bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of paediatric burns in low- and middle-income countries: assessing capacity using the World Health Organization Surgical Assessment Tool
Authors: Thomson Imogen K , Iverson Katie R , Innocent Simeon H S , Kaseje Neema , Johnson Walter D
Published: July 2019

Background

Burns are a leading cause of global disease burden, with children in low- and middle-income countries (LMICs) disproportionately affected. Effective management improves outcomes; however, the availability of necessary resources in LMICs remains unclear. We evaluated surgical centres in LMICs using the WHO Surgical Assessment Tool (SAT) to identify opportunities to optimize paediatric burn care.

Methods

We reviewed WHO SAT database entries for 2010–2015. A total of 1121 facilities from 57 countries met the inclusion criteria: facilities with surgical capacity in LMICs operating on children. Human resources, equipment and infrastructure relevant to paediatric burn care were analysed by WHO Regional and World Bank Income Classifications and facility type.

Results

Facilities had an average of 147 beds and performed 485 paediatric operations annually. Discrepancies existed between procedures performed and resource availability; 86% of facilities performed acute burn care, but only 37% could consistently provide intravenous fluids. Many, particularly tertiary, centres performed contracture release and skin grafting (41%) and amputation (50%).

Conclusions

LMICs have limited resources to provide paediatric burn care but widely perform many interventions necessary to address the burden of burns. The SAT may not capture innovative and traditional approaches to burn care. There remains an opportunity to improve paediatric burn care globally.
Genetic correlations between growth performance and carcass traits of purebred and crossbred pigs raised in tropical and temperate climates1
Authors: Godinho Rodrigo M , Bergsma Rob , Silva Fabyano F , Sevillano Claudia A , Knol Egbert F , Komen Hans , Guimarães Simone Eliza F , Lopes Marcos S , Bastiaansen John W M
Published: July 2019

In pig breeding, selection commonly takes place in purebred (PB) pigs raised mainly in temperate climates (TEMP) under optimal environmental conditions in nucleus farms. However, pork production typically makes use of crossbred (CB) animals raised in nonstandardized commercial farms, which are located not only in TEMP regions but also in tropical and subtropical regions (TROP). Besides the differences in the genetic background of PB and CB, differences in climate conditions, and differences between nucleus and commercial farms can lower the genetic correlation between the performance of PB in the TEMP (PBTEMP) and CB in the TROP (CBTROP). Genetic correlations (rg) between the performance of PB and CB growing-finishing pigs in TROP and TEMP environments have not been reported yet, due to the scarcity of data in both CB and TROP. Therefore, the present study aimed 1) to verify the presence of genotype × environment interaction (G × E) and 2) to estimate the rg for carcass and growth performance traits when PB and 3-way CB pigs are raised in 2 different climatic environments (TROP and TEMP). Phenotypic records of 217,332 PB and 195,978 CB, representing 2 climatic environments: TROP (Brazil) and TEMP (Canada, France, and the Netherlands) were available for this study. The PB population consisted of 2 sire lines, and the CB population consisted of terminal 3-way cross progeny generated by crossing sires from one of the PB sire lines with commercially available 2-way maternal sow crosses. G × E appears to be present for average daily gain, protein deposition, and muscle depth given the rg estimates between PB in both environments (0.64 to 0.79). With the presence of G × E, phenotypes should be collected in TROP when the objective is to improve the performance of CB in the TROP. Also, based on the rg estimates between PBTEMP and CBTROP (0.22 to 0.25), and on the expected responses to selection, selecting based only on the performance of PBTEMP would give limited genetic progress in the CBTROP. The rg estimates between PBTROP and CBTROP are high (0.80 to 0.99), suggesting that combined crossbred–purebred selection schemes would probably not be necessary to increase genetic progress in CBTROP. However, the calculated responses to selection show that when the objective is the improvement of CBTROP, direct selection based on the performance of CBTROP has the potential to lead to the higher genetic progress compared with indirect selection on the performance of PBTROP.
Floral Visitation Can Enhance Fitness of Helicoverpa armigera (Lepidoptera: Noctuidae) Long-Distance Migrants
Authors: Zhou Yan , Zhao Shengyuan , Wang Menglun , Yu Wenhua , Wyckhuys Kris A G , Wu Kongming
Published: July 2019

