bluuebunny/crossref_metadata_2025 huggingface dataset:
The Character of Papal Finance at the Turn of the Twelfth Century
Authors: Wiedemann Benedict G E
Published: March 2018

Recent approaches to twelfth-century papal finance have drawn a distinction between ‘voluntary’ gifts to the pope and the prescribed dues which clergy and laity across Europe were legally bound to pay. Such a distinction is often unhelpful; for both types of income, the onus and agency tended to be on the part of the payers themselves: most papal income was in fact voluntary. This had an effect on how income and expenditure were recorded in Rome. Since it was the payer who decided when to send money to the Curia, the papal financial administration had no consistent expectations of what their income might be. Consequently an itemised record of income was not a necessity in the later twelfth century. On the other hand, by the end of the twelfth century expenditure was being recorded in detail at the Curia: the Gesta of Pope Innocent III (1198–1216) includes a gift-list which has clearly been culled from a record of expenditure. As well as giving an insight into methods of accounting, this gift-list allows us to speculate about what forms—coins, fabrics, chalices—papal income took. Overall the character of papal finance is dissimilar to that of contemporary European monarchies because it depended to a greater extent on the will of the many people across Europe who chose to go to Rome.
A New Approach to the Law of Foreign Investments
Authors: Christian Vidal-León
Published: March 2018

This chapter analyzes South Africa's decision to terminate its investment treaties and the underlying objectives of South Africa's new investment regime, namely: (1) reinforcing the ‘sovereign right to regulate in the public interest’; (2) doing away with international investment arbitration; and (3) placing foreign and domestic investments on an equal footing. It examines the standards of investment protection not explicitly laid down in the Promotion and Protection of Investment Bill 2013 and inquires whether these standards are otherwise protected by the constitution or other laws. The chapter concludes that whilst South Africa's policy decision on its investment protection regime is open to debate, the government has followed a comprehensive, transparent, and inclusive process, in which relevant stakeholders have been heard and with which they have engaged.
The Investment Treaty Regime and Development Policy Space in Ghana
Authors: Dominic N Dagbanja
Published: March 2018

This chapter explores the relationship between Ghana's standards of investment protection by treaty and its development policy-making and implementation obligations under the constitution of the Republic of Ghana 1992 and general international law. It advances four theses. First, the state has the constitutional and general international law duty to make and implement development policies for the realization of the legal right to development in Ghana. Second, the power to make treaties, which derives from the constitution and general international law, requires the conclusion of treaties that promote development. Third, existing standards of investment protection by treaty are incompatible with the constitutional and general international law duty to make and implement development policies to the extent that they impose damages on the state for doing that which is required by the constitution and general international law. The fourth thesis is that Ghana's investment treaties were aimed at establishing standards of investment protection to attract foreign investment for development and not merely to protect foreign investment as an end.
Fragrant Harbour and Oyster Mirror
Authors: Chin Leng Lim
Published: March 2018

This chapter discusses the controversy in Sanum v Lao wherein a Macanese investor sought Beijing’s treaty protection before an investment arbitration tribunal. The chapter discusses, more widely, Beijing’s regime governing the application of Chinese treaties to Macao and Hong Kong, and it discusses the Sanum affair’s broader lessons for the application and interpretation of investment treaties in the face of a bespoke devolution treaty. Finally, it discusses how two tribunals and the Singapore courts have persistently failed to recognize a requirement under two devolution agreements—the Sino–Portuguese Joint Declaration and the Sino—British Joint Declaration-for the consultation of Macao and Hong Kong as a precondition to the application of a Chinese treaty to these special administrative regions. The chapter describes how both the tribunal and the Singapore Court of Appeal forced, instead, a treaty succession solution given by the moving treaty frontiers rule.
International investment law and arbitration
Authors: Ian A Laird , Borzu Sabahi , Frédéric Gilles Sourgens , Nicholas J Birch , Kabir Duggal
Published: March 2018

This chapter is organized into five sections, focusing on issues addressed by tribunals and courts in 2012 related to Jurisdiction, Merits, Compensation and Non-pecuniary Remedies, Procedure and Annulment, and Enforcement of Awards. Section A discusses the grounds for jurisdictional challenge by respondents. Section B provides a summary review of the merits decisions of the past year, showing that the fair and equitable treatment standard remains a primary basis for the awards of tribunals, with a resurgence of decisions by tribunals accepting that investments were expropriated without compensation. Section C reviews the eight awards in which compensation was granted in 2012. Section D addresses questions of procedure that arose in 2012. Finally, Section E reviews the two International Centre for Settlement of Investment Disputes ad hoc annulment committee decisions of the past year, plus a number of domestic court decisions regarding the enforcement of awards.
How May Tribunals Apply the Customary Necessity Rule to the Argentine Cases? An Analysis of ICSID Decisions with Respect to the Interaction between Article XI of the U.S.-Argentina BIT and the Customary Rule of Necessity
Authors: Javier El-Hage
Published: March 2018

