bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying Sequence Perturbations to an Intrinsically Disordered Protein that Determine Its Phase Separation Behavior
Authors: Schuster Benjamin S. , Dignon Gregory L. , Tang Wai Shing , Kelley Fleurie M. , Ranganath Aishwarya Kanchi , Jahnke Craig N. , Simpkins Alison G. , Regy Roshan Mammen , Hammer Daniel A. , Good Matthew C. , Mittal Jeetain 
Published: January 2020

AbstractPhase separation of intrinsically disordered proteins (IDPs) commonly underlies the formation of membraneless organelles, which compartmentalize molecules intracellularly in the absence of a lipid membrane. Identifying the protein sequence features responsible for IDP phase separation is critical for understanding physiological roles and pathological consequences of biomolecular condensation, as well as for harnessing phase separation for applications in bio-inspired materials design. To expand our knowledge of sequence determinants of IDP phase separation, we characterized variants of the intrinsically disordered RGG domain from LAF-1, a model protein involved in phase separation and a key component of P granules. Based on a predictive coarse-grained IDP model, we identified a region of the RGG domain that has high contact probability and is highly conserved between species; deletion of this region significantly disrupts phase separation in vitro and in vivo. We determined the effects of charge patterning on phase behavior through sequence shuffling. By altering the wild-type sequence, which contains well-mixed charged residues, to increase charge segregation, we designed sequences with significantly increased phase separation propensity. This result indicates the natural sequence is under negative selection to moderate this mode of interaction. We measured the contributions of tyrosine and arginine residues to phase separation experimentally through mutagenesis studies and computationally through direct interrogation of different modes of interaction using all-atom simulations. Finally, we show that in spite of these sequence perturbations, the RGG-derived condensates remain liquid-like. Together, these studies advance a predictive framework and identify key biophysical principles of sequence features important to phase separation.Significance StatementMembraneless organelles are assemblies of highly concentrated biomolecules that form through a liquid-liquid phase separation process. These assemblies are often enriched in intrinsically disordered proteins, which play an important role in driving phase separation. Understanding the sequence-to-phase behavior relationship of these disordered proteins is important for understanding the biochemistry of membraneless organelles, as well as for designing synthetic organelles and biomaterials. In this work, we explore a model protein, the disordered N-terminal domain of LAF-1, and highlight how three key features of the sequence control the protein’s propensity to phase separate. Combining predictive simulations with experiments, we find that phase behavior of this model IDP is dictated by the presence of a short conserved domain, charge patterning, and arginine-tyrosine interactions.
Anti-tumor effects of an Id antagonist with no acquired resistance
Authors: Wojnarowicz Paulina M. , Escolano Marta Garcia , Huang Yun-Han , Desai Bina , Chin Yvette , Shah Riddhi , Xu Sijia , Ouerfelli Ouathek , Soni Rajesh Kumar , Philip John , Montrose David C. , Healey John H. , Rajasekhar Vinagolu K. , Garland William A. , Norton Larry , Rosen Neal , Hendrickson Ronald C. , Zhou Xi Kathy , Iavarone Antonio , Massague Joan , Dannenberg Andrew J. , Lasorella Anna , Benezra Robert 
Published: January 2020

SummaryId proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. Id proteins inhibit basic HLH transcription factors through protein-protein interactions, often inhibiting differentiation and sustaining proliferation. We recently identified a small-molecule, AGX51, which targets Id proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impaired cell growth and viability that results from a dramatic increase in ROS production upon Id degradation. In mouse models, AGX51 treatment suppressed breast cancer colonization in the lung, regressed the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduced tumor burden in a model of sporadic colorectal neoplasia. Furthermore, in cells and mice, we failed to observe acquired resistance to AGX51 likely the result of the immutability of the binding pocket and efficient degradation of the Id proteins. Thus, AGX51 is a first-in-class compound that antagonizes Id proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
Functions of olfactory receptors are decoded from their sequence
Authors: Cong Xiaojing , Ren Wenwen , Pacalon Jody , de March Claire A. , Xu Lun , Matsunami Hiroaki , Yu Yiqun , Golebiowski Jérôme 
Published: January 2020

AbstractG protein-coupled receptors (GPCRs) conserve common structural folds and activation mechanisms, yet their ligand spectra and functions are highly diversified. This work investigated how the functional variations in olfactory GPCRs (ORs)-the largest GPCR family-are encoded in the primary sequence. With the aid of site-directed mutagenesis and molecular simulations, we built machine learning models to predict OR-ligand pairs as well as basal activity of ORs. In vitro functional assay confirmed 20 new OR-odorant pairs, including 9 orphan ORs. Residues around the odorant-binding pocket dictate the odorant selectivity/specificity of the ORs. Residues that encode the varied basal activities of the ORs were found to mostly surround the conserved motifs as well as the binding pocket. The machine learning approach, which is readily applicable to mammalian OR families, will accelerate OR-odorant mapping and the decoding of combinatorial OR codes for odors.
Modeling gene expression evolution with EvoGeneX uncovers differences in
evolution of species, organs and sexes
Authors: Pal Soumitra , Oliver Brian , Przytycka Teresa M. 
Published: January 2020

