bluuebunny/crossref_metadata_2025 huggingface dataset:
Floor and ceiling effects of the World Health Organization Disability Assessment Schedule 2.0 among patients with chronic musculoskeletal pain
Authors: Katajapuu Niina , Laimi Katri , Heinonen Ari , Saltychev Mikhail
Published: February 2019

The aim of this study was to investigate the floor and ceiling effects of 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS). This was a cross-sectional survey study at a university’s physical and rehabilitation medicine outpatient clinic of 1988 patients with chronic musculoskeletal pain. Floor and ceiling effects were calculated as relative frequencies of the lowest or the highest possible scores for each item. The probit plotting method was used to detect the non-normality of distribution of the total score graphically. A significant floor effect of 15–79% was observed in all 12 WHODAS 2.0 items. A substantial floor effect for total score was also detected graphically. No ceiling effects were observed. In this study, a significant floor effect was found for all WHODAS 2.0 items among patients with chronic musculoskeletal pain associated with mild or no disability.
Health Departments' Experience With Mumps Outbreak Response and Use of a Third Dose of Measles, Mumps, and Rubella Vaccine
Authors: Marlow Mariel A. , Moore Kelly , DeBolt Chas , Patel Manisha , Marin Mona
Published: February 2019

Context:

During January 2016 to June 2017, US health departments (HDs) reported 150 mumps outbreaks. Most occurred among populations with high 2-dose measles, mumps, and rubella (MMR) vaccine coverage, prompting the Advisory Committee on Immunization Practices to examine the evidence for use of a third dose of MMR vaccine.

Objective:

To evaluate HD experiences with mumps outbreak control and use of a third MMR dose during outbreaks.

Design:

An online survey assessing mumps outbreak characteristics, outbreak response measures, challenges, and lessons learned from previous outbreaks was distributed to all 81 Council of State and Territorial Epidemiologists member HDs in August 2017.

Results:

Sixty-one (75%) HDs responded; 46 (75%) had experience with ≥1 mumps outbreak(s) during January 2016 to August 2017. Twenty (43%) HDs recommended a third or outbreak MMR dose during mumps outbreaks; of these, 19 completed the section on use of a third dose and 8 (40%) rated the intervention “somewhat effective” or better. Health departments that used a third/outbreak dose suggested implementing the recommendation early and to a targeted group. Forty-three (73%) HDs reported having a policy for excluding persons without presumptive immunity from outbreak settings; of these, 37 (86%) had some degree of legal authority to implement this policy. Exclusion compliance improved with the use of personalized notification letters, focus groups of excluded persons and the community, and standardized messaging. Other outbreak control measures included cohorting of exposed or susceptible persons, mobile vaccination clinics and home visits, contact monitoring via text messaging, and facilitating student isolation with meal delivery and excused class absences.

Conclusions:

Our study revealed heterogeneity across HDs' mumps outbreak responses but also identified common challenges that will inform future Centers for Disease Control and Prevention guidance. These results were considered in the October 2017 Advisory Committee on Immunization Practices recommendation for use of a third dose of MMR vaccine for persons at increased risk for mumps during an outbreak and in the development of Centers for Disease Control and Prevention guidance for HDs when applying the Advisory Committee on Immunization Practices recommendation.
Assessing Readability: Are Urogynecologic Patient Education Materials at an Appropriate Reading Level?
Authors: Haller Jasmine , Keller Zachary , Barr Susan , Hadden Kristie , Oliphant Sallie S.
Published: February 2019

Objective

The National Institutes of Health recommends readability of patient material not exceed sixth-grade level. Our aim was to determine readability of American Urogynecologic Society (AUGS) and International Urogynecological Association (IUGA) patient education documents.

Methods

Available English- and Spanish-language IUGA patient information leaflets and AUGS patient fact sheets were scored for grade reading level. Readability assessment was performed using Flesch-Kincaid, Simple Measure of Gobbledygook, and Fry graph formulas for English documents. For Spanish documents, Fernandez-Huerta and SOL readability formulas were utilized. Each document was assessed by a health literacy expert using standards of plain language best practices.

Results

We assessed 86 documents: 18 AUGS, 34 IUGA, and 34 IUGA Spanish documents. Readability combined scores for English AUGS documents ranged from 8th to 12th grade level equivalents, whereas English IUGA documents ranged from 7th to 13th. Combined average readability score for AUGS sheets was 9.9 ± 1.2 grade level equivalents versus 10.5 ± 1.3 for IUGA leaflets. The AUGS documents had lower grade level equivalents on all 3 readability scales. Spanish-language IUGA leaflets had an average readability score of 5.9 ± 0.6 grade level equivalents, with a range of fifth to seventh. Health literacy expert analysis found only 1 document met all the criteria for plain language best practice.