Numerous insect species engage in seasonal, trans-latitudinal migration, in response to varying resource availability, climatic conditions and associated opportunities, to maximize fitness and reproductive success. For certain species, the interaction between migrant adults and individual host plants is well-studied under laboratory conditions, but scant knowledge exists on the nutritional ecology of wild (i.e., field-caught) moths. During 2017–2018, we trapped adults of the cotton bollworm Helicoverpa armigera (Hübner) along its migration pathway in northeastern China and used pollen grain analysis to assess its visitation of particular host plants. Next, we assessed life history effects of adult feeding on carbohydrate-rich resources, for migrant individuals. Pollen grain analysis revealed H. armigera visitation of 32 species from 28 families, with the largest carrier ratio for northward migrants. Evening primrose (Oenothera spp.) accounted for 48% of pollen grains, indicating a marked H. armigera feeding preference. Furthermore, feeding on sugar-rich foods benefited adult fitness, enhanced fecundity by 65–82% and increased flight distance by 38–55% as compared to unfed individuals. Also, the degree of enhancement of reproduction and flight performance following sugar feeding varied between different migratory cohorts. Our work combines (polymerase chain reaction [PCR]-assisted) palynology and laboratory-based life history trials to generate novel perspectives on the nutritional ecology of long-distance migratory insects. These findings can aid the development of population monitoring and ‘area-wide’ management strategies for a globally-important agricultural pest.
A Species of the Genus Eubulus (Coleoptera: Curculionidae): A New and More Destructive Cassava Pest in the Brazilian Cerrado
Authors: Oliveira Charles M , Vieira Eduardo A , Fialho Josefino F , Frizzas Marina R
Published: July 2019

In 2009, a new pest of cassava crops was observed in the Federal District (Brazil) and identified as Eubulus (Kirsch) sp. (Coleoptera: Curculionidae). The pest is currently distributed in the states of Goiás, Minas Gerais, Mato Grosso do Sul, and Paraná. The larvae consume roots, causing the tissue to rot and making it unfit for consumption. The damage can extend to 100% of the roots. Owing to the potential losses that this pest is capable of causing, studies are needed on its biology, ecology, and future management strategies aimed at minimizing the losses, allowing the continuity of cassava cultivation in Brazil. This study reports on the occurrence of the pest in Brazilian Cerrado, its distribution in Brazil, the symptoms of its infestation and estimates the damage caused.
A Reproductives Excluder for Subterranean Termites in Laboratory Experiments
Authors: Lee Sang-Bin , Chouvenc Thomas , Su Nan-Yao
Published: July 2019

As a social insect, termites have different castes and division of labor in a colony. Investigating the social behavior of subterranean termites is a challenge due to the cryptic nature and large colony size. Planar arenas are commonly used to study these termites under laboratory conditions, and have provided several advantages. However, there is no means to designate areas such as a royal chamber or central nest from foraging sites because reproductives can move freely across arenas. In this study, we examined the minimum passing size of different castes of Coptotermes formosanus Shiraki (Blattodea: Rhinotermitidae), in order to develop a reproductive excluder and correlated minimum passing size with head widths and heights. We found that workers and soldiers of C. formosanus were able to pass through a gap greater than or equal to 0.7 mm. Our results showed that there are significant differences in the head width and height based on castes and head height was more critical than head width to determine passing size. We further confirmed feasibilities of the reproductive excluders using incipient colonies of C. formosanus. Confining reproductives using the excluder in laboratory experiments will provide more chances to study the royal chamber and central nest independently of foraging sites.
Genome-Wide Association Study of Piscine Myocarditis Virus (PMCV) Resistance in Atlantic Salmon (Salmo salar)
Authors: Hillestad Borghild , Moghadam Hooman K
Published: July 2019

Cardiomyopathy syndrome is a severe, viral disease of Atlantic salmon that mostly affects farmed animals during their late production stage at sea. Caused by piscine myocarditis virus (PMCV), over the past few years outbreaks due to this disease have resulted in significant losses to the aquaculture industry. However, there is currently no vaccine that has proven effective against this virus. In this study, using a challenge model, we investigated the genetic variation for resistance to PMCV, by screening a large number of animals using a 55 K SNP array. In particular, we aimed to identify genetic markers that are tightly linked to higher disease resistance and can potentially be used in breeding programs. Using genomic information, we estimated a heritability of 0.51 ± 0.06, suggesting that resistance against this virus, to a great extent, is controlled by genetic factors. Through association analysis, we identified a significant quantitative trait locus (QTL) on chromosome 27, explaining approximately 57% of the total additive genetic variation. The region harboring this QTL contains various immune-related candidate genes, many of which have previously been shown to have a different expression profile between the naïve and infected animals. We also identified a suggestive association on chromosome 12, with the QTL linked markers located in 2 putatively immune-related genes. These results are of particular interest, as they can readily be implemented into breeding programs, can further assist in fine-mapping the causative mutations, and help in better understanding the biology of the disease and the immunological mechanisms underlying resistance against PMCV.
Is Language Necessary for the Social Transmission of Lithic Technology?
Authors: Shilton Dor
Published: July 2019

Recently, a growing number of studies have considered the role of language in the social transmission of tool-making skill during human evolution. In this article, I address this question in light of a new theory of language and its evolution, and review evidence from anthropology and experimental archaeology related to it. I argue that the specific function of language—the instruction of imagination—is not necessary for the social transmission of tool-making skill. Evidence from hunter-gatherer ethnographies suggests that social learning relies mainly on observation, participation, play, and experimentation. Ethnographies of traditional stone cultures likewise describe group activities with simple, context-bound interactions embedded in the here and now. Experiments comparing gestural and verbal teaching of tool-making skills also demonstrate that language is not necessary for that process. I conclude that there is no convincing evidence that language played an important role in the social transmission of lithic technology, although the possibility that linguistic instruction was involved as part of the social interactions accompanying tool-making cannot be excluded.
Municipal Government Form and Budget Outcomes: Political Responsiveness, Bureaucratic Insulation, and the Budgetary Solvency of Cities
Authors: Jimenez Benedict S
Published: July 2019

