bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of monensin source on in vitro rumen fermentation characteristics and performance of Bos indicus beef bulls offered a high-concentrate diet
Authors: Teixeira Daniel A A , Cappellozza Bruno I , Fernandes Juliano R , Nascimento Kaique S , Bonfim Lorena E L M , Lopes Catarina N , Ehrhardt Jorge A C , Peres José R , Harris Simon A , Simas José M C , Richardson Leo F
Published: October 2019

In Exp. 1, Brachiaria ruziziensis (11.1 % CP) was inoculated or not with two sources of monensin, resulting in three treatments: 1) no monensin inoculation (CONT), 2) 20 mg of monensin sodium-A/kg of DM (Elanco Animal Health; MON-A), and 3) 20 mg of monensin sodium-B/kg of DM (Shandong Qilu King-Phar Pharmaceutical Co. Ltd.; MON-B). Three rumen-fistulated Jersey steers were offered a cool-season forage-based diet and were used as the rumen inoculum donors. Volatile fatty acids concentrations were evaluated at 0, 6, 12, 24, 30, and 48 h after treatment inoculation. Overall, acetate and butyrate concentrations were reduced in MON-A vs. CONT (P ≤ 0.02), whereas both monensin products reduced Ac:Pr ratio vs. CONT (P ≤ 0.01); however, MON-A also (P = 0.05) reduced the Ac:Pr ratio vs. MON-B. A treatment × hour interaction was detected for rumen propionate concentration (P = 0.01), primarily because MON-A resulted in greater propionate than CONT and MON-B at 24 and 48 h (P ≤ 0.03), but no differences were observed between CONT vs. MON-B (P ≥ 0.27). In Exp. 2, 240 Nellore bulls (initial BW = 363.2 ± 40.9 kg) were ranked and blocked according to initial BW, and within blocks animals were allotted into pens (n = 10 pens/treatment). Pens were randomly assigned into one of three treatments: 1) corn-based diet with no monensin (CONT), 2) CONT plus 28 mg of MON-A/kg of DM, and 3) CONT plus 28 mg of MON-B/kg of DM. The CONT diet was composed of sugarcane bagasse, ground corn, DDGS, urea, and a mineral-vitamin mix. The experimental period lasted 106 d and was divided into a 21-d adaptation period and an 85-d finishing phase. During the adaptation phase, both monensin sources increased (P ≤ 0.01) BW change, ADG, and F:G, as well as reduced DMI variation (P = 0.02). When the entire experimental period was evaluated, no treatment effects were detected for final BW, DMI, and ADG (P ≥ 0.26). Nonetheless, DMI variation was reduced as monensin was included (P = 0.01) and only MON-A improved the efficiency by reducing F:G vs. CONT (P = 0.05) and biological efficiency vs. MON-B (P = 0.05). Additionally, carcass ADG tended (P = 0.10) to be greater for MON-A vs. MON-B, whereas no other differences in the carcass characteristics were observed (P ≥ 0.53). In summary, the source of monensin inoculated in vitro and offered to Nellore bulls during the feedlot phase significantly affected the energetic efficiency and the performance of the animals.
A novel 3'‐tRNAGlu‐derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin
Authors: Falconi Maurizio , Giangrossi Mara , Zabaleta Maria Elexpuru , Wang Junbiao , Gambini Valentina , Tilio Martina , Bencardino Daniela , Occhipinti Sergio , Belletti Barbara , Laudadio Emiliano , Galeazzi Roberta , Marchini Cristina , Amici Augusto
Published: September 2019

tRNA‐derived fragments (tRFs) have been defined as a novel class of small noncoding RNAs. tRFs have been reported to be deregulated in cancer, but their biologic function remains to be fully understood. We have identified a new tRF (named tRF3E), derived from mature tRNAGlu, that is specifically expressed in healthy mammary glands but not in breast cancer (BC). Consistently, tRF3E levels significantly decrease in the blood of patients with epidermal growth factor receptor 2 (HER2)‐positive BC reflecting tumor status (control > early cancer > meta‐static cancer). tRF3E down‐regulation was recapitulated in Δ16HER2 transgenic mice, representing a BC preclinical model. Pulldown assays, used to search for proteins capable to selectively bind tRF3E, have shown that this tRF specifically interacts with nucleolin (NCL), an RNA‐binding protein overexpressed in BC and able to repress the translation of p53 mRNA. The binding properties of NCL‐tRF3E complex, predicted in silico and analyzed by EMSA assays, are congruent with a competitive displacement of p53 mRNA by tRF3E, leading to an increased p53 expression and consequently to a modulation of cancer cell growth. Here, we provide evidence that tRF3E plays an important role in the pathogenesis of BC displaying tumor‐suppressor functions through a NCL‐mediated mechanism.—Falconi, M., Giangrossi, M., Elexpuru Zabaleta, M., Wang, J., Gambini, V., Tilio, M., Bencardino, D., Occhipinti, S., Belletti, B., Laudadio, E., Galeazzi, R., Marchini, C., Amici, A. A novel 39‐tRNAGlu‐derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin. FASEB J. 33, 13228–13240 (2019). www.fasebj.org
Hypoxic niches are endowed with a protumorigenic mechanism that supersedes the protective function of PTEN
Authors: Nascimento‐Filho Carlos H. V. , Webber Liana P. , Borgato Gabriell B. , Goloni‐Bertollo Eny M. , Squarize Cristiane H. , Castilho Rogerio M.
Published: September 2019

