bluuebunny/crossref_metadata_2025 huggingface dataset:
The Roots of Plant Frost Hardiness and Tolerance
Authors: Ambroise Valentin , Legay Sylvain , Guerriero Gea , Hausman Jean-Francois , Cuypers Ann , Sergeant Kjell
Published: October 2019

Frost stress severely affects agriculture and agroforestry worldwide. Although many studies about frost hardening and resistance have been published, most of them focused on the aboveground organs and only a minority specifically targets the roots. However, roots and aboveground tissues have different physiologies and stress response mechanisms. Climate models predict an increase in the magnitude and frequency of late-frost events, which, together with an observed loss of soil insulation, will greatly decrease plant primary production due to damage at the root level. Molecular and metabolic responses inducing root cold hardiness are complex. They involve a variety of processes related to modifications in cell wall composition, maintenance of the cellular homeostasis and the synthesis of primary and secondary metabolites. After a summary of the current climatic models, this review details the specificity of freezing stress at the root level and explores the strategies roots developed to cope with freezing stress. We then describe the level to which roots can be frost hardy, depending on their age, size category and species. After that, we compare the environmental signals inducing cold acclimation and frost hardening in the roots and aboveground organs. Subsequently, we discuss how roots sense cold at a cellular level and briefly describe the following signal transduction pathway, which leads to molecular and metabolic responses associated with frost hardening. Finally, the current options available to increase root frost tolerance are explored and promising lines of future research are discussed.
Responsibility and Comparative Pride – a Critical Discussion of Morgan-Knapp
Authors: Mason Cathy
Published: October 2019

Taking pride in being better than others in some regard is not uncommon. In a recent paper, Christopher Morgan-Knapp (2019) argues that such pride is misguided: it ‘presents things as being some way they are not’ (Morgan-Knapp 2019: 317). I argue that Morgan-Knapp's arguments do not succeed in showing that comparative pride is theoretically mistaken.
Temperature Shocks and Establishment Sales
Authors: Addoum Jawad M , Ng David T , Ortiz-Bobea Ariel
Published: October 2019

Combining granular daily data on temperatures across the continental United States with detailed establishment data from 1990 to 2015, we study the causal impact of temperature shocks on establishment sales and productivity. Using a large sample yielding precise estimates, we do not find evidence that temperature exposures significantly affect establishment-level sales or productivity, including among industries traditionally classified as “heat sensitive.” At the firm level, we find that temperature exposures aggregated across firm establishments are generally unrelated to sales, productivity, and profitability. Our results support existing findings of a tenuous relation between temperature and aggregate economic growth in rich countries.
Early response to anti-TNF predicts long-term outcomes including sustained remission: an analysis of the BSRBR-RA
Authors: Hamann Philip D H , Pauling John D , McHugh Neil , Hyrich Kimme , Shaddick Gavin ,   and the BSRBR-RA Contributors Group
Published: October 2019

Objective

To identify different trajectories of disease activity in patients with RA following initiation of a first anti-TNF.

Methods

Patients with RA starting their first anti-TNF between 2001 and 2013 were selected from the British Society for Rheumatology Biologics Register for RA. Six-monthly DAS28-ESR scores were used to identify trajectories of disease activity using latent class modelling. Data were included for six follow-ups after registration (approximately 3 years). Subgroup analysis examined changes in disease activity profiles over time.

Results

A total of 14 436 patients with RA starting their first anti-TNF were enrolled between 2001 and 2013 (13 115 between 2001 and 2008, 1321 between 2010 and 2013). The mean number of DAS28-ESR scores was 3.5/patient (s.d. 2.1), with a mean of 184.9 days (s.d. 69.9) between scores. The DAS28-ESR nadir was achieved within 250 days of commencing anti-TNF, although apparent trajectory divergence emerged by first 6-monthly follow-up at 180 days. Four distinct response trajectories comprised the most stable model. Most patients fitted into ‘modest’ (7986 patients; 55.3%) or ‘substantial’ (4676 patients; 32.4%) response trajectories. Of the remainder, 1254 (8.7%) and 520 (3.6%) fitted ‘maximal’ and ‘minimal’ response trajectories, respectively. There was a significant (P < 0.01) increase in proportion achieving ‘maximal’ response between 2001–2008 and 2010–2013.

Conclusion

This is the largest study to identify long-term response trajectories with anti-TNF. By 6 months, longer-term trajectory profiles of DAS28 could already be identified, with many patients identified earlier. The majority of patients had persistent moderate response, equivalent to maintained DAS28-ESR moderate disease activity. The maximal response trajectory (equivalent to sustained DAS2-ESR remission) was only achieved by approximately one-third of patients.
An updated matrix to predict rapid radiographic progression of early rheumatoid arthritis patients: pooled analyses from several databases
Authors: Vanier Antoine , Smolen Josef S , Allaart Cornelia F , Van Vollenhoven Ronald , Verschueren Patrick , Vastesaeger Nathan , Saevarsdottir Saedis , Visser Karen , Aletaha Daniel , Combe Bernard , Fautrel Bruno
Published: October 2019

Objective

In early RA, some patients exhibit rapid radiographic progression (RRP) after one year, associated with poor functional prognosis. Matrices predicting this risk have been proposed, lacking precision or inadequately calibrated. We developed a matrix to predict RRP with high precision and adequate calibration.

