bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Factors Associated With Opioid Consumption in the Month Following Major Surgery
Authors: Larach Daniel B. , Sahara Michael J. , As-Sanie Sawsan , Moser Stephanie E. , Urquhart Andrew G. , Lin Jules , Hassett Afton L. , Wakeford Joseph A. , Clauw Daniel J. , Waljee Jennifer F. , Brummett Chad M.
Published: August 2019

Objective:

The aim of this study was to determine preoperative patient characteristics associated with postoperative outpatient opioid use and assess the frequency of postoperative opioid overprescribing.

Summary Background Data:

Although characteristics associated with inpatient opioid use have been described, data regarding patient factors associated with opioid use after discharge are lacking. This hampers the development of individualized approaches to postoperative prescribing.

Methods:

We included opioid-naïve patients undergoing hysterectomy, thoracic surgery, and total knee and hip arthroplasty in a single-center prospective observational cohort study. Preoperative phenotyping included self-report measures to assess pain severity, fibromyalgia survey criteria score, pain catastrophizing, depression, anxiety, functional status, fatigue, and sleep disturbance. Our primary outcome measure was self-reported total opioid use in oral morphine equivalents. We constructed multivariable linear-regression models predicting opioids consumed in the first month following surgery.

Results:

We enrolled 1181 patients; 1001 had complete primary outcome data and 913 had complete phenotype data. Younger age, non-white race, lack of a college degree, higher anxiety, greater sleep disturbance, heavy alcohol use, current tobacco use, and larger initial opioid prescription size were significantly associated with increased opioid consumption. Median total oral morphine equivalents prescribed was 600 mg (equivalent to one hundred twenty 5-mg hydrocodone pills), whereas median opioid consumption was 188 mg (38 pills).

Conclusions:

In this prospective cohort of opioid-naïve patients undergoing major surgery, we found a number of characteristics associated with greater opioid use in the first month after surgery. Future studies should address the use of non-opioid medications and behavioral therapies in the perioperative period for these higher risk patients.
Prospective evaluation and comparison of the predictive ability of different frailty scores to predict outcomes in geriatric trauma patients
Authors: Hamidi Mohammad , Haddadin Zaid , Zeeshan Muhammad , Saljuqi Abdul Tawab , Hanna Kamil , Tang Andrew , Northcutt Ashley , Kulvatunyou Narong , Gries Lynn , Joseph Bellal
Published: August 2019

BACKGROUND

Different frailty scores have been proposed to measure frailty. No study has compared their predictive ability to predict outcomes in trauma patients. The aim of our study was to compare the predictive ability of different frailty scores to predict complications, mortality, discharge disposition, and 30-day readmission in trauma patients.

METHODS

We performed a 2-year (2016–2017) prospective cohort analysis of all geriatric (age, >65 years) trauma patients. We calculated the following frailty scores on each patient; the Trauma-Specific Frailty Index (TSFI), the Modified Frailty Index (mFI) derived from the Canada Study of Health and Aging, the Rockwood Frailty Score (RFS), and the International Association of Nutrition and Aging 5-item a frailty scale (FS). Predictive models, using both unadjusted and adjusted logistic regressions, were created for each outcome. The unadjusted c-statistic was used to compare the predictive ability of each model.

RESULTS

A total of 341 patients were enrolled. Mean age was 76 ± 9 years, median Injury Severity Score was 13 [9–18], and median Glasgow Coma Scale score was 15 [12–15]. The unadjusted models indicated that both the TSFI and the RFS had comparable predictive value, as indicated by their unadjusted c-statistics, for mortality, in-hospital complications, skilled nursing facility disposition and 30-day readmission. Both TSFI and RFS models had unadjusted c-statistics indicating a relatively strong predictive ability for all outcomes. The unadjusted mFI and FS models did not have a strong predictive ability for predicting mortality and in-hospital complications. They also had a lower predictive ability for skilled nursing facility disposition and 30-day readmissions.

CONCLUSION

There are significant differences in the predictive ability of the four commonly used frailty scores. The TSFI and the RFS are better predictors of outcomes compared with the mFI and the FS. The TSFI is easy to calculate and might be used as a universal frailty score in geriatric trauma patients.

LEVEL OF EVIDENCE

Prognostic, level III.
Dose optimization of valproic acid in a lethal model of traumatic brain injury, hemorrhage, and multiple trauma in swine
Authors: Biesterveld Ben E. , Williams Aaron M. , Pai Manjunath P. , Dennahy Isabel S. , Graham Nathan J. , Chtraklin Kiril , Siddiqui Ali Z. , O'Connell Rachel L. , Bhatti Umar F. , Liu Baoling , Russo Rachel M. , Li Yongqing , Alam Hasan B.
Published: August 2019

BACKGROUND

Trauma is a leading cause of death, and traumatic brain injury is one of the hallmark injuries of current military conflicts. Valproic acid (VPA) administration in high doses (300–400 mg/kg) improves survival in lethal trauma models, but effectiveness of lower doses on survival is unknown. This information is essential for properly designing the upcoming clinical trials. We, therefore, performed the current study to determine the lowest dose at which VPA administration improves survival in a model of lethal injuries.

