bluuebunny/crossref_metadata_2025 huggingface dataset:
Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein
Authors: Kim Artem , Le Douce Jérôme , Diab Farah , Ferovova Monika , Dubourg Christèle , Odent Sylvie , Dupé Valérie , David Véronique , Diambra Luis , Watrin Erwan , de Tayrac Marie
Published: April 2020

Synonymous single nucleotide variants (sSNVs) have been implicated in various genetic disorders through alterations of pre-mRNA splicing, mRNA structure and miRNA regulation. However, their impact on synonymous codon usage and protein translation remains to be elucidated in clinical context. Here, we explore the functional impact of sSNVs in the Sonic Hedgehog (SHH) gene, identified in patients affected by holoprosencephaly, a congenital brain defect resulting from incomplete forebrain cleavage. We identified eight sSNVs in SHH, selectively enriched in holoprosencephaly patients as compared to healthy individuals, and systematically assessed their effect at both transcriptional and translational levels using a series of in silico and in vitro approaches. Although no evidence of impact of these sSNVs on splicing, mRNA structure or miRNA regulation was found, five sSNVs introduced significant changes in codon usage and were predicted to impact protein translation. Cell assays demonstrated that these five sSNVs are associated with a significantly reduced amount of the resulting protein, ranging from 5% to 23%. Inhibition of the proteasome rescued the protein levels for four out of five sSNVs, confirming their impact on protein stability and folding. Remarkably, we found a significant correlation between experimental values of protein reduction and computational measures of codon usage, indicating the relevance of in silico models in predicting the impact of sSNVs on translation. Considering the critical role of SHH in brain development, our findings highlight the clinical relevance of sSNVs in holoprosencephaly and underline the importance of investigating their impact on translation in human pathologies.
Gray Matter Structure Is Associated with Reading Skill in Typically Developing Young Readers
Authors: Perdue Meaghan V , Mednick Joshua , Pugh Kenneth R , Landi Nicole
Published: April 2020

Research using functional and structural magnetic resonance imaging has identified areas of reduced brain activation and gray matter volume in children and adults with reading disability, but associations between cortical structure and individual differences in reading in typically developing children remain underexplored. Furthermore, the majority of research linking gray matter structure to reading ability quantifies gray matter in terms of volume, and cannot specify unique contributions of cortical surface area and thickness to these relationships. Here, we applied a continuous analytic approach to investigate associations between distinct surface-based properties of cortical structure and individual differences in reading-related skills in a sample of typically developing young children. Correlations between cortical structure and reading-related skills were conducted using a surface-based vertex-wise approach. Cortical thickness in the left superior temporal cortex was positively correlated with word and pseudoword reading performance. The observed positive correlation between cortical thickness in the left superior temporal cortex and reading may have implications for the patterns of brain activation that support reading.
Indirect effects of severe acute respiratory syndrome coronavirus 2 on the kidney in coronavirus disease patients
Authors: Couturier Aymeric , Ferlicot Sophie , Chevalier Kévin , Guillet Matthieu , Essig Marie , Jauréguiberry Stéphane , Collarino Rocco , Dargelos Mathilde , Michaut Alice , Geri Guillaume , Roque-Afonso Anne-Marie , Zaidan Mohamad , Massy Ziad A
Published: April 2020

Among patients hospitalized for novel coronavirus disease (COVID-19), between 10 and 14% develop an acute kidney injury and around half display marked proteinuria and haematuria. Post-mortem analyses of COVID-19 kidney tissue suggest that renal tubular cells and podocytes are affected. Here we report two cases of collapsing glomerulopathy and tubulointerstitial lesions in living COVID-19 patients. Despite our use of sensitive reverse transcription polymerase chain reaction techniques in this study, we failed to detect the virus in blood, urine and kidney tissues. Our observations suggest that these kidney lesions are probably not due to direct infection of the kidney by severe acute respiratory syndrome coronavirus 2.
Antitubercular Therapy Given to Differentiate Crohn’s Disease From Intestinal Tuberculosis Predisposes to Stricture Formation
Authors: Gupta Akshita , Pratap Mouli Venigalla , Mohta Srikant , Kante Bhaskar , Kalaivani Mani , Madhu Deepak , Sahu Pabitra , Kumar Sudheer , Sharma Raju , Sahni Peush , Das Prasenjit , Gupta Siddharth Datta , Makharia Govind , Kedia Saurabh , Ahuja Vineet
Published: April 2020

Background and Aim

Treatment trial with antitubercular therapy [ATT] is a common strategy in tuberculosis-endemic countries in case of a diagnostic dilemma between intestinal tuberculosis and Crohn’s disease [CD]. Our aim was to determine the long-term clinical course of patients who received ATT before an eventual diagnosis of CD was made.

