bluuebunny/crossref_metadata_2025 huggingface dataset:
Too much hot air? Informing ethical trapping in hot, dry environments
Authors: Read John. L. , Pedler Reece. D. , Kearney Michael R.
Published: March 2018

Context
Trapping of small vertebrates during their active hot summer periods is vital for conservation and impact assessment studies. Animal Ethics Committees (AECs) protect wildlife by enforcing arbitrary but restrictive temperature limits for trapping.

Aims
Empirical data were gathered on the temperatures reached in different trap configurations to inform pragmatic ethical guidelines.

Methods
Temperature was measured inside small vertebrate traps at two Australian arid zone sites to generate data on the thermal consequences of: (1) trap design and external shading; (2) provision of protective refuge substrates; and (3) timing of trap clearing.

Key results
Shading and increased trap depth significantly reduced temperatures within pitfall traps. A conservative stressful upper temperature limit of 36°C was never exceeded inside deep, shaded, narrow pitfall traps at one study site and only between 1100 and 1300 hours on 3 days at the hotter site, despite ambient temperatures reaching over 42°C. By contrast, potentially lethal upper temperatures were reached in wider, shallower bucket pit traps on most days at both sites, even when optimal shading and refuge substrates were employed. Deployment of surface traps under vegetation and with additional shading significantly reduced maximum temperatures experienced. Temperatures inside shaded Elliott and funnel traps generally tracked ambient air temperatures and thus typically exceeded conservative threshold temperatures between 0700 and 1900 hours when ambient temperatures exceeded 36°C.

Conclusions
Temperatures experienced in optimal deep, shaded traps when ambient temperatures exceeded 40°C were 31°C lower than surface temperatures and similar to temperatures recorded at 20 cm below the soil surface, where many species would typically take refuge at these times.

Implications
Data suggest that deep (60 cm), narrow pitfall traps with elevated lids for shade and shelter substrate inside should enable trapping to be conducted safely in the study region during summer (December to February). This is even the case in extremely hot weather, as long as trapped animals are removed within 4 h of sunrise. Ecophysiological studies of thermal tolerance within optimum trap arrangements revealed by the present study will allow field ecologists and AECs to develop informed site-specific trapping protocols.
Meaning and words in the conference interpreter’s
mind
Authors: Chmiel Agnieszka
Published: March 2018

The aim of the study was to examine how interpreter training and experience influence word recognition and cross-linguistic connections in the bilingual mental lexicon. Sixty-eight professional interpreters, interpreter trainees (tested at the beginning and end of their training) and bilingual controls were asked to complete a semantic priming study. Priming is a psycholinguistic research method used to examine connections between words and languages in the mind. Data analysis conducted by means of linear mixed models revealed that advanced trainees recognised words faster than beginners, but were not outperformed by professionals. A priming effect was found only in the L1-L2 direction, suggesting similar asymmetries between languages irrespective of the interpreting experience. It is the first study to adopt a priming paradigm and a longitudinal design to examine the interpreters’ mental lexicon. The study shows that word recognition is faster due to interpreter training, but is not modulated further by interpreting experience.
Investigating problem-solving strategies of translation trainees with high and low levels of self-efficacy
Authors: Araghian Roya , Ghonsooly Behzad , Ghanizadeh Afsaneh
Published: March 2018

Translatology adopts psychological and cognitive approaches to study the complex processes underlying translational phenomena. As such, it deals with both translations and the translators who produce them. The present study uses think-aloud protocols and keystroke logging to explore the impact of affective factors such as self-efficacy beliefs on the selection and application of translation problem-solving strategies by a group of trainee translators completing a translation task. Four translation trainees completed a Translation Self-efficacy Questionnaire. Participants with both high and low self-efficacy rankings were asked to translate a text using the Translog keylogger while simultaneously verbalizing their mental processes. Analysis of the verbal protocols indicated considerable differences within the group regarding the cognitive and metacognitive strategies that they chose to employ. The results suggested that low self-efficacy leads subjects to spend too much time translating, due to repeated attempts at production and extensive revision. Implications of the findings for translator training are discussed.
The effect of heat treatment on Ni–B–Ce electroless coatings
Authors: Qian Wei , Wei Huanming , Chen Haotian , Zhu Liying , Sun Yaoxin , Han Sheng , Lin Hualin , Jiang Jibo
Published: March 2018