Methods

Post-hoc analysis by pooling individual data from cohorts (ESPOIR and Leuven cohorts) and clinical trials (ASPIRE, BeSt and SWEFOT trials). Adult DMARD-naïve patients with active early RA for which the first therapeutic strategy after inclusion was to prescribe methotrexate or leflunomide were included. A logistic regression model to predict RRP was built. The best model was selected by 10-fold stratified cross-validation by maximizing the Area Under the Curve. Calibration and discriminatory power of the model were checked. The probabilities of RRP for each combination of levels of baseline characteristics were estimated.

Results

1306 patients were pooled. 20.6% exhibited RRP. Four predictors were retained: rheumatoid factor positivity, presence of at least one RA erosion on X-rays, CRP > 30mg/l, number of swollen joints. The matrix estimates RRP probability for 36 combinations of level of baseline characteristics with a greatly enhanced precision compared with previously published matrices (95% CI: from ± 0.02 minimum to ± 0.08 maximum) and model calibration is excellent (P = 0.79).

Conclusion

A matrix proposing RRP probability with high precision and excellent calibration in early RA was built. Although the matrix has moderate sensitivity and specificity, it is easily usable and may help physicians and patients to make treatment decisions in daily clinical practice.
TRITIUM ANALYSIS IN URINE BY THE TRIPLE-TO-DOUBLE COINCIDENCE RATIO METHOD WITH THE HIDEX 300 SL LIQUID SCINTILLATION COUNTER
Authors: Lecompte Yannick , Rosset Martine , Loess Jérôme , Chianea Nadine , Jourquin Flora , Cazoulat Alain , Cassette Philippe
Published: October 2019

The triple-to-double coincidence ratio (TDCR) method is a liquid scintillation primary method for the absolute activity measurement of pure β− and pure electron capture emitters. This method requires specific three-photomultiplier liquid scintillation counters. The aim of the present work is to assess the TDCR method performance for routine tritium analysis in urine using an HIDEX 300 SL, the only three-photomultiplier liquid scintillation counter designed for routine laboratories. The physical parameters and the semi-empirical Birks parameter (kB) of the prepared liquid scintillation source were firstly determined. TDCR model equations solving and detection efficiencies calculations for measured samples were performed by TDCR07c computing program. Accuracy, uncertainties and detection limit of TDCR method were assessed through the tritium analysis of six intercomparison urine samples. The results demonstrate that the analytical performance of the TDCR method implemented on the HIDEX 300 SL is conform to the recommendations for the monitoring of workers exposed to tritium.
The circadian system modulates the rate of recovery of systolic blood pressure after exercise in humans
Authors: Qian Jingyi , Scheer Frank Ajl , Hu Kun , Shea Steven A
Published: October 2019

Study Objectives

Recovery rates of systolic blood pressure (BP) and heart rate (HR) after exercise have been used to assess cardiovascular fitness, and slower recovery rates are predictors of coronary heart disease and cardiac mortality. The endogenous circadian system is known to modulate BP and HR at rest and during exercise. Here, we examined whether the post-exercise recovery rates of BP and HR are also under circadian control.

Methods

Twelve healthy adults (mean age = 26 ± 6 (SD) years; 6 female) participated in a 240 h forced desynchrony protocol in dim light where all behaviors, including 15 min cycle exercise tests at 60% maximal HR, were uniformly distributed across the circadian cycle. Circadian phases were assigned based on the rhythm of core body temperature. For each session, HR was measured continuously, and BP every 3–5 min throughout baseline, exercise, and recovery. Recovery was quantified as the proportional return to pre-exercise baseline levels following exercise ([peak exercise-recovery]/[peak exercise-baseline) × 100%], whereby 100% represents full recovery to baseline).

Results

There was a significant circadian rhythm in systolic BP recovery, with fastest recovery at the circadian phase corresponding to late afternoon (equivalent to ~5 pm) and slower recovery across the early morning (~8:30 am; p = 0.029, peak-to-trough: 9.2%). There were no significant circadian variations in post-exercise recovery rates of diastolic BP or HR.

Conclusions

The circadian system modulates the rate of recovery of systolic BP after exercise with fastest recovery in the biological afternoon. These data could have implications for exercise prescription and interpretation of clinical tests of stress recovery.
Effects of narasin supplementation on dry matter intake and rumen fermentation characteristics of Bos indicus steers fed a high-forage diet
Authors: Polizel Daniel M , Cappellozza Bruno I , Hoe Fernanda , Lopes Catarina N , Barroso José Paulo , Miszura Alexandre , Oliveira Gabriela B , Gobato Luiz , Pires Alexandre V
Published: October 2019

