bluuebunny/crossref_metadata_2025 huggingface dataset:
Time‐to‐reach Target Calprotectin Level in Newly Diagnosed Patients With Inflammatory Bowel Disease
Authors: Haisma Sjoukje‐Marije , Verkade Henkjan J. , Scheenstra Rene , van der Doef Hubert P.J. , Bodewes Frank A.J.A. , van Rheenen Patrick F.
Published: July 2019

Objectives:

Treatment targets in inflammatory bowel disease (IBD) move away from controlling symptoms towards complete recovery of the intestinal mucosa. Currently, the most frequently used noninvasive surrogate marker of mucosal healing is a faecal calprotectin concentration in the target range. This study tested if there was a relation between time‐to‐reach target calprotectin and first flare.

Methods:

We prospectively included new‐onset IBD patients ages 17 and younger in a cloud‐based registry (FastForwardCare) and followed them for at least 52 weeks. They were treated according to Dutch national guidelines that advocate a step‐up approach. Time‐to‐reach target was defined as the first calprotectin measurement below 250 μg/g after the start of induction therapy. Time‐to‐first flare was the time from the first calprotectin measurement below 250 μg/g until reappearance of symptoms with calprotectin values above 250 μg/g.

Results:

We included 76 patients (luminal Crohn disease [CD] 43); ulcerative colitis [UC] 33). Median age at diagnosis was, respectively 14.5 and 14.1 years. Median time‐to‐reach target calprotectin was 37 weeks in CD and 11 weeks in UC patients (Log‐rank test, P = 0.001). Once the calprotectin target was reached, time‐to‐first flare was significantly longer in CD than in UC patients (Log‐rank test, P = 0.001). CD patients with time‐to‐reach target calprotectin ≤12 weeks after conventional induction therapy (ie, exclusive enteral nutrition or steroids) had a more favorable disease course in the first year than those with time‐to‐reach target calprotectin >12 weeks (Log‐rank test, P = 0.057). In UC patients, time‐to‐reach target calprotectin ≤12 weeks is not associated with a favorable disease course in the first year.

Conclusions:

The findings of this prospective registry suggest that a quick response to conventional therapy predicts a favorable disease course in new‐onset paediatric CD, but not in UC. The concept “time‐to‐reach target calprotectin level” rationalizes the indefinite term “response to treatment” and is well suited for studying treatment effectiveness in real‐world practices.
Cough, an unresolved problem in interstitial lung diseases
Authors: van Manen Mirjam J.G. , Wijsenbeek Marlies S.
Published: July 2019

Purpose of review

Many patients with interstitial lung diseases (ILDs), especially fibrotic ILDs, experience chronic cough. Cough has a major impact on wellbeing, affecting both physical and psychological aspects of life. The pathophysiology of cough in ILDs is poorly understood and currently no good antitussive therapy exists.

Recent findings

Research on cough in ILDs is increasing. A recent proof-of-concept study with nebulized sodium cromoglycate for patients with idiopathic pulmonary fibrosis (IPF)-related cough showed a promising effect on cough. Observational data suggest that antifibrotic pirfenidone might reduce cough in IPF. Studies on the effect of acid inhibition on cough in ILDs show contradicting results.

The first steps in analyzing new treatment options for chronic cough in patients with ILDs, especially in IPF, have been taken, but an effective treatment is still lacking.
Heterogeneity of Human Pancreatic Islet Isolation Around Europe: Results of a Survey Study
Authors: Nano Rita , Kerr-Conte Julie A. , Scholz Hanne , Engelse Marten , Karlsson Marie , Saudek Frantisek , Bosco Domenico , Antonioli Barbara , Bertuzzi Federico , Johnson Paul R.V. , Ludwing Barbara , Ling Zhidong , De Paep Diedert L. , Keymeulen Bart , Pattou François , Berney Thierry , Korsgren Olle , de Koning Eelco , Piemonti Lorenzo
Published: July 2019

Background.

Europe is currently the most active region in the field of pancreatic islet transplantation, and many of the leading groups are actually achieving similar good outcomes. Further collaborative advances in the field require the standardization of islet cell product isolation processes, and this work aimed to identify differences in the human pancreatic islet isolation processes within European countries.

Methods.

A web-based questionnaire about critical steps, including donor selection, pancreas processing, pancreas perfusion and digestion, islet counting and culture, islet quality evaluation, microbiological evaluation, and release criteria of the product, was completed by isolation facilities participating at the Ninth International European Pancreas and Islet Transplant Association (EPITA) Workshop on Islet-Beta Cell Replacement in Milan.

Results.

Eleven islet isolation facilities completed the questionnaire. The facilities reported 445 and 53 islet isolations per year over the last 3 years from deceased organ donors and pancreatectomized patients, respectively. This activity resulted in 120 and 40 infusions per year in allograft and autograft recipients, respectively. Differences among facilities emerged in donor selection (age, cold ischemia time, intensive care unit length, amylase concentration), pancreas procurement, isolation procedures (brand and concentration of collagenase, additive, maximum acceptable digestion time), quality evaluation, and release criteria for transplantation (glucose-stimulated insulin secretion tests, islet numbers, and purity). Moreover, even when a high concordance about the relevance of one parameter was evident, thresholds for the acceptance were different among facilities.