We successfully obtained sonicated Ni–B–Ce coating on the surface of low carbon steel (Q235) through ultrasonic-assisted electroless plating with the deposition time of 60 minutes. The coatings were heat treated at 300, 500 and 800°C for 2 hours. The results showed the Ni–B–Ce coating changed from amorphous to crystallised and produced Ni3B and Ni2B phases after heat treatment. The addition of Ce changed the crystallisation temperatures of Ni–B–Ce coating after heat treatment to 562 and 692°C, which differed from those of Ni–B coating (298, 371 and 411°C). It also improved the activation energy to 156.85 and 214.11 kJ mol−1, which was much higher than those of Ni–B coating (32.23, 25.80 and 50.69 kJ mol−1). In addition, the 800°C annealed coatings showed notable improvement in hardness (1212 HV10) and corrosion properties (3.01 μA cm−2) which could be ascribed to the formation of Ni3B and Ni2B phases.
Branched-chain amino acid (BCAA) supplementation enhances adaptability to exercise training of mice with a muscle-specific defect in the control of BCAA catabolism
Authors: Xu Minjun , Kitaura Yasuyuki , Shindo Daichi , Shimomura Yoshiharu
Published: March 2018

Branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BDK) suppresses the branched-chain amino acid (BCAA) catabolism by inactivation of the BCKDH complex. The muscle-specific BDK-deficient (BDK-mKO) mice showed accelerated BCAA oxidation in muscle and decreased endurance capacity after training (Xu et al. PLoS One. 12 (2017) e0180989). We here report that BCAA supplementation overcompensated endurance capacity in BDK-mKO mice after training.
Feedback inhibition of actin on Rho mediates content release from large secretory vesicles
Authors: Segal Dagan , Zaritsky Assaf , Schejter Eyal D. , Shilo Ben-Zion
Published: March 2018

Secretion of adhesive glycoproteins to the lumen of Drosophila melanogaster larval salivary glands is performed by contraction of an actomyosin network assembled around large secretory vesicles, after their fusion to the apical membranes. We have identified a cycle of actin coat nucleation and disassembly that is independent of myosin. Recruitment of active Rho1 to the fused vesicle triggers activation of the formin Diaphanous and actin nucleation. This leads to actin-dependent localization of a RhoGAP protein that locally shuts off Rho1, promoting disassembly of the actin coat. When contraction of vesicles is blocked, the strict temporal order of the recruited elements generates repeated oscillations of actin coat formation and disassembly. Interestingly, different blocks to actin coat disassembly arrested vesicle contraction, indicating that actin turnover is an integral part of the actomyosin contraction cycle. The capacity of F-actin to trigger a negative feedback on its own production may be widely used to coordinate a succession of morphogenetic events or maintain homeostasis.
TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation
Authors: Malireddi R.K. Subbarao , Gurung Prajwal , Mavuluri Jayadev , Dasari Tejasvi Krishna , Klco Jeffery M. , Chi Hongbo , Kanneganti Thirumala-Devi
Published: March 2018

The NOD-like receptor (NLR)–P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-β activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis. Autocrine tumor necrosis factor (TNF) signaling in the absence of TAK1 induced spontaneous RIPK1-dependent NLRP3 inflammasome activation and cell death. We further showed that TAK1 suppressed homeostatic NF-κB and extracellular signal–related kinase (ERK) activation to limit spontaneous TNF production. Moreover, the spontaneous inflammation resulting from TAK1-deficient macrophages drives myeloid proliferation in mice, and was rescued by RIPK1 deficiency. Overall, these studies identify a critical role for TAK1 in maintaining NLRP3 inflammasome quiescence and preserving cellular homeostasis and survival.
Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD-1 cells differing in ploidy and chromosome stability
Authors: Viganó Cristina , von Schubert Conrad , Ahrné Erik , Schmidt Alexander , Lorber Thomas , Bubendorf Lukas , De Vetter Judith R. F. , Zaman Guido J. R. , Storchova Zuzana , Nigg Erich A.
Published: March 2018

Although aneuploidy is poorly tolerated during embryogenesis, aneuploidy and whole chromosomal instability (CIN) are common hallmarks of cancer, raising the question of how cancer cells can thrive in spite of chromosome aberrations. Here we present a comprehensive and quantitative proteomics analysis of isogenic DLD-1 colorectal adenocarcinoma cells lines, aimed at identifying cellular responses to changes in ploidy and/or CIN. Specifically, we compared diploid (2N) and tetraploid (4N) cells with posttetraploid aneuploid (PTA) clones and engineered trisomic clones. Our study provides a comparative data set on the proteomes and phosphoproteomes of the above cell lines, comprising several thousand proteins and phosphopeptides. In comparison to the parental 2N line, we observed changes in proteins associated with stress responses and with interferon signaling. Although we did not detect a conspicuous protein signature associated with CIN, we observed many changes in phosphopeptides that relate to fundamental cellular processes, including mitotic progression and spindle function. Most importantly, we found that most changes detectable in PTA cells were already present in the 4N progenitor line. This suggests that activation of mitotic pathways through hyper-phosphorylation likely constitutes an important response to chromosomal burden. In line with this conclusion, cells with extensive chromosome gains showed differential sensitivity toward a number of inhibitors targeting cell cycle kinases, suggesting that the efficacy of anti-mitotic drugs may depend on the karyotype of cancer cells.
Reducing falls in older adults recently discharged from hospital: a systematic review and meta-analysis
Authors: Naseri Chiara , Haines Terry P , Etherton-Beer Christopher , McPhail Steven , Morris Meg E , Flicker Leon , Netto Julie , Francis-Coad Jacqueline , Lee Den-Ching A , Shorr Ronald , Hill Anne-Marie
Published: March 2018

Background

older adults are known to have increased falls rates and functional decline following hospital discharge, with substantial economic healthcare costs. This systematic review aimed to synthesise the evidence for effective falls prevention interventions in older adults recently discharged from hospital.