One of the fundamental questions in democratic governance is whether policies are best decided by elected officials or by appointed bureaucrat-experts. The study examines this issue in the context of how municipal government form influences government-wide budgetary solvency. Government form creates distinct incentives for executive action that shape budget outcomes. In mayor–council governments, the elected executive’s desire to be reelected increases responsiveness to voters’ preferences. Vote maximization incentivizes the adoption of policies that are popular among voters but can lead to budgetary imbalance. In contrast, the appointed executive in the council–manager form is interested in career advancement, which she achieves by building a reputation for leading a fiscally sound government. Insulated from the demands of voters, the manager can rely on expert knowledge and professional norms to choose policies that result in balanced budgets. Using data from audited financial reports for 655 mid-sized and large city governments in the United States from fiscal years 2006 to 2013, the econometric analysis shows that council–manager cities have stronger budgetary solvency compared with mayor–council cities.
Ibrexafungerp: A novel oral glucan synthase inhibitor
Authors: Davis M R , Donnelley M A , Thompson G R
Published: July 2019

Ibrexafungerp is a novel glucan synthase inhibitor currently undergoing phase II and phase III clinical trials. This compound has demonstrated in vitro activity against clinically important fungal pathogens including Candida spp. and Aspergillus spp. It is able to retain activity against many echinocandin-resistant strains of Candida due to differential avidity for the target site compared to echinocandins. In vivo animal models have demonstrated efficacy in murine models of invasive candidiasis, aspergillosis, and pneumocystis. Due to high bioavailability, it can be administered both orally and intravenously. A favorable drug interaction and tolerability profile is observed with this compound. This review summarizes existing data that have either been published or presented at international symposia.
The COMBS survey – I. Chemical origins of metal-poor stars in the Galactic bulge
Authors: Lucey Madeline , Hawkins Keith , Ness Melissa , Asplund Martin , Bensby Thomas , Casagrande Luca , Feltzing Sofia , Freeman Kenneth C , Kobayashi Chiaki , Marino Anna F
Published: July 2019

Chemistry and kinematic studies can determine the origins of stellar population across the Milky Way. The metallicity distribution function of the bulge indicates that it comprises multiple populations, the more metal-poor end of which is particularly poorly understood. It is currently unknown if metal-poor bulge stars ([Fe/H] <−1 dex) are part of the stellar halo in the inner most region, or a distinct bulge population or a combination of these. Cosmological simulations also indicate that the metal-poor bulge stars may be the oldest stars in the Galaxy. In this study, we successfully target metal-poor bulge stars selected using SkyMapper photometry. We determine the stellar parameters of 26 stars and their elemental abundances for 22 elements using R∼ 47 000 VLT/UVES spectra and contrast their elemental properties with that of other Galactic stellar populations. We find that the elemental abundances we derive for our metal-poor bulge stars have lower overall scatter than typically found in the halo. This indicates that these stars may be a distinct population confined to the bulge. If these stars are, alternatively, part of the innermost distribution of the halo, this indicates that the halo is more chemically homogeneous at small Galactic radii than at large radii. We also find two stars whose chemistry is consistent with second-generation globular cluster stars. This paper is the first part of the Chemical Origins of Metal-poor Bulge Stars (COMBS) survey that will chemodynamically characterize the metal-poor bulge population.
Fullerenes in the IC 348 star cluster of the Perseus Molecular Cloud
Authors: Iglesias-Groth S
Published: July 2019

We present the detection of fullerenes C60 and C70 in the star-forming region IC 348 of the Perseus molecular cloud. Mid-IR vibrational transitions of C60 and C70 in emission are found in Spitzer IRS spectra of individual stars (LRLL 1, 2, 58), in the averaged spectrum of three other cluster stars (LRLL 21, 31 and 67) and in spectra obtained at four interstellar locations distributed across the IC 348 region. Fullerene bands appear widely distributed in this region with higher strength in the lines-of-sight of stars at the core of the cluster. Emission features consistent with three most intense bands of the C$_{60}^+$ and with one of C$_{60}^-$ are also found in several spectra, and if ascribed to these ionized species it would imply ionization fractions at 20 and 10 %, respectively. The stars under consideration host protoplanetary disks, however the spatial resolution of the spectra is not sufficient to disentangle the presence of fullerenes in them. If fullerene abundances in the cloud were representative of IC 348 protoplanetary disks, C60, the most abundant of the two species, could host ∼ 0.1 % of the total available carbon in the disks. This should encourage dedicated searches in young disks with upcoming facilities as JWST. Fullerenes provide a reservoir of pentagonal and hexagonal carbon rings which could be important as building blocks of prebiotic molecules. Accretion of these robust molecules in early phases of planet formation may contribute to the formation of complex organic molecules in young planets.
Insight into primordial magnetic fields from 21-cm line observation with EDGES experiment
Authors: Minoda Teppei , Tashiro Hiroyuki , Takahashi Tomo
Published: July 2019