This study evaluated the effects of narasin on intake and rumen fermentation characteristics of Bos indicus steers offered a high-forage diet for 140 d. On day 0 of the study, 30 rumen-fistulated Nellore steers [initial body weight (BW) = 281 ± 21 kg] were assigned to 30 individual pens in a randomized complete block design according to their initial BW. Animals were randomly assigned to 1 of the 3 treatments: 1) forage-based diet without narasin (CONT; n = 10), 2) CONT diet plus 13 ppm of narasin (13NAR; n = 10), and 3) CONT diet plus 20 ppm of narasin (20NAR; n = 10). The forage used was Tifton-85 (Cynodon dactylon spp.), whereas the carrier for narasin was a 50:50 mixture of soybean hull:corn. The experimental period was divided into 5 periods of 28 d each. Throughout the experimental period, total dry matter intake (DMI) was recorded daily, whereas mineral salt intake was recorded weekly. Blood and ruminal fluid samples were collected on day 0 (prior to treatment feeding), 28, 56, 84, 112, and 140 of the study. Moreover, total tract apparent nutrient digestibility was performed for a 5-d period every 28 d. No treatment effects were observed on forage, mineral, concentrate, or total DMI (P ≥ 0.22). Nonetheless, 13NAR tended to have a greater mineral intake vs. 20NAR cohorts (P = 0.08) Narasin-supplemented animals had reduced rumen acetate, Ac:Pr ratio, as well as greater (P ≤ 0.02) rumen propionate concentrations vs. CONT cohorts. Moreover, 13NAR increased rumen propionate and decreased butyrate, Ac:Pr vs. 20NAR cohorts (P ≤ 0.01). Throughout the experimental period, narasin-supplemented animals had reduced ammonia concentrations vs. CONT cohorts (P < 0.01), whereas no differences were observed between 13NAR and 20NAR (P = 0.80). No treatment or dose effects were observed (P ≥ 0.23) on DM, organic matter (OM), protein, neutral detergent fiber (NDF), acid detergent fiber (ADF), and mineral digestibility. Animals fed 13NAR had a reduced mean plasma urea concentration vs. CONT cohorts (P = 0.03), whereas no further differences were observed (P ≥ 0.12). In summary, narasin supplementation to beef steers offered a high-forage diet did not impact forage, mineral, and total DMI, as well as nutrient digestibility, whereas rumen fermentation characteristics, rumen ammonia, and plasma urea concentrations were positively impacted and lasted throughout the experimental period. Additionally, 13 ppm of narasin resulted in a reduced Ac:Pr ratio and rumen ammonia when compared to animals supplemented with 20 ppm.
noeM, a New Nodulation Gene Involved in the Biosynthesis of Nod Factors with an Open-Chain Oxidized Terminal Residue and in the Symbiosis with Mimosa pudica
Authors: Daubech Benoit , Poinsot Verena , Klonowska Agnieszka , Capela Delphine , Chaintreuil Clémence , Moulin Lionel , Marchetti Marta , Masson-Boivin Catherine
Published: October 2019

The β-rhizobium Cupriavidus taiwanensis is a nitrogen-fixing symbiont of Mimosa pudica. Nod factors produced by this species were previously found to be pentameric chitin-oligomers carrying common C18:1 or C16:0 fatty acyl chains, N-methylated and C-6 carbamoylated on the nonreducing terminal N-acetylglucosamine and sulfated on the reducing terminal residue. Here, we report that, in addition, C. taiwanensis LMG19424 produces molecules where the reducing sugar is open and oxidized. We identified a novel nodulation gene located on the symbiotic plasmid pRalta, called noeM, which is involved in this atypical Nod factor structure. noeM encodes a transmembrane protein bearing a fatty acid hydroxylase domain. This gene is expressed during symbiosis with M. pudica and requires NodD and luteolin for optimal expression. The closest noeM homologs formed a separate phylogenetic clade containing rhizobial genes only, which are located on symbiosis plasmids downstream from a nod box. Corresponding proteins, referred to as NoeM, may have specialized in symbiosis via the connection to the nodulation pathway and the spread in rhizobia. noeM was mostly found in isolates of the Mimoseae tribe, and specifically detected in all tested strains able to nodulate M. pudica. A noeM deletion mutant of C. taiwanensis was affected for the nodulation of M. pudica, confirming the role of noeM in the symbiosis with this legume.
TargeTALE: A Web Resource to Identify TALEs in Xanthomonas Genomes and Their Respective Targets
Authors: Kremer Frederico Schmitt , Guimarães Amanda Munari , Sanchez Christian Domingues , da Silva Pinto Luciano
Published: October 2019

The Xanthomonas genus, comprises more than 30 species of gram-negative bacteria, most of which are pathogens of plants with high economic value, such as rice, common bean, and maize. Transcription activator-like effectors (TALEs), which act by regulating the host gene expression, are some of the major virulence factors of these bacteria. We present a novel tool to identify TALE genes in the genome of Xanthomonas strains and their respective targets. The analysis of the results obtained by TargeTALE in a proof-of-concept validation demonstrate that, at optimum setting, approximately 93% of the predicted target genes with available expression data were confirmed as upregulated during the infection, indicating that the tool might be useful for researchers in the field.
Prep1 regulates angiogenesis through a PGC‐1α‐mediated mechanism
Authors: Cimmino Ilaria , Margheri Francesca , Prisco Francesco , Perruolo Giuseppe , D'Esposito Vittoria , Laurenzana Anna , Fibbi Gabriella , Paciello Orlando , Doti Nunzianna , Ruvo Menotti , Miele Claudia , Beguinot Francesco , Formisano Pietro , Oriente Francesco
Published: October 2019

