context-dependent advantageous and disadvantageous inequity aversion
Authors: Gao Xiaoxue , Yu Hongbo , Saez Ignacio , Blue Philip R. , Zhu Lusha , Hsu Ming , Zhou Xiaolin
Published: January 2018

Humans are capable of integrating social contextual information into decision-making processes to adjust their attitudes towards inequity. This context-dependency emerges both when individual is better off (i.e. advantageous inequity) and worse off (i.e. disadvantageous inequity) than others. It is not clear however, whether the context-dependent processing of advantageous and disadvantageous inequity rely on dissociable or shared neural mechanisms. Here, by combining an interpersonal interactive game that gave rise to interpersonal guilt and different versions of the dictator games that enabled us to characterize individual weights on aversion to advantageous and disadvantageous inequity, we investigated the neural mechanisms underlying the two forms of inequity aversion in the interpersonal guilt context. In each round, participants played a dot-estimation task with an anonymous co-player. The co-players received pain stimulation with 50% probability when anyone responded incorrectly. At the end of each round, participants completed a dictator game, which determined payoffs of him/herself and the co-player. Both computational model-based and model-free analyses demonstrated that when inflicting pain upon co-players (i.e., the guilt context), participants cared more about advantageous inequity and became less sensitive to disadvantageous inequity, compared with other social contexts. The contextual effects on two forms of inequity aversion are uncorrelated with each other at the behavioral level. Neuroimaging results revealed that the context-dependent representation of inequity aversion exhibited a spatial gradient in activity within the insula, with anterior parts predominantly involved in the aversion to advantageous inequity and posterior parts predominantly involved in the aversion to disadvantageous inequity. The dissociable mechanisms underlying the two forms of inequity aversion are further supported by the involvement of right dorsolateral prefrontal cortex and dorsomedial prefrontal cortex in advantageous inequity processing, and the involvement of right amygdala and dorsal anterior cingulate cortex in disadvantageous inequity processing. These results extended our understanding of decision-making processes involving inequity and the social functions of inequity aversion.
Identifying biomarkers of anti-cancer drug synergy using multi-task learning
Authors: Aben Nanne , de Ruiter Julian R. , Bosdriesz Evert , Kim Yongsoo , Bounova Gergana , Vis Daniel J. , Wessels Lodewyk F.A. , Michaut Magali
Published: January 2018

Combining anti-cancer drugs has the potential to increase treatment efficacy. Because patient responses to drug combinations are highly variable, predictive biomarkers of synergy are required to identify which patients are likely to benefit from a drug combination. To aid biomarker identification, the DREAM challenge consortium has recently released data from a screen containing 85 cell lines and 167 drug combinations. The main challenge of these data is the low sample size: per drug combination, a median of 14 cell lines have been screened. We found that widely used methods in single drug response prediction, such as Elastic Net regression per drug, are not predictive in this setting. Instead, we propose to use multi-task learning: training a single model simultaneously on all drug combinations, which we show results in increased predictive performance. In contrast to other multi-task learning approaches, our approach allows for the identification of biomarkers, by using a modified random forest variable importance score, which we illustrate using artificial data and the DREAM challenge data. Notably, we find that mutations in MYO15A are associated with synergy between ALK / IGFR dual inhibitors and PI3K pathway inhibitors in triple-negative breast cancer.

Author summary

Combining drugs is a promising strategy for cancer treatment. However, it is often not known which patients will benefit from a particular drug combination. To identify patients that are likely to benefit, we need to identify biomarkers, such as mutations in the tumor’s DNA, that are associated with favorable response to the drug combination. In this work, we identified such biomarkers using the drug combination data released by the DREAM challenge consortium, which contain 85 tumor cell lines and 167 drug combinations. The main challenge of these data is the extremely low sample size: a median of 14 cell lines have been screened per drug combination. We found that traditional methods to identify biomarkers for monotherapy response, which analyze each drug separately, are not suitable in this low sample size setting. Instead, we used a technique called multi-task learning to jointly analyze all drug combinations in a single statistical model. In contrast to existing multi-task learning algorithms, which are black-box methods, our method allows for the identification of biomarkers. Notably, we find that, in a subset of breast cancer cell lines,MYO15Amutations associate with response to the combination of ALK / IGFR dual inhibitors and PI3K pathway inhibitors.
Naa10p promotes metastasis by stabilizing matrix metalloproteinase-2 protein in human osteosarcomas
Authors: Chien Ming-Hsien , Lee Wei-Jiunn , Yang Yi-Chieh , Tan Peng , Pan Ke-Fan , Tsai Hsiao-Chi , Hsu Chun-Hua , Hsiao Michael , Hua Kuo-Tai
Published: January 2018