Conclusions.

The result highlighted the presence of a heterogeneity in the islet cell product process and product release criteria.
Empidine dance flies pollinate the woodland geranium as effectively as bees
Authors: Lefebvre Vincent , Daugeron Christophe , Villemant Claire , Fontaine Colin
Published: July 2019

Most flowering plants species rely on insects for pollination, a successful mutualism allowing them to reproduce over wide areas while flower-visitors are rewarded with food. This association is so conspicuous in the case of bees that other groups of potential pollinators, especially flies, have long been underestimated. However, visitors are not always pollinators. While the importance of flies in plant–visitor networks is now acknowledged, their pollination effectiveness has hardly been investigated. In this study, we assessed the pollination effectiveness ofGeranium sylvaticumflower-visitors using single-visit seed set experiments, in a subalpine meadow where flies are predominant. We found that: (i) empidine dance flies were the most frequent visitors ofG. sylvaticum; (ii) a single-visit by an empidine dance fly produced the same average number of seeds as a visit by a bee; (iii) large pollinators were more efficient than small pollinators irrespective of their identity. As a conclusion, large empidines were the main pollinators ofG. sylvaticum. Considering the high diversity and abundance of flower-visiting fly species, such results showing their ability to be as effective pollinators as bees should encourage further studies to develop a better understanding on their role in plant–pollinator networks.
The evolution of lying in well-mixed populations
Authors: Capraro Valerio , Perc Matjaž , Vilone Daniele
Published: July 2019

Lies can have profoundly negative consequences for individuals, groups and even for societies. Understanding how lying evolves and when it proliferates is therefore of significant importance for our personal and societal well-being. To that effect, we here study the sender–receiver game in well-mixed populations with methods of statistical physics. We use the Monte Carlo method to determine the stationary frequencies of liars and believers for four different lie types. We consider altruistic white lies that favour the receiver at a cost to the sender, black lies that favour the sender at a cost to the receiver, spiteful lies that harm both the sender and the receiver, and Pareto white lies that favour both the sender and the receiver. We find that spiteful lies give rise to trivial behaviour, where senders quickly learn that their best strategy is to send a truthful message, while receivers likewise quickly learn that their best strategy is to believe the sender’s message. For altruistic white lies and black lies, we find that most senders lie while most receivers do not believe the sender’s message, but the exact frequencies of liars and non-believers depend significantly on the payoffs, and they also evolve non-monotonically before reaching the stationary state. Lastly, for Pareto white lies we observe the most complex dynamics, with the possibility of both lying and believing evolving with all frequencies between 0 and 1 in dependence on the payoffs. We discuss the implications of these results for moral behaviour in human experiments.
Neurocognitive free will
Authors: Hills Thomas T.
Published: July 2019

Free will is an apparent paradox because it requires a historical identity to escape its history in a self-guided fashion. Philosophers have itemized design features necessary for this escape, scaling from action to agency and vice versa. These can be organized into a coherent framework that neurocognitive capacities provide and that form a basis for neurocognitive free will. These capacities include (1) adaptive access to unpredictability, (2) tuning of this unpredictability in the service of hierarchical goal structures, (3) goal-directed deliberation via search over internal cognitive representations, and (4) a role for conscious construction of the self in the generation and choice of alternatives. This frames free will as a process of generative self-construction, by which an iterative search process samples from experience in an adaptively exploratory fashion, allowing the agent to explore itself in the construction of alternative futures. This provides an explanation of how effortful conscious control modulates adaptive access to unpredictability and resolves one of free will's key conceptual problems: how randomness is used in the service of the will. The implications provide a contemporary neurocognitive grounding to compatibilist and libertarian positions on free will, and demonstrate how neurocognitive understanding can contribute to this debate by presenting free will as an interaction between our freedom and our will.
A weapons–testes trade-off in males is amplified in female traits
Authors: Miller Christine W. , Joseph Paul N. , Kilner Rebecca M. , Emberts Zachary
Published: July 2019

Sexually selected weapons are assumed to trade off with traits related to ejaculates, such as testes. However, remarkably little is known about what governs resource allocation and why trade-offs are found in some cases and not others. Often-used models depict competitive allocation occurring within the functional grouping of traits (e.g. reproduction); however, other factors including tissue expense and developmental timing may influence allocation. Experimental comparisons of investment across the sexes have the potential to illuminate allocation rules, because the sexes do not always use traits for the same functions. Here, we capitalize upon a species where females have weapons–testes homologues. We report that a documented trade-off in investment between hind-limb weapons and testes in leaf-footed cactus bugs,Narnia femorata, is even more pronounced in female hind limbs and ovaries. Female hind limbs in this species do not share the clear reproductive function of male hind limbs; therefore, this trade-off spans trait functional groups. Such patterns of investment suggest that future studies of reproductive trade-offs should consider factors such as tissue expense and developmental timing.
Morphological variation suggests that chitinozoans may be fossils of individual microorganisms rather than metazoan eggs
Authors: Liang Yan , Bernardo Joseph , Goldman Daniel , Nõlvak Jaak , Tang Peng , Wang Wenhui , Hints Olle
Published: July 2019