This chapter addresses the question of why the nine decisions from the International Centre for Settlement of Investment Disputes (ICSID) arising under the treaty between the United States of America and the Argentine Republic concerning the reciprocal encouragement and protection of investment have been so inconsistent in the face of largely undisputed facts and identical legal norms. It first sets forth, in abstract, a set of interpretive parameters and corresponding legal rationales that may be followed by tribunals when dealing with situations in which treaty and customary international law rules interact. It then analyzes each of the Argentine decisions according to the interaction rationales chosen by tribunals and committees, with a specific focus on the consistency of their own arguments for the application of the rule of necessity of customary international law.
Testing Mediators of Reduced Drinking for Veterans in Alcohol Care Management
Authors: Moskal Dezarie , Maisto Stephen A , Possemato Kyle , Lynch Kevin G , Oslin David W
Published: March 2018

Introduction

Alcohol Care Management (ACM) is a manualized treatment provided by behavioral health providers working in a primary care team aimed at increasing patients’ treatment engagement and decreasing their alcohol use. Research has shown that ACM is effective in reducing alcohol consumption; however, the mechanisms of ACM are unknown. Therefore, the purpose of this study is to examine the mechanisms of change in ACM in the context of a randomized clinical trial evaluating the effectiveness of ACM.

Materials and Methods

This study performed secondary data analysis of existing data from a larger study that involved a sample of U.S. veterans (N = 163) who met criteria for current alcohol dependence. Upon enrollment into the study, participants were randomized to receive either ACM or standard care. ACM was delivered in-person or by telephone within the primary care clinic and focused on the use of oral naltrexone and manualized psychosocial support. According to theory, we hypothesized several ACM treatment components that would mediate alcohol consumption outcomes: engagement in addiction treatment, reduced craving, and increased readiness to change. Parallel mediation models were performed by the PROCESS macro Model 4 in SPSS to test study hypotheses. The institutional review boards at each of the participating facilities approved all study procedures before data collection.

Results

As hypothesized, results showed that treatment engagement mediated the relation between treatment and both measures of alcohol consumption outcomes, the percentage of alcohol abstinent days, and the percentage of heavy drinking days. Neither craving nor readiness to change mediated the treatment effect on either alcohol consumption outcome.

Conclusions

Findings suggest that ACM may be effective in changing drinking patterns partially due to an increase in treatment engagement. Future research may benefit from evaluating the specific factors that underlie increased treatment engagement. The current study provides evidence that alcohol use disorder interventions should aim to increase treatment engagement and reduce barriers to care.
Impact of H3.3 K27M Mutation on Prognosis and Survival of Grade IV Spinal Cord Glioma on the Basis of New 2016 World Health Organization Classification of the Central Nervous System
Authors: Yi Seong , Choi Sunkyu , Shin Dong Ah , Kim Du Su , Choi Junjeong , Ha Yoon , Kim Keung Nyun , Suh Chang-Ok , Chang Jong Hee , Kim Se Hoon , Yoon Do Heum
Published: March 2018

BACKGROUND

Spinal cord glioma grade IV is a rare, diffuse midline glioma. H3 K27M-mutant was classified in a different entity in the 2016 World Health Organization (WHO) classification recently. No reports about prognosis of spinal cord glioma grade IV are available yet.

OBJECTIVE

To analyze the prognostic factors for spinal cord glioma grade IV.

METHODS

Twenty-five patients with spinal cord glioma of grade IV who underwent surgery in a single institute were selected. All grade IV spinal cord glioma histologically confirmed as glioblastoma or “diffuse midline glioma with H3 K27M-mutant” by the 2016 WHO classification of the central nervous system were included. Basic demographics, treatment modalities, and pathological tumor molecular profiles were investigated for prognosis.

RESULTS

Mean age was 39.1 yr; male to female ratio was 18 : 7. Tumor was located in thoracic cord (53.3%), cervical cord (40%), and lumbar area (6.7%). Median overall survival was 37.1 mo; median disease-free survival was 18.5 mo. Treatment modality showed no statistical difference. Only K27M profile showed significant prognostic value, 20 patients (80%) showed K27M mutation positive, K27M mutation patients showed longer overall survival (40.07 mo) than K27M negative patients (11.63 mo, P < .0001), and disease-free survival (20.85 vs 8.72 mo, P = .0241).

CONCLUSION

This study is the first and largest report of the prognosis of primary spinal cord grade IV glioma using the new WHO classification. This study reported survival analysis and prognostic factors, and revealed that H3.3 K27M mutation is not a major poor prognostic factor. Further studies to explore K27M mutations needed for risk stratification and therapy optimization.
Results of a Hepatitis C Virus Screening Program of the 1945–1965 Birth Cohort in a Large Emergency Department in New Jersey
Authors: Cornett Julia Kang , Bodiwala Vimal , Razuk Victor , Shukla Devangi , Narayanan Navaneeth
Published: March 2018

Background

Persons born between 1945 and 1965 account for an estimated 81% of those infected with hepatitis C virus (HCV) in the United States. However, up to 60% remain undiagnosed. Prior studies have reported HCV screening results from large urban emergency departments.