Methods

literature searches of six databases of quantitative studies conducted from 1990 to June 2017, reporting falls outcomes of falls prevention interventions for community-dwelling older adults discharged from hospital were included. Study quality was assessed using a standardised JBI critical appraisal tool (MAStARI) and data pooled using Rev-Man Review Manager®

Results

sixteen studies (total sample size N = 3,290, from eight countries, mean age 77) comprising 12 interventions met inclusion criteria. We found home hazard modification interventions delivered to those with a previous falls history (1 study), was effective in reducing the number of falls (RR 0.63, 95%CI 0.43, 0.93, Low GRADE evidence). Home exercise interventions (3 studies) significantly increased the proportion of fallers (OR 1.74, 95%CI 1.17, 2.60, Moderate GRADE evidence), and did not significantly reduce falls rate (RR 1.27, 95%CI 0.99, 1.62, Very Low GRADE evidence) or falls injury rate (RR 1.16, 95%CI, 0.83,1.63, Low GRADE evidence). Nutritional supplementation for malnourished older adults (1 study) significantly reduced the proportion of fallers (HR 0.41, 95% CI 0.19, 0.86, Low GRADE evidence).

Conclusion

the recommended falls prevention interventions for older adults recently discharged from hospital are to provide home hazard minimisation particularly if they have a recent previous falls history and consider nutritional supplementation if they are malnourished.
Association of Multimodal Pain Management Strategies with Perioperative Outcomes and Resource Utilization
Authors: Memtsoudis Stavros G. , Poeran Jashvant , Zubizarreta Nicole , Cozowicz Crispiana , Mörwald Eva E. , Mariano Edward R. , Mazumdar Madhu
Published: March 2018

Background

Multimodal analgesia is increasingly considered routine practice in joint arthroplasties, but supportive large-scale data are scarce. The authors aimed to determine how the number and type of analgesic modes is associated with reduced opioid prescription, complications, and resource utilization.

Methods

Total hip/knee arthroplasties (N = 512,393 and N = 1,028,069, respectively) from the Premier Perspective database (2006 to 2016) were included. Analgesic modes considered were opioids, peripheral nerve blocks, acetaminophen, steroids, gabapentin/pregabalin, nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, or ketamine. Groups were categorized into “opioids only” and 1, 2, or more than 2 additional modes. Multilevel models measured associations between multimodal analgesia and opioid prescription, cost/length of hospitalization, and opioid-related adverse effects. Odds ratios or percent change and 95% CIs are reported.

Results

Overall, 85.6% (N = 1,318,165) of patients received multimodal analgesia. In multivariable models, additions of analgesic modes were associated with stepwise positive effects: total hip arthroplasty patients receiving more than 2 modes (compared to “opioids only”) experienced 19% fewer respiratory (odds ratio, 0.81; 95% CI, 0.70 to 0.94; unadjusted 1.0% [N = 1,513] vs. 2.0% [N = 1,546]), 26% fewer gastrointestinal (odds ratio, 0.74; 95% CI, 0.65 to 0.84; unadjusted 1.5% [N = 2,234] vs. 2.5% [N = 1,984]) complications, up to a –18.5% decrease in opioid prescription (95% CI, –19.7% to –17.2%; 205 vs. 300 overall median oral morphine equivalents), and a –12.1% decrease (95% CI, –12.8% to –11.5%; 2 vs. 3 median days) in length of stay (all P < 0.05). Total knee arthroplasty analyses showed similar patterns. Nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors seemed to be the most effective modalities used.

Conclusions

While the optimal multimodal regimen is still not known, the authors’ findings encourage the combined use of multiple modalities in perioperative analgesic protocols.
Benefit versus Severe Side Effects of Opioid Analgesia
Authors: Roozekrans Margot , van der Schrier Rutger , Aarts Leon , Sarton Elise , van Velzen Monique , Niesters Marieke , Dahan Albert , Olofsen Erik
Published: March 2018

Background

Previous studies integrated opioid benefit and harm into one single function—the utility function—to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example.

Methods

Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic–pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression.