Conclusions

All assessed AUGS and IUGA patient information English documents had readability scores above National Institutes of Health–recommended reading level. Spanish IUGA documents were written at a lower reading level than their English counterparts. To best meet patient education needs, future materials development should emphasize readability and utilization of plain language best practices.
It sounds like an action potential: unification of electrical, chemical and mechanical aspects of acoustic pulses in lipids
Authors: Mussel Matan , Schneider Matthias F.
Published: February 2019

In an ongoing debate on the physical nature of the action potential (AP), one group adheres to the electrical model of Hodgkin and Huxley, while the other describes the AP as a nonlinear acoustic pulse propagating within an interface near a transition. However, despite remarkable similarities, acoustics remains a non-intuitive mechanism for APs for the following reason. While acoustic pulses are typically associated with the propagation of density, pressure and temperature variation, APs are most commonly measured electrically. Here, we show that this discrepancy is lifted upon considering the electrical and chemical aspects of the interface, in addition to its mechanical properties. Specifically, we demonstrate how electrical and pH aspects of acoustic pulses emerge from an idealized description of the lipid interface, which is based on classical physical principles and contains no fit parameters. The pulses that emerge from the model show similarities to APs not only in qualitative shape and scales (time, velocity and voltage), but also demonstrate saturation of amplitude and annihilation upon collision.
Early Prediction of Antigenic Transitions for Influenza A H3N2
Authors: Castro Lauren A , Bedford Trevor , Meyers Lauren Ancel
Published: March 2019

Influenza A/H3N2 is a rapidly evolving virus which experiences major antigenic transitions every two to eight years. Anticipating the timing and outcome of transitions is critical to developing effective seasonal influenza vaccines. Using simulations from a published phylodynamic model of influenza transmission, we identified indicators of future evolutionary success for an emerging antigenic cluster. The eventual fate of a new cluster depends on its initial epidemiological growth rate––which is a function of mutational load and population susceptibility to the cluster––along with the variance in growth rate across co-circulating viruses. Logistic regression can predict whether a cluster at 5% relative frequency will eventually succeed with ∼80% sensitivity, providing up to eight months advance warning. As a cluster expands, the predictions improve while the lead-time for vaccine development and other interventions decreases. By focusing surveillance efforts on estimating population-wide susceptibility to emerging viruses, we can better anticipate major antigenic transitions.
Association the 25(OH) vitamin D status with Upper Respiratory Tract Infections Morbidity in Water Sports Elite Athletes
Authors: Umarov Jamshid , Kerimov Fikrat , Toychiev Abdurakhim , Davis Nikolay , Osipova Svetlana
Published: March 2019

BACKGROUND

The aim of this study is to identify seasonal changes in total 25(OH) vitamin D (VD) concentrations and determine its influence on acute upper respiratory tract infection (URTI) morbidity among elite athletes engaged in water sports.

METHODS

The study was planned as a prospective, non-interventional, observational study. Study participants included 40 elite athletes and 30 control individuals. Serum levels of 25(OH) VD and TNF-α, IFN-γ, IL-4 and IL-6 were detected by ELISA technique. Morbidity and frequency of acute URTI in participants were determined by self-reported questionnaire during the year.

RESULTS

The predominance of VD insufficiency was found in both groups of elite athletes and in the control individuals. Prevalence of VD insufficiency/deficiency depends on the season, but independently on the season the highest values were observed among athletes. VD sufficiency was detected in 30% and 13.3% of the control individuals in August and February and only in 10% of swimmers in August. More than 3 episodes of URTI were detected only in the elite athletes in winter-spring. The elevated level of TNF-α, IL-4, IL-6 was detected in all athletes, but more expressed increase was observed in swimmers.

CONCLUSIONS

VD insufficiency is quite pronounced among elite athletes engaged in synchronized swimming and in swimmers. It is accompanied with a decrease of IFN-γ, increase of TNF-α, IL-4 and IL-6 level, and elevation of URTI morbidity. Seasonal monitoring and correction of the VD level for normalization of cytokine profile and decrease of URTI morbidity is definitely advised.
What Drives Symbiotic Calcium Signalling In Legumes? Insights And Challenges Of Imaging
Authors: Martins Teresa Vaz , Livina Valerie N.
Published: March 2019

We review the contribution of bioimaging in building a coherent understanding of Ca2+ signalling during legume-bacteria symbiosis. Currently, two different calcium signals are believed to control key steps of the symbiosis: a Ca2+ gradient at the tip of the legume root hair is involved in the development of an infection thread, while nuclear Ca2+ oscillations, the hallmark signal of this symbiosis, controls the formation of the root nodule, where bacteria fix nitrogen. Additionally, different Ca2+ spiking signatures have been associated with specific infection stages. Bioimaging is intrinsically a cross-disciplinary area that requires integration of image recording, processing and analysis. We use experimental examples to critically evaluate previously established conclusions and draw attention to challenges caused by the varying nature of the signal-to-noise ratio in live imaging. We hypothesise that nuclear Ca2+ spiking is a wide-range signal involving the entire root hair, and that Ca2+ signature may be related to cytoplasmic streaming.
Artificial Intelligence for Bioinformatics: Applications in Protein Folding Prediction
Authors: Staples Max , Chan Leong , Si Dong , Johnson Kasey , Whyte Connor , Cao Renzhi
Published: March 2019