Methods

This is a retrospective cohort study of patients in the 1945–1965 birth cohort tested for HCV in a large emergency department (ED) in New Jersey from June 1, 2016, through December 31, 2016. The purpose was to report HCV antibody and viral load results of this testing program located in a small urban/suburban area and to analyze specific characteristics associated with positive results, such as race/ethnicity and insurance status. Descriptive statistics were performed, and, using a multivariate logistic regression model, adjusted odds ratios and 95% confidence intervals were calculated.

Results

A total of 3046 patients were screened: 55.8% were white, and 17.9% were black; 52.1% had private insurance, 33.4% Medicare, 3.9% Medicaid. One hundred ninety-two were antibody positive (6.3%). Of 167 with HCV viral load testing results, 43% had a positive viral load. On multivariate analysis, black race and Medicaid were independently associated with a positive HCV viral load.

Conclusions

HCV antibody seropositivity was above 6% and twice as high as the Centers for Disease Control and Prevention estimated prevalence in this birth cohort. These results indicate that EDs outside of large urban cities are also important sites for routine HCV screening. Other findings of interest include 43% with chronic HCV infection and the persistent association between black race and positive HCV viral load even when adjusted for insurance status.
Inferring influence and leadership in moving animal groups
Authors: Strandburg-Peshkin Ariana , Papageorgiou Danai , Crofoot Margaret C. , Farine Damien R.
Published: March 2018

Collective decision-making is a daily occurrence in the lives of many group-living animals, and can have critical consequences for the fitness of individuals. Understanding how decisions are reached, including who has influence and the mechanisms by which information and preferences are integrated, has posed a fundamental challenge. Here, we provide a methodological framework for studying influence and leadership in groups. We propose that individuals haveinfluenceif their actions result in some behavioural change among their group-mates, and areleadersif they consistently influence others. We highlight three components of influence (influence instances, total influence and consistency of influence), which can be assessed at two levels (individual-to-individual and individual-to-group). We then review different methods, ranging from individual positioning within groups to information-theoretic approaches, by which influence has been operationally defined in empirical studies, as well as how such observations can be aggregated to give insight into the underlying decision-making process. We focus on the domain of collective movement, with a particular emphasis on methods that have recently been, or are being, developed to take advantage of simultaneous tracking data. We aim to provide a resource bringing together methodological tools currently available for studying leadership in moving animal groups, as well as to discuss the limitations of current methodologies and suggest productive avenues for future research.

This article is part of the theme issue ‘Collective movement ecology’.
Different bees, different needs: how nest-site requirements have shaped the decision-making processes in homeless honeybees (Apisspp.)
Authors: Beekman Madeleine , Oldroyd Benjamin P.
Published: March 2018

During reproductive swarming, a honeybee swarm needs to decide on a new nest site and then move to the chosen site collectively. Most studies of swarming and nest-site selection are based on one species,Apis mellifera. Natural colonies ofA. melliferalive in tree cavities. The quality of the cavity is critical to the survival of a swarm. Other honeybee species nest in the open, and have less strict nest-site requirements, such as the open-nesting dwarf honeybeeApis florea.Apis floreabuilds a nest comprised of a single comb suspended from a twig. For a cavity-nesting species, there is only a limited number of potential nest sites that can be located by a swarm, because suitable sites are scarce. By contrast, for an open-nesting species, there is an abundance of equally suitable twigs. While the decision-making process of cavity-nesting bees is geared towards selecting the best site possible, open-nesting species need to coordinate collective movement towards areas with potential nest sites. Here, we argue that the nest-site selection processes ofA. floreaandA. melliferahave been shaped by each species' specific nest-site requirements. Both species use the same behavioural algorithm, tuned to allow each species to solve their species-specific problem.

This article is part of the theme issue ‘Collective movement ecology’.
Synchronization, coordination and collective sensing during thermalling flight of freely migrating white storks
Authors: Nagy Máté , Couzin Iain D. , Fiedler Wolfgang , Wikelski Martin , Flack Andrea
Published: March 2018

Exploring how flocks of soaring migrants manage to achieve and maintain coordination while exploiting thermal updrafts is important for understanding how collective movements can enhance the sensing of the surrounding environment. Here we examined the structural organization of a group of circling white storks (
Ciconia ciconia
) throughout their migratory journey from Germany to Spain. We analysed individual high-resolution GPS trajectories of storks during circling events, and evaluated each bird's flight behaviour in relation to its flock members. Within the flock, we identified subgroups that synchronize their movements and coordinate switches in their circling direction within thermals. These switches in direction can be initiated by any individual of the subgroup, irrespective of how advanced its relative vertical position is, and occur at specific horizontal locations within the thermal allowing the storks to remain within the thermal. Using the motion of all flock members, we were able to examine the dynamic variation of airflow within the thermals and to determine the specific environmental conditions surrounding the flock. With an increasing amount of high-resolution GPS tracking, we may soon be able to use these animals as distributed sensors providing us with a new means to obtain a detailed knowledge of our environment.