Abstract
While DNA sequence evolution has been well studied, the expression of genes
is also subject to evolution, yet the evolution of gene expression is currently
not well understood. Recently, new tissue/organ-specific gene expression
datasets spanning several organisms across the tree of life, have become
available, providing the opportunity to study gene expression evolution in more
detail. While a theoretical model to study the evolution of continuous traits
exists, in practice computational methods often cannot confidently distinguish
between alternative evolutionary scenarios. This lack of power has been
attributed to modest numbers of species considered in these studies.
We hypothesised that biological replicates can be used to increase
predictive power of these models. With this in mind, we introduce EvoGeneX, a
computationally efficient method to uncover the mode of gene expression
evolution based on the Ornstein-Uhlenbeck process. Importantly, in addition to
modelling expression variations between species, EvoGeneX models within-species
variation.
Furthermore, to facilitate comparative analysis of gene expression
evolution, we introduce a formal approach, based on Michaelis-Menten equation,
to measure the dynamics of evolutionary divergence of a group of genes in terms
of group’s asymptotic divergence level and rate.
Finally, we used these tools to preform the first analysis the evolution of
gene expression across different body parts, species, and sexes of the
Drosophila genus. Our analysis revealed that
neutral expression evolution can be confidently rejected in favor of purifying
selection in nearly half of the genes. In addition, we quantified differences in
the evolutionary dynamics of male and female gonads and uncovered interesting
examples of adaptive gene expression evolution.
Understanding the diversity of alliance governance in OECD healthcare settings
Authors: Cousins Kimberly , Gauld Robin , Greatbanks Richard 
Published: January 2020

Purpose
Healthcare alliances are a mechanism for developing collaborative and integrated care governance and service delivery arrangements. Yet is not known how widespread alliance arrangements are in Organisation for Economic Co-operation and Development (OECD) countries, how alliances function or how effective they are. The purpose of this paper is to provide an overview of alliances in OECD countries, including key areas covered and how performance is measured.

Design/methodology/approach
A structured narrative review of literature published between 2010 and 2018 was undertaken, focussed on OECD countries. The literature included peer-reviewed articles as well as publications from key policy analysis organisations.

Findings
Many OECD countries have implemented integrated care models but only a small number had explicitly adopted health alliances that link primary and secondary providers under joint governance arrangements. Most alliances are pilot initiatives and not broadly adopted. Most had not adopted a unified performance measurement framework.

Practical implications
Policy makers and service providers interested in joint governance arrangements that support integration must consider the range of potential options overviewed in this paper, as well as how to create supportive performance measurement frameworks.

Originality/value
This is the first narrative review of alliance arrangements in OECD countries. It provides an overview of arrangements, while illustrating that there is considerable scope for further alliance development.
Household demand for basic foodstuffs in a recessed economy: a case study of Southwest Nigeria
Authors: Sowunmi Fatai Abiola , Daramola Oladunni Akinwande , Tijani Ishaq Adewale 
Published: January 2020

PurposeThe economic recession that Nigeria recently passed through caused distortions in economic and well-being of Nigerians. The purpose of this paper is to examine the effects of the economic recession on households’ demand for basic foodstuffs in Southwest Nigeria.Design/methodology/approachData were collected from 380 respondents drawn from urban areas of Lagos, Osun and Oyo states using multistage sampling technique. Descriptive statistics and Quadratic Almost Ideal Demand System were employed to analyze data collected.FindingsThe study showed sharp increase in the prices of basic foodstuffs during recession. Households were compelled to spend higher percentage of their monthly income on basic foodstuffs. Also, 51.1 percent of the respondents were government workers who experienced inconsistent or modulated monthly salary during the period. The percentage of households that were food insecure was 36.4 percent. Osun State had the highest monthly per capita expenditure (₦5,147.13) on foodstuffs, followed by Lagos and Oyo states while rice had the highest expenditure share (0.26), followed by yam (0.18), beans (0.106), vegetable oil (0.104) and garri (0.101). The breakdown also showed that 11.7, 18.1 and 17.7 percent of the total household monthly expenditures in Lagos, Osun and Oyo states, respectively, were spent on basic foodstuffs.Research limitations/implicationsThere purchasing power of naira reduced significantly during recession, thus compelled households to spend more on basic foodstuffs compared to similar purchases before economic recession.Practical implicationsThe reduction in purchasing power of naira affected the formal and informal sector. Irregular salary for civil servants reduced their expenditure on goods and services.Originality/valueThe study is original and topical, serving as literature of accounts that transpired among the households as far as demand for basic foodstuffs is concerned during the economic recession.
Impact of big data analytics capabilities on supply chain sustainability
Authors: Shokouhyar Sajjad , Seddigh Mohammad Reza , Panahifar Farhad 
Published: January 2020