METHODS

Swine were subjected to traumatic brain injury (10-mm cortical impact), 40% blood volume hemorrhage, and multiple trauma (femur fracture, rectus crush, and Grade V liver laceration). After 1 hour of shock, animals were randomized (n = 6/group) to four groups: normal saline (NS) resuscitation; or NS with VPA doses of 150 mg/kg (VPA 150) or 100 mg/kg (VPA 100) administered over 3 hours or 100 mg/kg over 2 hours (VPA 100 over 2 hours). Three hours after shock, packed red blood cells were given, and animals were monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test.

RESULTS

Without resuscitation, all of the injured animals died within 5 hours. Similar survival rates were observed in the NS (17%) and VPA 100 (0%) resuscitation groups. Survival rates in the 100-mg/kg VPA groups were significantly (p < 0.05) better when it was given over 2 hours (67%) compared to 3 hours (0%). 83% of the animals in the VPA 150 group survived, which was significantly higher than the NS and VPA 100 over 3 hours groups (p < 0.05).

CONCLUSION

A single dose of VPA (150 mg/kg) significantly improves survival in an otherwise lethal model of multiple injuries. This is a much lower dose than previously shown to have a survival benefit and matches the dose that is tolerated by healthy human subjects with minimal adverse effects.

LEVEL OF EVIDENCE

Therapeutic, level V.
The effect of cirrhosis on trauma outcomes: A systematic review and meta-analysis
Authors: Serrano Elina , Liu Pingyang , Nwabuo Adaobi I. , Langness Simone , Juillard Catherine
Published: August 2019

BACKGROUND

The negative effect of cirrhosis on mortality following traumatic injury has been quantified in multiple observational studies. However, to our knowledge, the information contained in these studies has never been synthesized. The aims of this study were: (1) to determine the magnitude of the effect of liver cirrhosis on mortality, morbidity, and hospital course among trauma patients and (2) to analyze sources of study heterogeneity that may lead to differing estimates in the observed mortality rate among patients with cirrhosis.

METHODS

A systematic search of EMBASE and PubMed was conducted. Data were extracted from eligible studies and analyzed using a random-effects model to compare trauma outcomes in cirrhotic and noncirrhotic patients (PROSPERO Registration CRD42018088464). Mortality was the primary outcome. Secondary outcomes included complication rate, length of hospital stay, length of intensive care unit stay, and mechanical ventilation days.

RESULTS

Title and abstract review of 15,958 articles led to the identification of 31 relevant articles. Ultimately, 18 observational studies were included in this meta-analysis. The pooled effect sizes for mortality (odds ratio [OR], 4.52; 95% confidence interval [CI], 3.13–6.54) and complication rate (OR, 1.92; 95% CI, 1.30–2.85) were higher in the cirrhotic group than the noncirrhotic group. Trauma patients with cirrhosis also incurred longer hospital stays (mean difference, 3.81 days; 95% CI, 1.22–6.41) and longer ICU stays (mean difference, 2.40 days; 95% CI, 0.65–4.15). There was no difference in days spent on mechanical ventilation.

CONCLUSION

Preexisting liver cirrhosis is associated with increased mortality rate, complication rate, and length of hospitalization among trauma patients, even after adjusting for confounding factors and potential sources of between-study heterogeneity. Trauma patients with cirrhosis would benefit from heightened surveillance and injury prevention interventions.

LEVEL OF EVIDENCE

Systematic review and meta-analysis, level III.
Role of resveratrol in protecting vasodilatation function in septic shock rats and its mechanism
Authors: Zhang Zi-sen , Zhao Hong-liang , Yang Guang-ming , Zang Jia-tao , Zheng Dan-yang , Duan Chen-yang , kuang Lei , Zhu Yu , Wu Yue , Li Tao , Liu Liang-ming
Published: August 2019

BACKGROUND

Vascular dysfunction is a major cause of sepsis-induced multiple-organ dysfunction. Resveratrol is a polyphenol compound with extensive pharmacological effects including anti-inflammation. The aim of this study was to determine the role and mechanism of resveratrol in protecting vascular function following sepsis.

METHODS

The cecal ligation and puncture method was used to establish a septic shock rat model. Resveratrol (5 mg/kg and 10 mg/kg) was administered intravenously immediately and at 12 hours after cecal ligation and puncture, respectively. The effects of resveratrol on vasodilatation function, blood flow velocity, hemodynamics, and vital organ function and its relationship to Rac-1 and HIF-1α were observed.

RESULTS

Vascular relaxation reactivity and blood flow velocity were significantly decreased after septic shock, both were significantly improved by resveratrol 5 mg/kg and 10 mg/kg, and the effect of 10 mg/kg was greater. The relaxation reactivity of the superior mesenteric artery to acetylcholine (Ach) was increased by 43.2%. The blood flow velocity of mesenteric arterioles and venules was increased by 47.1% and 51%, respectively, after resveratrol (10 mg/kg) administration compared with the septic shock group. The hemodynamics and both liver and kidney blood flow were significantly decreased after septic shock, which were significantly improved them by resveratrol, which enhanced the vascular relaxation reactivity in septic shock rats. The 72-hour survival rate of septic shock rats in the resveratrol group (62.5%) was significantly higher than that in the septic shock group (6.3%). Resveratrol significantly upregulated the expression of endothelial nitric oxide synthase (eNOS) and downregulated the expression of inducible NOS, Rac-1, and HIF-1α. Inhibitors of Rac-1 and HIF-1α significantly improved the expression of eNOS, and inhibition of eNOS (L-NAME, 5 mg/kg) antagonized the resveratrol-induced improvement in vascular relaxation reactivity and survival.