Results

The four conditions were successfully identified with probabilities varying depending on the opioid effect-site concentration. The optimum analgesia probability without serious respiratory depression is reached at an alfentanil effect-site concentration of 68 ng/ml, and exceeds the probability of the most unwanted effect, inadequate analgesia with severe respiratory depression (odds ratio, 4.0). At higher effect-site concentrations the probability of analgesia is reduced and exceeded by the probability of serious respiratory depression.

Conclusions

The utility function was successfully further developed, allowing assessment of specific conditions in terms of wanted and unwanted effects. This approach can be used to compare the toxic effects of drugs relative to their intended effect and may be a useful tool in the development of new compounds to assess their advantage over existing drugs.
Ocular Impression-Taking—Which Material Is Best?
Authors: Turner Jennifer M. , Purslow Christine , Murphy Paul J.
Published: March 2018

Objectives:

To assess the efficacy and effect on clinical signs of a polyvinylsiloxane (Tresident; Shütz Dental Group GmbH, Germany) compared with an irreversible hydrocolloid (Orthoprint; Zhermack SpA, Badia Polesine, Italy) for ocular impression-taking.

Methods:

Twenty subjects were recruited (13 female and 7 male), with mean age 31.1±4.6 years (SD) (range 25.8–39.7). Subjects attended for 2 sessions, each of 1-hr duration, on 2 separate days. Each session was scheduled at the same time on each day. At each visit, the subject underwent an ocular impression procedure, using either Tresident or Orthoprint, in random order and to one eye only. Investigator 2 was blind to this assignment. Two experienced practitioners conducted the study, investigator 1 performed the ocular impression procedures and investigator 2 observed and assessed the clinical signs: logMAR visual acuity, ocular surface staining, tear break-up time (TBUT), and ocular hyperemia.

Results:

Visual acuity was unaffected by either material; TBUT was marginally disrupted by both materials, but was not clinically significant according to published criteria; ocular redness increased with both materials; and corneal staining was significantly greater after Orthoprint impression. Less redness and clinically insignificant staining after impression-taking, with fewer clinical complications, was found after use of Tresident.

Conclusions:

Tresident offers a quicker, more effective, and clinically viable method of obtaining ocular impression topography compared with the traditional Orthoprint, and Orthoprint causes significantly more superficial punctuate staining of the corneal epithelium than Tresident.
The State of Technology in Craniosynostosis
Authors: Safran Tyler , Viezel-Mathieu Alex , Beland Benjamin , Azzi Alain J. , Galli Rafael , Gilardino Mirko
Published: March 2018

Introduction:

Craniosynostosis, the premature fusion of ≥1 cranial sutures, is the leading cause of pediatric skull deformities, affecting 1 of every 2000 to 2500 live births worldwide. Technologies used for the management of craniofacial conditions, specifically in craniosynostosis, have been advancing dramatically. This article highlights the most recent technological advances in craniosynostosis surgery through a systematic review of the literature.

Methods:

A systematic electronic search was performed using the PubMed database. Search terms used were “craniosynostosis” AND “technology” OR “innovation” OR “novel." Two independent reviewers subsequently reviewed the resultant articles based on strict inclusion and exclusion criteria. Selected manuscripts deemed novel by the senior authors were grouped by procedure categories.

Results:

Following review of the PubMed database, 28 of 536 articles were retained. Of the 28 articles, 20 articles consisting of 21 technologies were deemed as being novel by the senior authors. The technologies were categorized as diagnostic imaging (n = 6), surgical planning (n = 4), cranial vault evaluation (n = 4), machine learning (n = 3), ultrasound pinning (n = 3), and near-infrared spectroscopy (n = 1).

Conclusion:

Multiple technological advances have impacted the treatment of craniosynostosis. These innovations include improvement in diagnosis and objective measurement of craniosynostosis, preoperative planning, intraoperative procedures, communication between both surgeons and patients, and surgical education.
Successful Strategies for Dealing With Infected, Custom-Made Hydroxyapatite Cranioplasty
Authors: Zanotti Bruno , Zingaretti Nicola , Verlicchi Angela , Alfieri Alex , Parodi Pier Camillo
Published: March 2018

When a cranioplasty implant becomes infected, standard operating procedure dictates its removal and the initiation of a long course of antibiotic therapy. However, removing such a prosthesis can have a series of adverse consequences, including delayed cognitive and motor recovery, lack of brain tissue protection, unsightly deformity, and the need for two additional surgical procedures, not to mention the additional costs involved. To maintain the advantages of cranioplasty, we opted for a conservative approach (levofloxacin and rifampicin every 24 hours for 8 weeks) in a 68-year-old woman whose custom-made porous hydroxyapatite implant, fitted following aneurysm clipping, had become infected. The tissues overlying the implant were curettaged, and the patient's clinical condition, blood markers, and infection course were continuously monitored (local monitoring was performed by single-photon emission computed tomography [SPECT]/computed tomography [CT after intravenous administration of 99mTc-labeled antigranulocyte antibody). Blood tests and SPECT/CT evidenced a progressive reduction in phlogosis indices and infection locus, even 1 month after antibiotic therapy was commenced, and at 2 years from cranioplasty, the same tests and clinical examination were negative. At 6-year follow-up, clinical assessment revealed nothing out of the ordinary.

