bluuebunny/crossref_metadata_2025 huggingface dataset:
From the inside to the outside of the sentence
Authors: Shibasaki Reijirou
Published: November 2018

This study examines the development of the projector jijitsu ‘the fact is, in fact’ from the earlier nominal predicate jijitsu-nari/dearu/da/desu/dearimasu (fact-copulative verb) in Modern through Present-day Japanese. Evidence from corpus studies suggests that jijitsu undergoes both formal and functional changes from the inside of the sentence as a nominal predicate to the outside of the sentence as a projector, connecting preceding and following information, forming a larger discourse unit. This change is characteristic of ‘constructionalization’ in the sense of Traugott and Trousdale (2013). The nominal predicate use of jijitsu inside the sentence also goes through several formal changes in the choice of copulative verbs over time, i.e. ‘constructional changes’. Constructionalization attested in the history of jijitsu echoes the historical processes of similar constructions in European languages, which means that language users have the potential to make ‘discourse-pragmatic’ sense of a given context, and such a newly emergent sense is likely to be formally realized at the edge of a sentence.
Evaluation of palm oil supply chain’s performance, added value, and performance improvement: A case study at X Co.
Authors: Marimin  , Safriyana
Published: November 2018

In palm oil supply chain, when the productivity and export market are being increased, usually the negative impacts to sustainability issues (economic, social, and environmental aspects) will arise. It also has direct impacts to supply chain itself, so it required to recognize the supply chain performance position. The objectives of this research were to evaluate performance, added value, and develop sustainability improvement strategies to increase performance of palm oil supply chain at X Co. Palm oil supply chain’s performance measurement was obtained by SCOR (Supply Chain Operations Reference) approach. It showed the performance level of plantation was above average (91.24%) and manufacture was at average (86.19%). Added value ratio was measured by using modified Hayami method. It showedthat the added valued of plantation and manufacture were 21.86% and 37.55% respectively. ANP (Analytical Network Process) method with BOCR (benefit, opportunity, cost, and risk) analysis was used in selecting sustainability improvement strategies to increase performance of palm oil supply chain, the weighting results showed that production plan’s improvement was the highest.
Development of food security applying women’s entrepreneurship in South Sulawesi
Authors: Idayanti  , Rejeki S
Published: November 2018

Food is a basic human need that is most essential. Food security is very important and strategic. One of the efforts of the government to realize food security is by diversification of food is the effort to provide and consume non-rice food with a diverse and varied menu. As one of the national food granaries, the government of South Sulawesi realize the diversification of food by cooperating with the community through large industries and household industries In the small industry or women’s household industries that have a role in food processing starting from the preparation of raw materials, production process and sales. The method used in this paper is the method of Literature Studies. The study of literature is the solving of problems by tracing the sources of writing ever made before. The analysis of this paper is that food security in South Sulawesi is very closely related to economic stability and one of the strategies developed by the government is by product diversification. Agroindustrial diversification products become an opportunity for small industry women to be employed for them. This gets a positive response from the Government in South Sulawesi with the active participation of the government to participate and facilitate the entrepreneurship of women in South Sulawesi. In addition, food diversification is needed as one of the pillars for the stabilization of food security in South Sulawesi province because food diversification can contribute in increasing the production capacity of food and improvement of people’s income in South Sulawesi.
Incorporating Co‐Benefits and Environmental Data into Corporate Decision‐Making
Authors: Guertin France , Polzin Thomas , Rogers Martha , Witt Betsy
Published: November 2018

This case study deals with The Dow Chemical Company's (Dow) and the City of Midland, Michigan's decisions on how to restore two adjacent pieces of property. Dow aimed to restore a greenbelt area with historical issues, and the City of Midland aimed to restore a brownfield property that bordered Dow's greenbelt area. Dow has a stated goal to apply a “business‐decision process that values nature” and to deliver $1 billion in “value through projects that are good for business and good for ecosystems.” The City of Midland has developed a 20‐year Master Plan that includes goals for Midland to connect and maintain open spaces. In line with these goals, Dow and the City of Midland wanted to restore the greenbelt area and brownfield property by enhancing habitat and ecosystem services in a way that was also beneficial to Dow's bottom line and the residents of Midland, respectively. This case study presents three alternative restoration designs along with detailed financial cost and environmental data for each design. Students perform a cost‐benefit analysis, highlighting potential differences between how costs are calculated in a public setting relative to a private setting. In addition, students assess how the inclusion of important non‐financial environmental data may be used to inform decision making.
The Effects of COMT Polymorphism on Cortical Thickness and Surface Area Abnormalities in Children with ADHD
Authors: Jung Minyoung , Mizuno Yoshifumi , Fujisawa Takashi X , Takiguchi Shinichiro , Kong Jian , Kosaka Hirotaka , Tomoda Akemi
Published: November 2018