AI recently shows great promise in the field of bioinformatics, such as protein structure prediction. The Critical Assessment of protein Structure Prediction (CASP) is a nationwide experiment that takes place biannually, which centered around analyzing the best current systems for predicting protein tertiary structures. In this paper, we research on available AI methods and features, and then explore novel methods based on reinforcement learning. Such method will have profound implications for R&D in bioinformatics and add an additional platform to the management of innovation in biotechnology.
Interplay between the human gut microbiome and host metabolism
Authors: Visconti Alessia , Le Roy Caroline I. , Rosa Fabio , Rossi Niccolo , Martin Tiphaine C. , Mohney Robert P. , Li Weizhong , Rinaldis Emanuele de , Bell Jordana T. , Venter J. Craig , Nelson Karen E. , Spector Tim D. , Falchi Mario
Published: February 2019

The human gut is inhabited by a complex and metabolically active microbial ecosystem regulating host health. While many studies have focused on the effect of individual microbial taxa, the metabolic potential of the entire gut microbial ecosystem has been largely under-explored. We characterised the gut microbiome of 1,004 twins via whole shotgun metagenomic sequencing (average 39M reads per sample). We observed greater similarity, across unrelated individuals, for functional metabolic pathways (82%) than for taxonomic composition (43%). We conducted a microbiota-wide association study linking both taxonomic information and microbial metabolic pathways with 673 blood and 713 faecal metabolites (Metabolon, Inc.). Metabolic pathways associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species-level results identified less than 3,000 associations, suggesting that coordinated action of multiple taxa is required to affect the metabolome. Finally, we estimated that the microbiome mediated a crosstalk between 71% of faecal and 15% of blood metabolites, highlighting six key species (unclassified Subdoligranulum spp., Faecalibacterium prausnitzii, Roseburia inulinivorans, Methanobrevibacter smithii, Eubacterium rectale, and Akkermansia muciniphila). Because of the large inter-person variability in microbiome composition, our results underline the importance of studying gut microbial metabolic pathways rather than focusing purely on taxonomy to find therapeutic and diagnostic targets.
Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair
Authors: Herberg S. , McDermott A. M. , Dang P. N. , Alt D. S. , Tang R. , Dawahare J. H. , Varghai D. , Shin J-Y. , McMillan A. , Dikina A. D. , He F. , Lee Y. , Cheng Y. , Umemori K. , Wong P.C. , Park H. , Boerckel J. D. , Alsberg E.
Published: February 2019

Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation and is directed by local morphogen signals and mechanical cues. Here, we aimed to mimic these developmental conditions for regeneration of large bone defects. We hypothesized that engineered human mesenchymal stem cell (hMSC) condensations with in situ presentation of transforming growth factor-β1 (TGF-β1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles would promote endochondral regeneration of critical-sized rat femoral bone defects in a manner dependent on the in vivo mechanical environment. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with dual BMP-2 + TGF-β1 fully restoring mechanical bone function by week 12. In vivo ambulatory mechanical loading, initiated at week 4 by delayed unlocking of compliant fixation plates, significantly enhanced the bone formation rate in the four weeks after load initiation in the dual morphogen group. In vitro, local presentation of either BMP-2 alone or BMP-2 + TGF-β1 initiated endochondral lineage commitment of mesenchymal condensations, inducing both chondrogenic and osteogenic gene expression through SMAD3 and SMAD5 signaling. In vivo, however, endochondral cartilage formation was evident only in the BMP-2 + TGF-β1 group and was enhanced by mechanical loading. The degree of bone formation was comparable to BMP-2 soaked on collagen but without the ectopic bone formation that limits the clinical efficacy of BMP-2/collagen. In contrast, mechanical loading had no effect on autograft-mediated repair. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.

One Sentence Summary

Mimicking aspects of the cellular, biochemical, and mechanical environment during early limb development, chondrogenically-primed human mesenchymal stem cell condensations promoted functional healing of critical-sized femoral defects via endochondral ossification, and healing rate and extent was a function of the in vivo mechanical environment.
The kinesin-like protein Pavarotti functions non-canonically to regulate actin dynamics
Authors: Nakamura Mitsutoshi , Verboon Jeffrey M. , Prentiss Clara L. , Parkhurst Susan M.
Published: February 2019

Pavarotti, the Drosophila MKLP1 ortholog, is a kinesin-like protein that with Tumbleweed (MgcRacGAP) works together as the centralspindlin complex. This complex is essential for cytokinesis where it helps to organize the contractile actomyosin ring at the equator of dividing cells by activating the RhoGEF Pebble. Actomyosin rings also function as the driving force during cell wound repair. We previously showed that Tumbleweed and Pebble are required for the cell wound repair process. Here, we show that Pavarotti also functions during wound repair and confirm that while Pavarotti, Tumbleweed, and Pebble are utilized during this cellular repair, it is not as the conserved centralspindlin complex. Surprisingly,in vitroandin vivowork show that the classically microtubule-associated Pavarotti binds directly to actin and has a non-canonical role directly regulating actin dynamics. We show that Pavarotti also works independently from Tumbleweed in several actin-related processes during the normal developmental process of oogenesis.
Crosstalk with the GAR-3 receptor contributes to feeding defects inCaenorhabditis elegans eat-2mutants
Authors: Kozlova Alena A. , Lotfi Michele , Okkema Peter G.
Published: February 2019