Methods

We performed retrospective comparison between CD patients who received ≥6 months of ATT vs those who did not receive ATT. Outcomes assessed were change in disease behaviour during follow-up, requirement of surgery and medication use.

Results

In all, 760 patients with CD were screened for the study and, after propensity matching for location and behaviour of disease, 79 patients in each group were compared. Progression from inflammatory [B1] to stricturing/fistulising [B2/B3] phenotype was increased among CD patients who received ATT [B1, B2, B3: 73.4%, 26.6%, 0% at baseline vs: 41.8%, 51.9%, 6.3% at follow-up, respectively] as compared with those who did not receive ATT [B1, B2, B3: 73.4%, 26.6%, 0% at baseline vs: 72.2%, 27.8%, 0% at follow-up, respectively] with an odds ratio of 11.05[3.17–38.56]. The usage of 5-aminosalocylates, steroids, immunosuppressants and anti-tumour necrosis factor was similar between both the groups. On survival analysis, CD patients who received ATT had a lower probability of remaining free of surgery [45%] than those who did not [76%] at 14 years of follow-up (hazard ratio [HR] = 3.22, 95% confidence interval [CI], 1.46–7.12, p = 0.004].

Conclusions

Crohn’s disease patients diagnosed after a trial with antitubercular therapy had an unfavourable long-term disease course with higher rate of stricture formation and less chance of remaining free of surgery.
The Origins of the Interventionist State in France, 1830–1870
Authors: Greenfield Jerome
Published: April 2020

The historiography of the French state’s economic interventionism has focused primarily on the Ancien Régime and the period from the 1850s into the twentieth century. This article argues that, though often overlooked, the French state embarked on a major expansion in the 1830s and 1840s, as government spending on public works grew sharply. Most notably, the government contributed to the financing of railways and urban improvements. Following the 1848 revolution, rising pressure for fiscal rectitude forced a reconfiguration of the interventionist Orleanist state. While the new Bonapartist regime remained committed to public works, it relied more heavily on private finance than its predecessor, benefiting from the ‘great boom’ of the 1850s. Still, private enterprise remained inadequate to sustain public works without the support of public money, particularly once economic expansion began to slow in the 1860s. As a result, government spending on public works continued to rise under the Bonapartists. In this respect, they sustained the conception of an interventionist state developed by the Orleanists.
No antibiotic and toxic metabolites produced by the biocontrol agent Pseudomonas putida strain B2017
Authors: Daura-Pich Oriol , Hernández Iker , Pinyol-Escala Lola , Lara Jose M , Martínez-Servat Sonia , Fernández Carolina , López-García Belén
Published: April 2020

Pseudomonas putida and closely-related species such as Pseudomonas fluorescens and Pseudomonas brassicacearum have been reported as potential biocontrol agents and plant growth-promoters. Recently, we have described the biocontrol activity of P. putida B2017 against several phytopathogens of agricultural relevance. In this study, its ability to produce potential antibiotic / toxic metabolites was assessed by functional, chromatography-mass spectrometry and genomic analysis. Our results show that B2017 is not able to synthesize surfactants and common antibiotics produced by Pseudomonas spp., i.e. pyrrolnitrin, 2,4-diacetylphloroglucinol, pyoluteorin and pyocyanin, but it produces pyoverdine, a siderophore which is involved in its biocontrol activity. The non-production of other metabolites, such as cyanide, safracin, promysalin and lipopeptides between others, is also discussed. Our data suggest that the mode of action of B2017 is not mainly due to the production of antimicrobial / toxic metabolites. Moreover, these features make P. putida B2017 a promising biocontrol microorganism for plant protection without side effects on environment, non-target organisms and human health.
Apolipoprotein ɛ4 Allele and Subjective Cognitive Functioning in Parents of Adults With Disabilities
Authors: Song Jieun , Mailick Marsha R , Greenberg Jan S
Published: April 2020

Objectives

Parents of individuals with disabilities face ongoing responsibilities of providing care and support for their children, even during the child’s adulthood. Past research has shown that this caregiving role is linked to chronic stress and subsequent adverse health outcomes for parents, including impaired cognition. This study examines the impacts of genetic risk for cognitive impairment (apolipoprotein [APOE] ɛ4 allele) among parents of adults with disabilities and comparison parents whose adult children do not have disabilities.