CONCLUSION

Resveratrol was beneficial for vasodilatation function in rats with septic shock, which is the major contribution to resveratrol improving hemodynamics and organ perfusion. The mechanism involved resveratrol upregulating the expression of eNOS by inhibiting Rac-1 and HIF-1α.
Patterns of phenotypic plasticity among populations of three Mediterranean pine species and implications for evolutionary responses to climate change
Authors: Vizcaíno-Palomar Natalia , Fady Bruno , Alía Ricardo , Raffin Annie , Mutke Sven , Garzón Marta Benito
Published: August 2019

Aim

Under rapid environmental change, phenotypic plasticity, if adaptive, could increase the odds for organisms to persist. Environmental variation over time is an important source of phenotypic plasticity. Likewise, phenotypic plasticity can vary with age in many organisms. However, little is known on phenotypic plasticity variation across species’ ranges. Our aims are: (i) to assess whether populations’ phenotypic plasticity is related to the inter-annual climate variation under which populations have evolved during the last century; (ii) to compare phenotypic plasticity among developmental classes; and (iii) to predict phenotypic plasticity across’ species ranges.

Location

Europe and North-Africa.

Time period

1901-2014.

Major taxa studied

Pinus nigra, P. pinasterandP. pinea.

Methods

We used 372 646 individual tree height measurements at three developmental classes from a wide network of 38 common gardens in Europe and North Africa with provenances covering the distribution range of the species. With this data, we: i) build linear mixed-effect models of tree height as a function of tree age, population and climate; ii) estimate populations’ reaction norms from the fitted models; iii) calculate populations’ phenotypic plasticity indexes; iv) build models of populations’ phenotypic plasticity indexes as a function of inter-annual climate variation during the last century.

Results

We found that i) most populations that have evolved under high inter-annual climate variation, in either maximum or minimum values in temperature or precipitation, exhibited high values of plasticity in tree height; ii) phenotypic plasticity for tree height was higher in young trees than in older ones, iii) phenotypic plasticity did not follow any particular geographical pattern across species’ ranges.

Main conclusions

Phenotypic plasticity across the three Mediterranean pines’ ranges is related with the climate variation experienced over time and calls into question whether this plasticity could be adaptive and hence beneficial to cope with climate change in the short-term.
Inferring efficiency of translation initiation and elongation from ribosome profiling
Authors: Szavits-Nossan Juraj , Ciandrini Luca
Published: August 2019

One of the main goals of ribosome profiling is to quantify the rate of protein synthesis at the level of translation. Here, we develop a method for inferring translation elongation kinetics from ribosome profiling data using recent advances in the mathematical modelling of mRNA translation. Our method distinguishes between the elongation rate intrinsic to the ribosome’s stepping cycle and the actual elongation rate that takes into account ribosome interference. This distinction allows us to quantify the extent of ribosomal collisions along the transcript and identify individual codons where ribosomal collisions are likely. When examining ribosome profiling in yeast, we observe that translation initiation and elongation are close to their optima, and traffic is minimised at the beginning of the transcript to favour ribosome recruitment. However, we find many individual sites of congestion along the mRNAs where the probability of ribosome interference can reach 50%. Our work provides new measures of translation initiation and elongation efficiencies, emphasising the importance of rating these two stages of translation separately.
Small molecule modulation of a redox-sensitive stress granule protein dissolves stress granules with beneficial outcomes for familial amyotrophic lateral sclerosis models
Authors: Uechi Hiroyuki , Sridharan Sindhuja , Nijssen Jik , Bilstein Jessica , Iglesias-Artola Juan M. , Kishigami Satoshi , Casablancas-Antras Virginia , Poser Ina , Martinez Eduardo J. , Boczek Edgar , Wagner Michael , Tomschke Nadine , de Jesus Domingues António M. , Pal Arun , Doeleman Thom , Kour Sukhleen , Anderson Eric Nathaniel , Stein Frank , Lee Hyun O. , Zhang Xiaojie , Fritsch Anatol W. , Jahnel Marcus , Fürsch Julius , Murthy Anastasia C. , Alberti Simon , Bickle Marc , Fawzi Nicolas L. , Nadler André , David Della C. , Pandey Udai B. , Hermann Andreas , Stengel Florian , Davis Benjamin G. , Baldwin Andrew J. , Savitski Mikhail M. , Hyman Anthony A. , Wheeler Richard J.
Published: August 2019