Precise signaling at the neuromuscular junction (NMJ) is essential for proper muscle contraction. In theC. eleganspharynx, acetylcholine (ACh) released from the MC and M4 motor neurons stimulates two different types of contractions in adjacent muscle cells, termed pumping and isthmus peristalsis. MC stimulates rapid pumping through the nicotinic ACh receptor EAT-2, which is tightly localized at the MC NMJ, andeat-2mutants exhibit a slow pump rate. Surprisingly, we found thateat-2mutants also hyperstimulated peristaltic contractions, and these are characterized by increased and prolonged Ca2+transients in the isthmus muscles. This hyperstimulation depends on crosstalk with the GAR-3 muscarinic acetylcholine receptor asgar-3mutation specifically suppressed the prolonged contraction and increased Ca2+observed ineat-2mutant peristalses. Similar GAR-3 dependent hyperstimulation was also observed in mutants lacking theace-3acetylcholinesterase, and we suggest that NMJ defects ineat-2andace-3mutants result in ACh stimulation of extrasynaptic GAR-3 receptors in isthmus muscles.gar-3mutation also suppressed slow larval growth and prolonged lifespan phenotypes that result from dietary restriction ineat-2mutants, indicating that crosstalk with the GAR-3 receptor has a long-term impact on feeding behavior andeat-2mutant phenotypes.

Article Summary

Acetylcholine stimulates different contractions in adjacent muscle cells in theC. eleganspharynx called pumping and peristalsis. The signaling mechanisms stimulating pumping have been characterized, but how these mechanisms affect peristalsis is unknown. Here we examined muscle contractions and Ca2+transients during peristalsis in wild-type animals and acetylcholine signaling mutants. Surprisingly we found that while mutants affecting theeat-2nicotinic acetylcholine receptor exhibited reduced pumping, they also hyperstimulated peristalses. This hyperstimulation depends on crosstalk with the GAR-3 muscarinic acetylcholine receptor in adjacent cells, and it contributes to the well-characterized dietary restriction and extended adult lifespan observed ineat-2mutants.
Association between development of early cortical activity on amplitude-integrated EEG and 5-years neurodevelopmental outcome in the preterm infant
Authors: Feldmann Maria , Rousson Valentin , Nguyen Thi Dao , Bernet Vera , Hagmann Cornelia , Latal Beatrice , Natalucci Giancarlo
Published: March 2019

Aim

To analyse the association between early aEEG and cognitive outcome at early school-age in very preterm infants.

Methods

Prospective cohort study including infants with gestational age (GA) <32.0 weeks, undergoing continuous aEEG recording during first 4 days of life. Semiquantitative and quantitative (maximum/minimum amplitude) measures were averaged over the recording period. Cognitive outcome was assessed with the Kaufman-Assessment Battery for Children at 5 years of age. Uni- and multivariate logistic regressions were calculated between aEEG parameters and normal cognitive outcome (IQ≥85).

Results

Among 118 monitored preterm children, 89 were assessed at median(IQR) corrected age of 68.6 months (65.5-71.2) [48% female, median(IQR) GA 29.9(28.2,30.9) weeks, mean(SD) birth weight 1235(363) grams]. Mean(SD) IQ was 97.8(12.7). IQ<85 occurred in 21.3 %, cerebral palsy was found in 3.4%. Despite univariate associations of total maturity scores, cycling subscores, background pattern and minimum aEEG amplitude with normal cognitive outcome none of the associations remained significant after adjustment for confounders. Socioeconomic status was identified as independent predictor of neurodevelopmental outcome.

Conclusion

In this cohort of very preterm infants, early short-term aEEG was not predictive of later cognitive outcome. Further research is needed to explore how aEEG could help to inform long-term prognosis in this population group.

Key notes

Preterm born infants are at high risk for neurodevelopmental impairment.

Early amplitude integrated electroencephalography characteristics are univariately associated with cognitive outcome at 5 years of age in preterm born children.

However, socioeconomic factors and neonatal morbidity were stronger predictors of long-term neurodevelopmental outcome than early aEEG measures.
Optimised FRET pairs and quantification approaches to detect the activation of Aurora kinase A at mitosis
Authors: Bertolin Giulia , Sizaire Florian , Déméautis Claire , Chapuis Catherine , Mérola Fabienne , Erard Marie , Tramier Marc
Published: February 2019

Genetically-encoded Förster’s Resonance Energy Transfer (FRET) biosensors are indispensable tools to sense the spatiotemporal dynamics of signal transduction pathways. Investigating the crosstalk between different signalling pathways is becoming increasingly important to follow cell development and fate programs. To this end, FRET biosensors must be optimised to monitor multiple biochemical activities simultaneously and in single cells. In addition, their sensitivity must be increased to follow their activation even when the abundance of the biosensor is low.