Method

We performed rank order regression analysis of data from the Wisconsin Longitudinal Study (2004–2006 and 2010–2012 surveys and DNA samples). Participants included parents of adults with disabilities (247 mothers and 159 fathers) and comparison parents whose adult children were not disabled (1,482 mothers and 954 fathers).

Results

Mothers who had adult children with disabilities and who were APOE ɛ4 carriers reported significantly declining levels of subjective cognitive functioning over time, but mothers of adults with disabilities who did not have the APOE ɛ4 allele did not manifest this change. Among comparison group mothers, cognitive change over time was not a function of their APOE ɛ4 carrier status. Fathers’ cognitive function did not differ significantly by either parental status or APOE ɛ4 carrier status.

Discussion

The results show that older mothers of adults with disabilities are more susceptible to cognitive impairment than their age peers if they have the genetic risk factor of APOE ɛ4 allele.
Robust well-log based determination of rock thermal conductivity through machine learning
Authors: Meshalkin Yury , Shakirov Anuar , Popov Evgeniy , Koroteev Dmitry , Gurbatova Irina
Published: April 2020

Rock thermal conductivity is an essential input parameter for enhanced oil recovery methods design and optimization and for basin and petroleum system modelling. Absence of any effective technique for direct in situ measurements of rock thermal conductivity makes the development of well-log based methods for rock thermal conductivity determination highly desirable. A major part of the existing problem solutions is regression model-based approaches. Literature review revealed that there are only several studies performed to assess the applicability of neural network-based algorithms to predict rock thermal conductivity from well-logging data. In this research, we aim to define the most effective machine-learning algorithms for well-log based determination of rock thermal conductivity. Well-logging data acquired at a heavy oil reservoir together with results of thermal logging on cores extracted from two wells were the basis for our research. Eight different regression models were developed and tested to predict vertical variations of rock conductivity from well-logging data. Additionally, rock thermal conductivity was determined based on Lichtenecker–Asaad model. Comparison study of regression-based and theoretical-based approaches was performed. Among considered machine learning techniques Random Forest algorithm was found to be the most accurate at well-log based determination of rock thermal conductivity. From a comparison of the thermal conductivity—depth profile predicted from well-logging data with the experimental data, and it can be concluded that thermal conductivity can be determined with a total relative error of 12.54 per cent. The obtained results prove that rock thermal conductivity can be inferred from well-logging data for wells that are drilled in a similar geological setting based on the Random Forest algorithm with an accuracy sufficient for industrial needs.
Wave-equation dispersion spectrum inversion for near-surface characterization using fibre-optics acquisition
Authors: Zhang Zhen-dong , Alajami Mamdoh , Alkhalifah Tariq
Published: April 2020

Distributed acoustic sensing (DAS) acquisition is becoming more and more popular for its dense sampling at a lower cost than seismometers. However, data processing for DAS data is challenging, especially for surface-deployedfibers, in which only the horizontal component of strain variation is effectively recorded. Also, the coupling between the fiber and the Earth is usually poor and the recorded single-component data are noisy. Thus, we introduce data processing strategies dedicated to enhancing the ambient-noise and active-source seismic data recorded by a horizontally deployed tactical fiber-optics cable buried in a sand dune area in Saudi Arabia. We propose a similarity-weighted stacking of randomly selected short-time duration windows to generate virtual common shot gathers (CSG) from the recorded ambient noise. The similarity-weighted stacking only counts the primary contributions of coherent events, while a short-time correlation can suppress the crosstalk usually present in late arrivals. The stacking fold is preserved or even can be increased by generating plenty of random time segments compared to stacking the full recording time. For the recorded active-source data, we skip the interferometric step, but use the envelope of the CSG. The envelope is needed to mitigate the complexity of waveforms, while preserving the slopes of arrivals. Then, we use the wave-equation-based Rayleigh-wave dispersion spectrum inversion, which utilizes all the dispersion modes available and does not require picking the dispersion curve, in estimating the shallow S-wave velocities. The local cross-correlation objective function allows for additional freedom in matching the modelled and observed data, and thus, helps us avoid falling into a local minimum when starting with kinematically poor velocity models.
Randomized sketch descent methods for non-separable linearly constrained optimization
Authors: Necoara Ion , Takáč Martin
Published: April 2020