Neurodegeneràve diseases such as amyotrophic lateral sclerosis (ALS) are oten associated with mutàons in proteins that are associated with stress granules. Stress granules are condensates formed by liquid-liquid phase separàon which, when aberrant, can lead to altered condensàon behaviours and disease phenotypes. Here, we identified lipoamide, a small molecule which specifically prevents cytoplasmic condensàon of stress granule proteins. Thermal proteome profiling showed that lipoamide preferentially stabilises intrinsically disordered domain-containing proteins. These include SRSF1 and SFPQ, stress granule proteins necessary for lipoamide activity. The redox state of SFPQ correlates with its condensate-dissolving behaviour, in concordance with the importance of the dithiolane ring for lipoamide activity. In animals, lipoamide ameliorates aging-associated aggregàon of a stress granule reporter, improves neuronal morphology, and recovers motor defects caused by expression of ALS-associated FUS and TDP-43 mutants. In conclusion, lipoamide is a well-tolerated small molecule modulator of stress granule condensàon and dissection of its molecular mechanism identified a cellular pathway for redox regulàon of stress granule formàon.
Fluid shear stress coupled with narrow constrictions induce cell type-dependent morphological and molecular changes in circulating tumor cells
Authors: Cognart Hamizah Ahmad , Viovy Jean-Louis , Villard Catherine
Published: August 2019

Cancer mortality mainly arises from metastases, due to cells that escape from a primary tumor, circulate in the blood as circulating tumor cells (CTCs), permeate across blood vessels and nest in distant organs. It is still unclear how CTCs overcome the harsh conditions of fluid shear stress and mechanical constraints within the microcirculation. Here, a model of the blood microcirculation was established through the fabrication of microfluidic channels comprising constrictions. Metastatic breast cancer cells of epithelial-like and mesenchymal-like phenotypes were flowed into the microfluidic device. These cells were visualized during circulation, analyzed for their dynamical behavior and retrieved post-circulation. γ-H2AX staining showed significant increase of DNA damage response in epithelial-like SK-BR-3 cells, while gene expression analysis of key regulators of epithelial-to-mesenchymal transition revealed significant increase of Twist2 relative expression in mesenchymal-like MDA-MB-231 cells post-circulation. This work documents first results of the changes at the cellular, subcellular and molecular scales induced by the two main mechanical stimuli arising from circulatory conditions.
Hot-spots and their contribution to the self-assembly of the viral capsid: in-silico prediction and analysis
Authors: Díaz-Valle Armando , Falcón-González José Marcos , Carrillo-Tripp Mauricio
Published: August 2019

In order to rationally design biopolymers that mimic biological functions, first, we need to elucidate the molecular mechanisms followed by nature. For example, the viral capsid is a macromolecular complex formed by self-assembled proteins which, in many cases, are biopolymers with an identical amino acid sequence. Specific protein-protein interactions drive the capsid self-assembly process, leading to several distinct protein interfaces. Following the hot-spot hypothesis, we propose a conservation-based methodology to identify those interface residues that are crucial elements on the self-assembly and thermodynamic stability of the capsid. We validate our predictions by computational free energy calculations using an atomic-scale molecular model of an icosahedral virus. Our results show that a single mutation in any of the hot-spots significantly perturbs the quaternary interaction, decreasing the absolute value of the binding free energy, without altering the tertiary structure. Our methodology can lead to a strategy to rationally modulate the capsid’s thermodynamic properties.
Exponential Growth of GlioblastomaIn VivoDriven by Rapidly Dividing and Outwardly Migrating Cancer Stem Cells
Authors: Buchauer Lisa , Khan Muhammad Amir , Zhuo Yue , Shao Chunxuan , Zou Peng , Feng Weijun , Qian Mengran , Bekki Gözde , Bunne Charlotte , Neuerburg Anna , Acikgöz Azer Aylin , Tomaschko Mona , Zhu Zhe , Alter Heike , Hartmann Katharina , Friesen Olga , Hexel Klaus , Höfer Thomas , Liu Hai-Kun
Published: August 2019

How overall tumor growth emerges from the properties of functionally heterogeneous tumor cell subpopulations is a fundamental question of cancer biology. Here we combined lineage tracing, continuous monitoring of tumor mass, proliferation assays and transcriptomics with mathematical modeling and statistical inference to dissect the growth of glioblastoma in mice. We found that tumors grow exponentially at the rate of symmetric divisions of brain tumor stem cells (BTSCs). Spatial modeling predicts, and data show, that BTSCs accumulate at the tumor rim rather than in the core. The physiological differentiation hierarchy downstream of BTSCs is preserved in mice and humans: transit amplifying progenitors give rise to terminally differentiated cells. Consistent with our quantification of the mechanisms underlying tumor growth, molecular data show elevated expression of cell cycle-and migration-related genes in BTSCs. Our systematic approach reveals fundamental properties of glioblastoma and may be transferable to the study of other animal models of cancer.
Mammalian musculoskeletal regeneration is associated with reduced inflammatory cytokines and an influx of T cells
Authors: Gawriluk Thomas R. , Simkin Jennifer , Hacker Corin K. , Kimani John M. , Kiama Stephen G. , Ezenwa Vanessa O. , Seifert Ashley W.
Published: August 2019