This article is part of the theme issue ‘Collective movement ecology’.
Fitness trade-offs of group formation and movement by Thomson's gazelles in the Serengeti ecosystem
Authors: Fryxell John M. , Berdahl Andrew M.
Published: March 2018

Collective behaviours contributing to patterns of group formation and coordinated movement are common across many ecosystems and taxa. Their ubiquity is presumably due to altering interactions between individuals and their predators, resources and physical environment in ways that enhance individual fitness. On the other hand, fitness costs are also often associated with group formation. Modifications to these interactions have the potential to dramatically impact population-level processes, such as trophic interactions or patterns of space use in relation to abiotic environmental variation. In a wide variety of empirical systems and models, collective behaviour has been shown to enhance access to ephemeral patches of resources, reduce the risk of predation and reduce vulnerability to environmental fluctuation. Evolution of collective behaviour should accordingly depend on the advantages of collective behaviour weighed against the costs experienced at the individual level. As an illustrative case study, we consider the potential trade-offs on Malthusian fitness associated with patterns of group formation and movement by migratory Thomson's gazelles in the Serengeti ecosystem.

This article is part of the theme issue ‘Collective movement ecology’.
ICTV Virus Taxonomy Profile: Avsunviroidae
Authors: Di Serio Francesco , Li Shi-Fang , Matoušek Jaroslav , Owens Robert A. , Pallás Vicente , Randles John W. , Sano Teruo , Verhoeven Jacobus Th. J. , Vidalakis Georgios , Flores Ricardo ,   ICTV Report Consortium
Published: March 2018

Members of the family Avsunviroidae have a single-stranded circular RNA genome that adopts a rod-like or branched conformation and can form, in the strands of either polarity, hammerhead ribozymes involved in their replication in plastids through a symmetrical RNA–RNA rolling-circle mechanism. These viroids lack the central conserved region typical of members of the family Pospiviroidae. The family Avsunviroidae includes three genera, Avsunviroid, Pelamoviroid and Elaviroid, with a total of four species. This is a summary of the ICTV Report on the taxonomy of the family Avsunviroidae, which is available at http://www.ictv.global/report/avsunviroidae.
Deep Learning Based BCI Control of a Robotic Service Assistant Using Intelligent Goal Formulation
Authors: Kuhner D. , Fiederer L.D.J. , Aldinger J. , Burget F. , Völker M. , Schirrmeister R.T. , Do C. , Bödecker J. , Nebel B. , Ball T. , Burgard W.
Published: March 2018

As autonomous service robots become more affordable and thus available for the general public, there is a growing need for user-friendly interfaces to control these systems. Control interfaces typically get more complicated with increasing complexity of the robotic tasks and the environment. Traditional control modalities as touch, speech or gesture commands are not necessarily suited for all users. While non-expert users can make the effort to familiarize themselves with a robotic system, paralyzed users may not be capable of controlling such systems even though they need robotic assistance most. In this paper, we present a novel framework, that allows these users to interact with a robotic service assistant in a closed-loop fashion, using only thoughts. The system is composed of several interacting components: non-invasive neuronal signal recording and co-adaptive deep learning which form the brain-computer interface (BCI), high-level task planning based on referring expressions, navigation and manipulation planning as well as environmental perception. We extensively evaluate the BCI in various tasks, determine the performance of the goal formulation user interface and investigate its intuitiveness in a user study. Furthermore, we demonstrate the applicability and robustness of the system in real world scenarios, considering fetch-and-carry tasks and tasks involving human-robot interaction. As our results show, the system is capable of adapting to frequent changes in the environment and reliably accomplishes given tasks within a reasonable amount of time. Combined with high-level planning using referring expressions and autonomous robotic systems, interesting new perspectives open up for non-invasive BCI-based human-robot interactions.
RaftProt V2: understanding membrane microdomain function through lipid raft proteomes
Authors: Mohamed Ahmed , Shah Anup , Chen David , Hill Michelle M.
Published: March 2018

Cellular membranes feature dynamic submicrometer-scale lateral membrane domainsvariously referred to as lipid rafts, membrane rafts or glycosphingolipid-enriched microdomains (GEM). In order to understand the molecular functions of lipid rafts, numerous studies have utilized various biochemical methods to isolate and examine the protein composition of membrane rafts. However, interpretation of individual raft proteomics studies are confounded by the limitations of isolation methods and the dynamic nature of rafts. Knowledge-based approaches can facilitate biological data interpretation by integrating experimental evidence from existing studies. To this end, we previously developed RaftProt (http://lipid-raft-database.di.uq.edu.au/), a searchable database of mammalian lipid raft-associated proteins. Despite being a valuable and highly used resource, improvements in search capabilities and visualisation were still needed. Here, we present RaftProt V2 (http://raftprot.org), an improved update of RaftProt, enabling interrogation and integration of datasets at the cell/tissue type and UniRef/Gene level. Besides the addition of new datasets and re-mapping of all entries to both UniProt and UniRef IDs, we have annotated the level of experimental evidence for each protein entry. The search engine now allows for multiple protein or experiment searches where correlations, interactions or overlaps can be investigated. The web-interface has been completely re-designed and offers new interactive tools for data and subset selection, correlation analysis and network visualization. Overall, RaftProt aims to advance our understanding of lipid raft function by revealing the proteomes and pathways that are associated with membrane microdomains in diverse tissue and conditions.