The recent observation of the 21-cm global absorption signal by EDGES suggests that the intergalactic medium (IGM) gas has been cooler than the cosmic microwave background during 15 ≲ z ≲ 20. This result can provide a strong constraint on heating sources for the IGM gas at these redshifts. In this paper we study the constraint on the primordial magnetic fields (PMFs) by the EDGES result. The PMFs can heat the IGM gas through their energy dissipation due to the magnetohydrodynamic effects. By numerically solving the thermal evolution of the IGM gas with the PMFs, we find that the EDGES result gives a stringent limit on the PMFs as B1 Mpc ≲ 10−10 G.
De Novo Mutation Rate Estimation in Wolves of Known Pedigree
Authors: Koch Evan M , Schweizer Rena M , Schweizer Teia M , Stahler Daniel R , Smith Douglas W , Wayne Robert K , Novembre John
Published: July 2019

Knowledge of mutation rates is crucial for calibrating population genetics models of demographic history in units of years. However, mutation rates remain challenging to estimate because of the need to identify extremely rare events. We estimated the nuclear mutation rate in wolves by identifying de novo mutations in a pedigree of seven wolves. Putative de novo mutations were discovered by whole-genome sequencing and were verified by Sanger sequencing of parents and offspring. Using stringent filters and an estimate of the false negative rate in the remaining observable genome, we obtain an estimate of ∼4.5 × 10−9 per base pair per generation and provide conservative bounds between 2.6 × 10−9 and 7.1 × 10−9. Although our estimate is consistent with recent mutation rate estimates from ancient DNA (4.0 × 10−9 and 3.0–4.5 × 10−9), it suggests a wider possible range. We also examined the consequences of our rate and the accompanying interval for dating several critical events in canid demographic history. For example, applying our full range of rates to coalescent models of dog and wolf demographic history implies a wide set of possible divergence times between the ancestral populations of dogs and extant Eurasian wolves (16,000–64,000 years ago) although our point estimate indicates a date between 25,000 and 33,000 years ago. Aside from one study in mice, ours provides the only direct mammalian mutation rate outside of primates and is likely to be vital to future investigations of mutation rate evolution.
Binding of eIF3 in complex with eIF5 and eIF1 to the 40S ribosomal subunit is accompanied by dramatic structural changes
Authors: Zeman Jakub , Itoh Yuzuru , Kukačka Zdeněk , Rosůlek Michal , Kavan Daniel , Kouba Tomáš , Jansen Myrte E , Mohammad Mahabub P , Novák Petr , Valášek Leoš S
Published: July 2019

eIF3 is a large multiprotein complex serving as an essential scaffold promoting binding of other eIFs to the 40S subunit, where it coordinates their actions during translation initiation. Perhaps due to a high degree of flexibility of multiple eIF3 subunits, a high-resolution structure of free eIF3 from any organism has never been solved. Employing genetics and biochemistry, we previously built a 2D interaction map of all five yeast eIF3 subunits. Here we further improved the previously reported in vitro reconstitution protocol of yeast eIF3, which we cross-linked and trypsin-digested to determine its overall shape in 3D by advanced mass-spectrometry. The obtained cross-links support our 2D subunit interaction map and reveal that eIF3 is tightly packed with its WD40 and RRM domains exposed. This contrasts with reported cryo-EM structures depicting eIF3 as a molecular embracer of the 40S subunit. Since the binding of eIF1 and eIF5 further fortified the compact architecture of eIF3, we suggest that its initial contact with the 40S solvent-exposed side makes eIF3 to open up and wrap around the 40S head with its extended arms. In addition, we mapped the position of eIF5 to the region below the P- and E-sites of the 40S subunit.
Peer Financial Distress and Individual Leverage
Authors: Kalda Ankit
Published: July 2019

Using health shocks to identify financial distress situations, I document that peer distress leads to a decline in individual leverage and debt on average. Individual leverage declines by 5.7% and remains deflated for at least five years following peer distress. This decline occurs as individuals borrow less on the intensive margin, pay higher fractions of their debt and save more while their income remains unchanged. As a result, individuals are less likely to default during the period following peer distress. The heterogeneity in responses highlight the role of changes in beliefs and preferences as the underlying mechanism. (JEL D10, D12, D14, D84, H31, R20)

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Assessment of the many faces of PsA: single and composite measures in PsA clinical trials
Authors: McGagh Dylan , Coates Laura C
Published: July 2019

PsA is a complex, heterogeneous disease that can place a large burden on patients’ psychological and physical well-being. The multifaceted nature of PsA poses a significant assessment challenge, both in randomized control trials and in clinical practice. In recent years, there has been much progress in the development of unidimensional and composite measures of disease activity, as well as of questionnaires that capture the patient’s perspective of the condition. Despite these advances, there remains uncertainty around which tools to implement within a research setting. This review aims to summarize the currently available clinical and patient-derived assessment tools, providing a practical and informative resource for the assessment of PsA. This review will also explore recent advancements in digital approaches to the assessment of rheumatological conditions. This will highlight the potential for digitalization in the assessment and monitoring of PsA, outlining innovative means of capturing disease activity and treatment response.
Implementing the Children Act: The Seychellois Family Tribunal and Child Maintenance Cases
Authors: Mujuzi Jamil Ddamulira
Published: July 2019