PurposeThe purpose of this paper is to develop a theoretical model to explain the impact of big data analytics capabilities (BDAC) on company’s supply chain sustainability (CSCS). The secondary objective of the study is to assess the relationship between different dimensions of supply chain sustainability and companies’ BDAC.Design/methodology/approachThis research was carried out by conducting a survey among 234 pharmaceutical companies in Iran (a case study of Iran), using a standard questionnaire of BDAC and United Nations (UN) online self-assessment on supply chain sustainability. However, the respond of managers of 188 companies were usable in this research. Smart PLS3 was used to employ partial least squares method to examine the validity and reliability of the measurement and structural model.FindingsThe results of this study demonstrate that BDAC have a strong impact on both pharmaceutical supply chain sustainability, and the dimensions including vision, engage and internal. It is found that the relationships between BDAC and the other dimensions of supply chain sustainability including expect, scope and goals are not significant but positive.Research limitations/implicationsResearch on the relationship between BDAC and CSCS, especially in the pharmaceutical supply chain, is scanty, and this gap is highlighted in developing countries and the pharmaceutical supply chain that plays a prominent role in public health. This paper discusses several important barriers to forming a sustainable supply chain and strong BDA capabilities.Practical implicationsThis paper could be a guide to managers and consultants who are involved in big data analytics and sustainable development. Since UN urges companies do the online self-assessment, the results of this paper would be attractive and useful for UN global compact specialists.Originality/valueNo study has directly measured the relation between BDAC and CSCS and different dimensions of CSCS, using a comprehensive survey throughout all pharmaceutical companies in Iran. Moreover, this research assesses the different dimensions of BDA capabilities and supply chain sustainability. This paper represents the facts about situation of sustainability of pharmaceutical supply chain and BDAC in these companies, and discloses several related issues that are serious barriers to forming a sustainable supply chain and strong BDAC. In addition, this paper provided academic support for UN questionnaire about CSCS and used it in the survey.
Disentangling fire intensity and species’ susceptibility to fire in a species‐rich seasonal tropical forest
Authors: Trouvé Raphaël , Bunyavejchewin Sarayudh , Baker Patrick J. 
Published: January 2020

Abstract

Increasing temperatures and human activity are likely to reduce fire return intervals in the seasonal tropics. Anticipating how more frequent fires may alter forest community structure and composition requires understanding how fire intensity and species‐specific responses to fires interact to drive fire‐induced mortality for large numbers of species. We developed an analytical framework to estimate unobserved fire intensities and species‐ and size‐specific susceptibility to fire using observed mortality data.

We used census data from a 50‐ha forest dynamics plot in western Thailand to better understand species and community responses to a fire that burned ∼60% of the plot in 2005. Trees species, size and status (live, dead) were censused just before the fire (2004) and again 5 years later (2009). We jointly estimated a map of relative fire intensity and species‐specific size‐dependent background and fire‐induced mortality. We then calculated the time required for individuals of each species to reach a fire‐safe size threshold (the age at which the fire‐induced mortality probability was <50%). To better understand community‐level responses to fire, we compared results among different species groups (canopy status, forest‐type association).

Our model‐derived map of fire intensity closely matched the field survey taken in the days after the fire. On average, individuals growing at the 95th percentile growth rate for most species groups required ∼5 years to reach their species’ fire‐safe size threshold, while individuals growing at the median growth rate required ∼17 years (assuming growth <1 cm diameter at breast height was similar to growth >1 cm). However, understorey species associated with the seasonal evergreen forest took 1.8 times longer than average to reach their fire‐safe size threshold, with one species requiring up to 190 years.

Synthesis. Our approach provided insights into spatial patterning of fire intensity in a seasonal tropical forest and species‐ and size‐specific susceptibility to fire‐induced mortality. Our results suggest increasing fire frequency will have the greatest impact on slow‐growing understorey species of the evergreen forest. In addition, our model accurately predicts the growing dominance of a fast‐growing understorey species, Croton roxburghii; Euphorbiaceae, common to evergreen and deciduous forests that can reach its fire‐safe size threshold in 1.3 years.
Artificial Intelligence, Neom and Saudi Arabia's Economic Diversification from Oil and Gas
Authors: Hassan Oz 
Published: January 2020