Whether the immune response to injury contributes to tissue regeneration is not well understood. We quantified systemic and local cytokines during ear pinna repair to provide the first comprehensive comparison of the immune response to injury between mammalian regeneration (A. cahirinusandA. percivali) and fibrotic repair (M. musculus). Importantly, by comparing laboratory-reared and wild-caught animals we identified responses specifically associated with healing outcome. Fibrotic repair showed a greater local release of IL-6, CCL2 and CXCL1. Conversely, regeneration showed decreased circulating IL-5, IL-6, IL-17, CCL3 and CXCL1 and increased local IL-12 and IL-17. The differential IL-6 response was substantiated by increased pSTAT3 during the inflammatory phase of fibrotic repair and with blastema formation and tissue morphogenesis inAcomys. COX-2 inhibition was not sufficient to induce regeneration. Interestingly, a unique influx of lymphocytes was coupled with regeneration and RNA-expression analysis suggested they were regulatory T cells. Together, the data support regeneration-specific inflammation and T cell responses inAcomys.
Investigating the biomechanical properties of streptococcal polysaccharide capsules using atomic force microscopy
Authors: Marshall H , Aguayo S , Kilian M , Petersen FC , Bozec L , Brown JS
Published: August 2019

In common with many bacterial pathogens,Streptococcus pneumoniaehas a polysaccharide capsule, which facilitates immune evasion and is a key virulence determinant. However, recent data has shown that the closely relatedStreptococcus mitiscan also express polysaccharide capsules including those with an identical chemical structure toS. pneumoniaecapsular serotypes. We have used atomic force microscopy (AFM) techniques to investigate the biophysical properties ofS. mitisandS. pneumoniaestrains expressing the same capsular serotypes that might relate to their differences in virulence potential. When comparingS. mitisandS. pneumoniaestrains with identical capsule serotypesS. mitisstrains were more susceptible to neutrophil killing and imaging using electron microscopy and AFM demonstrated significant morphological differences. Force-volume mapping using AFM showed distinct force-curve profiles for the centre and edge areas of encapsulatedS. pneumoniaeandS. mitisstrains. This “edge effect” was not observed in the unencapsulated streptococcal strains and in an unencapsulatedStaphylococcus aureusstrain, and therefore was a direct representation of the mechanical properties of the bacterial capsule. When two strains ofS. mitisandS. pneumoniaeexpressed an identical capsular serotype, they presented also similar biomechanical characteristics. This would infer a potential relationship between capsule biochemistry and nanomechanics, independent of the bacterial strains. Overall, AFM was an effective tool to explore the biophysical properties of bacterial capsules of living bacteria by reproducibly quantifying the elastic and adhesive properties of bacterial cell surfaces. Using AFM to investigate capsule differences over a wider range of strains and capsular serotypes of streptococci and correlate the data with phenotypic differences will elucidate how the biophysical properties of the capsule can influence its biological role during infection.
Discovery of a polybrominated aromatic secondary metabolite from a planctomycete points at an ambivalent interaction with its macroalgae host
Authors: Panter Fabian , Garcia Ronald , Thewes Angela , Zaburannyi Nestor , Bunk Boyke , Overmann Jörg , Gutierrez Mary Victory , Krug Daniel , Müller Rolf
Published: August 2019

The roles of the majority of bacterial secondary metabolites, especially those from uncommon sources are yet elusive even though many of these compounds show striking biological activities. To further investigate the secondary metabolite repertoire of underexploited bacterial families, we chose to analyze a novel representative of the yet untapped bacterial phylum Planctomycetes for the production of secondary metabolites under laboratory culture conditions. Development of a planctomycetal high density cultivation technique in combination with high resolution mass spectrometric analysis revealed Planctomycetales strain 10988 to produce the plant toxin 3,5 dibromo p-anisic acid. This molecule represents the first secondary metabolite reported from any planctomycete. Genome mining revealed the biosynthetic origin of this doubly brominated secondary metabolite and a biosynthesis model for the com-pound was devised. Comparison of the biosynthetic route to biosynthetic gene clusters responsible for formation of polybrominated small aromatic compounds reveals evidence for an evolutionary link, while the compound’s herbicidal activity points towards an ambivalent role of the metabolite in the planctomycetal ecosystem.
Death is on Our Side: Paleontological Data Drastically Modify Phylogenetic Hypotheses
Authors: Koch Nicolás Mongiardino , Parry Luke A.
Published: August 2019

Fossils are the only remaining evidence of the majority of species that have ever existed, providing a direct window into events in evolutionary history that shaped the diversification of life on Earth. Phylogenies underpin our ability to make sense of evolution but are routinely inferred only from data available from living organisms. Although extinct taxa have been shown to add crucial information for inferring macroevolutionary patterns and processes including ancestral states, paleobiogeography and diversification dynamics, the role that fossils play in inferring the tree of life itself is controversial. Since the early years of phylogenetic systematics, different studies have dismissed the impact of fossils due to their incompleteness, championed their ability to overturn phylogenetic hypotheses or concluded that their behavior is indistinguishable from that of extant taxa. Here we show paleontological data has a remarkable effect in phylogenetic inference. Fossils often have higher levels of topological influence than extant taxa, while inducing unique topological rearrangements. Previous studies have proposed a suite of explanations for the topological behavior of fossils, such as their retention of unique morphologies or their ability to break long branches. We develop predictive models that demonstrate that the possession of distinctive character state combinations is the primary predictor of the degree of induced topological change, and that the relative impact of taxa (fossil and extant) can be predicted to some extent before any analysis. Our results bolster the consensus of recent empirical studies by showing the unique role of paleontological data in phylogenetic inference, and provide the first quantitative assessment of its determinants, with broad consequences for the design of taxon sampling in both morphological and total-evidence analyses.
Sequencing smart:De novosequencing and assembly approaches for non-model mammals
Authors: Etherington Graham J , Heavens Darren , Baker David , Lister Ashleigh , McNelly Rose , Garcia Gonzalo , Clavijo Bernardo , Macaulay Iain , Haerty Wilfried , Di Palma Federica
Published: August 2019