Hence, specific cases (hydroxyapatite prosthesis, intact dura, cranial CT and magnetic resonance imaging negative for empyema, well-vascularized scalp, antibiotic-responsive bacteria) of infected cranial implant can be treated using a conservative approach consisting of appropriate antibiotic therapy, accompanied by local debridement where necessary, and assiduous monitoring of phlogosis indices and local verification via labeled-leukocyte scintigraphy. Our report, which was compiled after a long-term follow-up period, shows that this conservative procedure appears to be a viable option in cases of infected, custom-made hydroxyapatite cranioplasty, provided that some basic rules concerning clinical and instrumental standards are adhered to, as clearly stated in our report.
Indexed variation graphs for efficient and accurate resistome profiling
Authors: Rowe Will P.M. , Winn Martyn D
Published: March 2018

Background

Antimicrobial resistance remains a major threat to global health. Profiling the collective antimicrobial resistance genes within a metagenome (the “resistome”) facilitates greater understanding of antimicrobial resistance gene diversity and dynamics. In turn, this can allow for gene surveillance, individualised treatment of bacterial infections and more sustainable use of antimicrobials. However, resistome profiling can be complicated by high similarity between reference genes, as well as the sheer volume of sequencing data and the complexity of analysis workflows. We have developed an efficient and accurate method for resistome profiling that addresses these complications and improves upon currently available tools.

Results

Our method combines a variation graph representation of gene sets with an LSH Forest indexing scheme to allow for fast classification of metagenomic sequence reads using similarity-search queries. Subsequent hierarchical local alignment of classified reads against graph traversals enables accurate reconstruction of full-length gene sequences using a scoring scheme. We provide our implementation, GROOT, and show it to be both faster and more accurate than a current reference-dependent tool for resistome profiling. GROOT runs on a laptop and can process a typical 2 gigabyte metagenome in 2 minutes using a single CPU.

Conclusion

We present a method for resistome profiling that utilises a novel index and search strategy to accurately type resistance genes in metagenomic samples. The use of variation graphs yields several advantages over other methods using linear reference sequences. Our method is not restricted to resistome profiling and has the potential to improve current metagenomic workflows. The implementation is written in Go and is available at https://github.com/will-rowe/groot (MIT license).
Rapid Reconstruction of Time-varying Gene Regulatory Networks
Authors: Pyne Saptarshi , Kumar Alok Ranjan , Anand Ashish
Published: March 2018

—Rapid advancements in high-throughput technologies has resulted in genome-scale time series datasets. Uncovering the temporal sequence of gene regulatory events, in the form of time-varying gene regulatory networks (GRNs), demands computationally fast, accurate and scalable algorithms. The existing algorithms can be divided into two categories: ones that are time-intensive and hence unscalable; others that impose structural constraints to become scalable. In this paper, a novel algorithm, namely ‘an algorithm for reconstructing Time-varying Gene regulatory networks with Shortlisted candidate regulators’ (TGS), is proposed. TGS is time-efficient and does not impose any structural constraints. Moreover, it provides such flexibility and time-efficiency, without losing its accuracy. TGS consistently outperforms the state-of-the-art algorithms in true positive detection, on three benchmark synthetic datasets. However, TGS does not perform as well in false positive rejection. To mitigate this issue, TGS+ is proposed. TGS+ demonstrates competitive false positive rejection power, while maintaining the superior speed and true positive detection power of TGS. Nevertheless, main memory requirements of both TGS variants grow exponentially with the number of genes, which they tackle by restricting the maximum number of regulators for each gene. Relaxing this restriction remains a challenge as the actual number of regulators is not known a priori.

Reproducibility

The datasets and results can be found at: https://github.com/aaiitg-grp/TGS. This manuscript is currently under review. As soon as it is accepted, the source code will be made available at the same link. There are mentions of a ‘supplementary document’ throughout the text. The supplementary document will also be made available after acceptance of the manuscript. If you wish to be notified when the supplementary document and source code are available, kindly send an email to saptarshipyne01@gmail.com with subject line ‘TGS Source Code: Request for Notification’. The email body can be kept blank.
Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis
Authors: Inoue Minoru , Enomoto Masahiro , Koike Yuhki , Di Grappa Marco A. , Zhao Xiao , Yip Kenneth , Huang Shao Hui , Waldron John N. , Ikura Mitsuhiko , Liu Fei-Fei , Bratman Scott V.
Published: March 2018