AbstractSaudi Arabia is diversifying its economy by becoming a global technological hub. Driven by its ‘Vision 2030' initiative, it has embarked on the most ambitious and far‐reaching transformation plan in the Kingdom's history. At the core of this transformation are the investment and development of artificial intelligence (AI) and its integration into a new mega‐city, Neom. Currently under construction, Neom is seeking to integrate robotics and AI seamlessly into every aspect of citizens' lives in a bid to generate revenues from key economic sectors for the future. This transition from an economy based on hydrocarbons to AI is, however, more than economic. It is a bid to secure the survival of the House of Saud and meet the growing challenges of constructing a state around oil. Nevertheless, what happens in Neom may provide insights into how AI will impact the world beyond a cross‐roads built on sand.
Arsonists Suffering From Schizophrenia—A Description in Comparison with Other Offenders with a Similar Diagnosis
Authors: Günther Moritz Philipp , Kirchebner Johannes , Lau Steffen 
Published: January 2020

AbstractThis study aims to describe the small and distinct subgroup of arsonists diagnosed with schizophrenia, their motives, personal, and crime scene characteristics. While prior research identified significant differences to other criminals, firesetters in general, or mentally disordered offenders, there are no comparisons with other offender patients with schizophrenia so far. In a forensic institution in Switzerland, a group of 30 arsonists with schizophrenia spectrum disorder (SSD) was compared to 340 other offender patients with SSD using retrograde file analysis and multiple adapted Fisher´s exact tests. While symptoms of SSD were most defining of both groups, arsonists with SSD were more often single, unemployed, prescribed psychiatric medication at index offense, had a smaller variety of criminal motives, and acted out of anger or revenge in the context of a relationship. In conclusion, symptoms of SSD may be more defining and useful in guiding clinical practice than aspects specific to arsonists.
Intensity of renal replacement therapy and outcomes in critically ill patients with acute kidney injury: Critical appraisal of the dosing recommendations
Authors: Schiffl Helmut 
Published: January 2020

AbstractThe current care of critically ill patients with severe acute kidney injury requiring dialysis (AKI‐D) is limited to supportive management in which renal replacement therapy (RRT) plays a central role. Renal replacement techniques are invasive bioincompatible procedures and are therefore associated with complications that may prove harmful to fragile patients. Inexperience with the standards and lacking or misinterpreted recommendations for the delivery of the RRT dose increases the risk of serious complications. Neither the optimal doses of intermittent or continuous RRTs nor the minimal or maximal effective doses are known. The Kidney Disease Improving Global outcomes (KDIGO) AKI guidelines for RRT dosing recommendations are inflexible, based on limited research, and may be at least partially outdated. High‐intensity therapy may be associated with clinically relevant alterations in systemic and renal hemodynamics, profound electrolyte imbalances, the loss of nutrients or thermal energy, and underdosing of antimicrobial agents. However, higher doses of continuous renal replacement therapy (CRRT) may confer a survival benefit for certain subgroups of intensive care patients with severe AKI. Lower CRRT doses than the recommended adequate dosage may not lead to negative health outcomes, at least in Asian patients. Future research should evaluate the demand‐capacity concept, recognizing that the delivery of the RRT dose is dynamic and should be modified in response to patient‐related factors. There is a need for large‐scale studies evaluating whether precision RRT dose modifications may improve patient‐centered outcomes in subgroups of critically ill patients.
Feedback survey on the Royal Australian and New Zealand College of Radiologists Faculty of Radiation Oncology trainee research requirement
Authors: Foley Elizabeth F , Roos Daniel E 
Published: January 2020

AbstractIntroductionThe Royal Australian and New Zealand College of Radiologists Faculty of Radiation Oncology (FRO) requires trainees to complete a research project prior to the exit (phase II) examinations. We report results of a survey of current FRO trainees and Fellows graduating since 2013, regarding their experience of the overall requirement, supervision, barriers to project completion and subsequent publication.MethodsA 32‐question online survey was sent via email to 285 FRO members in July 2019. Responses were anonymous.ResultsThe overall response rate was 32% (trainees 41%, Fellows 21%); 70% of respondents were trainees. About three‐quarters of projects were retrospective reviews (64%) or surveys (13%), 94% met College requirements at first submission, 71% were published, and 81% were presented at a scientific meeting. Most assistance was provided by the project supervisor (57%), statistician (47%), another consultant (36%) or the Director of Training (28%). Finding time amongst other clinical/curriculum commitments, rotating to another training site and availability of a suitable supervisor were notable obstacles. Over half (52%) of respondents were satisfied/very satisfied with the process overall and 20% dissatisfied/very dissatisfied; 19% and 30%, respectively, thought requiring acceptance for peer review and completion prior to the phase II examination unreasonable/very unreasonable. Four per cent reported being less likely to be involved in future research as a result of this experience.ConclusionWhile the majority of respondents perceive the FRO research requirements as reasonable, a significant minority are not satisfied with aspects of the programme. Amendment of the pre‐phase II stipulation may be worthy of consideration.