The Family Tribunal, the Tribunal, was established by section 77 of the Children Act with the mandate to, inter alia, ‘hear and determine matters relating to the care, custody, access or maintenance’. In the execution of its mandate, the Tribunal has applied the relevant sections of the Act which deal with the question of maintenance orders. In this article, the author read through 1020 files of the Tribunal (from 2014 to June 2019) to establish how it has understood and applied the relevant sections of the Act which are applicable to the maintenance of children. The author demonstrates that there are instances where the Tribunal has misunderstood the relevant sections of the Act which brings into question the validity of some of its orders. Decisions from the Tribunal are appealable to the Supreme Court. Where possible, the author refers to case law from the Supreme Court in which it has guided the Tribunal on the correct application of the Act. The author, based on the practice of the Tribunal, identifies some of the challenges the Tribunal has faced in implementing the relevant sections of the Act and suggests ways in which the Tribunal could implement the Act better or in which the Act may be amended to address those challenges.
Inapparent dengue virus infection among students in Mandalay, Myanmar
Authors: Kyaw Aung Kyaw , Ngwe Tun Mya Myat , Naing Shine Thura , Thida  , Htwe Thein Thein , Mar Tu Tu , Khaing Tin Moe , Aung Thidar , Aye Khin Saw , Thant Kyaw Zin , Morita Kouichi
Published: July 2019

Background

A school- and laboratory-based cross-sectional descriptive study was conducted to find out the burden of inapparent dengue virus (DENV) infection in Mandalay where DENV is endemic and there is circulation of all four DENV serotypes.

Methods

A total of 420 students who had no history of fever and visited the hospital within 6 months were recruited from three monastic schools. Serum samples were collected and the DENV genome was checked by conventional one-step RT-PCR and anti-DENV IgM and IgG antibodies were determined. Inapparent dengue (DEN) infection is defined as individuals who were either RT-PCR-positive or anti-DENV IgM-positive with no clinical manifestations or mild symptoms, and which are not linked to a visit to a healthcare provider.

Results

Among 420 students, 38 students (9.0%, 95% CI, 6.4 to 12.2) were confirmed as recent inapparent DEN infection. The DENV serotype-1 was detected in six students. Thirty-one out of 38 (81.6%) laboratory-confirmed inapparent DEN-infected students had primary infections and seven (18.4%) had secondary infections.

Conclusion

This study explored the prevalence of inapparent DEN infection rate in urban monastic schools in Mandalay and showed that the rate of primary infection among inapparent DENV-infected children was high.
Identification of drugs for leukaemia differentiation therapy by network pharmacology
Authors: Christodoulou Eleni G , Lee Lin Ming , Lee Kian Leong , Fung Tsz Kan , So Eric , Petretto Enrico , Ong S. Tiong , Rackham Owen JL
Published: July 2019

Acute leukaemias differ from their normal haematopoietic counterparts in their inability to differentiate. This phenomenon is thought to be the result of aberrant cellular reprogramming involving transcription factors (TFs). Here we leveraged on Mogrify, a network-based algorithm, to identify TFs and their gene regulatory networks that drive differentiation of the acute promyelocytic leukaemia (APL) cell line NB4 in response to ATRA (all-transretinoic acid). We further integrated the detected TF regulatory networks with the Connectivity Map (CMAP) repository and recovered small molecule drugs which induce similar transcriptional changes. Our method outperformed standard approaches, retrieving ATRA as the top hit. Of the other drug hits, dimaprit and mebendazole enhanced ATRA-mediated differentiation in both parental NB4 and ATRA-resistant NB4-MR2 cells. Thus, we provide proof-of-principle of our network-based computational platform for drug discovery and repositioning in leukaemia differentiation therapy, which can be extended to other dysregulated disease states.
Motor planning modulates neural activity patterns in early human auditory cortex
Authors: Gale Daniel J. , Areshenkoff Corson N. , Honda Claire , Johnsrude Ingrid S. , Flanagan J. Randall , Gallivan Jason P.
Published: July 2019

It is well established that movement planning recruits motor-related cortical brain areas in preparation for the forthcoming action. Given that an integral component to the control of action is the processing of sensory information throughout movement, we predicted that movement planning might also modulate early sensory cortical areas, readying them for sensory processing during the unfolding action. To test this hypothesis, we performed two human functional MRI studies involving separate delayed movement tasks and focused on pre-movement neural activity in early auditory cortex, given its direct connections to the motor system and evidence that it is modulated by motor cortex during movement in rodents. We show that effector-specific information (i.e., movements of the left vs. right hand in Experiment 1, and movements of the hand vs. eye in Experiment 2) can be decoded, well before movement, from neural activity in early auditory cortex. We find that this motor-related information is represented in a separate subregion of auditory cortex than sensory-related information and is present even when movements are cued visually instead of auditorily. These findings suggest that action planning, in addition to preparing the motor system for movement, involves selectively modulating primary sensory areas based on the intended action.
The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues
Authors: Muyas Francesc , Zapata Luis , Guigó Roderic , Ossowski Stephan
Published: July 2019

Background

Mosaic mutations acquired during early embryogenesis can lead to severe early-onset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few tissues and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues.