We describe here the development of a second generation of Aurora kinase A/AURKA biosensors. First, we adapt the original AURKA biosensor –GFP-AURKA-mCherry– to multiplex FRET by using dark acceptors as ShadowG or ShadowY. Then, we use the novel superYFP acceptor protein to measure FRET by 2-colour Fluorescence Cross-Correlation Spectroscopy, in cytosolic regions where the abundance of AURKA is extremely low and undetectable with the original AURKA biosensor.

These results pave the way to the use of FRET biosensors to follow AURKA activation in conjunction with substrate-based activity biosensors. In addition, they open up the possibility of tracking the activation of small pools of AURKA and its interaction with novel substrates, which would otherwise remain undetectable with classical biochemical approaches.
Axonemal doublet microtubules can split into two complete singlets in human sperm flagellum tips
Authors: Zabeo Davide , Croft Jacob T , Höög Johanna L
Published: February 2019

Motile flagella are crucial for human fertility and embryonic development. The distal tip of the flagellum is where growth and intra-flagellar transport are coordinated. In most, but not all, model organisms the distal tip includes a “singlet region”, where axonemal doublet microtubules terminate and only complete A-tubules extend as singlet microtubules to the tip. How a human flagellar tip is structured is unknown. Here, the flagellar tip structure of human spermatozoa was investigated by cryo-electron tomography, revealing the formation of two complete singlet microtubules from both the A-tubule and B-tubule of doublet microtubules. This different tip arrangement in human spermatozoa shows the need to investigate human flagella directly in order to understand their role in our health and disease.
Prototheca zopfiiGenotype II induces mitochondrial apoptosis in models of bovine mastitis
Authors: Shahid Muhammad , Cobo Eduardo R. , Chen Liben , Cavalcante Paloma A. , Barkema Herman W. , Gao Jian , Xu Siyu , Liu Yang , Knight Cameron G. , Kastelic John P. , Han Bo
Published: February 2019

Prototheca zopfiiis an alga increasingly isolated from bovine mastitis. Of the two genotypes ofP. zopfii(genotype I and II (GT-I and II)),P. zopfiiGT-II is the genotype associated with acute mastitis and decreased milk production by unknown mechanisms. The objective was to determine inflammatory and apoptotic roles ofP. zopfiiGT-II in cultured mammary epithelial cells (from cattle and mice) and murine macrophages and using a murine model of mastitis.Prototheca zopfiiGT-II (but not GT-I) invaded bovine and murine mammary epithelial cells (MECs) and induced apoptosis, as determined by the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay. ThisP. zopfiiGT-II driven apoptosis corresponded to mitochondrial pathways; mitochondrial transmembrane resistance (ΔΨm) was altered and modulation of mitochondrion-mediated apoptosis regulating genes changed (increased transcriptionalBax, cytochrome-c andApaf-1and downregulatedBcl-2), whereas caspase-9 and -3 expression increased. Apoptotic effects byP. zopfiiGT-II were more pronounced in macrophages compared to MECs. In a murine mammary infection model,P. zopfiiGT-II replicated in the mammary gland and caused severe inflammation with infiltration of macrophages and neutrophils and upregulation of pro-inflammatory genes (TNF-α,IL-1βandCxcl-1) and also apoptosis of epithelial cells. Thus, we concludedP. zopfiiGT-II is a mastitis-causing pathogen that triggers severe inflammation and also mitochondrial apoptosis.

Author summary

Bovine mastitis (inflammation of the udder) reduces milk production and quality, causing huge economic losses in the dairy industry worldwide. Although the algaPrototheca zopfiiis a major cause of mastitis in dairy cows, mechanisms by which it damages mammary tissues are not well known. Here, we used cell cultures and a mouse model of mastitis to determine howProtothecacaused inflammation and cell death in mammary tissues.Protothecainvaded mammary gland cells, from cattle and mice, as well as macrophages (white cells that take up and kill pathogens) and caused cell death by interfering with mitochondria. Furthermore,Protothecacauses severe inflammation and tissue damage when injected into the mammary glands of mice. Although there are two genotypes ofP. zopfii, only genotype II causes tissue damage, whereas gentotype I, common in farm environments, does not damage mammary tissues. SinceP. zopfiiis an alga and not a bacterium, antibiotic treatments, frequently used to treat mastitis in cattle, are not effective against this organism. Understanding howP. zopfiidamages mammary tissue and causes mastitis is important new knowledge to promote future development of evidence-based approaches to prevent and treat mammary gland infections with this organism.
A meta-analysis on the benefits and costs of hosting secondary endosymbionts in sap-sucking insects
Authors: Zytynska Sharon E. , Thighiouart Karim , Frago Enric
Published: March 2019