The catechol-O-methyltransferase (COMT) gene is associated with frontal cortex development and the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, how the COMT gene impacts brain structure and behavior in ADHD remains unknown. In the present study, we identify the effect of COMT on cortical thickness and surface area in children with ADHD and children with typically developing (TD) using a machine learning approach. In a sample of 39 children with ADHD and 34 age- and IQ-matched TD children, we found that cortical thickness and surface area differences were predominantly observed in the frontal cortex. Furthermore, a path analysis revealed that a COMT genotype affected abnormal development of the frontal cortex in terms of both cortical thickness and surface area and was associated with working memory changes in children with ADHD. Our study confirms that the role of COMT in ADHD is not restricted to the development of behavior but may also affect the cortical thickness and surface area. Thus, our findings may help to improve the understanding of the neuroanatomic basis for the relationship between the COMT genotype and ADHD pathogenesis.
Impact of procedural characteristics on coronary vessel wall healing following implantation of second-generation drug-eluting absorbable metal scaffold in patients with de novo coronary artery lesions: an optical coherence tomography analysis
Authors: Ozaki Yuichi , Garcia-Garcia Hector M , Hideo-Kajita Alexandre , Kuku Kayode O , Haude Michael , Ince Hüseyin , Abizaid Alexandre , Tölg Ralph , Lemos Pedro Alves , von Birgelen Clemens , Christiansen Evald Høj , Wijns William , Escaned Javier , Dijkstra Jouke , Waksman Ron
Published: November 2018

Aims 

Second-generation drug-eluting absorbable metal scaffold (DREAMS 2G) is an alternative novel device for treating coronary lesions. However, the relationship between in-scaffold dimensions after implantation of DREAMS 2G and vessel healing and luminal results at follow-up is unknown. The aim of this study is, therefore, to investigate whether the expansion index after implantation of DREAMS 2G as assessed by optical coherence tomography (OCT) impacts late luminal status and healing of the vessel wall.

Methods and results 

This study comprises of a total 65 out of 123 patients who were enrolled in the BIOSOLVE-II trial. We assessed both qualitative and quantitative OCT findings and the expansion index of DREAMS 2G after implantation frame by frame using OCT. Expansion index was defined as minimum scaffold area/mean reference lumen area. The over-expansion group was also defined with expansion index >1.0. The total number of analysed frames at post-procedure and 6-month follow-up was 8243 and 8263 frames, respectively. At 6-month follow-up, in-scaffold healing was documented by the reduction of 82% in dissections, 93% in attached intra-luminal mass (ILM), 65% in non-attached ILM, and 76% in jailed side branch. The over-expansion group had significantly greater in-scaffold luminal volume loss (LVL) compared with the non-over-expansion group [over-expansion: 35.0 (18.5–52.1) mm3 vs. non-over-expansion: 21.0 (11.6–37.9) mm3, P = 0.039].

Conclusion 

Excellent in vivo healing process after implantation of DREAMS 2G was observed at 6 months. We found that higher expansion indices were associated with higher in-scaffold LVL at 6 months assessed by OCT.
Efficacy and safety of reduced-dose non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a meta-analysis of randomized controlled trials
Authors: Wang Kang-Ling , Lopes Renato D , Patel Manesh R , Büller Harry R , Tan Doreen Su-Yin , Chiang Chern-En , Giugliano Robert P
Published: November 2018

Aims

Non-vitamin K antagonist oral anticoagulants (NOACs) require dose reductions according to patient or clinical factors for patients with atrial fibrillation (AF). In this meta-analysis, we aimed to assess outcomes with reduced-dose NOACs when given as pre-specified in pivotal trials.

Methods and results

Aggregated data abstracted from Phase III trials comparing NOACs with warfarin in patients with AF were assessed by treatment using risk ratios (RRs) and 95% confidence intervals (CIs) stratified by patient eligibility for NOAC dose reduction. Irrespective of treatments, annualized rates of stroke or systemic embolism and major bleeding were higher in patients eligible for reduced-dose NOACs than in those eligible for full-dose NOACs (2.70% vs. 1.60% and 4.35% vs. 2.87%, respectively). Effects of reduced-dose NOACs compared with warfarin in patients eligible for reduced-dose NOACs on stroke or systemic embolism [RR 0.84 (95% CI 0.69–1.03)] and on major bleeding [RR 0.70 (95% CI 0.50–0.97)] were consistent with those of full-dose NOACs relative to warfarin in those eligible for full-dose NOACs [RR 0.86 (95% CI 0.77–0.96) for stroke or systemic embolism and RR 0.87 (95% CI 0.70–1.08) for major bleeding; interaction P, 0.89 and 0.26, respectively]. In addition, NOACs were associated with reduced risks of haemorrhagic stroke, intracranial haemorrhage, fatal bleeding, and death regardless of patient eligibility for NOAC dose reduction (interaction P > 0.05 for each).