Results

Using RNA sequencing data from the Genotype-Tissue Expression (GTEx) cohort comprising 49 normal tissues and 570 individuals, we found that new-borns on average harbour 0.5 - 1 EMMs in the exome affecting multiple organs (1.3230 × 10−8 per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multi-individual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer.

Conclusion

In summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.
Area compressibility moduli of the monolayer leaflets of asymmetric bilayers from simulations
Authors: Nagle J. F.
Published: July 2019

Extraction from simulations of the area compressibility moduli of the monolayers in a bilayer is considered theoretically. A statistical mechanical derivation shows that the bilayer modulus is the sum of the two monolayer moduli, as is often supposed, but contrary to a recent study. Seemingly plausible assumptions regarding fluctuations are tested rigorously. Prospects for future research are discussed.

Significance

It is important to describe the properties of both leaflets of generally asymmetric Biomembranes. One such property is the area compressibility modulus. This MS rigorously establishes the fundamental theory that corrects a recent BJ paper. The theory is straightforward but substantial enough that it was not readily apparent why the previous theory was incorrect. This is why this MS should be considered a new paper and not just a comment. Another reason is that this MS points to an alternative method, used only once previously, for extracting the leaflet area compressibility modulus from simulations.
Megakaryocyte TGFβ1 Partitions Hematopoiesis into Immature Progenitor/Stem Cells and Maturing Precursors
Authors: Di Giandomenico Silvana , Kermani Pouneh , Molle Nicole , Yabut Maria Mia , Zeinah Ghaith Abu , Stephens Thomas , Messali Nassima , Rafii Shahin , Scandura Joseph M.
Published: July 2019

Erythropoiesis is a multiweek program coupling massive proliferation with progressive cellular differentiation ultimately enabling a limited number of hematopoietic stem cells (HSCs) to yield millions of erythrocytes per second1. Erythropoietin (Epo) is essential for red blood cell (RBC) production but this cytokine acts well after irreversible commitment of hematopoietic progenitor cells (HPCs) to an erythroid fate. It is not known if terminal erythropoiesis is tethered to the pool of available immature hematopoietic stem and progenitor cells (HSPCs). We now report that megakaryocyte-derived TGFβ1 compartmentalizes hematopoiesis by coupling HPC numbers to production of mature erythrocytes. Genetic deletion of TGFβ1 specifically in megakaryocytes (TGFβ1ΔMk/ΔMk) increased functional HSPCs including committed erythroid progenitors, yet total bone marrow and spleen cellularity and peripheral blood cell counts were entirely normal. Instead, excess erythroid precursors underwent apoptosis, predominantly those erythroblasts expressing the Epo receptor (Epor) but not Kit. Despite there being no deficiency of plasma Epo inTGFβ1ΔMk/ΔMkmice, exogenous Epo rescued survival of excess erythroid precursors and triggered exuberant erythropoiesis. In contrast, exogenous TGFβ1 caused anemia and failed to rescue erythroid apoptosis despite its ability to restore downstream TGFβ-mediated Smad2/3 phosphorylation in HSPCs. Thus, megakaryocytic TGFβ1 regulates the size of the pool of immature HSPCs and in so doing, improves the efficiency of erythropoiesis by governing the feed of lineage-committed erythroid progenitors whose fate is decided by extramedullary renal Epo-producing cells sensing the need for new RBCs. Independent manipulation of distinct immature Epo-unresponsive HSPCs within the hematopoietic compartments offers a new strategy to overcome chronic anemias or possibly other cytopenias.
BR-bodies provide selectively permeable condensates that stimulate mRNA decay and prevent release of decay intermediates
Authors: Al-Husini Nadra , Tomares Dylan T. , Pfaffenberger Zechariah , Muthunayake Nisansala S. , Samad Mohammad A. , Zuo Tiancheng , Bitar Obaidah , Aretakis James R. , Bharmal Mohammed-Husain M. , Gega Alisa , Biteen Julie S. , Childers W. Seth , Schrader Jared M.
Published: July 2019

Biomolecular condensates play a key role in organizing RNAs and proteins into membraneless organelles. Bacterial RNP-bodies (BR-bodies) are a biomolecular condensate containing the RNA degradosome mRNA decay machinery, but the biochemical function of such organization remains poorly defined. Here we define the RNA substrates of BR-bodies through enrichment of the bodies followed by RNA-seq. We find that long, poorly translated mRNAs, small RNAs, and antisense RNAs are the main substrates, while rRNA, tRNA, and other conserved ncRNAs are excluded from these bodies. BR-bodies stimulate the mRNA decay rate of enriched mRNAs, helping to reshape the cellular mRNA pool. We also observe that BR-body formation promotes complete mRNA decay, avoiding the build-up of toxic endo-cleaved mRNA decay intermediates. The combined selective permeability of BR-bodies for both, enzymes and substrates together with the stimulation of the sub-steps of mRNA decay provide an effective organization strategy for bacterial mRNA decay.
Aquatic biodiversity enhances multiple nutritional benefits to humans
Authors: Bernhardt Joey R. , O’Connor Mary I.
Published: July 2019

