bluuebunny/crossref_metadata_2025_split huggingface dataset:
1-Methyl-tryptophan enantiomers differently affect the cross-talking between mononuclear and tumor cells and interferon-γ production
Authors: Branquinho Maryana Stephany Ferreira , Silva Maysa Braga Barros , Clara Renan Orsati , Julio Ariane Rivellis , Engler Silvya Stuchi Maria , Junior Ernani Pinto , Campa Ana 
Published: March 2019

AbstractThe inhibition of the enzyme indoleamine-2,3-dioxygenase (IDO), that catalyzes the oxidation of the amino acid tryptophan to kynurenine (KYN), is considered a good target for immunoadjuvants in antineoplastic therapy. 1-Methyl-tryptophan (1-MT) is the most studied molecule for this purpose. Although L-1-MT is better than D-1-MT in inhibiting IDO, for an unknown reason the D-enantiomer has higher clinical efficacy. Here we took advantage of co-cultures of tumor cells (SK-Mel 19 melanoma line; 1×105 cells/well) with peripheral blood mononuclear cells (PBMC; 5×106 cells/well) to verify the effect of 1-MT enantiomers on cytokine production and tumoricidal activity. At a concentration that did not affect KYN production, 1-MT (50 µM) affected the production of TNF-α, IL-10, and IFN-γ measured in co-cultures supernatants. Stereospecificity was only observed for IFN-γ production. D-1-MT inhibited more than 30% of IFN-γ production, while L-1-MT had no effect. Stereospecific effect was also seen in PBMC tumoricidal activity, estimated by tumor cell viability (Trypan assay). The racemic mixture DL- and D-1-MT almost doubled the tumoricidal activity of PBMCs, while L-1-MT had no effect. These are previous unknown off-target effects of D-1-MT. Our data suggest the modulation of IFN-γ and the activation of tumor recognition and killing processes by immune cells as important features for the in vivo effects of the D-1-MT. These findings should be considered in future studies of immunoadjuvants for cancer treatment.
Constitutive Siglec-1 expression by human dendritic cell precursors enables HIV-1 replication and transmission
Authors: Ruffin Nicolas , Gea-Mallorquí Ester , Brouiller Flavien , Jouve Mabel , Silvin Aymeric , See Peter , Dutertre Charles-Antoine , Ginhoux Florent , Benaroch Philippe 
Published: March 2019

AbstractHuman dendritic cell (DC) lineage has been recently unraveled by high dimensional mapping revealing the existence of a discrete new population of blood circulating DC precursor (pre-DC also referred to as AS DC). Among all blood DC subsets, only pre-DC highly express Siglec-1, a lectin-like receptor able to bind HIV-1. We show that pre-DC are uniquely equipped among blood DC populations to promote HIV-1 replication and dissemination. Pre-DC stands out as the most susceptible DC population to infection by both HIV-1 CXCR4- and CCR5-tropic viral particles in a Siglec-1-dependent manner. HIV-1-infected pre-DC produce new viral progeny and transmit the virus to CD4+T cells. Upon TLR activation, pre-DC become resistant to HIV-1 fusion and thus to infection and switch to a replication-independent mechanism of virus transfer to activated primary T lymphocytes mediated by Siglec-1. Thus, beside their role in DC ontogeny, blood pre-DC possess stage-specific properties that HIV-1 may exploit for viral spreading and modulation of the immune response.
Changes in gene expression shift and switch genetic interactions
Authors: Li Xianghua , Lalic Jasna , Baeza-Centurion Pablo , Dhar Riddhiman , Lehner Ben 
Published: March 2019

SummaryAn important goal in disease genetics and evolutionary biology is to understand how mutations combine to alter phenotypes and fitness. Non-additive interactions between mutations occur extensively and change across conditions, cell types, and species, making genetic prediction a difficult challenge. To understand the reasons for this, we reduced the problem to a minimal system where we combined mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, a change in gene expression altered both the strength and type of genetic interactions. These seemingly complicated changes could, however, be predicted by a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. We show that similar changes will be observed for many genes. These results provide fundamental insights into genotype-phenotype maps and illustrate how changes in genetic interactions can be predicted using hierarchical mechanistic models.One sentence SummaryDeep mutagenesis of the lambda repressor reveals that changes in gene expression will alter the strength and direction of genetic interactions between mutations in many genes.HighlightsDeep mutagenesis of the lambda repressor at two expression levels reveals extensive changes in mutational effects and genetic interactionsGenetic interactions can switch from positive (suppressive) to negative (enhancing) as the expression of a gene changesA mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype accurately predicts changes in mutational effects and interactionsChanges in expression will alter mutational effects and interactions for many genesFor some genes, perfect mechanistic models will never be able to predict how mutations of known effect combine without measurements of intermediate phenotypes
Spheroplast-mediated carbapenem tolerance in Gram-negative pathogens
Authors: Cross Trevor , Ransegnola Brett , Shin Jung-Ho , Weaver Anna , Fauntleroy Kathy , VanNieuwenhze Michael , Westblade Lars F. , Dörr Tobias 
Published: March 2019