Conclusions

Patients eligible for reduced-dose NOACs were at elevated risk of thromboembolic and haemorrhagic complications when treated with anticoagulants. NOACs, when appropriately dose-adjusted, had an improved benefit-harm profile compared with warfarin. Our findings highlight the importance of prescribing reduced-dose NOACs for indicated patient populations.
Analysis of Defense-Related Gene Expression in Citrus Hybrids Infected by Xylella fastidiosa
Authors: Mauricio F. N. , Soratto T. A. T. , Diogo J. A. , Boscariol-Camargo R. L. , De Souza A. A. , Coletta-Filho H. D. , Silva J. A. A. , Medeiros A. H. , Machado M. A. , Cristofani-Yaly M.
Published: November 2018

Resistance to Xylella fastidiosa was evaluated in 264 hybrids of crosses between Murcott tangor (Citrus reticulata × Citrus sinensis) and Pera sweet orange (C. sinensis) under field conditions. Uninfected hybrids were grafted with buds collected from Pera sweet orange plants infected with X. fastidiosa, forming a plant with two scions (i.e., hybrid branches and Pera sweet orange branches). From these plants, we chose 10 genotypes with three biological replicates. We evaluated gene expression, bacterial multiplication, and citrus variegated chlorosis (CVC) symptom development in both scions. X. fastidiosa was not detected in most hybrid scions and none showed disease symptoms. In contrast, all Pera sweet orange scions were infected with X. fastidiosa and expressed symptoms of CVC. We quantified the expression of 12 defense-related genes by qPCR comparing resistant to susceptible scions. We suggest that some of these genes are involved in resistance of the hybrids to X. fastidiosa, since their expression was significantly higher in the resistant hybrid scions than in tolerant hybrids and scions originated from CVC symptomatic Pera sweet orange buds. However, we note that these data should be interpreted carefully, as the plant genotypes tested are related but necessarily distinct (hybrids of C. reticulata and C. sinensis, in relation to a C. sinensis control). A principal component analysis revealed a relationship between the expression of these genes and hybrid scions, and between scions that originated from infected buds and the presence of the bacteria and plant symptoms. Multiyear field trials are necessary to develop plant resistance to X. fastidiosa. While the experimental design used here had limitations, it allowed us to identify a set of genes potentially involved in Citrus sp. resistance to this pathogen. Future work on the role of these genes in plant defenses to X. fastidiosa infection is necessary to confirm their importance in the displayed resistance phenotype.
Saving killer whale populations from a global collapse: rebuttal against Desforges et al. (2018)
Authors: Witting Lars
Published: November 2018

In their Science paper, Desforges et al. (2018) address PCB pollution in killer whales, predicting a decline in calf survival and an associated collapse of killer whale populations worldwide. I refute the collapse, showing that it follows from a flawed model parametrisation. The result is not questioning contamination problems in killer whales, but only the bold prediction of global collapse.
Ecological and life history traits are associated with Ross River virus infection among sylvatic mammals in Australia
Authors: Walsh Michael G.
Published: November 2018

Background

Ross River virus (RRV) is Australia’s most important arbovirus given its annual burden of disease and the relatively large number of Australians at risk for infection. This mosquito-borne arbovirus is also a zoonosis, making its epidemiology and infection ecology complex and cryptic. Our grasp of enzootic, epizootic, and zoonotic RRV transmission dynamics is imprecise largely due to a poor understanding of the role of wild mammalian hosts in the RRV system.

Methods

The current study applied a piecewise structural equation model (PSEM) toward an interspecific comparison of sylvatic Australian mammals to characterize the ecological and life history profile of species with a history of RRV infection relative to those species with no such history among all wild mammalian species surveyed for RRV infection. The effects of species traits were assessed through multiple causal pathways within the PSEM framework.

Results

Sylvatic mammalian species with a history of RRV infection tended to express dietary specialization and smaller population density. These species were also characterized by a longer gestation length.

Conclusions

This study provides the first interspecific comparison of wild mammals for RRV infection and identifies some potential targets for future wildlife surveys into the infection ecology of this important arbovirus. An applied RRV macroecology may prove invaluable to the epidemiological modeling of RRV epidemics across diverse sylvatic landscapes, as well as to the development of human and animal health surveillance systems.
TCR and inflammatory signals tune human MAIT cells to exert specific tissue repair and effector functions
Authors: Leng Tianqi , Akther Hossain Delowar , Hackstein Carl-Philipp , King Thomas , Friedrich Matthias , Christoforidou Zoe , McCuaig Sarah , Neyazi Mastura , Arancibia-Cárcamo Carolina V. , Powrie Fiona ,   Oxford IBD Investigators, Marchi Emanuele , Peres Raphael Sanches , Millar Val , Ebner Danie , Willberg Chris , Klenerman Paul
Published: November 2018

MAIT cells are an abundant T-cell population enriched in peripheral tissues such as the liver. They are activated both through TCR-dependent and - independent mechanisms. However, the different specific functional responses of MAIT cells to these distinct signals remain elusive. We examined the impact of combinations of TCR-dependent and -independent signals in blood and tissue-derived human MAIT cells. TCR-independent activation of MAIT cells from blood and gut was maximised by extending the panel of cytokines to including TNF-superfamily member TL1A. RNAseq experiments revealed that TCR-dependent and -independent signals drive MAIT cells to exert overlapping and unique effector functions, impacting both host defence and tissue homeostasis. While TCR-triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells did show specific enrichment of tissue-repair functions at the level of gene expression, protein production and in in vitro assays and these functions were amplified by cytokine costimulation. Taken together, these data indicate the blend of TCR-dependent and -independent signalling to MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.
The Flowering Hormone Florigen Accelerates Secondary Cell Wall Biogenesis to Harmonize Vascular Maturation with Reproductive Development
Authors: Shalit-Kaneh Akiva , Eviatar–Ribak Tamar , Horev Guy , Suss Naomi , Aloni Roni , Eshed Yuval , Lifschitz Eliezer
Published: November 2018