Angiogenesis depends on a delicate balance between the different transcription factors, and their control should be considered necessary for preventing or treating diseases. Pre‐B‐cell leukemia transcription factor regulating protein 1 (Prep1) is a homeodomain transcription factor that plays a primary role in organogenesis and metabolism. Observations performed in a Prep1 hypomorphic mouse model, expressing 3‐5% of the protein, show an increase of embryonic lethality due, in part, to defects in angiogenesis. In this study, we provide evidence that overexpression of Prep1 in mouse aortic endothelial cells (MAECs) stimulates migration, proliferation, and tube formation. These effects are paralleled by an increase of several proangiogenic factors and by a decrease of the antiangiogenic gene neurogenic locus notch homolog protein 1 (Notch1). Prep1‐mediated angiogenesis involves the activation of the p160 Myb‐binding protein (p160)/peroxisome proliferator‐activated receptor g coactivator 1a (PGC‐1α) pathway. Indeed, Prep1 overexpression increases its binding with p160 and induces a 4‐fold increase of p160 and 70% reduction of PGC‐1α compared with control cells. Incubation of MAECs with a synthetic Prep1(54‐72) peptide, mimicking the Prep1 region involved in the interaction with p160, reverts the proangiogenic effects mediated by Prep1. In addition, Prep1 levels increase by 3.2‐fold during the fibroblast growth factor β (bFGF)‐mediated endothelial colony‐forming cells' activation, whereas Prep1(54‐72) peptide reduces the capability of these cells to generate tubular‐like structures in response to bFGF, suggesting a possible role of Prep1 both in angiogenesis from preexisting vessels and in postnatal vasculogenesis. Finally, Prep1 hypomorphic heterozygous mice, expressing low levels of Prep1, show attenuated placental angiogenesis and vessel formation within Matrigel plugs. All of these observations indicate that Prep1, complexing with p160, decreases PGC‐1α and stimulates angiogenesis.—Cimmino, I., Margheri, F., Prisco, F., Perruolo, G., D'Esposito, V., Laurenzana, A., Fibbi, G., Paciello, O., Doti, N., Ruvo, M., Miele, C., Beguinot, F., Formisano, P., Oriente, F. Prep1 regulates angiogenesis through a PGC‐1α‐mediated mechanism. FASEB J. 33, 13893‐13904 (2019). www.fasebj.org
Genetic convergence of industrial melanism in three geometrid moths
Authors: van't Hof Arjen E. , Reynolds Louise A. , Yung Carl J. , Cook Laurence M. , Saccheri Ilik J.
Published: October 2019

The rise of dark (melanic) forms of many species of moth in heavily coal-polluted areas of nineteenth- and twentieth-century Britain, and their post-1970s fall, point to a common selective pressure (camouflage against bird predators) acting at the community level. The extent to which this convergent phenotypic response relied on similar genetic and developmental mechanisms is unknown. We examine this problem by testing the hypothesis that the locus controlling melanism inPhigalia pilosariaandOdontopera bidentata, two species of geometrid moth that showed strong associations between melanism and coal pollution, is the same as that controlling melanism inBiston betularia, previously identified as the genecortex. Comparative linkage mapping using family material supports the hypothesis for both species, indicating a deeply conserved developmental mechanism for melanism involvingcortex. However, in contrast to the strong selective sweep signature seen in BritishB. betularia, no significant association was detected betweencortex-region markers and melanic morphs in wild-caught samples ofP. pilosariaandO. bidentata, implying much older, or diverse, origins of melanic morph alleles in these latter species.
Rapid induction of the heat hardening response in an Arctic insect
Authors: Sørensen Mathias Hamann , Kristensen Torsten Nygaard , Lauritzen Jannik Mørk Skovgaard , Noer Natasja Krog , Høye Toke Thomas , Bahrndorff Simon
Published: October 2019

The ability to cope with increasing and more variable temperatures, due to predicted climate changes, through plastic and/or evolutionary responses will be crucial for the persistence of Arctic species. Here, we investigate plasticity of heat tolerance of the Greenlandic seed bug
Nysius groenlandicus,
which inhabits areas with widely fluctuating temperatures. We test the heat tolerance and hardening capacity (plasticity) of
N. groenlandicus
using both static (heat knock down time, HKDT) and dynamic (critical thermal maximum, CT
max
) assays. We find that
N. groenlandicus
is able to tolerate short-term exposure to temperatures up to almost 50°C and that it can quickly increase heat resistance following heat hardening. Furthermore, we find that this hardening response is reversible within hours after hardening. These findings contrast with common observations from temperate and tropical insects and suggest high thermal plasticity in some Arctic insects which enables them to cope with extreme temperature variability in their habitats.
The forgotten typers: The rise and fall of Weimar bacteriophage-typing (1921–1935)
Authors: Kirchhelle Claas
Published: October 2019

Using bacteriophages to type (identify) bacteria was one of the most important tools of twentieth-century epidemiology. Challenging existing accounts’ focus on Anglophone research, this paper shows that modern phage-typing arose in German-speaking continental laboratories from 1921 onwards. Several factors contributed to this rise: the limitations of existing phenotypic systems; demobilized German bacteriologists’ interwar engagement with phages as a means to explore bacterial type variation; the existence of well-stocked and well-defined microbial culture collections with a strong focus on typhoid and paratyphoid; the standardization, free provision and calibration of phage diagnostic systems by a centralized laboratory network; and phage-typers’ implicit agreement to black-box ontological controversies about phages' nature in favour of a mission-oriented focus on practical epidemiological applications. The result was an experimental system that simultaneously treated phages as technical objects and epistemic things. Although the human network supporting phage-typing collapsed after the Nazi rise to power, Weimar-era phage researchers laid the foundation for modern phage-based diagnostics and epidemiology.
Detection of arterial wall abnormalities via Bayesian model selection
Authors: Larson Karen , Bowman Clark , Papadimitriou Costas , Koumoutsakos Petros , Matzavinos Anastasios
Published: October 2019