Humanity depends on biodiversity for health, well-being and a stable environment. As biodiversity change accelerates, we are still discovering the full range of consequences for human health and well-being. Here, we test the hypothesis -- derived from biodiversity - ecosystem functioning theory -- that species richness and ecological functional diversity allow seafood diets to fulfill multiple nutritional requirements, a condition necessary for human health. We analyzed a newly synthesized dataset of 7245 observations of nutrient and contaminant concentrations in 801 aquatic animal taxa, and found that species with different ecological traits have distinct and complementary micronutrient profiles, but little difference in protein content. The same complementarity mechanisms that generate positive biodiversity effects on ecosystem functioning in terrestrial ecosystems also operate in seafood assemblages, allowing more diverse diets to yield increased nutritional benefits independent of total biomass consumed. Notably, nutritional metrics that capture multiple micronutrients essential for human well-being depend more strongly on biodiversity than common ecological measures of function such as productivity, typically reported for grasslands and forests. Further, we found that increasing species richness did not increase the amount of protein in seafood diets, and also increased concentrations of toxic metal contaminants in the diet. Seafood-derived micronutrients are important for human health and are a pillar of global food and nutrition security. By drawing upon biodiversity-ecosystem functioning theory, we demonstrate that ecological concepts of biodiversity can deepen our understanding of nature’s benefits to people and unite sustainability goals for biodiversity and human well-being.

Significance statement

Food security is not simply about maintaining yields, it is also about the need for a stable supply of nutritionally diverse foods. Obtaining nutritious food is a major challenge facing humanity and diverse aquatic ecosystems can help meet this goal. To test how aquatic biodiversity affects human health, we assembled a new dataset of nutrients, contaminants and ecological traits of 801 aquatic species. We used ecological models to quantify the role of species richness and ecological functional diversity and found that these biodiversity dimensions enhanced seafood micronutrient provisioning by the same mechanisms that link biodiversity to productivity in grasslands, forests and other systems. Our results underscore the need to minimize aquatic biodiversity loss to sustain and improve human well-being.
Greb1is required for axial elongation and segmentation in vertebrate embryos
Authors: Prajapati Ravindra Singh , Mitter Richard , Vezzaro Annalisa , Ish-Horowicz David
Published: July 2019

During vertebrate embryonic development, the formation of axial structures is driven by a population of stem-like cells that reside in a region of the tailbud called the chordoneural hinge (CNH). We have compared the CNH transcriptome with those of surrounding tissues and shown that the CNH and tailbud mesoderm are transcriptionally similar, and distinct from the presomitic mesoderm. Amongst CNH-enriched genes are several that are required for axial elongation, includingWnt3a, Cdx2, Brachyury/TandFgf8, and androgen/estrogen receptor nuclear signalling components such asGreb1. We show that the pattern and duration of tailbudGreb1expression is conserved in mouse, zebrafish, and chicken embryos, and thatGreb1is required for axial elongation and somitogenesis in zebrafish embryos. The axial truncation phenotype ofGreb1morphant embryos is explained by much reduced expression ofNo tail(Ntl/Brachyury) which is required for axial progenitor maintenance. Posterior segmentation defects in the morphants (including misexpression of genes such asmespb, myoDandpapC) appear to result, in part, from lost expression of the segmentation clock gene,her7.
Next-Gen sequencing of novel pandemic swine flu [A(H1N1)pdm09] virus in India revealed novel mutations across the genome
Authors: Dash Paban Kumar , Pattabiraman Chitra , Tandel Kundan , Sharma Shashi , Kumar Jyoti S , Siddappa Shilpa , Gowda Malali , Krishna Sudhir , Parida Man Mohan
Published: July 2019

The Influenza A H1N1 virus of 2009 was the first pandemic flu virus of the 21st century. Identifying the emergence of mutations in rapidly mutating Influenza viruses that allow increased transmission or confer resistance are invaluable to global outbreak response. Here we recovered 5 complete Influenza A genomes from 4 oropharygeal swabs and one cell culture isolate from a severe Indian outbreak of flu in early 2015. Multiple amino acids substitutions including those known to confer resistance to Oseltamivir and increased pathogenecity in mice were found in the Neuraminidase gene. Additional mutations both reported and novel were found throughout the genome compared to the vaccine strain (California/04/2009). All eight segments of the complete genomes were found to be genetically related to the 2009 pandemic strain, A(H1N1)pdm09 and belonging to the emerging genogroup 6B. This group was found to be of south East Asian origin by time scale phylogentic analysis. A phylogeographic analysis revealed 39 significant migration events among globally circulating viruses. This study is the first extensive complete genome and phylogeographic analysis of 2015 Indian A(H1N1) pdm09 viruses. We report several novel mutations in the 2015 Indian strains which need to be evaluated for effect on viral replication, transmission and resistance to therapy. The identification of mutant A(H1N1)pdm09 from India warrants continuous monitoring of viral evolution for implementation of suitable medical countermeasures.
Responses of Neurons in the Rostral Ventrolateral Medulla (RVLM) of Conscious Felines to Anticipated and Passive Movements
Authors: Miller Derek M. , Joshi Asmita , Kambouroglos Emmanuel T. , Engstrom Isaiah C. , Bielanin John P. , Wittman Samuel R. , McCall Andrew A. , Barman Susan M. , Yates Bill J.
Published: July 2019