Herbivorous insects host various bacteria that help them to feed, grow, and survive. Sap-sucking insects, in particular, feed on a nutrient-poor resource and have evolved obligate symbioses with nutritional bacteria for survival. Additionally, sap-sucking insects have formed facultative associations with bacterial symbionts that are not essential for growth and survival but assumed to confer some benefits, such as resistance to natural enemies. Several recent reviews have highlighted the importance of these symbionts in understanding their hosts’ biology, but currently there is a lack of a quantitative and systematic analysis of the published evidences exploring whether the different endosymbionts are actually beneficial or not. In this meta-analysis we explored the potential costs and benefits associated with hosting facultative endosymbionts in sap-sucking insects. Our first result is that most of the empirical experimental data information is limited to a few species of aphid and one species of whiteflies. Through the meta-analysis we showed that hosting symbionts generally leads to costs through increased development time, reduced longevity, and reduced fecundity, and benefits via increased resistance to parasitic wasps in sap-sucking insects. However, the impact of these costs and benefits was strongly insect and symbiont species dependent. Many of the insects studied are agricultural pests, and understanding the impact of bacterial symbionts on their hosts across different environments can benefit sustainable management of greenhouses and agricultural land.
Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans
Authors: Martins D. A. , Mazibuko N. , Zelaya F. , Vasilakopoulou S. , Loveridge J. , Oates A. , Maltezos S. , Mehta M. , Wastling S. , Howard M. , McAlonan G. , Murphy D. , Williams S. C. R. , Fotopoulou A. , Schuschnig U. , Paloyelis Y.
Published: March 2019

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.
Harnessing patient-specific response dynamics to optimize evolutionary therapies for metastatic clear cell renal cell carcinoma – Learning to adapt
Authors: Sorribes I. C. , Basu A. , Brady R. , Enriquez-Navas P. M. , Feng X. , Kather J. N. , Nerlakanti N. , Stephens R. , Strobl M. , Tavassoly I. , Vitos N. , Lemanne D. , Manley B. , O’Farrelly C. , Enderling H.
Published: March 2019

Renal cell carcinoma (RCC) is one of the ten most common and lethal cancers in the United States. Tumor heterogeneity and development of resistance to treatment suggest that patient-specific evolutionary therapies may hold the key to better patients prognosis. Mathematical models are a powerful tool to help develop such strategies; however, they depend on reliable biomarker information. In this paper, we present a dynamic model of tumor-immune interactions, as well as the treatment effect on tumor cells and the tumor-immune environment. We hypothesize that the neutrophil-to-lymphocyte ratio (NLR) is a powerful biomarker that can be used to predict an individual patient’s response to treatment. Using randomly sampled virtual patients, we show that the model recapitulates patient outcomes from clinical trials in RCC. Finally, we use in silico patient data to recreate realistic tumor behaviors and simulate various treatment strategies to find optimal treatments for each virtual patient.
The complexity dividend: when sophisticated inference matters
Authors: Tavoni Gaia , Balasubramanian Vijay , Gold Joshua I.
Published: March 2019

Animals continuously infer latent properties of the world from noisy and changing observations. Complex approaches to this challenge such as Bayesian inference are accurate but cognitively demanding, requiring extensive working memory and adaptive learning. Simple strategies such as always using a prior bias or following the last observation are easy to implement but may be less accurate. What is the appropriate balance between complexity and accuracy? We construct a hierarchy of strategies that vary in complexity between these limits and find a power law of diminishing returns: increasing complexity gives progressively smaller gains in accuracy. Moreover, the rate at which the gain decrements depends systematically on the statistical uncertainty in the world, such that complex strategies do not provide substantial benefits over simple ones when uncertainty is too high or too low. In between, when the world is neither too predictable nor too unpredictable, there is a complexity dividend.
Synthetic Promoter Design in Escherichia coli based on Generative Adversarial Network
Authors: Wang Ye , Wang Haochen , Liu Liyang , Wang Xiaowo
Published: March 2019

Synthetic promoters are commonly applied elements in circuit design for fine-tuning the protein expression levels. Promoter engineering was mostly focused on the random mutation or combination of regulation elements such as transcription factor binding sites. However, the size of promoter sequence space is still overwhelming and better navigation method is required. On the other hand, the generative adversarial network (GAN) is known for its great ability to reduce the searching space by learning to generate new data on the similar manifold of original data. Here, we applied WGAN-GP model into de novo promoter sequence design to generate entirely new promoter sequences. In total, 83 of model-generated promoter sequences were tested in promoter activity screening by regulating the expression of sfGFP gene in Escherichia coli. As a result, 26 out of 83 newly designed promoters were found functional and successfully expressed with varying activities, with similarity score to natural promoters all less than 0.7. Moreover, 3 of them showed higher promoter strength than the wild type promoters and their highly expression mutants. The much higher successful rate and promoter activity with much lower similarity score in our model-designed novel promoters confirmed the effectiveness of promoter sequence learning. Our work provides insights into an area of navigation of novel functional promoter sequence space automatically, as well as speeding up evolution process of naturally existing promoters, indicating the potential ability for deep generative models to be applied into genetic element designing in the future.
Applying Citizen Science to Gene, Drug, Disease Relationship Extraction from Biomedical Abstracts
Authors: Tsueng Ginger , Nanis Max , Fouquier Jennifer T. , Mayers Michael , Good Benjamin M. , Su Andrew I
Published: March 2019