Database URL: http://raftprot.org
Pseudomonas syringaeevades phagocytosis in animal cells through type III effector-mediated inhibition of the LIM kinase-cofilin system
Authors: Yoon Sung-Jin , Lee Soohyun , Kim Jun-Seob , Lee Sang-Hyun , Choi Song , Min Jeong-Ki , Choi Inpyo , Park Young-Jun , Ryu Choong-Min
Published: March 2018

Certain animal and plant pathogenic bacteria have developed virulence factors (including effector proteins) that enable them to overcome host immunity. A plant pathogen,Pseudomonas syringaepv. tomato (Pto), secretes a large repertoire of effectors into plant cells via a type III secretory apparatus, thereby suppressing plant immunity. Here, we show that exposure toPtocaused sepsis in mice. Surprisingly, the effector HopQ1 disrupted phagocytosis by inhibiting actin rearrangement via a direct interaction with the LIM domain of the animal target protein LIM kinase, a key regulator of actin polymerization. The results provide new insights into cross-kingdom pathogenicity of bacteria. The current studies demonstrate that certain plant pathogenic bacteria such asPtocan be fatal in animals due to cross-kingdom host immune suppression.
Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome
Authors: Mylonas Roman , Beer Ilan , Iseli Christian , Chong Chloe , Pak HuiSong , Gfeller David , Coukos George , Xenarios Ioannis , Müller Markus , Bassani-Sternberg Michal
Published: March 2018

Spliced peptides are short protein fragments spliced together in the proteasome by peptide bond formation. True estimation of the contribution of proteasome-spliced peptides (PSPs) to the global Human Leukocyte Antigen (HLA) ligandome is critical. A recent study suggested that PSPs contribute up to 30% of the HLA ligandome. We performed a thorough reanalysis of the reported results using multiple computational tools and various validation steps and concluded that only a fraction of the proposed PSPs passes the quality filters. To better estimate the actual number of PSPs, we present an alternative workflow. We performed de-novo sequencing of the HLA-peptide spectra and discarded all de-novo sequences found in the UniProt database. We checked whether the remaining de-novo sequences could match spliced peptides from human proteins. The spliced sequences were appended to the UniProt fasta file, which was searched by two search tools at a FDR of 1%. We find that maximally 2-4% of the HLA ligandome could be explained as spliced protein fragments. The majority of these potential PSPs have good peptide-spectrum match properties and are predicted to bind the respective HLA molecules. However, it remains to be shown how many of these potential PSPs actually originate from proteasomal splicing events.
Large-scale neuroimaging and genetic study reveals genetic architecture of brain white matter microstructure
Authors: Zhao Bingxin , Zhang Jingwen , Ibrahim Joseph G. , Santelli Rebecca C. , Li Yun , Li Tengfei , Shan Yue , Zhu Ziliang , Zhou Fan , Liao Huiling , Nichols Thomas E. , Zhu Hongtu
Published: March 2018

Microstructural changes of white matter (WM) tracts are known to be associated with various neuropsychiatric disorders/diseases. Heritability of structural changes of WM tracts has been examined using diffusion tensor imaging (DTI) in family-based studies for different age groups. The availability of genetic and DTI data from recent large population-based studies offers opportunity to further improve our understanding of genetic contributions. Here, we analyzed the genetic architecture of WM tracts using DTI and single-nucleotide polymorphism (SNP) data of unrelated individuals in the UK Biobank (n ∼ 8000). The DTI parameters were generated using the ENIGMA-DTI pipeline. We found that DTI parameters are substantially heritable on most WM tracts. We observed a highly polygenic or omnigenic architecture of genetic influence across the genome as well as the enrichment of SNPs in active chromatin regions. Our bivariate analyses showed strong genetic correlations for several pairs of WM tracts as well as pairs of DTI parameters. We performed voxel-based analysis to illustrate the pattern of genetic effects on selected parts of the tract-based spatial statistics skeleton. Comparing the estimates from the UK Biobank to those from small population-based studies, we illustrated that sufficiently large sample size is essential for genetic architecture discovery in imaging genetics. We confirmed this finding with a simulation study.
Taxonomy annotation errors in 16S rRNA and fungal ITS sequence databases
Authors: Edgar Robert C.
Published: March 2018

Sequencing of the 16S ribosomal RNA (rRNA) gene and the fungal Internal Transcribed Spacer (ITS) region is widely used to survey microbial communities. Specialized ribosomal sequence databases have been developed to support this approach including Greengenes, SILVA and RDP. Most taxonomy annotations in these databases are predictions from sequence rather than authoritative assignments based on studies of type strains or isolates. Here, I investigate the error rates of taxonomy annotations in these databases. I found 253,485 sequences with conflicting annotations in SILVA v128 and Greengenes v13.5 at ranks up to phylum (9,644 conflicts), indicating that the annotation error rate in these databases is ~15%. I found that 34% of non-singleton genera have overlapping subtrees in the Greengenes tree from 2001 according to the RDP taxonomy, most of which are probably due to branching order errors in the Greengenes tree, which is therefore an unreliable guide to phylogeny. Using a blinded test, I estimated that the annotation error rate of the RDP database is ~10%.
Estimating the proportion of bystander selection for antibiotic resistance in the US
Authors: Tedijanto Christine , Olesen Scott , Grad Yonatan , Lipsitch Marc
Published: March 2018