N-α-Acetyltransferase 10 protein (Naa10p) mediates N-terminal acetylation of nascent proteins. Oncogenic or tumor suppressive roles of Naa10p were reported in cancers. Here, we report an oncogenic role of Naa10p in promoting metastasis of osteosarcomas. HigherNAA10transcripts were observed in metastatic osteosarcoma tissues compared to non-metastatic tissues and were also correlated with a worse prognosis of patients. Knockdown and overexpression of Naa10p in osteosarcoma cells respectively led to decreased and increased cell migratory/invasive abilities. Re-expression of Naa10p, but not an enzymatically inactive mutant, relieved suppression of the invasive abilityin vitroand metastasisin vivoimposed by Naa10p-knockdown. According to protease array screening, we identified that matrix metalloproteinase (MMP)-2 was responsible for the Naa10p-induced invasive phenotype. Naa10p was directly associated with MMP-2 protein through its acetyltransferase domain and maintained MMP-2 protein stability via NatA complex activity. MMP-2 expression levels were also significantly correlated with Naa10p levels in osteosarcoma tissues. These results reveal a novel function of Naa10p in the regulation of cell invasiveness by preventing MMP-2 protein degradation that is crucial during osteosarcoma metastasis.
Universal temporal rate of DNA replication origin firing: A balance between origin activation and passivation
Authors: Arbona Jean-Michel , Goldar Arach , Hyrien Olivier , Arneodo Alain , Audit Benjamin
Published: January 2018

The time-dependent rate I(t) of origin firing per length of unreplicated DNA presents a universal bell shape in eukaryotes that has been interpreted as the result of a complex time-evolving interaction between origins and limiting firing factors. Here we show that a normal diffusion of replication fork components towards localized potential replication origins (p-oris) can more simply account for the I(t) universal bell shape, as a consequence of a competition between the origin firing time and the time needed to replicate DNA separating two neighboring p-oris. We predict the I(t) maximal value to be the product of the replication fork speed with the squared p-ori density. We show that this relation is robustly observed in simulations and in experimental data for several eukaryotes. Our work underlines that fork-component recycling and potential origins localization are sufficient spatial ingredients to explain the universality of DNA replication kinetics.
OTX2 signals from the choroid plexus to regulate adult neurogenesis
Authors: Planques Anabelle , Moreira Vanessa Oliveira , Dubreuil Chantal , Prochiantz Alain , Di Nardo Ariel A
Published: January 2018

Proliferation and migration during adult neurogenesis are regulated by a microenvironment of signaling molecules originating from local vasculature, from cerebrospinal fluid produced by the choroid plexus, and from local supporting cells including astrocytes. Here, we focus on the function of OTX2 homeoprotein transcription factor in the mouse adult ventricular-subventricular zone (V-SVZ) which generates olfactory bulb neurons. We find that OTX2 secreted by choroid plexus is transferred to supporting cells of the V-SVZ and rostral migratory stream. Deletion ofOtx2in choroid plexus affects neuroblast migration and reduces the number of olfactory bulb newborn neurons. Adult neurogenesis was also decreased by expressing secreted single-chain antibodies to sequester OTX2 in the cerebrospinal fluid, demonstrating the importance of non-cell autonomous OTX2. We show that OTX2 activity modifies extracellular matrix components and signaling molecules produced by supporting astrocytes. Thus, we reveal a multi-level and non-cell autonomous role of a homeoprotein and reinforce the choroid plexus and astrocytes as key niche compartments affecting adult neurogenesis.