Chitinozoans are organic-walled microfossils widely recorded in Ordovician to Devonian (ca485–359 Mya) marine sediments and extensively used in high-resolution biostratigraphy. Their biological affinity remains unknown, but most commonly, they are interpreted as eggs of marine metazoans. Here, we provide new insights into their palaeobiology from three lines of inquiry. We examine morphological variation of a new, well-preserved Late Ordovician species,Hercochitina violana; analyse a compiled dataset of measurements on 378 species representing all known chitinozoan genera; and compare these data with the size variation of eggs of both extinct and extant aquatic invertebrates. The results indicate that the magnitude of size variation within chitinozoan species is larger than observed in fossil and modern eggs. Additionally, delicate morphological structures of chitinozoans, such as prosome and complex ornamentation, are inconsistent with the egg hypothesis. Distinct and continuous morphological variation inH.violanais more plausibly interpreted as an ontogenetic series of individual microorganisms, rather than as eggs.
Anti-diabetic effect of Ganjang and Doenjang in different aging periods
Authors: Yang Hye Jeong , Kim Min Jung , Hong Sang Pil
Published: July 2019

Fermented soybean-based foods such as ganjang and doenjang are familiar to Koreans. Current investigations have revealed that ganjang and doenjang impart antimutagenic, anticancer, and antiobesity effects. The aim of this study was to evaluate the antidiabetic activities of the commercialized soy foods, ganjang and doenjang, as a function of their aging period. The experimental groups were classified under four time periods- short (under 5 years), mid (under 10 years), long (under 15 years), and eternal (over 15 years). The antidiabetic effects of ganjang and doenjang were determined using the α-glucosidase inhibition assay and oral glucose tolerance test. Blood glucose levels were also analyzed after soy food treatment in normal mice model. The results showed that the antidiabetic activities, as determined using the α-glucosidase inhibition assay, increased significantly in the long period aging group for both ganjang and doenjang. Interestingly, the hyperglycemic effects showed aging period-dependent increase in the ganjang-treated group. In contrast, the doenjang-treated group showed significant differences only in long period aging group. Collectively, these results suggest that the traditional fermented soy foods have potential as dietary antidiabetic agents.
Isolation and identification of false positive and false negative strains on coliform dry rehydratable film
Authors: Lee Seo-Hyun , Mun Kwang-Ho , Kim Na-Ye-Seul , Kim Jung-Beom
Published: July 2019

The detection efficiency on dry rehydratable films and identification of false positive and false negative colonies to improve the detection accuracy of coliform dry rehydratable films were evaluated in this study. A total of 173 commercial spices and jeotgal were used in this study. The detection accuracy for coliform on 3M Petrifilm coliform count film was 97.9%, and false negative was 2.1% (nine strains). For Sanita-kun coliform count film, the detection accuracy was 97.3%, and false positive was 2.7% (six strains). The 3M Petrifilm coliform count film and Sanita-kun coliform count film showed similar detection accuracies. The biochemical identification of the false negative colonies on 3M Petrifilm coliform count film revealed the presence of Escherichia hermannii and Pantoea spp., which were included in the coliform group. The false positive colonies on Sanita-kun coliform count film were identified as Bacillus licheniformis, Bacillus rhizosphaerae, Bacillus clausi, Bacillus pumilus, and Bacillus safensis, which were gram positive and oxidase positive. In order to improve the detection accuracy for coliform, it is necessary to further incubate over 48 h to confirm the gas generation in 3M Petrifilm coliform count film. In Sanita-kun coliform count film, additional biochemical tests such as the gram stain and oxidase tests are necessary.
Nitrite scavenging activity and anti-inflammatory effects of standardized Cirsium setidens extract
Authors: Kwon Hee-Yeon , Choi Sun-Il , Cho Bong-Yeon , Choi Seung-Hyun , Sim Wan-Sup , Xionggao Han , Jang Gill-Woong , Lee Ok-Hwan
Published: July 2019

The purpose of this study was to determine nitrite scavenging activity and the anti-inflammatory effect of Cirsium setidens (C. setidens), which is perennial herb belonging to the Compositae family that is found mainly in Gangwon province, Korea. We studied nitrite scavenging ability, cell viability, nitric oxide production, and inflammatory-related gene expression in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Our results indicated that C. setidens extract increased the nitrite scavenging ability in a dose-dependent manner. In order to determine the cytotoxicity and the concentration range of C. setidens extract suitable for treating RAW 264.7 cells, the XTT assay was performed. C. setidens extract did not have any cytotoxic effect at contractions of 50, 100 and 200 μg/mL and the absorbance values were 103.30±9.61, 99,98±12.99 and 101.15±11.49%, respectively. Also, C. setidens extract decreased the nitric oxide production of RAW 264.7 cells in a dose-pendent manner. In order to determine whether C. setidens extract inhibits inflammation-related factors, such as COX-2, iNOS, IL-6 and TNF-α. In RAW 264.7 cells treated with C. setidens extract, COX-2, iNOS, IL-6 and TNF-α levels were decreased to 55, 84, 83 and 77%, respectively. Based on these results, C. setidens was revealed to have anti-inflammatory effect to be potentially material in functional food.
Predicting stimulus representations in the visual cortex using computational principles
Authors: Lage-Castellanos Agustin , De Martino Federico
Published: July 2019