AbstractAntibiotic tolerance, the ability to temporarily sustain viability in the presence of bactericidal antibiotics, constitutes an understudied, yet likely widespread cause of antibiotic treatment failure. We have previously shown that the Gram-negative pathogen Vibrio cholerae is able to tolerate exposure to the typically bactericidal β-lactam antibiotics by assuming a spherical morphotype devoid of detectable cell wall material. However, it is unclear how widespread tolerance is. Here, we have tested a panel of clinically significant Gram-negative pathogens for their response to the potent, broad-spectrum carbapenem antibiotic meropenem. We show that clinical isolates of Enterobacter cloacae, Klebsiella pneumoniae, and Klebsiella aerogenes, but not Escherichia coli, exhibit moderate to high levels of tolerance to meropenem, both in laboratory growth medium and in human serum. Importantly, tolerance was mediated by cell wall-deficient spheroplasts, which readily recovered to wild-type morphology and exponential growth upon removal of antibiotic. Our results suggest that carbapenem tolerance is prevalent in clinically significant bacterial species, and we suggest that this could contribute to treatment failure associated with these organisms.
An open resource of structural variation for medical and population genetics
Authors: Collins Ryan L. , Brand Harrison , Karczewski Konrad J. , Zhao Xuefang , Alföldi Jessica , Francioli Laurent C. , Khera Amit V. , Lowther Chelsea , Gauthier Laura D. , Wang Harold , Watts Nicholas A. , Solomonson Matthew , O’Donnell-Luria Anne , Baumann Alexander , Munshi Ruchi , Walker Mark , Whelan Christopher , Huang Yongqing , Brookings Ted , Sharpe Ted , Stone Matthew R. , Valkanas Elise , Fu Jack , Tiao Grace , Laricchia Kristen M. , Ruano-Rubio Valentin , Stevens Christine , Gupta Namrata , Margolin Lauren ,   Genome Aggregation Database Production Team,   Genome Aggregation Database Consortium, Taylor Kent D. , Lin Henry J. , Rich Stephen S. , Post Wendy , Chen Yii-Der Ida , Rotter Jerome I. , Nusbaum Chad , Philippakis Anthony , Lander Eric , Gabriel Stacey , Neale Benjamin M. , Kathiresan Sekar , Daly Mark J. , Banks Eric , MacArthur Daniel G. , Talkowski Michael E. 
Published: March 2019

SUMMARYStructural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.
Selection of a Malignant Subpopulation from a Colorectal Cancer Cell Line
Authors: Lai Pei-Lun , Chen Ting-Chun , Feng Chun-Yen , Lin Hsuan , Wu Ng , Chen Yun , Hsiao Michael , Lu Jean , Huang Hsiao-Chun 
Published: March 2019

AbstractColorectal cancer (CRC) is a leading cause of death from cancer worldwide. Thus, there is an emerging need for new experimental models that allow identification and validation of biomarkers for CRC-specific progression. In this study, we propose a repeated sphere-forming assay as a strategy to select a malignant subpopulation from a CRC line, HCT116. We validated our assay by confirming that three canonical stemness markers, Nanog, Oct4, and Lgr5, were up-regulated in the sphere state at every generation of the selection assay. The resulting line, after eight rounds of selection, exhibited an increased sphere-forming capacityin vitroand tumorgenicityin vivo. Furthermore, dipeptidase 1 (DPEP1) was identified as the major differentially expressed gene in the selected clone, and depletion of DPEP1 suppressed the elevated sphere-forming capacityin vitroand tumorgenicityin vivo. Overall, we have established an experimental strategy for the isolation of a malignant subpopulation from a CRC cell line. Results from our model also suggested that DPEP1 can serve as a promising prognostic biomarker for CRC.
Dynamic metabolic profiles of marine macroalgaUlva proliferaduring fragmentation-induced proliferation
Authors: He Yanli , Wang Yanhui , Hu Chaoyang , Sun Xue , Li Yahe , Xu Nianjun 
Published: March 2019