Neutrophil extracellular traps (NETs) entrap circulating tumor cells (CTCs) and promote metastasis within distant organs in preclinical models1,2. In these models, NETosis is triggered by exogenous massive inflammatory stimuli, and thus it remains unknown whether cancer hosts under physiologic inflammation-free conditions experience NETosis and consequent cancer metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis and cancer metastasis specifically in the lungs. Albumin is the major source of free thiol that maintains redox balance in vitro and in vivo. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of CTCs leading to pulmonary metastases in mouse models. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation and the resultant decline of plasma free thiol are associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.
Non-canonical HIF-1 stabilization is essential for intestinal tumorigenesis
Authors: Rohwer Nadine , Jumpertz Sandra , Erdem Merve , Egners Antje , Warzecha Klaudia T. , Fragoulis Athanassios , Kühl Anja A. , Kramann Rafael , Neuss Sabine , Rudolph Ines , Endermann Tobias , Zasada Christin , Apostolova Ivayla , Gerling Marco , Kempa Stefan , Hughes Russell , Lewis Claire E. , Brenner Winfried , Malinowski Maciej B. , Stockmann Martin , Schomburg Lutz , Faller William , Sansom Owen , Tacke Frank , Morkel Markus , Cramer Thorsten
Published: March 2018

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1’s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with nuclear HIF-1α in intestinal adenomas, pointing towards a functional importance of hypoxia-independent, i.e. non-canonical HIF-1 stabilization that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1α and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.
Multi-hierarchical Profiling the Structure-Activity Relationships of Engineered Nanomaterials at Nano-Bio Interfaces
Authors: Cai Xiaoming , Dong Jun , Liu Jing , Zheng Huizhen , Kaweeteerawat Chitrada , Wang Fangjun , Ji Zhaoxia , Li Ruibin
Published: March 2018

Increasingly raised concerns (nanotoxicity, clinical translation, etc) on nanotechnology require breakthroughs in structure-activity relationship (SAR) analyses of engineered nanomaterials (ENMs) at nano-bio interfaces. However, current nano-SAR assessments failed to disclosure sufficient information to understand ENM-induced bio-effects. Here we developed a multi-hierarchical nano-SAR assessment for a representative ENM, Fe2O3 by systematically examining cellular metabolite and protein changes. This nano-SAR profile allows visualizing the contributions of 7 basal properties of Fe2O3 to their diverse bio-effects. For instance, while surface reactivity is responsible for Fe2O3-induced cell migration, the inflammatory effects of Fe2O3 nanorods and nanoplates are determined by their aspect ratio and surface reactivity, respectively. We further discovered the detailed mechanisms, including NLRP3 inflammasome pathway and monocyte chemoattractant protein-1 involved signaling. Both effects were further validated in animal lungs. Our findings provide substantial new insights at nano-bio interfaces, which may facilitate the tailored design of ENMs to endow them with desired bio-effects.
Host factors influence the sex of nematodes parasitizing roots of Arabidopsis thaliana
Authors: Anjam Muhammad Shahzad , Shah Syed Jehangir , Matera Christiane , Różańska Elżbieta , Sobczak Miroslaw , Siddique Shahid , Grundler Florian M.W.
Published: March 2018

Plant-parasitic cyst nematodes induce hypermetabolic syncytial nurse cells in the roots of their host plants. Syncytia are their only food source. Cyst nematodes are sexually dimorphic, with their differentiation into male or female strongly influenced by host environmental conditions. Under favorable conditions with plenty of nutrients, more females develop, whereas mainly male nematodes develop under adverse conditions such as in resistant plants. Here, we developed and validated a method to predict the sex of beet cyst nematode (Heterodera schachtii) during the early stages of its parasitism in the host plant Arabidopsis thaliana. We collected root segments containing male-associated syncytia (MAS) or female-associated syncytia (FAS), isolated syncytial cells by laser microdissection, and performed a comparative transcriptome analysis. Genes belonging to categories of defense, nutrient deficiency, and nutrient starvation were overrepresented in MAS as compared to FAS. Conversely, gene categories related to metabolism, modification, and biosynthesis of cell walls were overrepresented in FAS. We used β-glucuronidase (GUS) analysis, qRT-PCR, and loss-of-function mutants to characterize FAS- and MAS-specific candidate genes. Our results demonstrated that various plant-based factors, including immune response, nutrient availability, and structural modifications, influence the sexual fate sex determination of cyst the nematodes.
Disruption in A-to-I editing levels affects C. elegans development more than a complete lack of editing
Authors: Ganem Nabeel S. , Ben-Asher Noa , Manning Aidan C. , Deffit Sarah N. , Washburn Michael C. , Wheeler Emily C. , Yeo Gene W. , Ben-Naim Zgayer Orna , Mantsur Einav , Hundley Heather A. , Lamm Ayelet T.
Published: March 2018