In this report we present a method for predicting representational dissimilarity matrices (RDM). This method was used during the MIT challenge 2019. The method consists in combining perceptual and categorical RDMs with RDMs extracted from deep neural networks.
Functionally critical residues in the aminoglycoside resistance-associated methyltransferase RmtC play distinct roles in 30S substrate recognition
Authors: Nosrati Meisam , Dey Debayan , Mehrani Atousa , Strassler Sarah E. , Zelinskaya Natalia , Hoffer Eric D. , Stagg Scott M. , Dunham Christine M. , Conn Graeme L.
Published: July 2019

Methylation of the small ribosome subunit rRNA in the ribosomal decoding center results in exceptionally high-level aminoglycoside resistance in bacteria. Enzymes that methylate 16S rRNA on N7 of nucleotide G1405 (m7G1405) have been identified in both aminoglycoside-producing and clinically drug-resistant pathogenic bacteria. Using a fluorescence polarization 30S-binding assay and a new crystal structure of the methyltransferase RmtC at 3.14 Å resolution, here we report a structure-guided functional study of 30S substrate recognition by the aminoglycoside resistance–associated 16S rRNA (m7G1405) methyltransferases. We found that the binding site for these enzymes in the 30S subunit directly overlaps with that of a second family of aminoglycoside resistance–associated 16S rRNA (m1A1408) methyltransferases, suggesting both groups of enzymes may exploit the same conserved rRNA tertiary surface for docking to the 30S. Within RmtC, we defined an N-terminal domain surface, comprising basic residues from both the N1 and N2 subdomains, that directly contributes to 30S-binding affinity. In contrast, additional residues lining a contiguous adjacent surface on the C-terminal domain were critical for 16S rRNA modification, but did not directly contribute to the binding affinity. The results from our experiments define the critical features of m7G1405 methyltransferase–substrate recognition and distinguish at least two distinct, functionally critical contributions of the tested enzyme residues: 30S-binding affinity and stabilizing a binding-induced 16S rRNA conformation necessary for G1405 modification. Our study sets the scene for future high-resolution structural studies of the 30S–methyltransferase complex and for potential exploitation of unique aspects of substrate recognition in future therapeutic strategies.
Cross-species transcriptomic and epigenomic analysis reveals key regulators of injury response and neuronal regeneration in vertebrate retinas
Authors: Hoang Thanh , Wang Jie , Boyd Patrick , Wang Fang , Santiago Clayton , Jiang Lizhi , Lahne Manuela , Yoo Sooyeon , Todd Levi J. , Saez Cristian , Keuthan Casey , Palazzo Isabella , Squires Natalie , Campbell Warren A. , Jia Meng , Rajaii Fatemeh , Parayil Trisha , Trinh Vickie , Kim Dong Won , Wang Guohua , Ash John , Fischer Andy J. , Hyde David R. , Qian Jiang , Blackshaw Seth
Published: July 2019

Injury induces retinal Müller glia of cold-blooded, but not mammalian, vertebrates to regenerate neurons. To identify gene regulatory networks that control neuronal reprogramming in retinal glia, we comprehensively profiled injury-dependent changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick and mice using bulk RNA-Seq and ATAC-Seq, as well as single-cell RNA-Seq. Cross-species integrative analysis of these data, together with functional validation, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis and neurogenesis. In zebrafish and chick, transition from the resting state to gliosis is essential for initiation of retinal regeneration, while in mice a dedicated network suppresses neurogenic competence and restores quiescence. Selective disruption of NFI family transcription factors, which maintain and restore quiescence, enables Müller glia to proliferate and generate neurons in adult mice following retinal injury. These findings may aid in the design of cell-based therapies aimed at restoring retinal neurons lost to degenerative disease.

Summary sentence

This study identifies gene regulatory networks controlling proliferative and neurogenic competence in retinal Müller glia.
Genome wide analysis inDrosophilareveals diet by gene interactions and uncovers diet-responsive genes
Authors: Francis Deanne , Ghazanfar Shila , Havula Essi , Krycer James R. , Senior Alistair , Minard Annabel Y. , Geddes Thomas , Weiss Fiona , Stöckli Jacqueline , Yang Jean Y.H. , James David E.
Published: July 2019

Genetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an individual’s genotype. Here, we sought to understand how such gene-diet interactions influenced nutrient storage and utilisation, a major determinant of metabolic disease. We subjected the Drosophila Genetic Reference Panel (DGRP), comprising 200 genetically divergent inbred fly strains, to diets varying in sugar, fat and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilisation that can be robustly measured. Diet influenced the starvation resistance of each strain, but this effect varied markedly between strains. This demonstrates that genetics plays a major role in the response to diet. Furthermore, heritability analysis revealed that the greatest variability arose from diets either high in sugar or high in protein. To uncover the genetic underpinnings of this variation, we mapped 1,239 diet-responsive SNPs in 534 genes, 325 of which have human orthologues. Using whole-body knockdown, we confirmed that 30 candidate genes were required for glucose tolerance, storage and utilization. In particular, we characterised CG4607, a GLUT6/GLUT8 homolog, as a key protein involved in sugar tolerance. Overall, this provides strong evidence that genetics is a major contributor to how individuals respond to diets of varying nutrient composition. It is likely that a similar principle may be applied to metabolic disease in higher organisms thus supporting the case for nutrigenomics as an important health strategy.
Designing and validating a staircase to leverage floor mounted force plates
Authors: Hullfish Todd J. , Baxter Josh R.
Published: July 2019