In this paper we consider large-scale smooth optimization problems with multiple linear coupled constraints. Due to the non-separability of the constraints, arbitrary random sketching would not be guaranteed to work. Thus, we first investigate necessary and sufficient conditions for the sketch sampling to have well-defined algorithms. Based on these sampling conditions we develop new sketch descent methods for solving general smooth linearly constrained problems, in particular, random sketch descent (RSD) and accelerated random sketch descent (A-RSD) methods. To our knowledge, this is the first convergence analysis of RSD algorithms for optimization problems with multiple non-separable linear constraints. For the general case, when the objective function is smooth and non-convex, we prove for the non-accelerated variant sublinear rate in expectation for an appropriate optimality measure. In the smooth convex case, we derive for both algorithms, non-accelerated and A-RSD, sublinear convergence rates in the expected values of the objective function. Additionally, if the objective function satisfies a strong convexity type condition, both algorithms converge linearly in expectation. In special cases, where complexity bounds are known for some particular sketching algorithms, such as coordinate descent methods for optimization problems with a single linear coupled constraint, our theory recovers the best known bounds. Finally, we present several numerical examples to illustrate the performances of our new algorithms.
Immunogenicity and Safety of Porcine Circovirus-Free Human Rotavirus Vaccine in Healthy Infants: A Phase 3 Randomized Trial
Authors: Salamanca de la Cueva Ignacio , Pahud Barbara , Huang Li-Min , Leonardi Michael , Garcia-Sicilia José , Céspedes Javier , Abdelnour Arturo , Tamura Tsuyoshi , Kuroki Haruo , Chiu Nan-Chang , Virta Miia , Kokko Satu , Horn Michael , Panzer Falko , Kim Jong-Hyun , Lee Jin , Moerman Leentje , Debacq Christophe , Parra Jose , Ugarte Ana , Bi Dan ,   Rota-081 Study Group
Published: April 2020

Background

Porcine circovirus type 1 (PCV-1) material was detected in the human rotavirus vaccine (HRV) in 2010. In this study we compared immunogenicity and safety of the PCV-free HRV vaccine (PCV-free HRV) with HRV. PCV-free HRV is an HRV with no detectable PCV-1 and PCV-2 according to the limit of detection of the tests used.

Methods

Healthy infants 6–12 weeks of age were randomized (1:1:1:1) to receive 2 doses of 1 of the 3 lots of PCV-free HRV or HRV. The study objectives were to demonstrate lot-to-lot consistency of the PCV-free HRV and noninferiority of PCV-free HRV as compared to HRV in terms of immunogenicity, 1–2 months post dose 2. Reactogenicity and safety were also assessed.

Results

Overall, 1612 infants were enrolled and 1545 completed the study. Study objectives were demonstrated because the predefined criteria were met. Among participants receiving PCV-free HRV and HRV, 79.27% and 81.76% seroconverted and geometric mean concentrations were 159.5 and 152.8 U/mL, respectively. The incidences of adverse events and serious adverse events were similar between the pooled PCV-free HRV and HRV groups.

Conclusions

The 3 PCV-free HRV lots demonstrated consistency and PCV-free HRV was noninferior compared to HRV in terms of immunogenicity.

Clinical trials registration

NCT02914184.
Challenges and Opportunities of Using Adoptive T-Cell Therapy as Part of an HIV Cure Strategy
Authors: Zhou Yuqi , Maldini Colby R , Jadlowsky Julie , Riley James L
Published: April 2020

HIV-infected individuals successfully controlling viral replication via antiretroviral therapy often have a compromised HIV-specific T-cell immune response due to the lack of CD4 T-cell help, viral escape, T-cell exhaustion, and reduction in numbers due to the withdrawal of cognate antigen. A successful HIV cure strategy will likely involve a durable and potent police force that can effectively recognize and eliminate remaining virus that may emerge decades after an individual undergoes an HIV cure regimen. T cells are ideally suited to serve in this role, but given the state of the HIV-specific T-cell response, it is unclear how to best restore HIV-specific T-cell activity prior initiation of a HIV cure strategy. Here, we review several strategies of generating HIV-specific T cells ex vivo that are currently being tested in the clinic and discuss how infused T cells can be part of an HIV cure strategy.
Unique Approach to Quality Assurance in Viscoelastic Testing
Authors: Leadbetter Nicole H , Givens Thomas B , Viola Francesco
Published: April 2020

Background

The Quantra QPlus System is a novel viscoelastic testing (VET) device designed for the management of coagulation function in critical care settings. The system is indicated and approved for use at the point-of-care and designed for use by nonlaboratory personnel.

Methods

We describe the comprehensive set of internal QC checks implemented in the Quantra and demonstrate the system’s unique capabilities made possible by its ultrasound core technology. Single- and multisite precision testing were performed following Clinical Laboratory Standards Institute guidelines and included multiple days of testing, multiple instruments, multiple lots of cartridges and controls, and multiple operators.