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide and is characterized by a fast‐paced growth. Like other solid tumors, the HNSCC growth rate results in the development of hypoxic regions identified by the expression of hypoxia‐inducible factor 1α (HIF‐1α). Interestingly, clinical data have shown that pharmacological induction of intratumoral hypoxia caused an unexpected rise in tumor metastasis and the accumulation of cancer stem cells (CSCs). However, little is known on the molecular circuitries involved in the presence of intratumoral hypoxia and the augmented population of CSCs. Here we explore the impact of hypoxia on the behavior of HNSCC and define that the controlling function of phosphatase and tensin homolog (PTEN) over HIF‐1α expression and CSC accumulation are de‐regulated during hypoxic events. Our findings indicate that hypoxic niches are poised to accumulate CSCs in a molecular process driven by the loss of PTEN activity. Furthermore, our data suggest that targeted therapies aiming at the PTEN/PI3K signaling may constitute an effective strategy to counteract the development of intratumoral hypoxia and the accumulation of CSCs.—Nascimento‐Filho, C. H. V., Webber, L. P., Borgato, G. B., Goloni‐Bertollo, E. M., Squarize, C. H., Castilho, R. M. Hypoxic niches are endowed with a protumorigenic mechanism that supersedes the protective function of PTEN. FASEB J. 33, 13435–13449 (2019). www.fasebj.org
Ceruloplasmin deficiency does not induce macrophagic iron overload: lessons from a new rat model of hereditary aceruloplasminemia
Authors: Kenawi Moussa , Rouger Emmanuel , Island Marie‐Laure , Leroyer Patricia , Robin François , Rémy Séverine , Tesson Laurent , Anegon Ignacio , Nay Kévin , Derbré Frédéric , Brissot Pierre , Ropert Martine , Cavey Thibault , Loréal Olivier
Published: September 2019

Hereditary aceruloplasminemia (HA), related to mutations in the ceruloplasmin (Cp) gene, leads to iron accumulation. Ceruloplasmin ferroxidase activity being considered essential for macrophage iron release, macrophage iron overload is expected, but it is not found in hepatic and splenic macrophages in humans. Our objective was to get a better understanding of the mechanisms leading to iron excess in HA. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) knockout of the Cp gene was performed on Sprague‐Dawley rats. We evaluated the iron status in plasma, the expression of iron metabolism genes, and the status of other metals whose interactions with iron are increasingly recognized. In Cp–/– rats, plasma ceruloplasmin and ferroxidase activity were absent, together with decreased iron concentration and transferrin saturation. Similarly as in humans, the hepatocytes were iron overloaded conversely to hepatic and splenic macrophages. Despite a relative hepcidin deficiency in Cp–/– rats and the loss of ferroxidase activity, potentially expected to limit the interaction of iron with transferrin, no increase of plasma non‐transferrin‐bound iron level was found. Copper was decreased in the spleen, whereas manganese was increased in the plasma. These data suggest that the reported role of ceruloplasmin cannot fully explain the iron hepatosplenic phenotype in HA, encouraging the search for additional mechanisms.—Kenawi, M., Rouger, E., Island, M.‐L., Leroyer, P., Robin, F., Remy, S., Tesson, L., Anegon, I., Nay, K., Derbré, F., Brissot, P., Ropert, M., Cavey, T., Loréal, O. Ceruloplasmin deficiency does not induce macrophagic iron overload: lessons from a new rat model of hereditary aceruloplasminemia. FASEB J. 33, 13492–13502 (2019). www.fasebj.org
Maternal Education in Early Life and Risk of Metabolic Syndrome in Young Adult American Females and Males
Authors: Huang Jonathan Yinhao , Gariépy Geneviève , Gavin Amelia R. , Rowhani-Rahbar Ali , Siscovick David S. , Enquobahrie Daniel A.
Published: October 2019

Background:

Maternal education in a child’s early life may directly affect the child’s adult cardiometabolic health, but this is difficult to disentangle from biological, social, and behavioral life course processes that are associated with maternal education. These processes may also differ between males and females.

Methods:

Using data from the National Longitudinal Study of Adolescent to Adult Health (1995–2009) (N = 4,026 females and 3,192 males), we estimated sex-stratified associations between maternal attainment of less than high school (<HS), high school diploma (HS), or college degree (CD) at the respondent’s birth and respondent’s risk of metabolic syndrome (MetS); we used marginal structural models (MSM) to account for the influence of major life course risk factors, such as childhood maltreatment, adolescent overweight, adult education, household income, smoking, and physical activity, in mediating associations between maternal education and offspring MetS risk.

Results:

Each higher level of maternal education was associated with a 36% (Relative Risk = 0.64 [95% Confidence Interval (CI): 0.50-0.82]) reduced risk of MetS among females, but only 19% (RR = 0.81 [95% CI: 0.64-1.01]) reduction among males (P-value interaction < 0.05). Stronger inverse associations were also observed for waist circumference and glycated hemoglobin (HbA1c) among females compared with males (−5 cm vs. −2.4 cm and −1.5% vs. −1.0%, respectively).

Conclusion:

High maternal education in early life was associated with a lower risk of MetS in young adulthood even after accounting for life course risk factors, particularly among females. Results were robust to altered model specifications.
Diagnosis of infective endocarditis using echocardiography
Authors: Yuan Xin-chun , Liu Ming , Hu Jia , Zeng Xi , Zhou Ai-yun , Chen Li
Published: October 2019

The aim of this study was to evaluate the application of transthoracic echocardiography for the diagnosis of infective endocarditis (IE) to provide a basis for the better treatment of IE. From October 2016 to October 2018, 87 consecutive patients with IE at our hospital were selected for this study. All the patients were subjected to transthoracic echocardiography. The morphology, structure, activity, and closure of the patients’ heart valves were observed for vegetation identification, and the size, number, location, morphology, and echo intensity of vegetation, as well as degree of valve involvement, were determined.