A-to-I RNA editing is widespread in eukaryotic transcriptomes and plays an essential role in the creation of proteomic and phenotypic diversity. Loss of ADARs, the proteins responsible for A-to-I editing, results in lethality in mammals. In C. elegans, knocking out both ADARs, ADR-1 and ADR-2, results in aberrant behavior and abnormal development. Studies have shown that ADR-2 can actively deaminate dsRNA while ADR-1 cannot. However, as most studies of C. elegans ADARs were performed on worms mutated in both ADAR genes, the effects observed cannot be attributed to a single ADAR or to the interactions between ADAR genes. Therefore, we set to study the effects of each C. elegans ADAR on RNA editing, gene expression, protein levels and the contribution of each of ADAR to the phenotypes observed in worms mutated in both genes, in order to elucidate their distinct functions. We found significant differences in the phenotypes observed in worms mutated in a single ADAR gene. Worms harboring adr-1 mutations have a significant reduction in their lifespan, while worms harboring adr-2 mutations have extended lifespan. We also observed severe abnormalities in vulva formation in adr-1 mutants, and we suggest that these phenotypes are a result of an RNA editing independent function of ADR-1. Mutations in each ADAR resulted in expressional changes in hundreds of genes, and a significant downregulation of edited genes. However, very few changes in the protein levels were observed. In addition, we found that ADR-1 binds many edited genes and primarily promotes editing at the L4 stage of development. While editing still occurs in the absence of ADR-1, most of the editing occurs in genes that are edited in wildtype worms, suggesting that ADR-1 does not prevent editing by binding to and protecting the RNA but rather enhances or promotes editing. Our results suggest that ADR-1 plays a significant role in the RNA editing process and by altering editing levels it causes the severe phenotypes that we observed. In contrast, a complete lack of RNA editing is less harmful to the worms. Furthermore, our results indicate that the effect of RNA editing on the protein content in the cell is minor and probably the main purpose of these modifications is to antagonize or enhance other gene regulatory mechanisms that act on RNA.
Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites
Authors: Cantor Aaron J. , Shah Neel H. , Kuriyan John
Published: March 2018

Upon activation, the epidermal growth factor receptor (EGFR) phosphorylates tyrosine residues in its cytoplasmic tail, which triggers the binding of Src Homology 2 (SH2) and Phosphotyrosine Binding (PTB) domains and initiates downstream signaling. The sequences flanking the tyrosine residues (referred to as phosphosites) must be compatible with phosphorylation by the EGFR kinase domain and the recruitment of adapter proteins, while minimizing phosphorylation that would reduce the fidelity of signal transmission. In order to understand how phosphosite sequences encode these functions within a small set of residues, we carried out high-throughput mutational analysis of three phosphosite sequences in the EGFR tail. We used bacterial surface-display of peptides, coupled with deep sequencing, to monitor phosphorylation efficiency and the binding of the SH2 and PTB domains of the adapter proteins Grb2 and Shc1, respectively. We found that the sequences of phosphosites in the EGFR tail are restricted to a subset of the range of sequences that can be phosphorylated efficiently by EGFR. Although efficient phosphorylation by EGFR can occur with either acidic or large hydrophobic residues at the −1 position with respect to the tyrosine, hydrophobic residues are generally excluded from this position in tail sequences. The mutational data suggest that this restriction results in weaker binding to adapter proteins, but also disfavors phosphorylation by the cytoplasmic tyrosine kinases c-Src and c-Abl. Our results show how EGFR-family phosphosites achieve a trade-off between minimizing off-pathway phosphorylation while maintaining the ability to recruit the diverse complement of effectors required for downstream pathway activation.
Decoding neural responses with minimal information loss
Authors: Berkowitz John A. , Sharpee Tatyana O.
Published: March 2018

Cortical tissue has a circuit motif termed the cortical column, which is thought to represent its basic computational unit but whose function remains unclear. Here we propose, and show quantitative evidence, that the cortical column performs computations necessary to decode incoming neural activity with minimal information loss. The cortical decoder achieves higher accuracy compared to simpler decoders found in invertebrate and subcortical circuits by incorporating specific recurrent network dynamics. This recurrent dynamics also makes it possible to choose between alternative stimulus categories. The structure of cortical decoder predicts quadratic dependence of cortex size relative to subcortical parts of the brain. We quantitatively verify this relationship using anatomical data across mammalian species. The results offer a new perspective on the evolution and computational function of cortical columns.
Stochastic models of cell invasion with fluorescent cell cycle indicators
Authors: Simpson Matthew J , Jin Wang , Vittadello Sean T , Tambyah Tamara A , Ryan Jacob M , Gunasingh Gency , Haass Nikolas K , McCue Scott W
Published: March 2018