The protein hormone florigen is a universal systemic inducer of flowering and a generic growth terminator across meristems. To understand the developmental rational for its pleiotropic functions and to uncover the deep cellular systems mobilized by florigen beyond flowering we explored termination of radial expansion of stems. Employing the power of tomato genetics along with RNAseq and histological validations we show that endogenous, mobile, or induced florigen accelerates secondary cell wall biogenesis (SCWB), and hence vascular maturation, independently of flowering. This finding is supported by a systemic florigen antagonist from the non-floweringGinkgo biloba, which arrests SCWB and byMADSandMIFgenes downstream of florigen that similarly suppress or enhance, respectively, vascular maturation independent of flowering. We also show that florigen is remarkably stable and distributed to all organs regardless of existing endogenous levels. By accelerating SCWB, florigen reprograms the distribution of resources, signals and mechanical loads required for the ensuing reproductive phase it had originally set into motion.

Developmental Highlights

Florigen accelerates SCWB: A prime case for a long-range regulation of a complete metabolic network by a plant hormone.

The dual acceleration of flowering and vascular maturation by Florigen provides a paradigm for a dynamic regulation of global, independent, developmental programs.

The growth termination functions of florigen and the auto-regulatory mechanism for its production and distribution provide a communication network enveloping the shoot system.

A stable florigen provides a possible mechanism for the quantitative regulation of flowering

Lateral stimulation of xylem differentiation links the phloem-travelling florigen with the annual rings in trunks.

MADS genes are common relay partners in Florigen circuits; vascular maturation in stems and reproductive transition in apical meristems.
Multi-stage models for the failure of complex systems, cascading disasters, and the onset of disease
Authors: Webster Anthony J.
Published: November 2018

Complex systems can fail through different routes, often progressing through a series of (rate-limiting) steps and modified by environmental exposures. The onset of disease, cancer in particular, is no different. Multi-stage models provide a simple but very general mathematical framework for studying the failure of complex systems, or equivalently, the onset of disease. They include the Armitage-Doll multi-stage cancer model as a particular case, and have potential to provide new insights into how failures and disease, arise and progress. A method described by E.T. Jaynes is developed to provide an analytical solution for a large class of these models, and highlights connections between the convolution of Laplace transforms, sums of random variables, and Schwinger/Feynman parameterisations. Examples include: exact solutions to the Armitage-Doll model, the sum of Gamma-distributed variables with integer-valued shape parameters, a clonal-growth cancer model, and a model for cascading disasters. Applications and limitations of the approach are discussed in the context of recent cancer research. The model is sufficiently general to be used in many contexts, such as engineering, project management, disease progression, and disaster risk for example, allowing the estimation of failure rates in complex systems and projects. The intended result is a mathematical toolkit for applying multi-stage models to the study of failure rates in complex systems and to the onset of disease, cancer in particular.
Realtime 2-5A kinetics suggests interferons β and λ evade global arrest of translation by RNase L
Authors: Chitrakar Alisha , Rath Sneha , Donovan Jesse , Demarest Kaitlin , Li Yize , Sridhar Raghavendra Rao , Weiss Susan R. , Kotenko Sergei V. , Wingreen Ned S. , Korennykh Alexei
Published: November 2018

Cells of all mammals recognize double-stranded RNA (dsRNA) as a foreign material. In response, they release interferons (IFNs) and activate a ubiquitously expressed pseudokinase/endoribonuclease RNase L. RNase L executes regulated RNA decay and halts global translation. Here we developed a biosensor for 2’,5’-oligoadenylate (2-5A), the natural activator of RNase L. We found that 2-5A was acutely synthesized by cells in response to dsRNA sensing, which immediately triggered cellular RNA cleavage by RNase L and arrested host protein synthesis. However, translation-arrested cells still transcribed IFN-stimulated genes (ISGs) and secreted IFNs of types I and III (IFN-β and IFN-λ). Our data suggests that IFNs escape from the action of RNase L on translation. We propose that 2-5A/RNase L pathway serves to rapidly and accurately suppress basal protein synthesis, preserving privileged production of defense proteins of the innate immune system.

Significance

RNase L is a mammalian enzyme that can stop global protein synthesis during interferon response. Cells must balance the need to make interferons (which are proteins) with the risk to lose cell-wide translation due to RNase L. This balance can most simply be achieved if RNase L was activated late in the interferon response. However, we show by engineering a biosensor for the RNase L pathway, that on the contrary, RNase L activation precedes interferon synthesis. Further, translation of interferons evades the action of RNase L. Our data suggest that RNase L facilitates a switch of protein synthesis from homeostasis to specific needs of innate immune signaling.
Temporal shifts in intraspecific and interspecific diet variation: effects of predator body size and identity across seasons in a stream community
Authors: Falke Landon P. , Henderson Jeremy S. , Novak Mark , Preston Daniel L.
Published: November 2018