Considerable evidence demonstrates that the vestibular system contributes to regulating sympathetic nerve activity and blood pressure. Initial studies in decerebrate animals showed that presumed pre-sympathetic neurons in the rostral ventrolateral medulla (RVLM) respond to small-amplitude (<10°) rotations of the body, as in other brain areas that process vestibular signals, despite the fact that such movements do not appreciably affect blood distribution in the body. However, a subsequent experiment in conscious animals showed that few RVLM neurons respond to small-amplitude movements. This study tested the hypothesis that vestibular inputs to RVLM neurons are modulated in conscious animals, such that vestibulosympathetic responses are only elicited when changes in body position are large enough to require changes in sympathetic nerve activity. The activity of approximately a third of RVLM neurons whose firing rate was related to the cardiac cycle, and thus likely received baroreceptor inputs, responded to vestibular inputs elicited by 40° head-up tilts in conscious cats, but not during 10° sinusoidal rotations in the pitch plane that affected the activity of neurons in brain regions providing inputs to the RVLM. These data suggest the existence of brain circuitry that suppresses vestibular influences on the activity of RVLM neurons and the sympathetic nervous system unless these inputs are physiologically warranted. We also determined that RVLM activity is not altered prior to tilts when a light cue is provided signaling the movement. The simplest interpretation of this findings is that feedforward cardiovascular responses are associated with active movement such as occurs during exercise, but not passive movements that require cardiovascular adjustments.
Efficient generation of zebrafish maternal-zygotic mutants through transplantation of ectopically induced and Cas9/gRNA targeted PGCs
Authors: Zhang Fenghua , Li Xianmei , He Mudan , Ye Ding , Xiong Feng , Amin Golpour , Zhu Zuoyan , Sun Yonghua
Published: July 2019

The CRISPR/Cas9 technology has been widely utilized for knocking out genes involved in various biological processes in zebrafish. Despite this technology is efficient for generating different mutations, one of the main drawbacks is low survival rates during embryogenesis when knocking out some embryonic lethal genes. To overcome this problem, we developed a novel strategy using a combination of CRISPR/Cas9 mediated gene knockout with primordial germ cells (PGCs) transplantation to facilitate and speed up the process of zebrafish mutant generation, particularly for embryonic lethal genes. First, we optimized the procedure for gRNA targeted PGCs transplantation (PGCT), by increasing the efficiencies of genome mutation in PGCs and induction of PGCs fates in donor embryos for PGCT. Second, the combined CRISPR/Cas9 with PGCT was utilized for generation of maternal zygotic (MZ) mutants oftcf7l1a(essential gene for head development),pou5f3(essential gene for zygotic genome activation) andchd(essential gene for dorsal development) at F1 generation with high efficiency. Finally, we revealed some novel phenotypes in the maternal zygotic mutant oftcf7l1aandchd, while MZtcf7l1ashowed elevated neural crest development, and MZchdhave stronger ventralization than its zygotic counterparts. Therefore, this study presents an efficient and powerful method for generating MZ mutants of embryonic lethal genes in zebrafish.
HORMA domain proteins and a Pch2-like ATPase regulate bacterial cGAS-like enzymes to mediate bacteriophage immunity
Authors: Ye Qiaozhen , Lau Rebecca K. , Mathews Ian T. , Watrous Jeramie D. , Azimi Camillia S. , Jain Mohit , Corbett Kevin D.
Published: July 2019

Bacteria are continually challenged by foreign invaders including bacteriophages, and have evolved a variety of defenses against these invaders. Here, we describe the structural and biochemical mechanisms of a bacteriophage immunity pathway found in a broad array of bacteria, including pathogenic E. coli and Pseudomonas aeruginosa. This pathway employs eukaryotic-like HORMA domain proteins that recognize specific peptides, then bind and activate a cGAS/DncV-like nucleotidyltransferase (CD-NTase) to generate a cyclic tri-AMP (cAAA) second messenger; cAAA in turn activates an endonuclease effector, NucC. Signaling is attenuated by a homolog of the AAA+ ATPase Pch2/TRIP13, which binds and likely disassembles the active HORMA-CD-NTase complex. When expressed in non-pathogenic E. coli, this pathway confers immunity against bacteriophage λ infection. Our findings reveal the molecular mechanisms of a bacterial defense pathway integrating a cGAS-like nucleotidyltransferase with HORMA domain proteins for threat sensing through protein detection, and negative regulation by a Pch2-like ATPase.