Results

Percent CVs for total imprecision were 3.6% to 8.0% for all measured parameters. CVs for replicate imprecision (“repeatability”) were 2.7% to 7.7% for all measured parameters. Replicate imprecision was the largest component of variability for most parameters.

Conclusions

The Quantra QPlus System is a new-generation cartridge-based VET device that can operate with reduced oversight from the central laboratory while easily integrating into the Individualized Quality Control Plan framework.
The First Reported Case of a Synthetic Cannabinoid Ethyl Ester Detected in a Postmortem Blood Toxicological Analysis
Authors: Apirakkan Orapan , Hudson Simon , Couchman Lewis , Cowan David , Morley Stephen , Abbate Vincenzo
Published: April 2020

Metabolites of synthetic cannabinoids (SCs) are widely used as markers for identifying SCs’ intake. Polydrug use involving SCs and ethanol may generate new metabolites, namely SC ethyl esters, hereby shown for the first time as new blood markers of SC-alcohol concomitant abuse. We report a case involving both the presence of 5F-PB22 and ethanol and the detection of their transesterifcation product, namely 5F-PB22 ethyl ester, in a postmortem blood sample. This marker was found retrospectively in a preserved femoral blood analyzed via liquid chromatography–high-resolution mass spectrometry. A single-point calibration was used to estimate the concentration of 5F-PB22-Et in the sample, which found to be 0.4 μg/L. Retention time and fragment ions (within ±1 mmu extraction window) of 5F-PB22-Et in the sample gave a remarkable match with a synthetic reference material. To the best of our knowledge, this is the first case report of an SC ethyl ester in a biological sample to indicate SCs and ethanol co-consumption.
A UHPLC–MS-MS Method for the Determination of 84 Drugs of Abuse and Pharmaceuticals in Blood
Authors: Orfanidis Amvrosios , Gika Helen G , Theodoridis Georgios , Mastrogianni Orthodoxia , Raikos Nikolaos
Published: April 2020

The analysis of blood samples for forensic or clinical intoxication cases is a daily routine in an analytical laboratory. The list of ‘suspect’ drugs of abuse and pharmaceuticals that should be ideally screened is large, so multi-targeted methods for comprehensive detection and quantification are a useful tool in the hands of a toxicologist. In this study, the development of an ultra-high performance liquid chromatography (LC)–tandem mass spectrometry (MS-MS) method is described for the detection and quantification of 84 drugs and pharmaceuticals in postmortem blood. The target compounds comprise pharmaceutical drugs (antipsychotics, antidepressants, etc.), some of the most important groups of drugs of abuse: opiates, cocaine, cannabinoids, amphetamines, benzodiazepines and new psychoactive substances. Sample pretreatment was studied applying a modified Mini-QuEChERS single step, and the best results were obtained after adding a mixture of 20 mg MgSO4, 5 mg K2CO3 and 5 mg NaCl together with 600 μL of cold acetonitrile in 200 μL of sample. After centrifugation, the supernatant was collected for direct injection. LC–MS analysis took place on a C18 column with a gradient elution over 17 min. The method was found to be selective and sensitive, offering limits of detection ranging from 0.01 to 9.07 ng/mL. Validation included evaluation of limit of quantification, recovery, carryover, matrix effect, accuracy and precision of the method. The method performed satisfactorily in relation to established bioanalytical criteria and was therefore applied to the analysis of blood obtained postmortem from chronic drug abusers, offering unambiguous identification and quantitative determination of drugs in postmortem blood.
Media and Crime Perceptions: Evidence from Mexico
Authors: Ramírez-Álvarez Aurora Alejandra
Published: April 2020

This article examines whether individuals’ crime perceptions and crime avoidance behavior respond to changes in crime news coverage. I use data from Mexico, where major media groups agreed to reduce coverage of violence in March 2011. Using a unique dataset on national news content and machine learning techniques, I document that after the Agreement, crime news coverage on television, radio, and newspapers decreases relative to the national homicide rate. Using survey data, I find robust evidence that crime perceptions respond to this change in content. After the Agreement, individuals with higher media exposure are less likely to report that they feel insecure and that their country, state, or municipality is insecure, relative to individuals with lower media exposure. Finally, I show that smaller changes on conspicuous consumption and food consumed outside the home accompany these changes in crime perceptions; while I do not find effects on stated crime avoidance behavior. (JEL: D83, K42, L82).
The tale of caspase homologues and their evolutionary outlook: deciphering programmed cell death in cyanobacteria
Authors: Bhattacharjee Samujjal , Mishra Arun Kumar
Published: April 2020