Navigating stairs is a challenging task for many patient populations. Unfortunately, assessing lower extremity kinetics is not practical in many laboratories due in part to methodologic constraints. In this study, we designed, fabricated, and calibrated a staircase that accurately measured ground reaction forces applied to the second and fourth step. This implementation met several design criteria that included low-cost, ability to quickly move the staircase in and out of motion capture spaces, stable and safe staircase, and easily modifiable to meet the constraints of different lab layouts. We built the staircase as an outer and inner staircase assembly constructed using a modular aluminum framing system. Once positioned on our force plates that were embedded in the lab floor, we used an instrumented pole to apply known loads to a series of surface locations on the force plates and steps that were resting on top of the force plates. This calibration procedure reduced the center of pressure errors by approximately 50% for the embedded force plates and lower step (step 2) and 3-fold for the higher step (step 4). Next, we demonstrated that these steps can be integrated into a clinical gait analysis workflow. A single healthy-young adult navigated the stairs, the ground reaction forces were transformed into stair reaction forces, and these external loads were used to solve the inverse dynamics problem. This staircase provides other researchers with a new tool to assess stair navigation biomechanics. In this study, we provided the bill of materials, mechanical drawings, and calibration code necessary to modify and implement this staircase paradigm into other lab layouts.
Bifidobacteriumis enriched in gut microbiome of Kashmiri women with polycystic ovary syndrome
Authors: Hassan Saqib , Kaakinen Marika A , Draisma Harmen , Ganie Mohd Ashraf , Rashid Aafia , Balkhiyarova Zhanna , Kiran George Seghal , Vogazianos Paris , Shammas Christos , Selvin Joseph , Antoniades Athos , Demirkan Ayse , Prokopenko Inga
Published: July 2019

Polycystic ovary syndrome (PCOS) is a common endocrine condition in women of reproductive age understudied in non-European populations. In India, PCOS affects the life of up to 19.4 million women of age 14-25 years. Gut microbiome composition might contribute to PCOS susceptibility. We profiled the microbiome in DNA isolated from faecal samples by 16S rRNA sequencing in 19/20 women with/without PCOS from Kashmir, India. We assigned genera to sequenced species with an average 121k reads depth and included bacteria detected in at least 1/3 of the subjects or with average relative abundance ≥0.1%. We compared the relative abundances of 40/58 operational taxonomic units in family/genus level between cases and controls, and in relation to 33 hormonal and metabolic factors, by multivariate analyses adjusted for confounders, and corrected for multiple testing. Seven genera were significantly enriched in PCOS cases:Sarcina, AlkalibacteriumandMegasphaera, and previously reported for PCOSBifidobacterium, Collinsella, ParaprevotellaandLactobacillus. We identified significantly increased relative abundance ofBifidobacteriaceae(median 6.07% vs. 2.77%) andAerococcaceae(0.03% vs. 0.004%), whereas we detected lower relative abundancePeptococcaceae(0.16% vs. 0.25%) in PCOS cases. For the first time, we identified a significant direct association between butyrate producingEubacteriumand follicle-stimulating hormone levels. We observed increased relative abundance ofCollinsellaandParaprevotellawith higher fasting blood glucose levels, andParaprevotellaandAlkalibacteriumwith larger hip and waist circumference, and weight. We show a relationship between gut microbiome composition and PCOS linking it to specific reproductive health metabolic and hormonal predictors in Indian women.
Role and impact of the gut microbiota in aDrosophilamodel for parkinsonism
Authors: Feltzin Virzhiniya , Wan Kenneth H. , Celniker Susan E. , Bonini Nancy M.
Published: July 2019

Drosophilais poised to be a powerful model organism for studies of the gut-brain axis due to the relative simplicity of its microbiota, similarity to mammals, and efficient methods to rear germ-free flies. We examined the gut-brain axis inDrosophilamodels of autosomal recessive parkinsonism and discovered a relationship between the gut microbiota andparkinloss of function. The number of live bacteria was increased approximately five-fold in the gut of agedparkinnull animals. Conditional RNAi showed thatparkinis required in gut enterocytes and not in neurons or muscle to maintain microbial load homeostasis. To examine the significance of gut microbiota, we reared germ-freeparkinflies and discovered that removal of microbes in the gut improves the animals’ resistance to paraquat. Sequencing of 16S rDNA revealed microbial species with altered relative abundance inparkinnull flies compared to controls. These data reveal a role forparkinactivity in maintaining microbial composition and abundance in the gut, suggesting a relationship betweenparkinfunction and the gut microbiota, and deepening our understanding ofparkinand the impacts upon loss ofparkinfunction.
Social interaction with an alcohol-intoxicated or cocaine-injected peer selectively alters social behaviors and drinking in adolescent male and female rats
Authors: Gamble Danielle M. , Josefson Chloe C. , Hennessey Mary K. , Davis Ashley M. , Waters Renee C. , Jones Brooke N. , Belton Destiny M. , Hall Nzia I. , Costen Taylor J. , Kirstein Cheryl L. , Maldonado-Devincci Antoniette M.
Published: July 2019

Background

Drinking alcohol is facilitated by social interactions with peers, especially during adolescence. The importance of peer social influences during adolescence on alcohol and substance use have recently received more attention. We have shown that social interaction with an alcohol-intoxicated peer influences adolescent alcohol drinking differently in male and female rats using the demonstrator-observer paradigm. The present set of experiments analyzed the social interaction session to determine behaviors that influence alcohol drinking in adolescent male and female rats.