Background

Whilst much sequencing effort has focused on key mammalian model organisms such as mouse and human, little is known about the correlation between genome sequencing techniques for non-model mammals and genome assembly quality. This is especially relevant to non-model mammals, where the samples to be sequenced are often degraded and low quality. A key aspect when planning a genome project is the choice of sequencing data to generate. This decision is driven by several factors, including the biological questions being asked, the quality of DNA available, and the availability of funds. Cutting-edge sequencing technologies now make it possible to achieve highly contiguous, chromosome-level genome assemblies, but relies on good quality high-molecular-weight DNA. The funds to generate and combining these data are often only available within large consortiums and sequencing initiatives, and are often not affordable for many independent research groups. For many researchers, value-for-money is a key factor when considering the generation of genomic sequencing data. Here we use a range of different genomic technologies generated from a roadkill European Polecat (Mustela putorius) to assess various assembly techniques on this low-quality sample. We evaluated different approaches forde novoassemblies and discuss their value in relation to biological analyses.

Results

Generally, assemblies containing more data types achieved better scores in our ranking system. However, when accounting for misassemblies, this was not always the case for Bionano and low-coverage 10x Genomics (for scaffolding only). We also find that the extra cost associated with combining multiple data types is not necessarily associated with better genome assemblies.

Conclusions

The high degree of variability between eachde novoassembly method (assessed from the seven key metrics) highlights the importance of carefully devising the sequencing strategy to be able to carry out the desired analysis. Adding more data to genome assemblies not always results in better assemblies so it is important to understand the nuances of genomic data integration explained here, in order to obtain cost-effective value-for-money when sequencing genomes.
Topological data analysis to uncover the shape of immune responses during co-infection
Authors: Sasaki Karin , Bruder Dunja , Hernandez-Vargas Esteban
Published: August 2019

Co-infections by multiple pathogens have important implications in many aspects of health, epidemiology and evolution. However, how to disentangle the contributing factors of the immune response when two infections take place at the same time is largely unexplored. Using data sets of the immune response during influenza-pneumococcal co-infection in mice, we employ here topological data analysis to simplify and visualise high dimensional data sets.

We identified persistent shapes of the simplicial complexes of the data in the three infection scenarios: single viral infection, single bacterial infection, and co-infection. The immune response was found to be distinct for each of the infection scenarios and we uncovered that the immune response during the co-infection has three phases and two transition points. During the first phase, its dynamics is inherited from its response to the primary (viral) infection. The immune response has an early (few hours post co-infection) and then modulates its response to finally react against the secondary (bacterial) infection. Between 18 to 26 hours post co-infection the nature of the immune response changes again and does no longer resembles either of the single infection scenarios.

Author summary

The mapper algorithm is a topological data analysis technique used for the qualitative analysis, simplification and visualisation of high dimensional data sets. It generates a low-dimensional image that captures topological and geometric information of the data set in high dimensional space, which can highlight groups of data points of interest and can guide further analysis and quantification.

To understand how the immune system evolves during the co-infection between viruses and bacteria, and the role of specific cytokines as contributing factors for these severe infections, we use Topological Data Analysis (TDA) along with an extensive semi-unsupervised parameter value grid search, and k-nearest neighbour analysis.

We find persistent shapes of the data in the three infection scenarios, single viral and bacterial infections and co-infection. The immune response is shown to be distinct for each of the infections scenarios and we uncover that the immune response during the co-infection has three phases and two transition points, a previously unknown property regarding the dynamics of the immune response during co-infection.
Fine-scale seascape genomics of an exploited marine species, the common cockle Cerastoderma edule, using a multi-modelling approach
Authors: Coscia Ilaria , Wilmes Sophie B. , Ironside Joseph E. , Goward-Brown Alice , O’Dea Enda , Malham Shelagh K. , McDevitt Allan D. , Robins Peter E.
Published: August 2019

Population dynamics of marine species that are sessile as adults are driven by oceanographic dispersal of larvae from spawning to nursery grounds. This is mediated by life-history traits such as the timing and frequency of spawning, larval behaviour and duration, and settlement success. Here, we use 1725 single nucleotide polymorphisms (SNPs) to study the fine scale spatial genetic structure in the commercially important cockle species Cerastoderma edule and compare it to environmental variables and current-mediated larval dispersal within a modelling framework. Hydrodynamic modelling employing the NEMO Atlantic Margin Model (AMM15) was used to simulate larval transport and estimate connectivity between populations during spawning months (April - September), factoring in larval duration and seasonal variability of ocean currents. Results at neutral loci reveal the existence of three separate genetic clusters (mean FST=0.021) within a relatively fine spatial scale in the northwest Atlantic. Environmental association (EA) analysis indicates that oceanographic currents and geographical distance between the populations explain over 20% of the variance observed at neutral loci, while genetic variance (71%) at outlier loci was explained by sea surface temperatures extremes. These results fill an important knowledge gap in the management of a commercially important, overexploited species, and bring us closer to understanding the role of larval dispersal in connecting populations at a fine geographical scale.
Hot-spots and their contribution to the self-assembly of the viral capsid: in-vitro validation
Authors: Valdez-Lara Alejandra Gabriela , Andrade-Medina Mariana , Alemán-Vilis Josué Alejandro , Pérez-Montoya Aldo Adrián , Pineda-Aguilar Nayely , Martínez-Guerra Eduardo , Roldán-Salgado Abigail , Gaytán Paul , Carrillo-Tripp Mauricio
Published: August 2019