Patient-specific modelling of haemodynamics in arterial networks has so far relied on parameter estimation for inexpensive or small-scale models. We describe here a Bayesian uncertainty quantification framework which makes two major advances: an efficient parallel implementation, allowing parameter estimation for more complex forward models, and a system for practical model selection, allowing evidence-based comparison between distinct physical models. We demonstrate the proposed methodology by generating simulated noisy flow velocity data from a branching arterial tree model in which a structural defect is introduced at an unknown location; our approach is shown to accurately locate the abnormality and estimate its physical properties even in the presence of significant observational and systemic error. As the method readily admits real data, it shows great potential in patient-specific parameter fitting for haemodynamical flow models.
Interactive effects of foundation species on ecosystem functioning and stability in response to disturbance
Authors: Narwani Anita , Reyes Marta , Pereira Aaron Louis , Penson Hannele , Dennis Stuart R. , Derrer Samuel , Spaak Piet , Matthews Blake
Published: October 2019

A major challenge in ecology is to understand determinants of ecosystem functioning and stability in the face of disturbance. Some important species can strongly shape community structure and ecosystem functioning, but their impacts and interactions on ecosystem-level responses to disturbance are less well known. Shallow ponds provide a model system in which to study the effects of such species because some taxa mitigate transitions between alternative ecosystem states caused by eutrophication. We performed pond experiments to test how two foundation species (a macrophyte and a mussel) affected the biomass of planktonic primary producers and its stability in response to nutrient additions. Individually, each species reduced phytoplankton biomass and tended to increase rates of recovery from disturbance, but together the species reversed these effects, particularly with larger nutrient additions. This reversal was mediated by high cyanobacterial dominance of the community and a resulting loss of trait evenness. Effects of the foundation species on primary producer biomass were associated with effects on other ecosystem properties, including turbidity and dissolved oxygen. Our work highlights the important role of foundation species and their interactive effects in determining responses of ecosystem functioning to disturbance.
Quantitative real-time PCR assay for the rapid identification of the intrinsically multidrug-resistant bacterial pathogen Stenotrophomonas maltophilia
Authors: Fraser Tamieka A. , Bell Mikaela G. , Harris Patrick N. A. , Bell Scott C. , Bergh Haakon , Nguyen Thuy-Khanh , Kidd Timothy J. , Nimmo Graeme R. , Sarovich Derek S. , Price Erin P.
Published: October 2019

Stenotrophomonas maltophilia

is emerging as an important cause of disease in nosocomial and community-acquired settings, including bloodstream, wound and catheter-associated infections. Cystic fibrosis (CF) airways also provide optimal growth conditions for various opportunistic pathogens with high antibiotic tolerance, including

S. maltophilia

. Currently, there is no rapid, cost-effective and accurate molecular method for detecting this potentially life-threatening pathogen, particularly in polymicrobial specimens, suggesting that its true prevalence is underestimated. Here, we used large-scale comparative genomics to identify a specific genetic target for

S. maltophilia

, with subsequent development and validation of a real-time PCR assay for its detection. Analysis of 167

Stenotrophomonas

spp. genomes identified a conserved 4 kb region in

S. maltophilia

, which was targeted for Black Hole Quencher assay design. Our assay yielded the positive detection of 89 of 89 (100%) clinical

S. maltophilia

strains, and no amplification of 23 non-

S. maltophilia

clinical isolates.

S. maltophilia

was detected in 10 of 16 CF sputa, demonstrating the assay's utility for direct detection in respiratory specimens. The assay demonstrated good sensitivity, with limits of detection and quantitation on pure culture of ~10 and ~100 genome equivalents, respectively. Our assay provides a highly specific, sensitive and cost-effective method for the accurate identification of

S. maltophilia

, and will improve the diagnosis and treatment of this under-recognized pathogen by enabling its accurate and rapid detection from polymicrobial clinical and environmental samples.
Computer-assisted craniometric evaluation for diagnosis and follow-up of craniofacial asymmetries: SymMetric v. 1.0
Authors: Lopes Alho Eduardo Joaquim , Rondinoni Carlo , Furokawa Fabio Okuda , Monaco Bernardo A.
Published: October 2019

Purpose

The current assessment of patients with craniofacial asymmetries is accomplished by physical examination, anamnesis and radiological imaging.

We propose a semi-automated, computer-assisted craniofacial evaluation (SymMetric v 1.0) based on orthogonal photography of the patient’s head in 3 positions. The system is simple, low-cost, no-radiation or special resources needed. Although it does not substitute CT in cases of doubt between craniosynostosis and positional plagiocephaly, multiple numeric evaluations indicate regional deformities and severity of the asymmetry, which can help in the clinical decision of indicating or not the orthosis in positional deformities, determining treatment duration or evaluating surgical outcomes after correction.

Methods

A Matlab-based tool was developed for digital processing of photographs taken in 3 positions (anterior, superior and lateral). The software guides the user to select visible and reproducible landmarks in each photograph acquisition and calculates multiple indexes and metrics, generating a set of comprehensive plots to offer the user an overview of head and facial symmetry across the orthogonal views. For purposes of demonstration, we evaluated 2 patients (one control and one with non-sinostotic deformity).