Intraspecific variation is increasingly recognized as an important factor in ecological interactions, sometimes exceeding the role of interspecific variation. Few studies, however, have examined how intra-versus interspecific variation affect trophic interactions over time within a seasonally dynamic food web. We collected stomach contents from 2028 reticulate sculpin (Cottus perplexus), 479 cutthroat trout (Oncorhynchus clarkii clarkii), and 107 Pacific giant salamanders (Dicamptodon tenebrosus) in western Oregon streams and compared diets among predator species and size classes over three seasons. Predator body size and species identity both showed strong effects on dietary niche breadth, proportional prey composition, and prey size, with seasonal variation in the relative magnitudes of intraspecific and interspecific diet variation. Size-associated diet variation was high in summer and fall but was heavily outweighed by species-associated diet variation in spring. This pattern was driven primarily by a 50-fold increase in the consumption of terrestrial thrips (Order: Thysanoptera) by cutthroat trout in spring compared to summer and fall. Mean dietary niche breadth generally increased with body size and was roughly half as wide in sculpin as in trout and was intermediate in salamanders. Predator-specific responses to the seasonality of terrestrial prey availability were associated with interspecific differences in foraging mode (e.g., benthic vs drift-feeding) and contributed to temporal variation in the roles of predator size and identity in trophic niche differentiation. Our results thereby demonstrate that intraspecific and interspecific diet variation can exhibit strong seasonality in stream predators, emphasizing the dynamic nature of food webs and the need to incorporate sampling over relevant temporal scales in efforts to understand species interactions.
Human IL-2 receptor β mutations associated with defects in immunity and peripheral tolerance
Authors: Zhang Zinan , Gothe Florian , Pennamen Perrine , James John , MacDonald David , Mata Carlos P. , Modis Yorgo , Acres Meghan , Haller Wolfram , Bowen Claire , Doffinger Rainer , Sinclair Jan , Brothers Shannon , Alazami Anas , Zhang Yu , Matthews Helen , Naudion Sophie , Pelluard Fanny , Yamazaki Yasuhiro , Notarangelo Luigi , Almousa Hamoud , Thaventhiran James , Engelhardt Karin R. , Hambleton Sophie , Rooryck Caroline , Smith Ken , Lenardo Michael J.
Published: November 2018

Interleukin-2, which conveys essential signals for effective immunity and immunological tolerance, operates through a heterotrimeric receptor comprised of α, β and γ chains. Genetic deficiency of the α or γ chain causes debilitating disease. Here we identify human interleukin-2 receptor (IL-2R) β chain (CD122) gene defects as a cause of life-threatening dysregulation of immunity and peripheral tolerance. We report homozygous mutations in the human IL-2Rβ gene from four consanguineous families, comprising either recessive missense mutations in five children or an early stop-gain mutation in two deceased fetuses and a premature neonate. All patients surviving to childhood presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, and dermatological abnormalities, as well as cytomegalovirus disease in most cases. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to normally respond to high-dose IL-2 stimulation. By contrast, patient natural killer (NK) cells retained partial IL-2Rβ expression and cytotoxic function. IL-2Rβ loss of function was recapitulated in a recombinant system, in which endoplasmic reticulum sequestration was revealed as the mechanism by which certain missense mutations cause disease. Hematopoietic stem cell transplant resulted in resolution of clinical symptoms in one patient. The hypomorphic nature of this disease highlights the significance of variable IL-2Rβ expression in different lymphocyte subsets as a means of modulating immune function. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.
Two distributed semi-supervised algorithms for mining of complex networks using Giraph
Authors: Maleki Erfan Farhangi , Ghadiri Nasser , Shahreza Maryam Lotfi , Maleki Zeinab
Published: November 2018

Background and Objective

Heterogeneous complex networks are large graphs consisting of different types of nodes and edges. The process of mining and knowledge extraction from these networks is so complicated. Moreover, the scale of these networks is steadily increasing. Thus, scalable methods are required.

Methods

In this paper, two distributed label propagation algorithms for heterogeneous networks, namely DHLP-1 and DHLP-2 have been introduced. Biological networks are one type of the heterogeneous complex networks. As a case study, we have measured the efficiency of our proposed DHLP-1 and DHLP-2 algorithms on a biological network consisting of drugs, diseases, and targets. The subject we have studied in this network is drug repositioning but our algorithms can be used as general methods for heterogeneous networks other than the biological network.

Results

We compared the proposed algorithms with similar non-distributed versions of them namely MINProp and Heter-LP. The experiments revealed the good performance of the algorithms in terms of running time and accuracy.
Molecular complexity of the major urinary protein system of the Norway rat,Rattus norvegicus
Authors: Gómez-Baena Guadalupe , Armstrong Stuart D. , Halstead Josiah O. , Prescott Mark , Roberts Sarah A. , McLean Lynn , Mudge Jonathan M. , Hurst Jane L. , Beynon Robert J.
Published: November 2018