Significance Statement

Cerebrospinal fluid, local vasculature and non-neurogenic astrocytes are niche compartments that provide a microenvironment for regulating adult mouse neurogenesis. We show that OTX2 homeoprotein secreted by choroid plexus into the cerebrospinal fluid is transferred into non-neurogenic astrocytes of the ventricular-subventricular zone and rostral migratory stream where it regulates extracellular matrix and signaling factors. This non-cell-autonomous activity impacts the number of newborn neurons that integrate the olfactory bulb. Thus, we reveal a multi-level role for OTX2 and reinforce the choroid plexus as a key niche compartment affecting adult neurogenesis.
Neural evidence for representationally specific prediction in language processing
Authors: Wang Lin , Kuperberg Gina , Jensen Ole
Published: January 2018

Previous studies suggest that people generate predictions during language comprehension at multiple linguistic levels. It has been hypothesized that, under some circumstances, this can result in the pre-activation of specific lexico-semantic representations. We asked whether such representationally specific semantic pre-activation can be detected in the brain ahead of encountering bottom-up input. We measured MEG activity as participants read highly constraining sentences in which the final word could be predicted. We found that both spatial and temporal patterns of the brain activity prior to the onset of this word were more similar when the same words were predicted than when different words were predicted. This pre-activation was transient and engaged a left inferior and medial temporal region. These results suggest that unique spatial patterns of neural activity associated with the pre-activation of distributed semantic representations can be detected prior to the appearance of new sensory input, and that the left inferior and medial temporal regions may play a role in temporally binding such representations, giving rise to specific lexico-semantic predictions.
Homology-directed repair of a defective glabrous gene in Arabidopsis with Cas9-based gene targeting
Authors: Hahn Florian , Eisenhut Marion , Mantegazza Otho , Weber Andreas P.M.
Published: January 2018

The CRISPR/Cas9 system has emerged as a powerful tool for targeted genome editing in plants and beyond. Double-strand breaks induced by the Cas9 enzyme are repaired by the cell’s own repair machinery either by the non-homologous end joining pathway or by homologous recombination. While the first repair mechanism results in random mutations at the double-strand break site, homologous recombination uses the genetic information from a highly homologous repair template as blueprint for repair of the break. By offering an artificial repair template, this pathway can be exploited to introduce specific changes at a site of choice in the genome. However, frequencies of double-strand break repair by homologous recombination are very low. In this study, we compared two methods that have been reported to enhance frequencies of homologous recombination in plants. The first method boosts the repair template availability through the formation of viral replicons, the second method makes use of an in planta gene targeting approach. Additionally, we comparatively applied a nickase instead of a nuclease for target strand priming. To allow easy, visual detection of homologous recombination events, we aimed at restoring trichome formation in a glabrous Arabidopsis mutant by repairing a defective glabrous1 gene. Using this efficient visual marker, we were able to regenerate plants repaired by homologous recombination at frequencies of 0.12% using the in planta gene targeting approach, while both approaches using viral replicons did not yield any trichome-bearing plants.
Comparative Network Reconstruction using Mixed Integer Programming
Authors: Bosdriesz Evert , Prahallad Anirudh , Klinger Bertram , Sieber Anja , Bosma Astrid , Bernards René , Blüthgen Nils , Wessels Lodewyk FA
Published: January 2018

New anti-cancer drugs that specifically target oncogenes involved in signalling show great clinical promise. However, the effectiveness of such targeted treatments is often hampered by innate or acquired resistance due to feedbacks, crosstalks or network adaptations in response to drug treatment. Addressing this problem requires an understanding of these networks and how they differ between cells with different oncogenic mutations or between sensitive and resistant cells. Here, we present Comparative Network Reconstruction (CNR), a computational method to reconstruct signaling networks based on incomplete perturbation data, and to identify which edges differ quantitatively between two or more signalling networks. Prior knowledge about network topology is not required but can straightforwardly be incorporated. We extensively tested our approach using simulated data and applied it to perturbation data from a BRAF mutant cell line that developed resistance to BRAF inhibition. Comparing the reconstructed networks of sensitive and resistant cells suggests that the resistance mechanism involves re-establishing wildtype MAPK signaling, possibly through an alternative RAF-isoform.
Graph theory approaches to functional network organization in brain disorders: A critique for a brave new small-world
Authors: Hallquist Michael N. , Hillary Frank G.
Published: January 2018