Results

The results show a clear differentiation of the control and plagiocephalic patient metrics mainly in the superior view, showing potential for diagnosis of the condition, and also detected the clinical improvement during helmet treatment in the follow-up, 3 and 5 months after orthosis’ use.

Conclusion

We presented a proof-of-concept for a low cost, no radiation evaluation system for craniofacial asymmetries, that can be useful in a clinical context for diagnosis and follow-up of patients.
NeuroMark: a fully automated ICA method to identify effective fMRI markers of brain disorders
Authors: Du Yuhui , Fu Zening , Sui Jing , Gao Shuang , Xing Ying , Lin Dongdong , Salman Mustafa , Rahaman Md Abdur , Abrol Anees , Chen Jiayu , Hong L Elliot , Kochunov Peter , Osuch Elizabeth A. , Calhoun Vince D. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2019

Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. Standardized approaches for capturing reproducible and comparable biomarkers are greatly needed. Here, we propose a method,NeuroMark, which leverages a priori-driven independent component analysis to effectively extract functional brain network biomarkers from functional magnetic resonance imaging (fMRI) data.NeuroMarkautomatically estimates features adaptable to each individual and comparable across subjects by taking advantage of the replicated brain network templates extracted from 1828 healthy controls as guidance to initialize the individual-level networks. Four studies including 2454 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, depression, bipolar disorder, mild cognitive impairment and Alzheimer’s disease) to evaluate the proposed method from different perspectives (replication, cross-study comparison, subtle difference identification, and multi-disorder classification). Results demonstrate the great potential ofNeuroMarkin its feasibility to link different datasets/studies/disorders and enhance sensitivity in identifying biomarkers for patients with challenging mental illnesses.

Significance Statement

Increasing evidence highlights that features extracted from resting fMRI data can be leveraged as potential biomarkers of brain disorders. However, it has been difficult to replicate results using different datasets, translate findings across studies, and differentiate brain disorders sharing similar clinical symptoms. It is important to systematically characterize the degree to which unique and similar impaired patterns are reflective of brain disorders. We propose a fully automated method (calledNeuroMark) that leverages priori-driven independent component analysis (ICA) using replicated brain network templates to estimate individual-subject network features. Evaluated by four studies involving six different brain disorders, we show thatNeuroMarkcan effectively link the comparison of biomarkers across different studies/datasets/disorders and enable classification between complex brain disorders, while also providing information about relevant aspects of whole brain functional connectivity.
Efficacy and safety of Nab-paclitaxel in breast cancer: a meta-analysis
Authors: Yadav Upendra , Kumar Pradeep , Rai Vandana
Published: October 2019

Worldwide breast cancer is the leading cause of cancer related death in women. Paclitaxel is an effective drug used for the treatment of breast cancer but it has many side effects. Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) is an FDA approved drug for the treatment of breast cancer. Currently many clinical trials are conducted to deliver nab-paclitaxel into the tumor cells. But the efficacy and safety of this nab-paclitaxel over conventional paclitaxel still remains questionable. So, we performed a meta-analysis to evaluate the efficacy and safety of nab-paclitaxel in breast cancer treatment.

Electronic databases were searched for the suitable studies using key terms “nab-paclitaxel”, “paclitaxel”, and “clinical trial” with the combination of “breast cancer” up to August 11, 2019. Risk ratio (RR) and odds ratio (OR) with corresponding 95% confidence intervals (CIs) were calculated. All statistical analyses were performed by the Open Meta-Analyst program. A total of eight studies which fulfilled our criteria were included in this study. For efficacy we retrieved data of 12 months progression free survival, 24 months progression free survival, and overall survival (up to 3 years) and for the safety we took data of nausea, anemia, leukopenia, neutropenia, fatigue, diarrhea and pain.

We did not found any difference in efficacy of nab-paclitaxel over paclitaxel (12 months progression free survival-RRFE= 0.86, 95%CI= 0.77-0.97, p= 0.02, I2= 25.07%; 24 months progression free survival-RRFE= 0.86, 95% CI= 0.64-1.16, p= 0.34, I2= 0%; and 3 years survival-RRFE= 1.20, 95%CI= 0.92-1.56, p= 0.16, I2= 37.55%). The meta-analysis of studies used nab-paclitaxel showed reduced adverse effect of anemia (ORFE= 1.66, 95% CI= 1.26-2.19; p= <0.001; I2= 0%) and leukopenia (ORFE= 1.37; 95%CI= 1.06-1.75; p= 0.01; I2= 48.63%). However, in case of other adverse effects no significant association was found with nab-paclitaxel (nausea-ORFE=1.15, 95%CI= 0.94-1.41, p= 0.15, I2= 50.12%; neutropenia-ORRE= 0.75, 95%CI= 0.30-1.87, p= 0.54, I2= 94.45%; fatigue-ORRE= 1.11, 95%CI= 0.77-1.62, p= 0.55, I2= 56.02; diarrhea-ORFE= 1.11, 95%CI= 0.77-1.62, p= 0.55; I2= 34.26; pain-ORRE= 1.15, 95%CI= 0.78-1.69, p= 0.45, I2= 52.96%).In conclusion the use of nab-paclitaxel has reduces the side effects of anemia and leukopenia in breast cancer treatment in comparison to paclitaxel but nab-paclitaxel has no effect on the overall survival of the patients.
BRAFmutation testing of MSI CRCs in Lynch syndrome diagnostics: performance and efficiency according to patient’s age
Authors: Bläker Hendrik , Haupt Saskia , Morak Monika , Holinski-Feder Elke , Arnold Alexander , Horst David , Sieber-Frank Julia , Seidler Florian , von Winterfeld Moritz , Alwers Elizabeth , Chang-Claude Jenny , Brenner Hermann , Roth Wilfried , Engel Christoph , Löffler Markus , Möslein Gabriela , Schackert Hans-Konrad , Weitz Jürgen , Perne Claudia , Aretz Stefan , Hüneburg Robert , Schmiegel Wolff , Vangala Deepak , Rahner Nils , Steinke-Lange Verena , Heuveline Vincent , von Knebel Doeberitz Magnus , Ahadova Aysel , Hoffmeister Michael , Kloor Matthias ,   the German Consortium for Familial Intestinal Cancer
Published: October 2019