Methods

Specifically, in experiment one we determined which behaviors were altered during social interaction with an alcohol-intoxicated demonstrator and assessed changes in ethanol intake in adolescent observers. Experiment two examined changes in voluntary saccharin consumption to determine if social interaction with an alcohol-intoxicated demonstrator altered consumption of a palatable solution. In experiment three, we administered a low (5 mg/kg) or high (20 mg/kg) dose of cocaine to the demonstrator and assessed changes in the adolescent observers to determine if social interaction with a ‘drugged’ peer altered social behaviors and voluntary ethanol intake.

Results

We showed that social interaction with an alcohol-intoxicated demonstrator (1) decreased social play and increased social investigation and social contact in adolescent male and female observers, (2) did not alter non-social behaviors, (3) did not alter saccharin consumption and (4) increased voluntary ethanol intake in adolescent female but not male observers. When the peer was injected with cocaine (1) social play was dose-dependently decreased, (2) there were no changes in other social or non-social behaviors, and (3) voluntary ethanol intake in adolescent male and female observers was unaffected.

Conclusions

The present results are consistent and extend our previous work showing that social interaction with an alcohol-intoxicated peer selectively alters social behaviors and alcohol-drinking in adolescent rats. Females appear to be more sensitive to elevating effects of social interaction on voluntary ethanol consumption.
Alternative splicing of circadian clock genes correlates with temperature in field-grown sugarcane
Authors: Dantas Luíza L. B. , Calixto Cristiane P. G. , Dourado Maira M. , Carneiro Monalisa S. , Brown John W. S. , Hotta Carlos T.
Published: July 2019

Alternative Splicing (AS) is a mechanism that generates different mature transcripts from precursor mRNAs (pre-mRNAs) of the same gene. In plants, a wide range of physiological and metabolic events are related to AS, as well as fast responses to changes in temperature. AS is present in around 60% of intron-containing genes in Arabidopsis, 46% in rice and 38% in maize and it is widespread among the circadian clock genes. Little is known about how AS influences the circadian clock of C4 plants, like commercial sugarcane, a C4 crop with a complex hybrid genome. This work aims to test if the daily dynamics of AS forms of circadian clock genes are regulated by environmental factors, such as temperature, in the field. A systematic search for AS in five sugarcane clock genes, ScLHY, ScPRR37, ScPRR73, ScPRR95 and ScTOC1 using different organs of sugarcane sampled during winter, with 4 months old plants, and during summer, with 9 months old plants, revealed temperature- and organ-dependent expression of at least one alternatively spliced isoform in all genes. Expression of AS isoforms varied according to the season. Our results suggest that AS events in circadian clock genes are correlated with temperature.
Integrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism
Authors: Ramaswami Gokul , Won Hyejung , Gandal Michael J. , Haney Jillian , Wang Jerry C. , Wong Chloe C.Y. , Sun Wenjie , Prabhakar Shyam , Mill Jonathan , Geschwind Daniel H.
Published: July 2019

Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental disorder. Despite this heterogeneity, previous studies have shown patterns of molecular convergence in post-mortem brain tissue from autistic subjects. Here, we integrate genome-wide measures of mRNA expression, miRNA expression, DNA methylation, and histone acetylation from ASD and control brains to identify a convergent molecular subtype of ASD with shared dysregulation across both the epigenome and transcriptome. Focusing on this convergent subtype, we substantially expand the repertoire of differentially expressed genes in ASD and identify a component of upregulated immune processes that are associated with hypomethylation. We utilize eQTL and chromosome conformation datasets to link differentially acetylated regions with their cognate genes and identify an enrichment of ASD genetic risk variants in hyperacetylated noncoding regulatory regions linked to neuronal genes. These findings help elucidate how diverse genetic risk factors converge onto specific molecular processes in ASD.
Nek8445, a protein kinase required for microtubule regulation and cytokinesis inGiardia lamblia
Authors: Hennessey Kelly M. , Alas Germain C.M. , Rogiers Ilse , Li Renyu , Merritt Ethan A. , Paredez Alexander R.
Published: July 2019

Giardiahas 198 Nek kinases whereas humans have only 11.Giardiahas a complex microtubule cytoskeleton that includes eight flagella and several unique microtubule arrays that are utilized for parasite attachment and facilitation of rapid mitosis and cytokinesis. The need to regulate these structures may explain the parallel expansion of the number of Nek family kinases. Here we use live and fixed cell imaging to uncover the role of Nek8445 in regulatingGiardiacell division. We demonstrate that Nek8445 localization is cell cycle regulated and this kinase has a role in regulating overall microtubule organization. Nek8445 depletion results in short flagella, aberrant ventral disc organization, loss of the funis, defective axoneme exit and altered cell shape. The axoneme exit defect is specific to the caudal axonemes, which exit from the posterior of the cell, and this defect correlates with rounding of the cell posterior and loss of the funis. Our findings implicate a role for the funis in establishingGiardia’scell shape and guiding axoneme docking. On a broader scale our results support the emerging view that Nek family kinases have a general role in regulating microtubule organization.
Engineered Th17 cell differentiation using a photo-activatable immune modulator
Authors: Parasar Bibudha , Chang Pamela V.
Published: July 2019