Biomedical literature is growing at a rate that outpaces our ability to harness the knowledge contained therein. In order to mine valuable inferences from the large volume of literature, many researchers have turned to information extraction algorithms to harvest information in biomedical texts. Information extraction is usually accomplished via a combination of manual expert curation and computational methods. Advances in computational methods usually depends on the generation of gold standards by a limited number of expert curators. This process can be time consuming and represents an area of biomedical research that is ripe for exploration with citizen science. Citizen scientists have been previously found to be willing and capable of performing named entity recognition of disease mentions in biomedical abstracts, but it was uncertain whether or not the same could be said of relationship extraction. Relationship extraction requires training on identifying named entities as well as a deeper understanding of how different entity types can relate to one another. Here, we used the web-based application Mark2Cure (https://mark2cure.org) to demonstrate that citizen scientists can perform relationship extraction and confirm the importance of accurate named entity recognition on this task. We also discuss opportunities for future improvement of this system, as well as the potential synergies between citizen science, manual biocuration, and natural language processing.
Estimation of neural network model parameters from local field potentials (LFPs)
Authors: Skaar Jan-Eirik W. , Stasik Alexander J. , Hagen Espen , Ness Torbjørn V. , Einevoll Gaute T.
Published: March 2019

Most modeling in systems neuroscience has beendescriptivewhere neural representations, that is, ‘receptive fields’, have been found by statistically correlating neural activity to sensory input. In the traditional physics approach to modelling, hypotheses are represented bymechanisticmodels based on the underlying building blocks of the system, and candidate models are validated by comparing with experiments. Until now validation of mechanistic cortical network models has been based on comparison with neuronal spikes, found from the high-frequency part of extracellular electrical potentials. In this computational study we investigated to what extent the low-frequency part of the signal, the local field potential (LFP), can be used to infer properties of the neuronal network. In particular, we asked the question whether the LFP can be used to accurately estimate synaptic connection weights in the underlying network. We considered the thoroughly analysed Brunel network comprising an excitatory and an inhibitory population of recurrently connected integrate-and-fire (LIF) neurons. This model exhibits a high diversity of spiking network dynamics depending on the values of only three synaptic weight parameters. The LFP generated by the network was computed using a hybrid scheme where spikes computed from the point-neuron network were replayed on biophysically detailed multicompartmental neurons. We assessed how accurately the three model parameters could be estimated from power spectra of stationary ‘background’ LFP signals by application of convolutional neural nets (CNNs). All network parameters could be very accurately estimated, suggesting that LFPs indeed can be used for network model validation.

Significance statement

Most of what we have learned about brain networksin vivohave come from the measurement of spikes (action potentials) recorded by extracellular electrodes. The low-frequency part of these signals, the local field potential (LFP), contains unique information about how dendrites in neuronal populations integrate synaptic inputs, but has so far played a lesser role. To investigate whether the LFP can be used to validate network models, we computed LFP signals for a recurrent network model (the Brunel network) for which the ground-truth parameters are known. By application of convolutional neural nets (CNNs) we found that the synaptic weights indeed could be accurately estimated from ‘background’ LFP signals, suggesting a future key role for LFP in development of network models.
Predicting nucleation sites in chemotaxing Dictyostelium discoideum
Authors: Asante-Asamani E.O. , Rawal Devarshi , Santiago Zully , Brazill Derrick , Loustau John
Published: March 2019

Blebs, pressure driven protrusions of the plasma membrane, facilitate the movement of cell such as the soil amoeba Dictyostelium discoideum in a three dimensional environment. The goal of the article is to develop a means to predict nucleation sites. We accomplish this through an energy functional that includes the influence of cell membrane geometry (membrane curvature and tension), membrane-cortex linking protein lengths as well as local pressure differentials. We apply the resulting functional to the parameterized microscopy images of chemotaxing Dictyostelium cells. By restricting the functional to the cell boundary influenced by the cyclic AMP (cAMP) chemo-attractant (the cell anterior), we find that the next nucleation site ranks high in the top 10 energy values. More specifically, if we look only at the boundary segment defined by the extent of the expected bleb, then 96.8% of the highest energy sites identify the nucleation.

Author summary

This work concerns the prediction of nucleation sites in the soil amoeba-like Dictyostelium discoideum. We define a real valued functional combining input from cortex and membrane geometry such as membrane curvature and tension, cortex to membrane separation and local pressure differences. We show that the functional may be used to predict the location of bleb nucleation. In the region influenced by the cAMP gradient (the cell anterior), the next blebbing site lies in the ten highest energy functional values 70% of the time. The correctness increases to 96.8% provided we restrict attention to the segment in the general location of the next bleb. We verify these claims through the observation of microscopy images. The images are sequential at 1.66 and 0.8 seconds per image. We first identify the earliest sign of the bleb. We then use several observational factors to identify the nucleation site and estimate the corresponding location in the prior image.
‘Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks
Authors: Selleri Licia , Zappavigna Vincenzo , Ferretti Elisabetta
Published: March 2019