The 87 patients investigated in this study included 38 cases of congenital heart disease, 27 cases of nonrheumatic valvular heart disease, 12 patients who underwent valve surgery, 5 cases of rheumatic valvular heart disease, and 5 patients with no obvious signs of heart disease. The most common clinical manifestations were heart murmur in 80 cases and fever in 60 cases. The most common complications were heart failure in 35 cases, followed by organ embolism in 12 cases. There were 36 cases of positive blood cultures, including 26 cases of Gram-positive cocci and 10 cases of Gram-negative bacilli. Echocardiography showed aortic valve involvement in 37 cases, mitral valve involvement in 34 cases, tricuspid valve involvement in 10 cases, pulmonary valve involvement in 2 cases, and the involvement of an artificial valve in 5 cases. Twenty-six of these cases showed multiple valve involvement, and 20 patients exhibited serious complications. No significant differences were found between echocardiography and actual surgical observations with respect to their accuracy in detecting the size, number, and location of vegetation in the 69 patients who underwent surgery (P > .05). Echocardiography could detect the occurrence of severe complications, namely, the rupture of chordae tendineae, valve prolapse, valve perforation, and paravalvular abscess, and no significant difference in diagnostic accuracy was found between echocardiography and surgical observations (P > .05).

Transthoracic echocardiography can rapidly and accurately detect IE vegetation and its complications and has important clinical value for guiding clinical treatment and determining prognosis.
The efficacy and safety of long-term add-on treatment of azithromycin in asthma
Authors: Wang Xiaohu , Luo Jian , Wang Dan , Liu Bicui , Liu Chuntao
Published: October 2019

Aim:

Effects of azithromycin on asthma reported in clinical trials are less consistent. We aimed to further clarify the efficacy and safety of azithromycin in treatment of asthma.

Methods:

The protocol registration number was CRD42017074318 (http://www.crd.york.ac.uk/Prospero). We searched PubMed, EMBASE, Cochrane databases, China National Knowledge Internet (CNKI), and Wanfang databases for the randomized controlled trials (RCTs) with prolonged treatment of azithromycin for more than 3 weeks. Random-effects or fixed-effects model was applied to calculate risk ratio (RR) and mean difference (MD) for dichotomous and continuous data respectively.

Results:

A total of eight studies were included for analysis. The pooled result of adjunctive azithromycin therapy in asthma showed a small, but statistically significant increase in forced expiratory volume in one second (FEV1) (MD = 0.06, 95% confidence interval [CI]: 0.01–0.12, P = .02), but no significant differences in exacerbation frequency (MD = −0.42, 95%CI: −1.13 to 0.30, P = .25) and peak expiratory flow (PEF) (MD = 0.20, 95% CI: −0.05 to 0.44, P = .12), fractional exhaled nitric oxide (FeNO) (MD = 4.12, 95% CI: −2.06 to 10.30, P = .19), asthma quality of life questionnaire (AQLQ) (MD: 0.05, 95% CI: −0.17 to 0.28, P = .65), asthma control questionnaire (ACQ) (MD: −0.03, 95% CI: −0.21 to 0.15, P = .75). The subgroup analysis revealed that azithromycin could decrease FeNO among Asian asthma (MD = 15.04, 95% CI: 6.18–23.90, P = .0009).

Conclusions:

Add-on therapy of azithromycin in asthma patients could improve the FEV1, but failed to improve asthma exacerbations, PEF, ACQ, AQLQ, and FeNO. Subgroup analysis indicated that azithromycin could improve FeNO in Asian group asthmatics.
Comparative evaluation of a website for drug incompatibility
Authors: Suzuki Shinya , Mochizuki Nobuo , Iwamoto Aya Ikeuchi , Yoshida Mikinori , Murakami Akio , Ikegawa Kiwako , Yamaguchi Masakazu , Vigneron Jean
Published: October 2019

Background:

This study was conducted to evaluate the benefit of Stabilis through a survey of the listings of incompatibility data.

Methods:

The review was performed in December 2014 to compare the number of incompatible drugs cited by the Stabilis website, “Injectable Drug Audit Manual, 4th edition” (AM) and “Handbook on Injectable Drugs, 17th edition” (ID). We used the data on incompatible drugs to compare each database. We selected 10 frequently used anticancer medicines to compare the drugs cited in Stabilis, AM and ID. In addition, we compared Stabilis and AM in 23 frequently used antibiotics as an additional evaluation.

Results:

Stabilis had 678 drugs including 456 injectable drugs, AM had 496 injectable drugs and ID had 332 injectable drugs, as of December 2014. Compared with the fact that most references in AM were unofficial data from manufacturers, Stabilis cited 1722 references and ID cited 2830 references. For the 10 selected anticancer drugs, the total number of listed drugs was 118 in Stabilis, compared to 51 in AM and 82 in ID. Overall, mean and median duplication rates were 4.5% and 0% in AM and 60.7% and 59.0% in ID, respectively. For the 23 selected antibiotics, the total number of listed drugs was 463 in Stabilis, compared to 238 in AM. Overall, mean and median duplication rates were 20.1% and 16.0% in Stabilis and 10.3% and 8.0% in AM, respectively.