T helper 17 (Th17) cells, an important subset of CD4+ T cells, help to eliminate extracellular infectious pathogens that have invaded our tissues. Despite the critical roles of Th17 cells in immunity, how the immune system regulates the production and maintenance of this cell type remains poorly understood. In particular, the plasticity of these cells, or their dynamic ability to trans-differentiate into other CD4+ T cell subsets, remains mostly uncharacterized. Here, we report a synthetic immunology approach using a photo-activatable immune modulator (PIM) to increase Th17 cell differentiation on demand with spatial and temporal precision to help elucidate this important and dynamic process. In this chemical strategy, we developed a latent agonist that, upon photochemical activation, releases a small-molecule ligand that targets the aryl hydrocarbon receptor (AhR) and ultimately induces Th17 cell differentiation. We used this chemical tool to control AhR activation with spatiotemporal precision within cells and to modulate Th17 cell differentiation on demand by using UV light illumination. We envision that this approach will enable an understanding of the dynamic functions and behaviors of Th17 cells in vivo during immune responses and in mouse models of inflammatory disease.
Age-dependent effects of reduced mTor signalling on life expectancy through distinct physiology
Authors: Simons Mirre J P , Hartshorne Laura , Trooster Suzan , Thomson Jessica , Tatar Marc
Published: July 2019

Research on the mechanisms of ageing has identified ways via which lifespan can be extended in model organisms, increasing the potential for translation of these findings to our own species. However, the large majority of research on animal models involves dietary, genetic or pharmacological treatments throughout life – limiting translational potential and ignoring age-dependent effects. Previously, we have suggested using demographic meta-analysis that reduced mTor signalling has the potential to instantly rejuvenate. We have now tested this prediction experimentally using large-scale demographic data (N > 10,000) combined with conditional knockdown of mTor in Drosophila melanogaster. Indeed, reduced mTor decreased mortality rate when applied during old age. Interestingly, we found that transient treatment during early adult life had long-lasting benefits. Age-dependent deep-RNAseq indicated that these effects arose from distinct physiology and implicate alternative splicing as a potential mechanism for the long-lasting benefits of transient mTor reduction. These findings suggest that reducing mTor short term or during old age could be used to combat ageing. In addition, our findings suggest that the results from experimental research on mTor signalling, and potentially other mechanisms of ageing, that employ life-long interventions are likely to be a complex composite of age-dependent effects that counteract or enhance each other.
Matrix-matched calibration curves for assessing analytical figures of merit in quantitative proteomics
Authors: Pino Lindsay K , Yang Han-Yin , Noble William Stafford , Searle Brian C , Hoofnagle Andrew N , MacCoss Michael J
Published: July 2019

Mass spectrometry is a powerful tool for quantifying protein abundance in complex samples. Advances in sample preparation and the development of data independent acquisition (DIA) mass spectrometry approaches have increased the number of peptides and proteins measured per sample. Here we present a series of experiments demonstrating how to assess whether a peptide measurement is quantitative by mass spectrometry. Our results demonstrate that increasing the number of detected peptides in a proteomics experiment does not necessarily result in increased numbers of peptides that can be measured quantitatively.
Modeling predicts that CRISPR-based activators, unlike CRISPR-based repressors, scale well with increasing gRNA competition and dCas9 bottlenecking
Authors: Clamons Samuel , Murray Richard
Published: July 2019

Synthetic transcriptional networks built from CRISPR-based repressors (CRISPRi) rely on shared use of a core dCas9 protein. In E. coli, CRISPRi cannot support more than about a dozen simultaneous gRNAs before the fold repression of any individual gRNA drops below 10x. We show with a simple model based on previous characterization of competition in CRISPRi that activation by CRISPR-based activators (CRISPRa) is much less sensitive to dCas9 bottle-necking than CRISPRi. We predict that E. coli should be able to support dozens to hundreds of CRISPRa gRNAs at >10-fold activation.
Musical expertise generalizes to superior temporal scaling in a Morse code tapping task
Authors: Slayton Matthew A. , Romero-Sosa Juan L. , Shore Katrina , Buonomano Dean V. , Viskontas Indre V.
Published: July 2019

A key feature of the brain’s ability to tell time and generate complex temporal patterns is its capacity to produce similar temporal patterns at different speeds. For example, humans can tie a shoe, type, or play an instrument at different speeds or tempi—a phenomenon referred to as temporal scaling. While it is well established that training improves timing precision and accuracy, it is not known whether expertise improves temporal scaling. We quantified temporal scaling and timing precision in musicians and non-musicians as they learned to tap a Morse code sequence. We found that controls improved significantly over the course of days of training at the standard speed. In contrast, musicians exhibited a high level of temporal precision on the first day, which did not improve significantly with training. Although there was no significant difference in performance at the end of training at the standard speed, musicians were significantly better at temporal scaling—i.e., at reproducing the learned Morse code pattern at faster and slower speeds. Interestingly, both musicians and non-musicians exhibited a Weber-speed effect, where absolute temporal precision sharpened when producing patterns at the faster speed. These results are the first to establish that the ability to generate the same motor patterns at different speeds improves with extensive training and generalizes to non-musical domains.
The Relationship between Resilient Mangroves and Fish Populations in the Largest Marine Reserve in Belize: A Case for Conservation
Authors: Osborne Chetwynd , Cho-Ricketts Leandra , Salazar Jané
Published: July 2019