Bystander selection -- the selective pressures exerted by antibiotics on microbial flora that are not the target pathogen of treatment -- is critical to understanding the total impact of broad-spectrum antibiotic use; however, to our knowledge, this effect has never been quantified. Using the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (NAMCS/NHAMCS), the Human Microbiome Project, and additional carriage and etiological data from existing literature, we estimate the magnitude of bystander selection for a range of clinically relevant antibiotic-species pairs as the proportion of all exposures of an antibiotic experienced by a species for conditions in which that species was not the causative pathogen (“proportion of bystander exposures”). For outpatient prescribing in the United States, we find that this proportion over all included antibiotics is over 80% for 8 out of 9 organisms of interest. Low proportions of bystander exposure are often associated with infrequent bacterial carriage or a high proportion of antibiotic prescribing focused on conditions caused by the species of interest. Using the proportion of bystander exposures, we roughly estimate that S. aureus and E. coli may benefit from 90.7% and 99.7%, respectively, of the estimated reduction in antibiotic use due to pneumococcal conjugate vaccination, despite not being the pathogen targeted by the vaccine. These results underscore the importance of considering antibiotic exposures to bystanders, in addition to the targeted pathogen, in measuring the impact of antibiotic resistance interventions.

Significance Statement

The forces that contribute to changing population prevalence of antibiotic resistance are not well understood. Bystander selection -- the inadvertent pressures imposed by antibiotics on the microbial flora other than the pathogen targeted by treatment -- is hypothesized to be a major factor in the propagation of antibiotic resistance, but its extent has not been characterized. We estimate the proportion of bystander exposures across a range of antibiotics and organisms and describe factors driving variability of these proportions. Impact estimates for antibiotic resistance interventions, including vaccination, are often limited to effects on a target pathogen. However, the reduction of antibiotic treatment for illnesses caused by the target pathogen may have the broader potential to decrease bystander selection pressures for resistance on many other organisms.
Transcriptional deconvolution reveals consistent functional subtypes of pancreatic cancer epithelium and stroma
Authors: He Jing , Maurer H. Carlo , Holmstrom Sam R. , Su Tao , Ahmed Aqeel , Hibshoosh Hanina , Chabot John A. , Oberstein Paul E. , Sepulveda Antonia R. , Genkinger Jeanine M. , Zhang Jiapeng , Iuga Alina C. , Califano Andrea , Bansal Mukesh , Olive Kenneth P.
Published: March 2018

Bulk tumor tissues comprise intermixed populations of neoplastic cells and multiple lineages of stromal cells. We used laser capture microdissection and RNA sequencing to disentangle the transcriptional programs active in the malignant epithelium and stroma of pancreatic ductal adenocarcinoma (PDA). This led to the development of a new algorithm (ADVOCATE) that accurately predicts the compartment fractions of bulk tumor samples and can computationally purify bulk gene expression data from PDA. We also present novel stromal subtypes, derived from 110 microdissected PDA stroma samples, that were enriched in extracellular matrix– and immune–associated processes. Finally, we applied ADVOCATE to systematically evaluate cross–compartment subtypes spanning four patient cohorts, revealing consistent functional classes and survival associations despite substantial compositional differences.
A mutation-led search for novel functional domains in MeCP2
Authors: Guy Jacky , Alexander-Howden Beatrice , FitzPatrick Laura , DeSousa Dina , Koerner Martha V. , Selfridge Jim , Bird Adrian
Published: March 2018

Most missense mutations causing Rett syndrome affect domains of MeCP2 that have been shown to either bind methylated DNA or interact with a transcriptional co-repressor complex. Several mutations, however, including the C-terminal truncations that account for ~10% of cases, fall outside these characterised domains. We studied the molecular consequences of four of these “non-canonical” mutations in cultured neurons and mice to see if they reveal additional essential domains without affecting known properties of MeCP2. The results show that the mutations partially or strongly deplete the protein and also in some cases interfere with co-repressor recruitment. These mutations therefore impact the activity of known functional domains and do not invoke new molecular causes of Rett syndrome. The finding that a stable C-terminal truncation does not compromise MeCP2 function raises the possibility that small molecules which stabilise these mutant proteins may be of therapeutic value.
Cell-lineage specificity of primary cilia during epididymis post-natal development
Authors: Bernet Agathe , Bastien Alexandre , Soulet Denis , Jerczynski Olivia , Roy Christian , Alves Maira Bianchi Rodrigues , Lecours Cynthia , Tremblay Marie-Ève , Bailey Janice , Robert Claude , Belleannée Clémence
Published: March 2018