Conclusions:

Stabilis offers a beneficial database for checking drug incompatibilities in a manner similar to ID.
Cortical RORβ is required for layer 4 transcriptional identity and barrel integrity
Authors: Clark Erin A. , Rutlin Michael , Capano Lucia , Aviles Samuel , Saadon Jordan R. , Taneja Praveen , Zhang Qiyu , Bullis James , Lauer Timothy , Myers Emma , Schulmann Anton , Forrest Douglas , Nelson Sacha
Published: September 2019

Retinoic Acid-Related Orphan Receptor Beta (RORβ) is a transcription factor (TF) and marker of layer 4 (L4) neurons, which are distinctive both in transcriptional identity and the ability to form aggregates such as barrels in rodent somatosensory cortex. However, the relationship between transcriptional identity and L4 cytoarchitecture is largely unknown. We find RORβ is required in the cortex for L4 aggregation into barrels and thalamocortical afferent (TCA) segregation. Interestingly, barrel organization also degrades with age. Loss of RORβ delays excitatory input and disrupts gene expression and chromatin accessibility, with downregulation of L4 and upregulation of L5 genes, suggesting a shift in cellular identity. Expression and binding site accessibility change for many other TFs, including closure of neurodevelopmental TF binding sites and increased expression and binding capacity of activity-regulated TFs. Lastly, a putative target of RORβ,Thsd7a, is downregulated without RORβ, andThsd7aknockout alone disrupts TCA organization in adult barrels.
GWAS-Flow: A GPU accelerated framework for efficient permutation based genome-wide association studies
Authors: Freudenthal Jan A. , Ankenbrand Markus J. , Grimm Dominik G. , Korte Arthur
Published: September 2019

Motivation

Genome-wide association studies (GWAS) are one of the most commonly used methods to detect associations between complex traits and genomic polymorphisms. As both genotyping and phenotyping of large populations has become easier, typical modern GWAS have to cope with massive amounts of data. Thus, the computational demand for these analyses grew remarkably during the last decades. This is especially true, if one wants to implement permutation-based significance thresholds, instead of using the naïve Bonferroni threshold. Permutation-based methods have the advantage to provide an adjusted multiple hypothesis correction threshold that takes the underlying phenotypic distribution into account and will thus remove the need to find the correct transformation for non Gaussian phenotypes. To enable efficient analyses of large datasets and the possibility to compute permutation-based significance thresholds, we used the machine learning framework TensorFlow to develop a linear mixed model (GWAS-Flow) that can make use of the available CPU or GPU infrastructure to decrease the time of the analyses especially for large datasets.

Results

We were able to show that our applicationGWAS-Flowoutperforms custom GWAS scripts in terms of speed without loosing accuracy. Apart from p-values,GWAS-Flowalso computes summary statistics, such as the effect size and its standard error for each individual marker. The CPU-based version is the default choice for small data, while the GPU-based version ofGWAS-Flowis especially suited for the analyses of big data.

Availability

GWAS-Flowis freely available on GitHub (https://github.com/Joyvalley/GWAS_Flow) and is released under the terms of the MIT-License.
Panmixia across elevation in thermally sensitive Andean dung beetles
Authors: Linck Ethan , Celi Jorge E. , Sheldon Kimberly S.
Published: September 2019

Janzen’s seasonality hypothesis predicts that organisms inhabiting environments with limited climatic variability will evolve a reduced thermal tolerance breadth compared with organisms experiencing greater climatic variability. In turn, narrow tolerance breadth may select against dispersal across strong temperature gradients, such as those found across elevation. This can result in narrow elevational ranges and generate a pattern of isolation-by-environment, or neutral genetic differentiation correlated with environmental variables that is independent of geographic distance. We tested for signatures of isolation-by-environment across elevation using genome-wide SNP data from five species of Andean dung beetles (subfamily Scarabaeinae) with well-characterized, narrow thermal physiologies and narrow elevational distributions. Contrary to our expectations, we found no evidence of population genetic structure associated with elevation and little signal of isolation- by-environment. Further, elevational ranges for four of five species appear to be at equilibrium and show no evidence of demographic constraints at range limits. Taken together, these results suggest physiological constraints on dispersal may primarily operate outside of a stable realized niche.

Abstract Figure
A Measure of Whole-Brain White Matter Topography
Authors: Wang Junyan , Shi Yonggang
Published: September 2019

The unprecedentedly high-quality large-scale brain imaging datasets, from such as the Human Connectome Project (HCP) and UK-Biobank, provide a unique opportunity for measuring the white matter topography of the human brain. By leveraging the multi-shell diffusion MRI data from the original young adult HCP, we systematically develop a reliable measure of the whole-brain white matter topography, and we coin ittopographic vector. As the main result, we find that the three most dominant dimensions of the topographic vectors strongly and linearly correlate with the coordinates of the corresponding streamlines of the whole-brain tractograms. Our results support the earlier prescient hypothesis that brain development follows a “base-plan” established by three (main) chemotactic gradients of early embryogenesis, and they implicate that the whole brain white matter tracts can be represented by vectors of a natural coordinate system.
Interfering with a memory without erasing its trace
Authors: Lange Gesa , Senden Mario , Radermacher Alexandra , De Weerd Peter
Published: September 2019