Programmed cell death (PCD), a genetically orchestrated mechanism of cellular demise, is paradoxically required to support life. As in lower eukaryotes and bacteria, PCD in cyanobacteria is poorly appreciated, despite recent biochemical and molecular evidence that supports its existence. Cyanobacterial PCD is an altruistic reaction to stressful conditions that significantly enhances genetic diversity and inclusive fitness of the population. Recent bioinformatic analysis has revealed an abundance of death-related proteases, i.e. orthocaspases (OCAs) and their mutated variants, in cyanobacteria, with the larger genomes of morphologically complex strains harbouring most of them. Sequence analysis has depicted crucial accessory domains along with the proteolytic p20-like sub-domain in OCAs, predicting their functional versatility. However, the cascades involved in sensing death signals, their transduction, and the downstream expression and activation of OCAs remain to be elucidated. Here, we provide a comprehensive description of the attempts to identify mechanisms of PCD and the existence and importance of OCAs based on in silico approaches. We also review the evolutionary and ecological significance of PCD in cyanobacteria. In the future, the analysis of cyanobacterial PCD will identify novel proteins that have varied functional roles in signalling cascades and also help in understanding the incipient mechanism of PCD morphotype(s) from where eukaryotic PCD might have originated.
The importance of accurate developmental staging
Authors: Ober Eric S , Howell Phil , Thomelin Pauline , Kouidri Allan
Published: April 2020

This article comments on:

Fernández-Gómez J, Talle B, Tidy A, Wilson ZA. 2020. Accurate staging of reproduction development in Cadenza wheat by non-destructive spike analysis. Journal of Experimental Botany71, 3475–3484.
Reionization with galaxies and active galactic nuclei
Authors: Dayal Pratika , Volonteri Marta , Choudhury Tirthankar Roy , Schneider Raffaella , Trebitsch Maxime , Gnedin Nickolay Y , Atek Hakim , Hirschmann Michaela , Reines Amy
Published: April 2020

In this work we investigate the properties of the sources that reionized the intergalactic medium (IGM) in the high-redshift Universe. Using a semi-analytical model aimed at reproducing galaxies and black holes in the first ∼1.5 Gyr of the Universe, we revisit the relative role of star formation and black hole accretion in producing ionizing photons that can escape into the IGM. Both star formation and black hole accretion are regulated by supernova feedback, resulting in black hole accretion being stunted in low-mass haloes. We explore a wide range of combinations for the escape fraction of ionizing photons (redshift-dependent, constant, and scaling with stellar mass) from both star formation ($\langle f_{\rm esc}^{\rm sf} \rangle$) and AGN ($f_{\rm esc}^{\rm bh}$) to find: (i) the ionizing budget is dominated by stellar radiation from low stellar mass ($M_*\lt 10^9 \, {\rm \rm M_\odot }$) galaxies at z > 6 with the AGN contribution (driven by $M_{bh}\gt 10^6 \, {\rm \rm M_\odot }$ black holes in $M_* \gtrsim 10^9\, {\rm \rm M_\odot }$ galaxies) dominating at lower redshifts; (ii) AGN only contribute $10-25{{\ \rm per\ cent}}$ to the cumulative ionizing emissivity by z = 4 for the models that match the observed reionization constraints; (iii) if the stellar mass dependence of $\langle f_{\rm esc}^{\rm sf} \rangle$ is shallower than $f_{\rm esc}^{\rm bh}$, at z < 7 a transition stellar mass exists above which AGN dominate the escaping ionizing photon production rate; (iv) the transition stellar mass decreases with decreasing redshift. While AGN dominate the escaping emissivity above the knee of the stellar mass function at z ∼ 6.8, they take-over at stellar masses that are a tenth of the knee mass by z = 4.
Visible and near-infrared observations of interstellar comet 2I/Borisov with the 10.4-m GTC and the 3.6-m TNG telescopes
Authors: de León J , Licandro J , de la Fuente Marcos C , de la Fuente Marcos R , Lara L M , Moreno F , Pinilla-Alonso N , Serra-Ricart M , De Prá M , Tozzi G P , Souza-Feliciano A C , Popescu M , Scarpa R , Font Serra J , Geier S , Lorenzi V , Harutyunyan A , Cabrera-Lavers A
Published: April 2020