Fluorescent cell cycle labelling in cell biology experiments provides real time information about the location of individual cells, as well as the phase of the cell cycle of individual cells. We develop a stochastic, lattice-based random walk model of a two-dimensional scratch assay where the total population is composed of three distinct subpopulations which we visualise as red, yellow and green subpopulations. Our model mimics FUCCI technology in which cells in the G1 phase of the cell cycle fluoresce red, cells in the early S phase fluoresce yellow, and cells in the S/G2/M phase fluoresce green. The model is an exclusion process so that any potential motility or proliferation event that would place an agent on an occupied lattice site is aborted. Using experimental images and previous experimental measurements, we explain how to apply the stochastic model to simulate a scratch assay initialised with a low to moderate density monolayer of human melanoma cell line. We obtain additional mathematical insight by deriving an approximate partial differential equation (PDE) description of the stochastic model, leading to a novel system of three coupled nonlinear reaction diffusion equations. Comparing averaged simulation data with the solution of the continuum limit model confirms that the PDE description is accurate for biologically-relevant parameter combinations.
New formula and conversion factor to compute tree species basic wood density from a global wood technology database
Authors: Vieilledent Ghislain , Jörg Fischer Fabian , Chave Jérôme , Guibal Daniel , Langbour Patrick , Gérard Jean
Published: March 2018

Premise of the study

Basic wood density is an important ecological trait for woody plants. It is used to characterize species performance and fitness in community ecology, and to compute tree and forest biomass in carbon cycle studies. While wood density has been historically measured at 12% moisture, it is convenient for ecological purposes to convert this measure to basic wood density, i.e. the ratio of dry mass over green volume. Basic wood density can then be used to compute tree dry biomass from living tree volume.

Methods

Here, we derive a new, exact formula to compute the basic wood density Db from the density at moisture content w denoted Dw, the fibre saturation point S, and the volumetric shrinkage coefficient R. We estimated a new conversion factor using a global wood technology database where values to use this formula are available for 4022 trees collected in 64 countries (mostly tropical) and representing 872 species.

Key results

We show that previous conversion factors used to convert densities at 12% moisture into basic wood densities are inconsistent. Based on theory and data, we found that basic wood density could be inferred from the density at 12% moisture using the following formula: Db = 0.828D122. This value of 0.828 provides basic wood density estimates 4-5% smaller than values inferred from previous conversion factors.

Conclusions

This new conversion factor should be used to derive basic wood densities in global wood density databases. This would prevent overestimating global forest carbon stocks and allow predicting better tree species community dynamics from wood density.
Tripartite chromatin localization of budding yeast Shugoshin involves higher-ordered architecture of mitotic chromosomes
Authors: Deng Xiexiong , Kuo Min-Hao
Published: March 2018

The spindle assembly checkpoint (SAC) is key to faithful segregation of chromosomes. One requirement that satisfies SAC is appropriate tension between sister chromatids at the metaphase-anaphase juncture. Proper tension generated by poleward pulling of mitotic spindles signals biorientation of the underlying chromosome. In the budding yeast, the tension status is monitored by the conserved Shugoshin protein, Sgo1p, and the tension sensing motif (TSM) of histone H3. ChIP-seq reveals a unique TSM-dependent, tripartite domain of Sgo1p in each mitotic chromosome. This domain consists of one centromeric and two flanking peaks 3 – 4 kb away, and is present exclusively in mitosis. Strikingly, this trident motif coincides with cohesin localization, but only at the centromere and the two immediate adjacent loci, despite that cohesin is enriched at numerous regions throughout mitotic chromosomes. The TSM-Sgo1p-cohesin triad is at the center stage of higher-ordered chromatin architecture for error-free segregation.
Repeat-specific functions for the C-terminal domain of RNA polymerase II in budding yeast
Authors: Babokhov Michael , Mosaheb Mohammad M. , Baker Richard W. , Fuchs Stephen M.
Published: March 2018

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeastSaccharomyces cerevisiae, the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD.
Electrodiffusion model of synaptic potentials in dendritic spines
Authors: Lagache Thibault , Jayant Krishna , Yuste Rafael
Published: March 2018

When modeling electric current flow in neurons and excitable cells, traditional cable theory ignores electrodiffusion (i.e. the interaction between electric fields and ionic diffusion) as it assumes that concentration changes associated with ionic currents are negligible. This assumption, while true for large neuronal compartments, fails when applied to femto-liter size compartments such as dendritic spines - small protrusions that form the main site of synaptic inputs in the brain. Here, we use the Poisson (P) and Nernst-Planck (NP) equations, which relate electric field to charge and couple Fick’s law of diffusion to the electric field, to model ion concentration dynamics in dendritic spines. We use experimentally measured voltage transients from spines with nanoelectrodes to explore these dynamics with realistic parameters. We find that (i) passive diffusion and electrodiffusion jointly affect the kinetics of spine excitatory post-synaptic potentials (EPSPs); (ii) spine geometry plays a key role in shaping EPSPs; and, (iii) the spine-neck resistance dynamically decreases during EPSPs, leading to short-term synaptic facilitation. Our formulation can be easily adopted to model ionic biophysics in a variety of nanoscale bio-compartments.