Background and aims

BRAFV600E mutations have been reported to be associated with sporadic microsatellite-unstable (MSI) colorectal cancer (CRC), while rarely detected in CRCs of Lynch syndrome (LS) patients. Therefore, current international diagnostic guidelines recommend somaticBRAFmutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadicBRAF-mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy ofBRAFtesting in LS diagnostics may be age-dependent.

Methods

We systematically compared the prevalence ofBRAFV600E mutations in LS-associated CRCs and MSI CRCs from population-based cohorts in different age groups as available from published studies, databases, and population-based patient cohorts. Cost calculations and sensitivity analysis of theBRAFtesting for exclusion of LS was performed.

Results

Among 969 MSI CRCs from LS mutation carriers from the literature and German HNPCC Consortium, 15 (1.6%, 95% CI: 0.9-2.6%) harboredBRAFmutations. 6/7 LS patients withBRAF-mutant CRC and reported age were <50 years. Among unselected MSI CRCs, 44.8% (339/756) harboredBRAFmutations, 92.3% (313/339) of which were detected in patients >60 years. In MSI CRC patients <50,BRAFmutations were detected only in 0.6% (2/339), and the inclusion ofBRAFtesting led to increased costs and higher risk of missing LS patients (1.2%) compared to other age groups.

Conclusion

BRAFtesting in patients <50 years is cost-inefficient and carries the highest risk of missing LS patients among different age groups. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without priorBRAFtesting.
Association of polygenic risk scores for coronary artery disease with subsequent events amongst established cases
Authors: Howe Laurence J. , Dudbridge Frank , Schmidt A. Floriaan , Finan Chris , Denaxas Spiros , Asselbergs Folkert W. , Hingorani Aroon D. , Patel Riyaz S.
Published: October 2019

Background

There is growing evidence that polygenic risk scores (PRS) can be used to identify individuals at high lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify risk of subsequent events among those surviving a first CAD event remains uncertain.

Methods

Using two subsamples of UK Biobank, defined at baseline as prevalent CAD (N=10,287) and without CAD (N=393,108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes, during a median follow up of 7.8 years.

Results

A 1 S.D. higher PRS was associated with increased risk of incident MI in participants without CAD (OR 1.33; 95% C.I. 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% C.I. 1.06, 1.25); heterogeneity P =0.0012. Additionally, among prevalent CAD cases, we found evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% C.I. 0.85, 0.98) compared to those without CAD (OR 1.01; 95% C.I. 0.99, 1.03); heterogeneity P =0.0041. A similar inverse association was found for ischaemic stroke (Prevalent CAD (OR 0.78; 95% C.I. 0.67, 0.90); without CAD (OR 1.09; 95% C.I. 1.04, 1.15), heterogeneity P <0.001).

Conclusions

Bias induced by case stratification and survival into UK Biobank may attenuate, or reverse, associations of polygenic risk scores derived from case-control studies or populations initially free of disease. Polygenic risk scores for subsequent events should be derived from new genome wide association studies conducted in patients with established disease.

Key messages

CAD PRS are positively associated with incident myocardial infarction risk amongst established CAD cases.

However, the effect size is attenuated compared to estimates from CAD-free populations.

CAD PRS are inversely associated with mortality and stroke risk amongst established CAD cases.

These associations may reflect index event bias induced by stratifying on case status.

Dedicated GWAS of coronary disease progression are required to improve prediction of subsequent event risk.
C-terminal tail polyglycylation and polyglutamylation alter microtubule mechanical properties
Authors: Wall Kathryn P. , Hart Harold , Lee Thomas , Page Cynthia , Hawkins Taviare L. , Hough Loren
Published: October 2019

Microtubules are biopolymers that perform diverse cellular functions. The regulation of microtubule behavior occurs in part through post-translational modification of both theα- andβ- subunits of tubulin. One class of modifications is the heterogeneous addition of glycine and glutamate residues to the disordered C-terminal tails of tubulin. Due to their prevalence in stable, high stress cellular structures such as cilia, we sought to determine if these modifications alter the intrinsic stiffness of microtubules. Here we describe the purification and characterization of differentially-modified pools of tubulin fromTetrahymena thermophila. We found that glycylation on theα-C-terminal tail is a key determinant of microtubule stiffness, but does not affect the number of protofilaments incorporated into microtubules. We measured the dynamics of the tail peptide backbone using nuclear magnetic resonance spectroscopy. We found that the spin-spin relaxation rate (R2) showed a pronounced decreased as a function of distance from the tubulin surface for theα-tubulin tail, indicating that theα-tubulin tail interacts with the dimer surface. This suggests that the interactions of theα-C-terminal tail with the tubulin body contributes to the stiffness of the assembled microtubule, providing insight into the mechanism by which glycylation and glutamylation can alter microtubule mechanical properties.