Primary cilia are sensory organelles that orchestrate major signaling pathways during organ development and homeostasis. By using a double Arl13b/mCherry-Cetn2/GFP transgenic mouse model, we characterized the spatio-temporal localization of primary cilia in the epididymis, from birth to adulthood. We report here a constitutive localisation of primary cilia in peritubular myoid cells and a dynamic profiling in differentiated epithelial cells throughout post-natal development. While primary cilia are present at the apical pole of the undifferentiated epithelial cells from birth to puberty, they are absent from the apical pole of the epithelium in adults, where they appear exclusively associated with cytokeratin 5-positive basal cells. Exogenous labeling of primary cilia marker Arl13b and IFT88 confirmed the cell lineage specific localization of primary cilia in basal cells and myoid cells in human epididymides. From whole epididymis tissues and serum-free cultures of DC2 murine epididymal principal cell lines we determined that primary cilia from the epididymis are associated with the polycystic kidney disease-related proteins polycystin 1 (PC1) and polycystin 2 (PC2), and Gli3 Hedgehog signaling transcription factor. Thus, our findings unveil the existence of primary cilia sensory organelles, which have the potential to mediate mechano/ chemo-signaling events in the epididymis.
Large-Scale Structure and Individual Fingerprints of Locally Coupled Sleep Oscillations
Authors: Cox Roy , Mylonas Dimitris S , Manoach Dara S , Stickgold Robert
Published: March 2018

The temporal coordination of slow oscillations and sleep spindles is believed to underlie processes of sleep-dependent memory consolidation and reorganization. Accumulating evidence of the predominantly local expression of these individual oscillatory rhythms suggests that their interaction may have a similar local component. However, it is unclear whether local coupling holds uniformly across the cortex, and whether and how these dynamics differ between fast and slow spindles, and sleep stages. Moreover, substantial individual variability in the expression of both spindles and slow oscillations raise the possibility that their cross-frequency interactions show similar individual differences. Using two nights of multi-channel electroencephalography recordings from 24 healthy individuals, we characterized the topography of slow oscillation-spindle coupling. We found that locally coupled oscillations occur over widespread cortical areas, but that their dynamics vary with spindle class, sleep stage, and location. Moreover, the phase of the slow oscillation cycle at which spindles were expressed differed markedly across individuals but was stable across nights. However, individual variability of coupling phase was not correlated with overnight memory change. These findings both add an important spatial aspect to our understanding of the temporal coupling of sleep oscillations and demonstrate the heterogeneity of coupling dynamics, which must be taken into account when formulating mechanistic accounts of sleep-related memory processing.
Semiology, clustering, periodicity and natural history of seizures in an experimental visual cortical epilepsy model
Authors: Chang Bao-Luen , Marco Leite , Snowball Albert , Chabrol Elodie , Lieb Andreas , Walker Matthew C. , Kullmann Dimitri M. , Schorge Stephanie , Wykes Robert C.
Published: March 2018

Objective

To characterize a rat model of focal neocortical epilepsy for use in developing novel therapeutic strategies in a type of epilepsy that represents a significant unmet need.

Methods

Intracortical tetanus toxin (TeNT) injection was used to induce epilepsy in rats. Seizures and their behavioural manifestations were evaluated with continuous video-electrocorticography telemetry.

Results

TeNT injection into rat primary visual cortex induced focal neocortical epilepsy without preceding status epilepticus. The latency to first seizure ranged from 3 to 7 days. Seizure duration was bimodal, with both short (approximately 30s) and long-lasting (>100s) seizures occurring in the same animals. Seizures were accompanied by non-motor features such as behavioural arrest, or motor seizures with or without evolution to generalized tonic-clonic seizures. Seizures were commoner during the sleep phase of a light-dark cycle. Seizure occurrence was not random, and tended to cluster with significantly higher probability of recurrence within 24 hours of a previous seizure. Across animals, the number of seizures in the first week could be used to predict the number of seizures in the following 22 days.

Significance

The TeNT model of visual cortical epilepsy is a robust model of acquired focal neocortical epilepsy, and is well suited for preclinical evaluation of novel anti-epileptic strategies. We provide here a detailed analysis of the epilepsy phenotype, seizure activity, electrographic features, and the semiology. In addition we provide a predictive framework that can be used to reduce variation and consequently animal use in pre-clinical studies of potential treatments.

Key Points

Tetanus toxin injection into rat visual cortex induces focal cortical epilepsy.

Electrographic seizures were associated with non-motor and motor features with or without evolution to generalized tonic-clonic seizures.

Seizures could not be provoked by intermittent photic stimulation.

Seizures were clustered in time and exhibited a circadian variation in frequency.