AbstractUlva prolifera, a type of marine macroalgae, is the causative species behind green tides mainly in the Yellow Sea and adjacent regions, nevertheless, it can be used as food or animal feed in South China. The vegetative fragments ofU. proliferaare an important seed source for successive green tide blooms. Fragmentation shortens the transition time from the vegetative state to the reproductive state. However, the translation of the algal metabolites during gametogenesis was far from well understood. In this study, the dynamic metabolic profiles ofU. proliferathallus during fragmentation-induced proliferation were investigated using non-targeted metabolomics approach in a time series of experiments in June 2017. After a 30 min low temperature shock, fragmentation induced a reproductive response of 91.57% ofU. proliferain 48 h, whereas that was only 21.43% in the control group. A total of 156 chromatographic peaks were detected, and 63 metabolites were significantly changed inU. proliferaduring reproduction. The results of the Kinetic metabolic pattern showed that the fragments not only induced the formation of sporangium, but also complicated their metabolites accumulation. During fragmentation-induced proliferation,U. proliferaconsumed different sugars at different time points. γ-aminobutyric acid (GABA), glutamic acid, gallic acid, and malic acid may play important roles in germ cell formation and release ofU. prolifera, whereas n-hexanol, 2-methyl-3-phenylindole, and 3-indoleacetonitrile may be beneficial in biotic stress resistance. Compared with the control group, the metabolites, such as alcohol and organic acid, also showed significant difference with the photoperiod at the initial stage of proliferation (before 60 h). In conclusion, that the metabolites including sugars, organic acids, and alcohol changed with different photoperiod may be the strategy forU. proliferato cope with adverse environment and rapid proliferation.
China-North Korea relations: at a crossroad or same old, same old
Authors: Kim Young Joon 
Published: March 2019

Purpose
The purpose of this paper is to examine the nature of the China–North Korea alliance that has been often described as “Lips and Teeth” or “Blood Tied.”

Design/methodology/approach
In order to make accurate assessment of the China–North Korea relations, this paper conducts indepth historical analysis of the relations. The relations between two countries were formed in 1940s and lasts until today.

Findings
However, by looking into the history of two countries, this paper argues that the bilateral relations are not an extraordinary but an ordinary state-to-state relations dictated by national interests. Changes in their calculus of national interests affect their relations. They cooperate with each other when they see mutual benefit in doing so and tension arises when there is a conflict of interests. What should be noted is that the changes in the nature of relations is different from the deterioration in the relations. Recent improvement of their relations supports this paper’s argument.

Originality/value
This paper suggests new look at the China–North Korea relations that has been considered as an extraordinary relations. The findings of this paper suggest that the alliance relation is not different from other state-to-state relations where conflict and cooperation occurs based on their national interests.
The effects of physical and social attributes of place on place attachment
Authors: Özkan Doruk Görkem , Yilmaz Serap 
Published: March 2019

PurposeThe purpose of this paper is to determine the required physical and social attributes of open spaces and demonstrate the effects of these attributes on place dependency, which is the functional dimension of place attachment. In this context, the paper only focused on the effects of the physical and social attributes of the environment on the place attachment.Design/methodology/approachThe general framework of the study design included the determination of the place attachment value for the space through identification of its physical and social attributes by the users. The research method included the evaluation of the physical and social attributes and the place attachment.FindingsThe study model demonstrated that the place attachment increased in successful urban spaces where user needs are met at a higher level. It was demonstrated that the social attributes, in particular the social environment, had a higher impact on the functional attachment of the users when compared to the physical attributes.Research limitations/implicationsThe present study investigated the factors that affected place attachment in urban open spaces within the context of human–environment interaction and specifically in the context of Trabzon square parks.Practical implicationsThe study findings are considered important for both urban planners and administrators, who are responsible for protection and development of urban spaces, and the users.Originality/valueThe present study attempted to investigate the effects of physical and social attributes of the place on place dependence.
Studio teaching experiments – spatial transitioning for autism schools
Authors: Love Joan Scott 
Published: March 2019

Purpose
The purpose of this paper is to evaluate a teaching model involving an experimental studio project for first-year interior architecture university students.

Design/methodology/approach
Content, process, teaching style and feedback are examined in a project, run over five years, concerning transitioning between environments for people with autism in an attempt to advance design of autism schools. Research methodology, teaching model, outcomes and group dynamics are critiqued.

Findings
Feedback from experienced autism-specific teachers across eight case study schools raise recurring issues framing a series of design problems navigated by students. The teaching model enhances student exploration of how sensory processing difficulties, through spatial transitioning strategies, might be approached, whilst furthering their specialist knowledge as future designers of inclusive spaces.