Over the past two decades, resting-state functional connectivity (RSFC) methods have provided new insights into the network organization of the human brain. Studies of brain disorders such as Alzheimer’s disease or depression have adapted tools from graph theory to characterize differences between healthy and patient populations. Here, we conducted a review of clinical network neuroscience, summarizing methodological details from 106 RSFC studies. Although this approach is prevalent and promising, our review identified four challenges. First, the composition of networks varied remarkably in terms of region parcellation and edge definition, which are fundamental to graph analyses. Second, many studies equated the number of connections across graphs, but this is conceptually problematic in clinical populations and may induce spurious group differences. Third, few graph metrics were reported in common, precluding meta-analyses. Fourth, some studies tested hypotheses at one level of the graph without a clear neurobiological rationale or considering how findings at one level (e.g., global topology) are contextualized by another (e.g., modular structure). Based on these themes, we conducted network simulations to demonstrate the impact of specific methodological decisions on case-control comparisons. Finally, we offer suggestions for promoting convergence across clinical studies in order to facilitate progress in this important field.
Environmental and evolutionary drivers of the modular gene regulatory network underlying phenotypic plasticity for stress resistance in the nematodeCaenorhabditis remanei
Authors: Sikkink Kristin L. , Reynolds Rose M. , Ituarte Catherine M. , Cresko William A. , Phillips Patrick C.
Published: January 2018

In response to changing environmental conditions, organisms can acclimate through phenotypic plasticity or adapt by evolving mechanisms to cope with novel stressors. Changes in gene expression, whether dynamic or evolved, are an important way in which environmental responses are mediated; however, much is still unknown about how the molecular networks underlying plastic phenotypes evolve. Here, we compare transcriptional responses to acute heat stress among four populations of the nematodeCaenorhabditis remanei—one selected to withstand heat stress, one selected under oxidative stress, an unselected control, and the ancestral population. We used a weighted gene coexpression network analysis within these lines to identify transcriptional modules, which are sets of genes that respond similarly to stress via plastic responses, evolutionary responses, or both. The transcriptional response to acute heat stress is dominated by a plastic response that is shared in the ancestor and all evolved populations. However, we also identified several modules that respond to artificial selection by (1) changing the baseline level of expression, (2) altering the magnitude of the plastic response, or (3) a combination of the two. Our findings reveal that while it is possible to perturb the nature of the transcriptional response network with short bouts of intense selection, the overall structure of transcriptional plasticity is dominated by inherent, ancestral regulatory systems.
Separating intrinsic interactions from extrinsic correlations in a network of sensory neurons
Authors: Ferrari Ulisse , Deny Stéphane , Chalk Matthew , Tkačik Gašper , Marre Olivier , Mora Thierry
Published: January 2018

Correlations in sensory neural networks have both extrinsic and intrinsic origins. Extrinsic or stimulus correlations arise from shared inputs to the network, and thus depend strongly on the stimulus ensemble. Intrinsic or noise correlations reflect biophysical mechanisms of interactions between neurons, which are expected to be robust to changes of the stimulus ensemble. Despite the importance of this distinction for understanding how sensory networks encode information collectively, no method exists to reliably separate intrinsic interactions from extrinsic correlations in neural activity data, limiting our ability to build predictive models of the network response. In this paper we introduce a general strategy to infer population models of interacting neurons that collectively encode stimulus information. The key to disentangling intrinsic from extrinsic correlations is to infer the couplings between neurons separately from the encoding model, and to combine the two using corrections calculated in a mean-field approximation. We demonstrate the effectiveness of this approach on retinal recordings. The same coupling network is inferred from responses to radically different stimulus ensembles, showing that these couplings indeed reflect stimulus-independent interactions between neurons. The inferred model predicts accurately the collective response of retinal ganglion cell populations as a function of the stimulus.
Maximum entropy models reveal the correlation structure in cortical neural activity during wakefulness and sleep
Authors: Nghiem Trang-Anh , Telenczuk Bartosz , Marre Olivier , Destexhe Alain , Ferrari Ulisse
Published: January 2018

Maximum Entropy models can be inferred from large data-sets to uncover how local interactions generate collective dynamics. Here, we employ such models to investigate the characteristics of neurons recorded by multielectrode arrays in the cortex of human and monkey throughout states of wakefulness and sleep. Taking advantage of the separation of excitatory and inhibitory types, we construct a model including this distinction. By comparing the performances of Maximum Entropy models at predicting neural activity in wakefulness and deep sleep, we identify the dominant interactions between neurons in each brain state. We find that during wakefulness, dominant functional interactions are pairwise while during sleep, interactions are population-wide. In particular, inhibitory neurons are shown to be strongly tuned to the inhibitory population. This shows that Maximum Entropy models can be useful to analyze data-sets with excitatory and inhibitory neurons, and can reveal the role of inhibitory neurons in organizing coherent dynamics in cerebral cortex.