Previous research has shown that performance of a novice skill can be easily interfered with by subsequent training of another skill. We address the open questions whether extensively trained skills show the same vulnerability to interference as novice skills and which memory mechanism regulates interference between expert skills. We developed a recurrent neural network model of V1 able to learn from feedback experienced over the course of a long-term orientation discrimination experiment. After first exposing the model to one discrimination task for 3480 consecutive trials, we assessed how its performance was affected by subsequent training in a second, similar task. Training the second task strongly interfered with the first (highly trained) discrimination skill. The magnitude of interference depended on the relative amounts of training devoted to the different tasks. We used these and other model outcomes as predictions for a perceptual learning experiment in which human participants underwent the same training protocol as our model. Specifically, over the course of three months participants underwent baseline training in one orientation discrimination task for 15 sessions before being trained for 15 sessions on a similar task and finally undergoing another 15 sessions of training on the first task (to assess interference). Across all conditions, the pattern of interference observed empirically closely matched model predictions. According to our model, behavioral interference can be explained by antagonistic changes in neuronal tuning induced by the two tasks. Remarkably, this did not stem from erasing connections due to earlier learning but rather from a reweighting of lateral inhibition.
Safeguarding the genetic integrity of native pollinators requires stronger regulations on commercial lines
Authors: Bartomeus Ignasi , Molina Francisco P. , Hidalgo-Galiana Amparo , Ortego Joaquín
Published: September 2019

Every year more than one million commercial bumblebee colonies are deployed in greenhouses worldwide for its pollination services to several commercially important crops such as tomato and different species of berries. While commercial pollinators have been an enormous benefit for the production of essential food crops and for achieving higher yields and better fruit quality at a low cost, their use is emerging also as an important threat to wild pollinators. Commercial pollinators have been linked to pathogen spillover to wild species, and its introduction outside its native area have had devastating effects on native pollinator populations. However, a more pervasive, but underappreciated threat is their potential impact on the genetic integrity of native pollinators. Here, we show clear evidence of generalized hybridization between native and introduced commercial bumblebee lineages in southern Spain. The signal of genetic introgression is widespread and already expands up to 60 km from main commercial bumblebee release areas. As pollination services demand is predicted to increase in the coming years, only a more restrictive regulation of commercial lines could mitigate their negative impacts on the genetic integrity of native pollinators and prevent the disruption of local adaptations.
Human gut microbiota networks disturbance by parasites in indigenous communities: Effect on bacteria genera related to depression incidence subnetworks
Authors: Ramírez-Carrillo Elvia , Gaona Osiris , Nieto Javier , Sánchez-Quinto Andrés , Cerqueda-García Daniel , Falcon Luisa I. , Rojas-Ramos Olga , González-Santoyo Isaac
Published: September 2019

If you think you are in control of your behavior, think again. Evidence suggests that behavioral modifications, as development and persistence of depression, may be the consequence of a complex network of communication between macro (i.e. parasites) and micro-organisms capable of modifying the physiological axis of the host. Some parasites cause significant nutritional deficiencies for the host and impair the effectiveness of cognitive processes such as memory, teaching or non-verbal intelligence. Bacterial communities mediate the establishment of parasites and vice versa but this complexity approach remains little explored. We study the gut microbiota-parasite interactions using novel techniques of network analysis using data of individuals from two indigenous communities in the state of Guerrero, Mexico. Our results suggest that A. Lumbricoides, induce a gut microbiota perturbation affecting subnetworks of key species related to depression, consisting in the loss of network features such as path length, heterogeneity, number of nodes and neighbors; and especially by the loss of information emergence. Emergence is related with adaptability that has been linked to the concept of health as a critical balance between (adaptability) and self-organization (robustness). In this way, the loss of emergence means a depart from criticality and ultimately loss of health.
Rap-protein paralogs ofB. thuringiensis: a multifunctional and redundant regulatory repertoire for the control of collective functions
Authors: Gastélum Gabriela , de la Torre Mayra , Rocha Jorge
Published: September 2019

Quorum Sensing (QS) are mechanisms of synthesis and detection of signaling molecules to regulate gene expression and coordinate behaviors in bacterial populations. InBacillus subtilis(Bs), multiple paralog Rap-Phr QS systems (receptor-signaling peptide) are highly redundant and multifunctional, interconnecting the regulation of differentiation processes such as sporulation and competence. However, their functions in theB. cereusgroup are largely unknown. We evaluated the diversification of Rap-Phr systems in theB. cereusgroup as well as their functions, usingBacillus thuringiensisBt8741 as model. Bt8741 codes for eight Rap-Phr systems; these were overexpressed to study their participation in sporulation, biofilm formation, extracellular proteolytic activity and spreading. Our results show that five Rap-Phr systems (RapC, K, F, I and RapLike) inhibit sporulation, two of which (RapK and RapF) probably dephosphorylate of Spo0F from the Spo0A phosphorelay; these two Rap proteins also inhibit biofilm formation. Five systems (RapC, F, F2, I1 and RapLike) decrease extracellular proteolytic activity; finally, four systems (RapC, F1, F2 and RapLike) participate in spreading inhibition. Our bioinformatic analyses showed that Rap proteins from theB. cereusgroup diversified into five pherogroups, and we foresee that functions performed by Rap proteins of Bt8741 could also be carried out by Rap homologs in other species within the group. These results indicate that Rap-Phr systems constitute a highly multifunctional and redundant regulatory repertoire that enables bacteria from theB. cereusgroup to efficiently regulate collective functions during the bacterial life cycle, in the face of changing environments.