Pbx genes encode transcription factors that belong to the TALE (three-amino-acid loop extension) superclass of homeodomain proteins. We have witnessed a surge in information about the roles of this gene family as leading actors in the transcriptional control of development. PBX proteins represent a clear example of how transcription factors can regulate developmental processes by combinatorial properties, acting within multimeric complexes to implement activation or repression of transcription depending on their interaction partners. Here, we revisit long-emphasized functions of PBX transcription factors as cofactors for HOX proteins, major architects of the body plan. We further discuss new knowledge on roles of PBX proteins in different developmental contexts as upstream regulators of Hox genes—as factors that interact with non-HOX proteins and can work independently of HOX—as well as potential pioneer factors. Committed to building a perfect body, PBX proteins govern regulatory networks that direct essential morphogenetic processes and organogenesis in vertebrate development. Perturbations of PBX-dependent networks can cause human congenital disease and cancer.
RNAi in Drosophila S2 Cells by dsRNA Soaking
Authors: Li Chengjian , Zamore Phillip D.
Published: March 2019

This is a simple method for inducing RNAi in Drosophila S2 cells by soaking the cells in medium containing dsRNAs. In comparison with transfection, soaking requires fewer procedures and avoids the cost of transfection reagents, making it the method of choice for high-throughput RNAi screening. Moreover, soaking avoids potential toxicity associated with transfection reagents. However, delivery of dsRNA to S2 cells by soaking is less efficient than transfection, and genes whose expression has proved difficult to repress using soaked dsRNA often can be suppressed by transfecting the dsRNA multiple times.
Phenomenological and numerical analysis of power evolution and bunching in single-pass X-ray FELs. Erratum
Authors: Zhukovsky K. , Kalitenko A.
Published: February 2019

A correction is made to the paper by Zhukovsky & Kalitenko (2019). [J. Synchrotron Rad.
26, 159–169].
Structure of mammalian plasma fetuin-B and its mechanism of selective metallopeptidase inhibition
Authors: Cuppari Anna , Körschgen Hagen , Fahrenkamp Dirk , Schmitz Carlo , Guevara Tibisay , Karmilin Konstantin , Kuske Michael , Olf Mario , Dietzel Eileen , Yiallouros Irene , de Sanctis Daniele , Goulas Theodoros , Weiskirchen Ralf , Jahnen-Dechent Willi , Floehr Julia , Stoecker Walter , Jovine Luca , Gomis-Rüth F. Xavier
Published: March 2019

Mammalian fetuin-A and fetuin-B are abundant serum proteins with pleiotropic functions. Fetuin-B is a highly selective and potent inhibitor of metallopeptidases (MPs) of the astacin family, which includes ovastacin in mammals. By inhibiting ovastacin, fetuin-B is essential for female fertility. The crystal structure of fetuin-B was determined unbound and in complex with archetypal astacin, and it was found that the inhibitor has tandem cystatin-type modules (CY1 and CY2). They are connected by an exposed linker with a rigid, disulfide-linked `CPDCP-trunk', and are followed by a C-terminal region (CTR) with little regular secondary structure. The CPDCP-trunk and a hairpin of CY2 form a bipartite wedge, which slots into the active-site cleft of the MP. These elements occupy the nonprimed and primed sides of the cleft, respectively, but spare the specificity pocket so that the inhibitor is not cleaved. The aspartate in the trunk blocks the catalytic zinc of astacin, while the CY2 hairpin binds through a QWVXGP motif. The CY1 module assists in structural integrity and the CTR is not involved in inhibition, as verified byin vitrostudies using a cohort of mutants and variants. Overall, the inhibition conforms to a novel `raised-elephant-trunk' mechanism for MPs, which is reminiscent of single-domain cystatins that target cysteine peptidases. Over 200 sequences from vertebrates have been annotated as fetuin-B, underpinning its ubiquity and physiological relevance; accordingly, sequences with conserved CPDCP- and QWVXGP-derived motifs have been found from mammals to cartilaginous fishes. Thus, the raised-elephant-trunk mechanism is likely to be generally valid for the inhibition of astacins by orthologs of fetuin-B.
Evaluation of the performance of classification algorithms for XFEL single-particle imaging data
Authors: Shi Yingchen , Yin Ke , Tai Xuecheng , DeMirci Hasan , Hosseinizadeh Ahmad , Hogue Brenda G. , Li Haoyuan , Ourmazd Abbas , Schwander Peter , Vartanyants Ivan A. , Yoon Chun Hong , Aquila Andrew , Liu Haiguang
Published: March 2019

Using X-ray free-electron lasers (XFELs), it is possible to determine three-dimensional structures of nanoscale particles using single-particle imaging methods. Classification algorithms are needed to sort out the single-particle diffraction patterns from the large amount of XFEL experimental data. However, different methods often yield inconsistent results. This study compared the performance of three classification algorithms: convolutional neural network, graph cut and diffusion map manifold embedding methods. The identified single-particle diffraction data of the PR772 virus particles were assembled in the three-dimensional Fourier space for real-space model reconstruction. The comparison showed that these three classification methods lead to different datasets and subsequently result in different electron density maps of the reconstructed models. Interestingly, the common dataset selected by these three methods improved the quality of the merged diffraction volume, as well as the resolutions of the reconstructed maps.