Major urinary proteins (MUP) are the major component of the urinary protein fraction in house mice (Musspp.) and rats (Rattusspp.). The structure, polymorphism and functions of these lipocalins have been well described in the western European house mouse (Mus musculus domesticus), clarifying their role in semiochemical communication. The complexity of these roles in the mouse raises the question of similar functions in other rodents, including the Norway rat,Rattus norvegicus. Norway rats express MUPs in urine but information about specific MUP isoform sequences and functions is limited. In this study, we present a detailed molecular characterization of the MUP proteoforms expressed in the urine of two laboratory strains, Wistar Han and Brown Norway, and wild caught animals, using a combination of manual gene annotation, intact protein mass spectrometry and bottom-up mass spectrometry-based proteomic approaches. Detailed sequencing of the proteins reveals a less complex pattern of primary sequence polymorphism than the mouse. However, unlike the mouse, rat MUPs exhibit added complexity in the form of post-translational modifications including phosphorylation and exoproteolytic trimming of specific isoforms. The possibility that urinary MUPs may have different roles in rat chemical communication than those they play in the house mouse is also discussed.
Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer
Authors: El-Kenawi Asmaa , Gatenbee Chandler , Robertson-Tessi Mark , Bravo Rafael , Dhillon Jasreman , Balagurunathan Yoganand , Berglund Anders , Visvakarma Naveen , Ibrahim-Hashim Arig , Choi Jung , Luddy Kimberly , Gatenby Robert , Pilon-Thomas Shari , Anderson Alexander , Ruffell Brian , Gillies Robert
Published: November 2018

Tumors rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. Here we demonstrate that acidity, independent from lactate, augments the pro-tumor phenotype of macrophages. We used zwitterionic buffers to show that activating macrophages at pH 6.8 in vitro enhanced an IL-4-driven phenotype as measured by gene expression, cytokine profiling, and functional assays. These results were recapitulated in vivo wherein neutralizing intratumoral acidity reduced the pro-tumor phenotype of macrophages, while also decreasing tumor incidence and invasion in the TRAMP model of prostate cancer. These results were recapitulated using an in silico mathematical model that simulate macrophage responses to environmental signals. By turning off acid-induced cellular responses, our in silico mathematical modeling shows that acid-resistant macrophages can limit tumor progression. In summary, this study suggests that tumor acidity contributes to prostate carcinogenesis by altering the state of macrophage activation.
Reverse vaccinology approach to design a novel multi-epitope subunit vaccine against avian influenza A (H7N9) virus
Authors: Hasan Mahmudul , Ghosh ProggaParomita , Azim KaziFaizul , Mukta Shamsunnahar , Abir Ruhshan Ahmed , Nahar Jannatun , Hasan Khan Mohammad Mehedi
Published: November 2018

H7N9, a novel strain of avian origin influenza was the first recorded incidence where a human was transited by a N9 type influenza virus. Effective vaccination against influenza A (H7N9) is a major concern, since it has emerged as a life threatening viral pathogen. Here, an in silico reverse vaccinology strategy was adopted to design a unique chimeric subunit vaccine against avian influenza A (H7N9). Induction of humoral and cell-mediated immunity is the prime concerned characteristics for a peptide vaccine candidate, hence both T cell and B cell immunity of viral proteins were screened. Antigenicity testing, transmembrane topology screening, allergenicity and toxicity assessment, population coverage analysis and molecular docking approach were adopted to generate the most antigenic epitopes of avian influenza A (H7N9) proteome. Further, a novel subunit vaccine was designed by the combination of highly immunogenic epitopes along with suitable adjuvant and linkers. Physicochemical properties and secondary structure of the designed vaccine were assessed to ensure its thermostability, hydrophilicity, theoretical PI and structural behavior. Homology modeling, refinement and validation of the designed vaccine allowed to construct a three dimensional structure of the predicted vaccine, further employed to molecular docking analysis with different MHC molecules and human immune TLR8 receptor present on lymphocyte cells. Moreover, disulfide engineering was employed to lessen the high mobility region of the designed vaccine in order to extend its stability. Furthermore, we investigated the molecular dynamic simulation of the modeled subunit vaccine and TLR8 complexed molecule to strengthen our prediction. Finally, the suggested vaccine was reverse transcribed and adapted forE. colistrain K12 prior to insertion within pET28a(+) vector for checking translational potency and microbial expression.
B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma
Authors: Griss Johannes , Bauer Wolfgang , Wagner Christine , Maurer-Granofszky Margarita , Simon Martin , Chen Minyi , Steinberger Peter , Grabmeier-Pfistershammer Katharina , Roka Florian , Penz Thomas , Bock Christoph , Zhang Gao , Herlyn Meenhard , Glatz Katharina , Laubli Heinz , Mertz Kirsten D , Petzelbauer Peter , Wiesner Thomas , Hartl Markus , Pickl Winfried , Somasundaram Rajasekharan , Wagner Stephan N
Published: November 2018

Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses. Here we show that tumor-associated B cells are vital to tumor associated inflammation. Autologous B cells were directly induced by melanoma conditioned medium, expressed pro- and anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro. We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.
Quantitative Estimation of Long-Range Interactions at the Nanoscale
Authors: Sood Vishesh , Dhar Sunandan , Katti Dhirendra S.
Published: November 2018