Importance

TheBacillus cereusgroup of bacteria includes species of high economic, clinical, biological warfare and biotechnological interest, e.g.B. anthracisin bioterrorism,B. cereusin food intoxications andB. thuringiensisin biocontrol. Knowledge on the ecology of these bacteria is hindered due to our limited understanding about the regulatory circuits that control differentiation and specialization processes. Here, we uncover the participation of eight Rap quorum-sensing receptors in collective functions ofB. thuringiensis. These proteins are highly multifunctional and redundant in their functions, linking ecologically relevant processes such as sporulation, biofilm formation, extracellular proteolytic activity, spreading, and probably other additional functions in species from theB. cereusgroup.
Exome sequencing of bulked segregants identified a novel TaMKK3-A allele linked to the wheat ERA8 ABA-hypersensitive germination phenotype
Authors: Martinez Shantel A. , Shorinola Oluwayesi , Conselman Samantha , See Deven , Skinner Daniel Z. , Uauy Cristobal , Steber Camille M.
Published: September 2019

Preharvest sprouting (PHS) is the germination of mature grain on the mother plant when it rains before harvest. The ENHANCED RESPONSE TO ABA8 (ERA8) mutant increases seed dormancy and, consequently, PHS tolerance in soft white wheat ‘Zak’. ERA8 was mapped to chromosome 4A in a Zak/‘ZakERA8’ backcross population using bulked segregant analysis of exome sequenced DNA (BSA-exome-seq). ERA8 was fine-mapped relative to mutagen-induced SNPs to a 4.6 Mb region containing 70 genes. In the backcross population, the ERA8 ABA hypersensitive phenotype was strongly linked to a missense mutation TaMKK3-A-G1093A (LOD 16.5), a gene associated with natural PHS tolerance in barley and wheat. The map position of ERA8 was confirmed in an ‘Otis’/ZakERA8 but not in a ‘Louise’/ZakERA8 mapping population. This is likely because Otis carries the same natural PHS susceptible MKK3-A-A660S allele as Zak, whereas Louise carries the PHS tolerant MKK3-A-C660R allele. Thus, the variation for grain dormancy and PHS tolerance in the Louise/ZakERA8 population likely resulted from segregation of other loci rather than segregation for PHS tolerance at the MKK3 locus. This inadvertent complementation test suggests that the MKK3-A-G1093A mutation causes the ERA8 phenotype. Moreover, MKK3 was a known ABA signaling gene in the 70-gene 4.6 Mb ERA8 interval. None of these 70 genes showed the differential regulation in wild-type Zak versus ERA8 expected of a promoter mutation. Thus, the working model is that the ERA8 phenotype results from the MKK3-A-G1093A mutation.

Key Message

Using bulked segregant analysis of exome sequence, we fine-mapped the ABA hypersensitive mutant ERA8 in a wheat backcross population to the TaMKK3-A locus of chromosome 4A.
Loss of cerebellar function selectively affects intrinsic rhythmicity of eupneic breathing
Authors: Liu Yu , Qi Shuhua , Thomas Fridtjof , Correia Brittany L. , Taylor Angela P. , Sillitoe Roy V. , Heck Detlef H.
Published: September 2019

Respiration is controlled by central pattern generating circuits in the brain stem, whose activity can be modulated by inputs from other brain areas to adapt respiration to autonomic and behavioral demands. The cerebellum is known to be part of the neuronal circuitry activated during respiratory challenges, such as hunger for air, but has not been found to be involved in the control of unobstructed breathing at rest (eupnea). Here we applied a measure of intrinsic rhythmicity, the CV2, which evaluates the similarity of subsequent intervals and is thus sensitive to changes in rhythmicity at the temporal resolution of individual respiratory intervals. The variability of intrinsic respiratory rhythmicity was reduced in a mouse model of cerebellar ataxia compared to their healthy littermates. Irrespective of that difference, the average respiratory rate and the average coefficient of variation (CV) were comparable between healthy and ataxic mice. We argue that these findings are consistent with a proposed role of the cerebellum in the coordination of respiration with other rhythmic orofacial movements, such as fluid licking and swallowing.
Analysis of spatiotemporal specificity of small RNAs regulating hPSC differentiation and beyond
Authors: Li Lu , Li Jin Feng , Cao Dan Dan , Papadopoulos Vassilios , Chan Wai Yee
Published: September 2019

We present a quantitative analysis of small RNA dynamics during the transition from hPSCs to the three germ layer lineages to identify spatiotemporal-specific small RNAs that may be involved in hPSC differentiation. To determine the degree of spatiotemporal specificity, we utilized two algorithms, namely normalized maximum timepoint specificity index (NMTSI) and across-tissue specificity index (ASI). NMTSI could identify spatiotemporal-specific small RNAs that go up or down at just one timepoint in a specific lineage. ASI could identify spatiotemporal-specific small RNAs that maintain high expression from intermediate timepoints to the terminal timepoint in a specific lineage. Beyond analyzing single small RNAs, we also quantified the spatiotemporal-specificity of microRNA families and observed their differential expression patterns in certain lineages. To clarify the regulatory effects of group miRNAs on cellular events during lineage differentiation, we performed a gene ontology (GO) analysis on the downstream targets of synergistically up-and downregulated microRNAs. To provide an integrated interface for researchers to access and browse our analysis results, we designed a web-based tool at https://keyminer.pythonanywhere.com/km/.
Architectural RNA is required for heterochromatin organization
Authors: Thakur Jitendra , Fang He , Llagas Trizia , Disteche Christine M. , Henikoff Steven
Published: September 2019

In addition to its known roles in protein synthesis and enzyme catalysis, RNA has been proposed to stabilize higher-order chromatin structure. To distinguish presumed architectural roles of RNA from other functions, we applied a ribonuclease digestion strategy to our CUT&RUN in situ chromatin profiling method (CUT&RUN.RNase). We find that depletion of RNA compromises association of the murine nucleolar protein Nucleophosmin with pericentric heterochromatin and alters the chromatin environment of CCCTC-binding factor (CTCF) bound regions. Strikingly, we find that RNA maintains the integrity of both constitutive (H3K9me3 marked) and facultative (H3K27me3 marked) heterochromatic regions as compact domains, but only moderately stabilizes euchromatin. To establish the specificity of heterochromatin stabilization by RNA, we performed CUT&RUN on cells deleted for the Firre long non-coding RNA and observed disruption of H3K27me3 domains on several chromosomes. We conclude that RNA maintains local and global chromatin organization by acting as a structural scaffold for heterochromatic domains.
A conserved regulatory switch controls phosphatase activity and specificity
Authors: Ho Kristin , Bradshaw Niels
Published: September 2019