Research limitations/implications
Each transitioning platform requires deeper research to form a realistic interior typology. A further project to install and evaluate specific “transitioning insertions” into circulation spaces of an autism school is proposed for future research.

Practical implications
The identification of this teaching model illustrates how to embed design for autism in the university curriculum.

Social implications
The project brief helps address the National Autistic Society’s public autism awareness campaign “Too Much Information” highlighting anxieties that “unexpected change” causes. Effective design of transitioning spaces can help people with autism to cope with their environment, reducing behaviours and improving learning.

Originality/value
The creation of the “Co-specialist ASD-educator model” will be of value to universities. “Ten Spatial Transitioning Platforms” were uncovered relating to Transitions. This will be of importance to autism researchers and eventually design practitioners.
Informing sustainable building design
Authors: Landgren Mathilde , Jakobsen Signe Skovmand , Wohlenberg Birthe , Jensen Lotte Bjerregaard 
Published: March 2019

Purpose
In recent decades there has been a focus on reducing the overall emissions from the built environment, which increases the complexity of the building design process. More specialized knowledge, a greater common understanding and more cooperation between the stakeholders are required. Interdisciplinary design teams need simple and intuitive means of communication. Architects and engineers are starting to increase their focus on improving interdisciplinary communication, but it is often unclear how to do so. The purpose of this paper is to define the impact of visually communicating engineering knowledge to architects in an interdisciplinary design team and to define how quantifying architectural design decisions have an impact during the early phases of sustainable building design.

Design/methodology/approach
This work is based on a study of extensive project materials consisting of presentations, reports, simulation results and case studies. The material is made available by one of the largest European Engineering Consultancies and by a large architectural office in the field of sustainable architecture in Denmark. The project material is used for mapping communication concepts from practice.

Findings
It is demonstrated that visual communication by engineers increases the level of technical knowledge in the design decisions made by architects. This is essential in order to reach the goal of designing buildings with low environmental impact. Conversely, quantification of architectural quality improved the engineer’s acceptance of the architects’ proposals.

Originality/value
This paper produces new knowledge through the case study processes performed. The main points are presented as clearly as possible; however, it should be stressed that it is only the top of the iceberg. In all, 17 extensive case studies design processes were performed with various design teams by the 3 authors of the paper Mathilde, Birthe and Signe. The companies that provided the framework for the cases are leading in Europe within sustainability in the built environment, and in the case of Sweco also in regards to size (number of employees). Data are thus first hand and developed by the researchers and authors of this paper, with explicit consent from the industry partners involved as well as assoc. Professor Lotte B. Jensen Technical University of Denmark (DTU). This material is in the DTU servers and is in the PhD dissertation by Mathilde Landgren (successful defence was in January 2019). The observations and reflection is presented in selected significant case examples. The methods are descriped in detail, and if further information on method is required a more in depth description is found in Mathilde Landgrens PhD Dissertation. There is a lack in existing literature of the effect of visualisation in interdisciplinary design teams and though the literature (e.g. guidelines) of integrated design is extensive, there is not much published on this essential part of an integrated design process.
Architect–client relationship and value addition in private residential projects
Authors: Angral Akash 
Published: March 2019

Purpose
The purpose of this paper is to contextualise the architect–client relationship and evaluate the factors responsible for its deterioration, and then define the impact of these factors on the future needs of architects and clients, including how such knowledge can help emerging architects to develop an understanding of the profession at an early stage. It will attempt to reveal new insights and build consensus around issues, such as functionality and aesthetics, per cent-based fee structure, conflict of interest amongst architects, contractors and clients.

Design/methodology/approach
A combination of qualitative online survey, semi-structured interviews and online focus group discussions under the comprehensive umbrella of the case study method has been used to construct a pragmatic framework. The data collection was focused on revealed preferences rather than stated preferences, in terms of likes and dislikes, in a standard survey.

Findings
Overall, this paper strengthens the idea that the predicament of the profession and the marginalisation of architects is due to their detachment from clients. The findings suggest that the fee structure might be a major source of discontent and there is an urgent need for alternative routes of procurement, particularly for private residential clients. While most clients prefer functionality over aesthetics and want architects to be affordable, they are more willing to invest their trust in architects who can deliver from concept to completion.

Research limitations/implications
The arguments contested in this paper attempt to demystify the dynamics that are at play during the construction stage. It looks at power sharing, responsibilities and silent hierarchies that transpire between architects, clients and contractors, particularly in private residential projects.

Originality/value
The main recommendation of this paper is that to secure the future of the architecture profession emerging architects need to be trained more in client-centric skills than design-centric aptitude.