SIGNIFICANCE

Microtubules are regulated in part by post-translational modifications including the heterogeneous addition of glycine and glutamate residues to the C-terminal tails. By producing and characterizing differentially-modified tubulin, this work provides insight into the molecular mechanisms of how these modifications alter intrinsic microtubule properties such as flexibility. These results have broader implications for mechanisms of how ciliary structures are able to function under high stress.
Cathepsin g degrades synovial fluid lubricin: relevance for osteoarthritis pathogenesis
Authors: Huang Shan , Thomsson Kristina A. , Jin Chunsheng , Alweddi Sally , Struglics André , Rolfson Ola , Björkman Lena I , Kalamajski Sebastian , Schmidt Tannin A. , Jay Gregory D. , Krawetz Roman , Karlsson Niclas G. , Eisler Thomas
Published: October 2019

Lubricin (PRG4) is a mucin type protein that plays an important role in maintaining normal joint function by providing lubrication and chondroprotection. Improper lubricin modification and degradation has been observed in idiopathic osteoarthritis (OA), while the detailed mechanism still remains unknown. We hypothesized that the protease cathepsin G (CG) may participate in degrading lubricin in synovial fluid (SF). The presence of endogenous CG in SF was confirmed in 16 patients with knee OA. Recombinant human lubricin (rhPRG4) and native lubricin purified from the SF of patients were incubated with exogenous CG and lubricin degradation was monitored using western blot, staining by Coomassie or Periodic Acid-Schiff in gels, and with proteomics. Full length lubricin (∼300 kDa), was efficiently digested with CG generating a 25-kDa protein fragment, originating from the densely glycosylated mucin domain (∼250 kDa). The 25-kDa fragment was present in the SF from OA patients, and the amount was increased after incubation with CG. A CG digest of rhPRG4 revealed 135 peptides and 72 glycopeptides, and confirmed that the protease could cleave in different domains of lubricin. Our results suggest that synovial CG may take part in the degradation of lubricin, which could affect the lubrication of OA joints.
Reconstructing the history of variation in effective population size along phylogenies
Authors: Brevet Mathieu , Lartillot Nicolas
Published: October 2019

Abstract

The nearly-neutral theory predicts specific relations between effective population size (Ne) and patterns of divergence and polymorphism, which depend on the shape of the distribution of fitness effects (DFE) of new mutations. However, testing these relations is not straightforward, owing to the difficulty in estimating Ne. Here, we introduce an integrative framework allowing for an explicit reconstruction of the phylogenetic history of Ne, thus leading to a quantitative test of the nearly-neutral theory and an estimation of the allometric scaling of the ratios of non-synonymous over synonymous polymorphism (πN /πS) and divergence (dN/dS) with respect to Ne. As an illustration, we applied our method to primates, for which the nearly-neutral predictions were mostly verified. Under a purely nearly-neutral model with a constant DFE across species, we find that the variation in πN /πS and dN/dS as a function of Ne is too large to be compatible with current estimates of the DFE based on site frequency spectra. The reconstructed history of Ne shows a ten-fold variation across primates. The mutation rate per generation u, also reconstructed over the tree by the method, varies over a three-fold range and is negatively correlated with Ne. As a result of these opposing trends for Ne and u, variation in πS is intermediate, primarily driven by Ne but substantially influenced by u. Altogether, our integrative framework provides a quantitative assessment of the role of Ne and u in modulating patterns of genetic variation, while giving a synthetic picture of their history over the clade.

Significance statement

Natural selection tends to increase the frequency of mutants of higher fitness and to eliminate less fit genetic variants. However, chance events over the life of the individuals in the population are susceptible to introduce deviations from these trends, which are expected to have a stronger impact in smaller populations. In the long-term, these fluctuations, called random drift, can lead to the accumulation of mildly deleterious mutations in the genomes of living species, and for that reason, the effective population size (usually denoted Ne, and which captures the relative strength of drift, relative to selection) has been proposed as a major determinant of the evolution of genome architecture and content. A proper quantitative test of this hypothesis, however, is hampered by the fact that Ne is difficult to estimate in practice. Here, we propose a Bayesian integrative approach for reconstructing the broad-scale variation in Ne across an entire phylogeny, which in turns allows for quantifying how Ne correlates with life history traits and with various measures of genetic diversity and selection strength, between and within species. We apply this approach to the phylogeny of primates, and observe that selection is indeed less efficient in primates characterized by smaller effective population sizes.
A cost-efficient open source laser engine for microscopy
Authors: Schröder Daniel , Deschamps Joran , Dasgupta Anindita , Matti Ulf , Ries Jonas
Published: October 2019

Scientific-grade lasers are costly components of modern microscopes. For high-power applications, such as single-molecule localization microscopy, their price can become prohibitive. Here, we present an open-source high-power laser engine that can be built for a fraction of the cost. It uses affordable, yet powerful laser diodes at wavelengths of 405 nm, 488 nm and 640 nm and optionally a 561 nm diode-pumped solid-state laser. The light is delivered to the microscope via an agitated multimode fiber in order to suppress speckles. We provide the part lists, CAD files and detailed descriptions, allowing any research group to build their own laser engine.