Protein phosphatases must be regulated and specific for their substrates; how this control is achieved is critical for signaling by reversible phosphorylation. We recently reported the discovery of a regulatory switch that controls the activity of the PP2C family serine/threonine phosphatase SpoIIE from the bacterium Bacillus subtilis. This regulatory switch activates SpoIIE during spore development by forming the catalytically essential metal-binding site that is conserved across the PP2C family. We hypothesized that this switch is a conserved platform for regulating other PP2C phosphatases. An orthologous phosphatase from B. subtilis, RsbU, is activated under stress conditions and responds to different signals and acts on a different phosphoprotein substrate than SpoIIE. Using a combination of biochemical and genetic approaches, we find that broad features of the regulatory mechanism are conserved between SpoIIE and RsbU but that each phosphatase has adapted its response to be most appropriate for the distinct biological outputs it controls. In both cases, the switch accomplishes this by integrating substrate binding and recognition with regulatory inputs to control metal cofactor binding and catalysis. Thus, the switch is a conserved and mechanistically flexible regulatory platform that controls phosphatase activity and substrate specificity.
Pseudomonas aeruginosaleucine aminopeptidase influences early biofilm composition and structure via vesicle-associated anti-biofilm activity
Authors: Esoda Caitlin N. , Kuehn Meta J.
Published: September 2019

Pseudomonas aeruginosa, known as one of the leading causes of disease in cystic fibrosis (CF) patients, secretes a variety of proteases. These enzymes contribute significantly toP. aeruginosapathogenesis and biofilm formation in the chronic colonization of CF patient lungs, as well as playing a role in infections of the cornea, burn wounds and chronic wounds. We previously characterized a secretedP. aeruginosapeptidase, PaAP, that is highly expressed in chronic CF isolates. This leucine aminopeptidase is highly expressed during infection and in biofilms, and it associates with bacterial outer membrane vesicles (OMVs), structures known to contribute to virulence mechanisms in a variety of Gram-negative species and one of the major components of the biofilm matrix. We hypothesized that PaAP may play a role inP. aeruginosabiofilm formation. Using a lung epithelial cell/bacterial biofilm coculture model, we show that PaAP deletion in a clinicalP. aeruginosabackground alters biofilm microcolony composition to increase cellular density, while decreasing matrix polysaccharide content, and that OMVs from PaAP expressing strains but not PaAP alone or in combination with PaAP deletion strain-derived OMVs could complement this phenotype. We additionally found that OMVs from PaAP expressing strains could cause protease-mediated biofilm detachment, leading to changes in matrix and colony composition. Finally, we showed that the OMVs could also mediate the detachment of biofilms formed by both non-selfP. aeruginosastrains andKlebsiella pneumoniae, another respiratory pathogen. Our findings represent novel roles for OMVs and the aminopeptidase in the modulation ofP. aeruginosabiofilm architecture.

Importance

Biofilm formation by the bacterial pathogenP. aeruginosais known to contribute to drug- resistance in nosocomial infections and chronic lung infections of cystic fibrosis patients. In order to treat these infections more successfully, the mechanisms of bacterial biofilm development must be elucidated. While both bacterially-secreted aminopeptidase and outer membrane vesicles have been shown to be abundant inP. aeruginosabiofilm matrices, the contributions of each of these factors to the steps in biofilm generation have not been well studied. This work provides new insight as to how these bacterial components mediate the formation of a robust, drug-resistant extracellular matrix and implicates outer membrane vesicles as active components of biofilm architecture, expanding our overall understanding ofP. aeruginosabiofilm biology.
The APL1 immune factor is encoded by a single ancestral gene in mostAnophelesspecies and expanded to three paralogs with distinct function in theAnopheles gambiaecomplex
Authors: Mitri Christian , Bischoff Emmanuel , Eiglmeier Karin , Holm Inge , Dieme Constentin , Brito-Fravallo Emma , Raz Abbasali , Zakeri Sedigheh , Nejad Mahdokht I. K. , Djadid Navid D. , Vernick Kenneth D. , Riehle Michelle M.
Published: September 2019

Background

The recent reference genome assembly and annotation of the Asian malaria vectorAnopheles stephensirevealed only one gene encoding the leucine-rich repeat immune factor APL1, while inAnopheles gambiaeand siblingAnopheles coluzzii, APL1 factors are encoded by a family of three paralogs. The phylogeny and biological function of the unique APL1 gene inA. stephensihave not yet been specifically examined.

Methods

The APL1 locus was manually sequenced to confirm the computationally predicted single APL1 gene inA. stephensi, and APL1 evolution withinAnopheleswas explored by phylogenomic analysis. The single or paralogous APL1 genes were silenced inA. stephensiandA. coluzzii, respectively, followed by mosquito survival analysis, experimental infection withPlasmodium, and expression analysis.