Nano-bio interfaces attune nanoparticle-mediated biological responses. The nano-bio interface, like all interfacial interactions, is governed by non-covalent long-range interactions (LRIs). These LRIs include electrostatic, electrodynamic and acid-base interactions. There is a lack of understanding about the contribution of LRIs at the nano-bio interface for want of suitable methods for the estimation of dispersive, acidic, and basic components of the surface tension of nanoparticles. To address this, we developed an experimental and theoretical framework for the estimation of surface tension components of nanoparticles and biomacromolecules by partitioning them in a biphasic system. The work presented here is the first instance in the literature for estimating the surface tension components of nanoparticles and biomacromolecules suspended in aqueous suspensions. We also observed that LRIs have a deterministic role in biologically relevant phenomena such as salt-induced nanoparticle agglomeration and protein-nanoparticle interaction. Collectively, the results presented in this work provide a rapid and inexpensive framework for predicting the energetics of nanoparticle-nanoparticle and nanoparticle-protein interactions by estimating average ensemble surface characteristics like surface tension and surface charge density.
Historical contingency shapes adaptive radiation in Antarctic fishes
Authors: Daane Jacob M. , Dornburg Alex , Smits Patrick , MacGuigan Daniel J. , Hawkins M. Brent , Near Thomas J. , Detrich H. William , Harris Matthew P.
Published: November 2018

Adaptive radiation illustrates the links between ecological opportunity, natural selection, and the generation of biodiversity (1). Central to adaptive radiation is the association between a diversifying lineage and the evolution of key traits that facilitate the utilization of novel environments or resources (2, 3). However, is not clear whether adaptive evolution or historical contingency is more important for the origin of key phenotypic traits in adaptive radiation (4, 5). Here we use targeted sequencing of >250,000 loci across 46 species to examine hypotheses concerning the origin and diversification of key traits in the adaptive radiation of Antarctic notothenioid fishes. Contrary to expectations of adaptive evolution, we show that notothenioids experienced a punctuated burst of genomic diversification and evolved key skeletal modifications before the onset of polar conditions in the Southern Ocean. We show that diversifying selection in pathways associated with human skeletal dysplasias facilitates ecologically important variation in buoyancy among Antarctic notothenioid species, and demonstrate the sufficiency of alteredtrip11, col1a2andcol1a1function in zebrafish (Danio rerio) to phenocopy skeletal reduction in Antarctic notothenioids. Rather than adaptation being driven by the cooling of the Antarctic (6), our results highlight the role of exaptation and historical contingency in shaping the adaptive radiation of notothenioids. Understanding the historical and environmental context for the origin of key traits in adaptive radiations provides context in forecasting the effects of climate change on the stability and evolvability of natural populations.
Lipid Droplet metabolism dependent microbial defense in pre-immune zebrafish embryos
Authors: Dutta Asmita , Banerjee Sampali , Sinha Deepak Kumar
Published: November 2018

Microbes present survival challenge to pre-immune embryos. Our study provides evidence for antimicrobial-secretion-based strategy of zebrafish embryos against microbes during pre-immune stages. Chorion prevents physical contact between embryos and microbes, yet microbes compromise embryonic survival through their secretions. Development of embryos in microbe-free medium involves secretion of pro-microbial compounds that bacteria utilize to accelarete growth. Embryo senses presence of microbes through microbial secretions. They respond by altering their secretions to include antimicrobial compounds along with regular pro-microbial ones. Upon sensing embryonic anti-microbial secretions, microbes too alter their secretions to include more potent toxins for embryos. In response to this embryos alter their secretions to include more potent antimicrobial compounds. Ability of embryos to secrete antimicrobial compounds is positively correlated with amount of lipid droplets (LDs) in them. Inhibition of LD metabolism prevents antimicrobial secretions by embryos. Thus, LDs protect zebrafish embryos from microbes. This manuscript establishes that pre-immune embryos employ dynamically evolving biochemical warfare to protect themselves from harmful microbes.
A SOSEKI-based coordinate system interprets global polarity cues in Arabidopsis
Authors: Yoshida Saiko , Schuren Alja van der , van Dop Maritza , van Galen Luc , Saiga Shunsuke , Adibi Milad , Möller Barbara , Marhavy Peter , Smith Richard , Friml Jiri , Weijers Dolf
Published: November 2018

Multicellular development requires coordinated cell polarization relative to body axes, and translation to oriented cell division. In plants, it is unknown how cell polarities are connected to organismal axes and translated to division. Here, we identifyArabidopsisSOSEKI (SOK) proteins that integrate apical-basal and radial organismal axes to localize to polar cell edges. Localization does not depend on tissue context, requires cell wall integrity and is defined by a transferrable, protein-specific motif. SOK proteins structurally resemble the DIX oligomerization domain in the animal Dishevelled polarity regulator. The DIX-like domain self-interacts and is required for edge localization and for influencing division orientation. Our work identifies a plant compass, interpreted by SOK proteins. Furthermore, despite fundamental differences, polarity in plants and animals converge upon the same protein domain.
High-Throughput, Lysis-free Screening for Sulfatase Activity Using Escherichia coli Autodisplay in Microdroplets
Authors: van Loo Bert , Heberlein Magdalena , Mair Philip , Zinchenko Anastasia , Schüürmann Jan , Eenink Bernard D. G. , Holstein Josephin M. , Dilkaute Carina , Jose Joachim , Hollfelder Florian , Bornberg-Bauer Erich
Published: November 2018