The number of seizures in first week after seizure onset could be used to predict the total number of seizures in the following 3 weeks.
Development of a Cx46 targeting strategy for cancer stem cells
Authors: Mulkearns-Hubert Erin E. , Torre-Healy Luke A. , Silver Daniel J. , Eurich Jennifer T. , Serbinowski Emily , Hitomi Masahiro , Zhou John , Przychodzen Bartlomiej , Zhang Renliang , Sprowls Samuel A. , Hale James S. , Alban Tyler , Berezovsky Artem , Bell Brent A. , Lockman Paul R. , Jha Babal K. , Lathia Justin D.
Published: March 2018

Gap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.
Diverse lipid conjugates for functional extra-hepatic siRNA deliveryin vivo
Authors: Biscans Annabelle , Coles Andrew , Haraszti Reka , Echeverria Dimas , Hassler Matthew , Osborn Maire , Khvorova Anastasia
Published: March 2018

RNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, siRNA delivery into extra-hepatic tissues remains an obstacle, limiting the use of siRNA-based therapies. Here we report on a first example of chemical engineering of lipophilic conjugates to enable extra-hepatic delivery. We synthesized a panel of fifteen lipophilic siRNA and evaluated the impact of their chemical configuration on siRNA tissue distribution profile. Generally, lipophilic conjugates allow siRNA distribution to a wide range of tissues, where the degree of lipophilicity defines the ratio of liver/spleen to kidney distribution. In addition to primary clearance tissues, several conjugates achieve significant siRNA distribution to lung, heart, adrenal glands, fat, muscle. siRNA tissue accumulation leads to productive silencing, shown with two independent targets. siRNA concentrations necessary for productive silencing are tissue and conjugate dependent, varying significantly from 5 to 200 ng/mg. The collection of conjugated siRNA described here enables functional gene modulationin vivoin lung, muscle, fat, heart, adrenal glands opening these tissues for future therapeutic intervention.
Transmission of a TP53 germline mutation from unaffected male carrier associated with pediatric glioblastoma in his child and gestational choriocarcinoma in his female partner
Authors: Cotter Jennifer A. , Szymanski Linda , Karimov Catherine , Boghossian Lara , Margol Ashley , Dhall Girish , Tamrazi Benita , Varaprasathan G. Isaac , Parham David M. , Judkins Alexander R. , Biegel Jaclyn A.
Published: March 2018

Li–Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene TP53. LFS is associated with numerous malignancies including astrocytoma. Sanger sequencing and chromosomal microarray studies of blood and tumor tissue from a 4-yr-old boy with glioblastoma demonstrated a germline TP53 mutation with loss of heterozygosity for the short arm of Chromosome 17 as the second inactivating event in the tumor. There was no family history of LFS, but the child's mother had recently died from metastatic choriocarcinoma after antecedent normal term delivery of a then 6-mo-old daughter. The choriocarcinoma contained the same TP53 mutation detected in the proband and the 6-mo-old daughter was confirmed to be a carrier. Unexpectedly, the germline TP53 mutation was found to be inherited from the unaffected father. We report here the second genetically confirmed case of TP53-mutated choriocarcinoma in the partner of an LFS patient. Based on this case and recent literature, female partners of LFS patients may have increased risk of choriocarcinoma due to transmission of germline TP53 mutation from male carriers. Although the Toronto protocol has established an effective approach to detect tumors and improve survival in children and adults with LFS, there is a need to expand the current criteria to include surveillance of female partners of LFS patients for choriocarcinoma and other gestational trophoblastic disease. Recognition of this unique mode of transmission of TP53 mutations should be considered in genetic counseling for cancer risk assessment and family planning.
The thermal expansion of gold: point defect concentrations and pre-melting in a face-centred cubic metal
Authors: Pamato Martha G. , Wood Ian G. , Dobson David P. , Hunt Simon A. , Vočadlo Lidunka
Published: March 2018

On the basis of ab initio computer simulations, pre-melting phenomena have been suggested to occur in the elastic properties of hexagonal close-packed iron under the conditions of the Earth's inner core just before melting. The extent to which these pre-melting effects might also occur in the physical properties of face-centred cubic metals has been investigated here under more experimentally accessible conditions for gold, allowing for comparison with future computer simulations of this material. The thermal expansion of gold has been determined by X-ray powder diffraction from 40 K up to the melting point (1337 K). For the entire temperature range investigated, the unit-cell volume can be represented in the following way: a second-order Grüneisen approximation to the zero-pressure volumetric equation of state, with the internal energy calculated via a Debye model, is used to represent the thermal expansion of the `perfect crystal'. Gold shows a nonlinear increase in thermal expansion that departs from this Grüneisen–Debye model prior to melting, which is probably a result of the generation of point defects over a large range of temperatures, beginning at T/T
m > 0.75 (a similar homologous T to where softening has been observed in the elastic moduli of Au). Therefore, the thermodynamic theory of point defects was used to include the additional volume of the vacancies at high temperatures (`real crystal'), resulting in the following fitted parameters: Q = (V
0
K
0)/γ = 4.04 (1) × 10−18 J, V
0 = 67.1671 (3) Å3, b = (K
0′ − 1)/2 = 3.84 (9), θD = 182 (2) K, (v
f/Ω)exp(s
f/k
B) = 1.8 (23) and h
f = 0.9 (2) eV, where V
0 is the unit-cell volume at 0 K, K
0 and K
0′ are the isothermal incompressibility and its first derivative with respect to pressure (evaluated at zero pressure), γ is a Grüneisen parameter, θ
D is the Debye temperature, v
f, h
f and s
f are the vacancy formation volume, enthalpy and entropy, respectively, Ω is the average volume per atom, and k
B is Boltzmann's constant.