Results

APL1 is present as a single ancestral gene in mostAnophelesincludingA. stephensi, but has expanded to three paralogs in an African lineage that includes only the Gambiae species complex andAnopheles christyi. Silencing of the unique APL1 copy inA. stephensiresults in significant mosquito mortality. Elevated mortality of APL1-depletedA. stephensiis rescued by antibiotic treatment, suggesting that bacteria are the cause of mortality, and that the unique APL1 gene is essential for host survival. SuccessfulPlasmodiumdevelopment inA. stephensidepends upon APL1 activity for protection from high host mortality, probably caused by exposure to enteric bacteria when parasites cross the midgut epithelial barrier. In contrast, silencing of all three APL1 paralogs inA. coluzziidoes not result in elevated mortality, either with or withoutPlasmodiuminfection. Expression of the single APL1 gene is regulated by both the Imd and Toll immune pathways, while control by the two pathways is subdivided to different paralogs in the expanded APL1 locus.

Conclusions

APL1 underwent neofunctionalization with both loss and gain of functions concomitant with expansion from a single ancestral gene to three paralogs in one lineage of AfricanAnopheles. The evolution of an expanded APL1 gene family could be a factor contributing to the exceptional levels of malaria transmission mediated by human-feeding members of the Gambiae complex in Africa.
Prominin-1-Radixin Axis controls hepatic gluconeogenesis by regulating PKA activity
Authors: Lee Hyun , Yu Dong-Min , Park Jun Sub , Lee Hwayeon , Kim Jun-Seok , Koo Seung-Hoi , Lee Jae-Seon , Lee Sungsoo , Ko Young-Gyu
Published: September 2019

Prominin-1 (Prom1) is a major cell surface marker of cancer stem cells, but its physiological functions in the liver have not been elucidated. We analyzed the levels of mRNA transcripts in serum-starved primary Prom1+/+ and Prom1-/- mouse hepatocytes using RNA-sequencing (RNA-seq) data, and found that CREB target genes were down-regulated. This initial observation led us to determine that the Prom1 deficiency inhibited cAMP response element binding protein (CREB) activation and gluconeogenesis, but not cyclic AMP (cAMP) accumulation, in glucagon-, epinephrine-, or forskolin-treated liver tissues and primary hepatocytes, and mitigated glucagon-induced hyperglycemia. Because Prom1 interacted with radixin, the Prom1 deficiency prevented radixin from localizing to the plasma membrane. Moreover, systemic adenoviral knockdown of radixin inhibited CREB activation and gluconeogenesis in glucagon-treated liver tissues and primary hepatocytes, and mitigated glucagon-elicited hyperglycemia. Based on these results, we conclude that Prom1 regulates hepatic PKA signaling via radixin functioning as an A kinase-anchored protein (AKAP).
Large-scale network analysis captures biological features of bacterial plasmids
Authors: Acman Mislav , van Dorp Lucy , Santini Joanne M. , Balloux Francois
Published: September 2019

Many bacteria can exchange genetic material through horizontal gene transfer (HGT) mediated by plasmids and plasmid-borne transposable elements. Here, we study the population structure and dynamics of over 10,000 bacterial plasmids, by quantifying their genetic similarities and reconstructing a network based on their shared k-mer content. We use a community detection algorithm to assign plasmids into cliques, which correlate with plasmid gene content, bacterial host range, GC content, and existing classifications based on replicon and mobility (MOB) types. Further analysis of plasmid population structure allows us to uncover candidates for yet undescribed replicon genes and to identify transposable elements as the main drivers of HGT at broad phylogenetic scales. Our work illustrates the potential of network-based analyses of the bacterial ‘mobilome’ and opens up the prospect of a natural, exhaustive classification framework for bacterial plasmids.
Clinical evaluation of postoperative analgesia and serum biochemical changes of paracetamol compared to meloxicam and carprofen in bitches undergoing ovariohysterectomy
Authors: Hernández-Avalos Ismael , Valverde Alexander , Ibancovichi-Camarillo José Antonio , Sánchez-Aparicio Pedro , Recillas-Morales Sergio , Osorio-Avalos Jorge , Rodríguez-Velázquez Desiderio , Miranda-Cortés Agatha Elisa
Published: September 2019

Background

In veterinary medicine, the administration of nonsteroidal anti-inflammatory analgesics (NSAIDs) for the control of postsurgical pain in dogs and cats is common given the anti-inflammatory, analgesic, and antipyretic effects of these drugs. This study compared the serum biochemical changes and postoperative analgesic effects of paracetamol, meloxicam, and carprofen in bitches submitted to an ovariohysterectomy using the Dynamic Interactive Visual Analog Scale (DIVAS) and Pain Scale of the University of Melbourne (UMPS) scoring systems.

Methods

Thirty bitches of different breeds underwent elective ovariohysterectomies and were randomly assigned to one of three treatment groups: a paracetamol group [15 mg kg-1intravenous (IV)], a carprofen group (4 mg kg-1IV), and a meloxicam group (0.2 mg kg-1IV). All treatments were administered 30 minutes prior to surgery. Paracetamol was administered every 8 hours postoperatively for 48 hours total, while carprofen and meloxicam were intravenously administered every 24 hours. An evaluation of post-surgical pain was done with the DIVAS and the UMPS. The first post-surgical pain measurement was performed 1 hour after surgery and then 2, 4, 6, 8, 12, 16, 20, 24, 36, and 48 hours after surgery.

Results

All groups exhibited a gradual reduction in pain throughout the postoperative period in both scales; however, neither scale significantly differed between the three treatment groups (P> 0.05) during the 48 postoperative hours.

Conclusions

Paracetamol was as effective as meloxicam and carprofen for post-surgical analgesia in bitches subjected to elective ovariohysterectomy. The present study demonstrates that paracetamol may be considered a tool for the effective treatment of acute perioperative pain in dogs. Furthermore, this drug led to no adverse reactions or changes in the parameters assessed in the present study, indicating its safety.