In this work, we present the results of an observational study of 2I/Borisov carried out with the 10.4-m Gran Telescopio Canarias (GTC) and the 3.6-m Telescopio Nazionale Galileo (TNG), both telescopes located at the Roque de Los Muchachos Observatory, in the island of La Palma (Spain). The study includes images in the visible and near-infrared, as well as visible spectra in the 3600–9200 Å wavelength range. N-body simulations were also performed to explore its orbital evolution and Galactic kinematic context. The comet’s dust continuum and near-infrared colours are compatible with those observed for Solar system comets. From its visible spectrum on the nights of 2019 September 24 and 26, we measured CN gas production rates Q(CN) = (2.3 ± 0.4) × 1024 mol s−1 and Q(CN) = (9.5 ± 0.2) × 1024 mol s−1, respectively, in agreement with measurements reported by other authors on similar nights. We also obtained an upper limit for the C2 production rate of Q(C2) < (4.5 ± 0.1) × 1024 mol s−1. Dust modelling results indicate a moderate dust production rate of ∼50 kg s−1 at heliocentric distance rh = 2.6 au, with a differential power-law dust size distribution of index ∼–3.4, within the range reported for many comet comae. Our simulations show that the Galactic velocity of 2I/Borisov matches well that of known stars in the solar neighbourhood and also those of more distant regions of the Galactic disc.
Revealing thermodynamics of DNA origami folding via affine transformations
Authors: Majikes Jacob M , Patrone Paul N , Schiffels Daniel , Zwolak Michael , Kearsley Anthony J , Forry Samuel P , Liddle J Alexander
Published: April 2020

Structural DNA nanotechnology, as exemplified by DNA origami, has enabled the design and construction of molecularly-precise objects for a myriad of applications. However, limitations in imaging, and other characterization approaches, make a quantitative understanding of the folding process challenging. Such an understanding is necessary to determine the origins of structural defects, which constrain the practical use of these nanostructures. Here, we combine careful fluorescent reporter design with a novel affine transformation technique that, together, permit the rigorous measurement of folding thermodynamics. This method removes sources of systematic uncertainty and resolves problems with typical background-correction schemes. This in turn allows us to examine entropic corrections associated with folding and potential secondary and tertiary structure of the scaffold. Our approach also highlights the importance of heat-capacity changes during DNA melting. In addition to yielding insight into DNA origami folding, it is well-suited to probing fundamental processes in related self-assembling systems.
AWSEM-Suite: a protein structure prediction server based on template-guided, coevolutionary-enhanced optimized folding landscapes
Authors: Jin Shikai , Contessoto Vinicius G , Chen Mingchen , Schafer Nicholas P , Lu Wei , Chen Xun , Bueno Carlos , Hajitaheri Arya , Sirovetz Brian J , Davtyan Aram , Papoian Garegin A , Tsai Min-Yeh , Wolynes Peter G
Published: April 2020

The accurate and reliable prediction of the 3D structures of proteins and their assemblies remains difficult even though the number of solved structures soars and prediction techniques improve. In this study, a free and open access web server, AWSEM-Suite, whose goal is to predict monomeric protein tertiary structures from sequence is described. The model underlying the server’s predictions is a coarse-grained protein force field which has its roots in neural network ideas that has been optimized using energy landscape theory. Employing physically motivated potentials and knowledge-based local structure biasing terms, the addition of homologous template and co-evolutionary restraints to AWSEM-Suite greatly improves the predictive power of pure AWSEM structure prediction. From the independent evaluation metrics released in the CASP13 experiment, AWSEM-Suite proves to be a reasonably accurate algorithm for free modeling, standing at the eighth position in the free modeling category of CASP13. The AWSEM-Suite server also features a front end with a user-friendly interface. The AWSEM-Suite server is a powerful tool for predicting monomeric protein tertiary structures that is most useful when a suitable structure template is not available. The AWSEM-Suite server is freely available at: https://awsem.rice.edu.
Structural disruption of exonic stem–loops immediately upstream of the intron regulates mammalian splicing
Authors: Saha Kaushik , England Whitney , Fernandez Mike Minh , Biswas Tapan , Spitale Robert C , Ghosh Gourisankar
Published: April 2020