Directed evolution of enzymes toward improved catalytic performance has become a powerful tool in protein engineering. To be effective, a directed evolution campaign requires the use of high-throughput screening. In this study we describe the development of a high-throughput lysis-free procedure to screen for improved sulfatase activity by combining microdroplet-based single-variant activity sorting with E. coli autodisplay. For the first step in a 4-step screening procedure we quantitatively screened >105 variants of the homodimeric arylsulfatase from Silicibacter pomeroyi (SpAS1), displayed on the E. coli cell surface, for improved sulfatase activity using fluorescence activated droplet sorting. Display of the sulfatase variants on living E. coli cells ensured the continuous linkage of genotype and phenotype during droplet sorting and allowed for direct recovery by simple regrowth of the sorted cells. The use of autodisplay on living cells simplified and reduced the degree of liquid handling during all steps in the screening procedure to the single event of simply mixing substrate and cells. The percentage of apparent improved variants was enriched >10-fold as a result of droplet sorting. We ultimately identified 25 SpAS1-variants with improved performance toward 4-nitrophenyl sulfate (up to 6.2-fold) and/or fluorescein disulfate (up to 30-fold). In SpAS1 variants with improved performance toward the bulky fluorescein disulfate, many of the beneficial mutations occur in residues that form hydrogen bonds between α-helices in the C-terminal oligomerization region, suggesting a non-trivial, previously unknown role for the dimer interface in shaping the substrate binding site of SpAS1.

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Using the modified male osteoporosis self-assessment tool for Taiwan to predict osteoporosis onset – a sub-study of the Taiwan osteoporosis survey
Authors: Liu Dung-Huan , Cheng Tien-Tsai , Chen Jia-Feng , Yu Shan-Fu , Chiu Wen-Chan , Hsu Chung-Yuan , Chen Ying-Chou
Published: November 2018

Purpose

To develop a risk index by item reduction from multiple variable regression, which can identify male Taiwanese patients at risk of developing osteoporosis.

Methods

To develop the model, a risk index was identified by item reduction from multivariate regression analysis. Using receiver operating characteristic (ROC) curve analysis and their sensitivity/specificity, MOSTAi was validated in a separate cohort of Taiwanese men and its performance with compared with the National Osteoporosis Foundation recommendations (NOF 2013).

Results

Between 2008 and 2011 a total of 4,323 males were enrolled for bone mineral density (BMD) measurements. Univariate analysis identified four major risk factors for osteoporosis, including age, body weight (BW), previous fracture and body height. The ROC analysis showed the area under the curve (AUC) for the model based on the three-variable, two-variable (age and BW), and one-variable models (BW), was 0.701 (p<0.001, 95% confidence interval [CI] 0.658-0.744), 0.700 (p<0.001, 95% CI, 0.656-0.742), and 0.690 (p<0.001, 95% CI, 0.646-0.734), respectively. Using the optimal cutoff value (−2) for the OSTA, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) in the validation cohort were 64.0%, 65.7%, 26.9% and 90.2%, respectively. The ROC curves for predicting osteoporosis by MOSTAi, OSTA and NOF 2013 and the AUC for MOSTAi, OSTA and NOF 2013 was 0.706 (p<0.001, 95% CI: 0.664-0.748) and 0.697(p<0.001, 95% CI: 0.657-0.738), respectively.

Conclusion

The results showed that MOSTAi could be a more precise model than OSTA and NOF 2013, for identifying men in Taiwan with osteoporosis who require referrals for DXA scans. It was demonstrated that MOSTAi is a simple tool with fair sensitivity/specificity and PPV, and high NPV. MOSTAi could also be a more accurate model than OSTA for identifying men in Taiwan at risk of osteoporosis. In comparison with NOF 2013, MOSTAi is a more accurate and simpler tool for the referral of Taiwanese men for DXA scans.
Acute and chronic stage adaptations of vascular architecture and cerebral blood flow in a mouse model of TBI
Authors: Steinman Joe , Cahill Lindsay S. , Koletar Margaret M. , Stefanovic Bojana , Sled John G.
Published: November 2018

The 3D organization of cerebral blood vessels determines the overall capacity of the cerebral circulation to meet the metabolic requirements of the brain. This study used Arterial Spin Labeling (ASL) MRI with a hypercapnic challenge and ex vivo Serial Two-Photon Tomography (STPT) to examine the relationship between blood flow and 3D microvascular structure following traumatic brain injury (TBI) in a mouse. Mice were exposed to a controlled cortical impact TBI and allowed to recover for either 1 day or 4 weeks. At each time point, ASL MRI was performed to quantify cerebral perfusion and the brain vasculature was imaged in 3D with STPT. Registration of ASL to STPT enabled flow changes to be related to the underlying microvascular structure in each ASL voxel. Hypoperfusion under rest and hypercapnia was observed both 1 day and 4 weeks post-TBI. Vessel density and vascular volume were reduced 1 day post-TBI, recovering by 4 weeks; however, the reorganized vasculature at the latter time point possessed an abnormal radial pattern. Our findings demonstrate functionally significant long-term changes in the vascular architecture following injury and illustrate why metrics beyond traditional measures of vessel density are required to understand the impact of vascular structure on function.