The viral capsid is a macromolecular complex formed by self-assembled proteins (CPs) which, in many cases, are biopolymers with an identical amino acid sequence. Specific CP-CP interactions drive the capsid self-assembly process. However, it is believed that only a small set of protein-protein interface residues significantly contribute to the formation of the capsid; the so-called “hot-spots”. Here, we investigate the effect of in-vitro point-mutations on the Bromoviridae family structure-conserved interface residues of the icosahedral Cowpea Chlorotic Mottle Virus, previously hypothesized as hot-spots. We study the self-assembly of those mutated recombinant CPs for the formation of capsids by Thermal Shift Assay (TSA). We show that the TSA biophysical technique is a reliable way to characterize capsid assembly. Our results show that point-mutations on non-conserved interface residues produce capsids indistinguishable from the wild-type. In contrast, a single mutation on structure-conserved residues E176 or V189 prevents the formation of the capsid while maintaining the tertiary fold of the CP. Our findings provide experimental evidence of the in-silico conservation-based hot-spot prediction accuracy. As a whole, our methodology provides a framework that could aid in the rational development of molecules to inhibit virus formation, or advance capsid bioengineering to design for their stability, function and applications.
Characterization of Genetic and Phenotypic Heterogeneity of Obstructive Sleep Apnea Using Electronic Health Records
Authors: Veatch Olivia J. , Bauer Christopher R. , Josyula Navya , Mazzotti Diego R. , Keenan Brendan T. , Bagai Kanika , Malow Beth A. , Robishaw Janet D. , Pack Allan I. , Pendergrass Sarah A.
Published: August 2019

Obstructive sleep apnea (OSA) is defined by frequent episodes of reduced or complete cessation of airflow during sleep and is linked to negative health outcomes. Understanding the genetic factors influencing expression of OSA may lead to new treatment strategies. Electronic health records can be leveraged to both validate previously reported OSA-associated genomic variation and detect novel relationships between these variants and comorbidities. We identified candidate single nucleotide polymorphisms (SNPs) via systematic literature review of existing research. Using datasets available at Geisinger (n=39,407) and Vanderbilt University Medical Center (n=24,084), we evaluated associations between 48 SNPs and OSA diagnosis, defined using clinical codes. We also evaluated associations between these SNPs and OSA severity measures obtained from sleep reports at Geisinger (n=6,571). Finally, we used a phenome-wide approach to perform discovery and replication analyses testing associations between OSA candidate SNPs and other clinical codes and laboratory values. Ten SNPs were associated with OSA diagnosis in at least one dataset, and one additional SNP was associated following meta-analysis across all datasets. Three other SNPs were solely associated in subgroups defined by established risk factors (i.e., age, sex, and BMI). Five OSA diagnosis-associated SNPs, and 16 additional SNPs, were associated with OSA severity measures. SNPs associated with OSA diagnosis were also associated with codes reflecting cardiovascular disease, diabetes, celiac disease, peripheral nerve disorders and genitourinary symptoms. Results highlight robust OSA-associated SNPs, and provide evidence of convergent mechanisms influencing risk for co-occurring conditions. This knowledge can lead to more personalized treatments for OSA and related comorbidities.
Crocodylomorph cranial shape evolution and its relationship with body size and ecology
Authors: Godoy Pedro L.
Published: August 2019

Crocodylomorpha, which includes living crocodylians and their extinct relatives, has a rich fossil record, extending back for more than 200 million years. Unlike modern semi-aquatic crocodylians, extinct crocodylomorphs exhibited more varied lifestyles, ranging from marine to fully terrestrial forms. This ecological diversity was mirrored by a remarkable morphological disparity, particularly in terms of cranial morphology, which seems to be closely associated with ecological roles in the group. Here, I use geometric morphometrics to comprehensively investigate cranial shape variation and disparity in Crocodylomorpha. I quantitatively assess the relationship between cranial shape and ecology (i.e. terrestrial, aquatic, and semi-aquatic lifestyles), as well as possible allometric shape changes. I also characterise patterns of cranial shape evolution and identify regime shifts. I found a strong link between shape and size, and a significant influence of ecology on the observed shape variation. Terrestrial taxa, particularly notosuchians, have significantly higher disparity, and shifts to more longirostrine regimes are associated with large-bodied aquatic or semi-aquatic species. This demonstrates an intricate relationship between cranial shape, body size and lifestyle in crocodylomorph evolutionary history. Additionally, disparity-through-time analyses were highly sensitive to different phylogenetic hypotheses, suggesting the description of overall patterns among distinct trees. For crocodylomorphs, most results agree in an early peak during the Early Jurassic and another in the middle of the Cretaceous, followed by nearly continuous decline until today. Since only crown-group members survived through the Cenozoic, this decrease in disparity was likely the result of habitat loss, which narrowed down the range of crocodylomorph lifestyles.
Modular transcriptional programs separately define axon and dendrite connectivity
Authors: Kurmangaliyev Yerbol Z. , Yoo Juyoun , LoCascio Samuel A. , Zipursky S. Lawrence
Published: August 2019

Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on Drosophila T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.
Building clone-consistent ecosystem models
Authors: Ansmann Gerrit , Bollenbach Tobias
Published: August 2019

Many ecological studies employ general models that can feature an arbitrary number of populations. A critical requirement imposed on such models is clone consistency: If the individuals from two populations are indistinguishable, joining these populations into one shall not affect the outcome of the model. Otherwise a model produces different outcomes for the same scenario. Using functional analysis, we comprehensively characterize all clone-consistent models: We prove that they are necessarily composed from basic building blocks, namely linear combinations of parameters and abundances. These strong constraints enable a straightforward validation of model consistency or reveal implicit assumptions required to achieve it. We show that such implicit assumptions can considerably limit the applicability of models and the generality of results obtained with them. Moreover, our insights facilitate building new clone-consistent models, which we illustrate for a data-driven model of microbial communities. Finally, our insights point to new relevant forms of general models for theoretical ecology. Our framework thus provides a systematic way of comprehending ecological models, which can guide a wide range of studies.
Topology-Dependent Interference of Circuit Function by Growth Feedback
Authors: Zhang Rong , Li Jiao , Melendez-Alvarez Juan , Chen Xingwen , Sochor Patrick , Zhang Qi , Goetz Hanah , Ding Tian , Wang Xiao , Tian Xiao-Jun
Published: August 2019

Growth-mediated feedback between synthetic gene circuits and host organisms leads to diverse emerged behaviors, including growth bistability and enhanced ultrasensitivity. However, the range of possible impacts of growth feedback on different gene circuits remains underexplored. Here, we mathematically and experimentally demonstrated that growth feedback affects the functions of memory gene circuits in a network topology-dependent way. Specifically, the memory of the self-activation circuit is quickly lost due to the fast growth-mediated dilution of the circuit products. Decoupling of growth feedback reveals its memory, manifested by its hysteresis property across a broad range of stimulus. On the contrary, the toggle switch is more refractory to the growth-mediated dilution and can retrieve its memory after the fast-growth phase. The underlying principle lies in the different dependence of active and repressive regulations in these circuits on the growth-mediated dilution. Our results unveil the topology-dependent mechanism on how growth-mediated feedback influences the behaviors of gene circuits.
Inositol Trisphosphate Kinase and Diphosphoinositol Pentakisphosphate Kinase Enzymes Constitute the Inositol Pyrophosphate Synthesis Pathway in Plants
Authors: Adepoju Olusegun , Williams Sarah P. , Craige Branch , Cridland Caitlin A. , Sharpe Amanda K. , Brown Anne M. , Land Eric , Perera Imara Y. , Mena Didier , Sobrado Pablo , Gillaspy Glenda E.
Published: August 2019

Inositol pyrophosphates (PP-InsPs) are an emerging class of “high-energy” intracellular signaling molecules containing one or two diphosphate groups attached to an inositol ring, with suggested roles in bioenergetic homeostasis and inorganic phosphate (Pi) sensing. Information regarding the biosynthesis of these unique class of signaling molecules in plants is scarce, however the enzymes responsible for their biosynthesis in other eukaryotes have been well described. Here we report the characterization of the two Arabidopsis VIP kinase domains, a newly discovered activity of the Arabidopsis ITPK1 and ITPK2 enzymes, and the subcellular localization of the enzymes involved in the synthesis of InsP6and PP-InsPs. Our data indicate that AtVIP1-KD and AtVIP2-KD act primarily as 1PP-specific Diphosphoinositol Pentakisphosphate Kinases (PPIP5) Kinases. The AtITPK enzymes, in contrast, can function as InsP6kinases, and thus are the missing enzyme in the plant PP-InsP synthesis pathway. Together, these enzyme classes can function in plants to produce PP-InsPs, which have been implicated in signal transduction and Pisensing pathways. We measured a higher InsP7level (increased InsP7/InsP8ratio) invip1/vip2double loss-of-function mutants, and an accumulation of InsP8(decreased InsP7/InsP8ratio) in the 35S:VIP2overexpression line relative to wild-type plants. We also report that enzymes involved in the synthesis of InsPs and PP-InsPs accumulate within the nucleus and cytoplasm of plant cells. Our work defines a molecular basis for understanding how plants synthesize PP-InsPs which is crucial for determining the roles of these signaling molecules in processes such as Pisensing.

SIGNIFICANCE STATEMENT

Inositol pyrophosphate signaling molecules are of agronomic importance as they can control complex responses to the limited nutrient, phosphate. This work fills in the missing steps in the inositol pyrophosphate synthesis pathway and points to a role for these molecules in the plant cell nucleus. This is an important advance that can help us design future strategies to increase phosphate efficiency in plants.