Mangrove forests are one of the most bio-diverse and productive wetland environments on earth. However, these unique tropical forest environments that occupy coastal areas are among the most threatened habitats globally. Approximately one-third of the world’s mangrove forests in tropical and subtropical coastlines have been lost to logging, conversion of land for agriculture and mariculture, and degradation due to general pollution over the past 50 years. The large population of mangroves occupying the Turneffe Atoll area in Belize face growing anthropogenic threats such as permanent clearing of land for housing and infrastructural development as well as pollution and natural factors (climate change). Despite these threats, mangroves have high resilience due to their fast rates of microbial decomposition and nutrient flux, large storage of nutrients below-ground, numerous feedbacks, keystone species redundancy and self-design, and highly efficient biotic controls. Given the few formal studies done to evaluate mangrove resilience at Turneffe Atoll, the purpose of this study was to evaluate mangrove resilience and nursery functions in the Turneffe Atoll Marine Reserve. Mangrove fish abundance, forest structure, and prop root length was assessed by means of visual census and point centred quarter method (PCQM) for 11 sites that span across conservation and general use zones. This study found that resilient mangroves (lower vulnerability ranks, higher standing biomass, and higher fish biomass and abundance) exist in conservation and general use zones and warrant the need for improved mangrove conservation measures. Some conservation measures include: greater reduction of non-climate stressors, establishment of more mangrove conservation areas, and implementation of more outreach and educational programmes.
Cdc24, the source of active Cdc42, transiently interacts with septins to create a positive feedback between septin assembly and bud site formation in yeast cells
Authors: Chollet Julian , Dünkler Alexander , Bäuerle Anne , Vivero-Pol Laura , Gronemeyer Thomas , Johnsson Nils
Published: July 2019

Yeast cells select at the beginning of each cell cycle the position of their new bud. The recruitment of the septins to this prospective bud site (PBS) is one of the critical events in a complex assembly pathway that culminates in the outgrowth of a new daughter cell. The septin-rods follow hereby the high concentration of Cdc42GTPthat is generated by the focused location of its GEF Cdc24. We show that Cdc24 not only activates Cdc42 but temporarily interacts shortly before budding with Cdc11, the subunit that caps septin rods at its both ends. Mutations in Cdc24 that reduce the affinity to Cdc11 impair septin assembly and decrease the stability of the polarity patch. The interaction between septins and Cdc24 thus reinforces bud assembly at sites where septin structures are formed. Once the septins polymerize into the ring, Cdc24 transfers to its center and directs from there the further outgrowth of the membrane.
The role ofatoh1genes in the development of the lower rhombic lip during zebrafish hindbrain morphogenesis
Authors: Belzunce Ivan , Pujades Cristina
Published: July 2019

BACKGROUND

The Lower Rhombic Lip (LRL) is a transient neuroepithelial structure of the dorsal hindbrain, which expands from r2 to r7, and gives rise to deep nuclei of the brainstem, such as the vestibular and auditory nuclei and most posteriorly the precerebellar nuclei. Although there is information about the contribution of specific proneural-progenitor populations to specific deep nuclei, and the distinct rhombomeric contribution, little is known about how progenitor cells from the LRL behave during neurogenesis and how their transition into differentiation is regulated.

RESULTS

In this work, we investigated theatoh1gene regulatory network operating in the specification of LRL cells, and the kinetics of cell proliferation and behavior ofatoh1a-derivatives by using complementary strategies in the zebrafish embryo. We unveiled thatatoh1ais necessary and sufficient for specification of LRL cells by activatingatoh1b, which worked as a differentiation gene to transition progenitor cells towards neuron differentiation in a Notch-dependent manner. This cell state transition involved the release ofatoh1a-derivatives from the LRL:atoh1aprogenitors contributed first toatoh1bcells, which are committed non-proliferative precursors, and to thelhx2b-neuronal lineage as demonstrated by cell fate studies and functional analyses. Usingin vivocell lineage approaches we showed that the proliferative cell capacity, as well as their mode of division, relied on the position of theatoh1aprogenitors within the dorsoventral axis.

CONCLUSIONS

Our data demonstrates that the zebrafish provides an excellent model to study thein vivobehavior of distinct progenitor populations to the final neuronal differentiated pools, and to reveal the subfunctionalization of ortholog genes. Here, we unveil thatatoh1abehaves as the cell fate selector gene, whereasatoh1bfunctions as a neuronal differentiation gene, contributing to thelhx2bneuronal population.atoh1a-progenitor cell dynamics (cell proliferation, cell differentiation, and neuronal migration) relies on their position, demonstrating the challenges that progenitor cells face in computing positional information from a dynamic two-dimensional grid in order to generate the stereotyped neuronal structures in the embryonic hindbrain.