Recognition of highly degenerate mammalian splice sites by the core spliceosomal machinery is regulated by several protein factors that predominantly bind exonic splicing motifs. These are postulated to be single-stranded in order to be functional, yet knowledge of secondary structural features that regulate the exposure of exonic splicing motifs across the transcriptome is not currently available. Using transcriptome-wide RNA structural information we show that retained introns in mouse are commonly flanked by a short (≲70 nucleotide), highly base-paired segment upstream and a predominantly single-stranded exonic segment downstream. Splicing assays with select pre-mRNA substrates demonstrate that loops immediately upstream of the introns contain pre-mRNA-specific splicing enhancers, the substitution or hybridization of which impedes splicing. Additionally, the exonic segments flanking the retained introns appeared to be more enriched in a previously identified set of hexameric exonic splicing enhancer (ESE) sequences compared to their spliced counterparts, suggesting that base-pairing in the exonic segments upstream of retained introns could be a means for occlusion of ESEs. The upstream exonic loops of the test substrate promoted recruitment of splicing factors and consequent pre-mRNA structural remodeling, leading up to assembly of the early spliceosome. These results suggest that disruption of exonic stem–loop structures immediately upstream (but not downstream) of the introns regulate alternative splicing events, likely through modulating accessibility of splicing factors.
Protein tolerance to random circular permutation correlates with thermostability and local energetics of residue-residue contacts
Authors: Atkinson Joshua T , Jones Alicia M , Nanda Vikas , Silberg Jonathan J
Published: April 2020

Adenylate kinase (AK) orthologs with a range of thermostabilities were subjected to random circular permutation, and deep mutational scanning was used to evaluate where new protein termini were nondisruptive to activity. The fraction of circularly permuted variants that retained function in each library correlated with AK thermostability. In addition, analysis of the positional tolerance to new termini, which increase local conformational flexibility, showed that bonds were either functionally sensitive to cleavage across all homologs, differentially sensitive, or uniformly tolerant. The mobile AMP-binding domain, which displays the highest calculated contact energies, presented the greatest tolerance to new termini across all AKs. In contrast, retention of function in the lid and core domains was more dependent upon AK melting temperature. These results show that family permutation profiling identifies primary structure that has been selected by evolution for dynamics that are critical to activity within an enzyme family. These findings also illustrate how deep mutational scanning can be applied to protein homologs in parallel to differentiate how topology, stability, and local energetics govern mutational tolerance.
cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis
Authors: Worrell Julie C , Leslie Jack , Smith Graham R , Zaki Marco Y W , Paish Hannah L , Knox Amber , James Michelle L , Cartwright Tyrell N , O’Reilly Steven , Kania Gabriela , Distler Oliver , Distler Jörg H W , Herrick Ariane L , Jeziorska Maria , Borthwick Lee A , Fisher Andrew J , Mann Jelena , Mann Derek A , Oakley Fiona
Published: April 2020

Objectives

NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc.

Methods

Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel−/− murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls.

Results

cRel expression was elevated in murine lung and skin fibrosis models. Rel−/− mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts.

Conclusion

cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease.
Baseline Sensitivity and Toxic Action of the Sterol Demethylation Inhibitor Flusilazole Against Botrytis cinerea
Authors: Wang Yong , Wang Miaomaio , Xu Letian , Sun Yang , Feng Juntao
Published: April 2020

In the present study, a total of 95 Botrytis cinerea single-spore strains collected from different hosts in Shaanxi Province of China were characterized for their sensitivity to the sterol demethylation inhibitor fungicide flusilazole. The effective concentration for 50% inhibition of mycelial growth (EC50) of flusilazole ranged from 0.021 to 0.372 µg/ml, with an average value of 0.093 µg/ml. Cross-resistance between flusilazole and commonly used fungicides was not detected, and no flusilazole-resistant mutants were induced. Both on detached strawberry leaves and in greenhouse experiments, flusilazole was more effective than the commonly used fungicide carbendazim at reducing gray mold. After culture on PDA plates or detached strawberry leaves, no difference in sclerotia production or pathogenicity was detected between two strains, WG12 (most sensitive to flusilazole) and MX18 (least sensitive to flusilazole). After treatment with flusilazole, however, the two strains lost the ability to produce sclerotia, and oxalic acid and ergosterol contents in mycelium decreased. Interestingly, the inhibition rate of ergosterol content in MX18 was significantly lower than that in WG12. Expression of Cyp51, BcatrD, and Bcmfs1 genes all increased after treatment with flusilazole, especially the Cyp51 and BcatrD genes. However, the expression of Cyp51 gene or BcatrD gene in WG12 and MX18 were significantly different from each other after treatment with flusilazole. In addition, no point mutations in Cyp51 gene were found in MX18. These data suggest flusilazole is a promising fungicide for resistance management of gray mold and also provided novel insights into understanding the resistance mechanism of flusilazole against plant pathogens.
Acute abdominal pain from epiploic appendagitis
Authors: Peña Santiago , Wilkin Zebulon
Published: April 2020

Evaluating patients for abdominal pain is common in the ED and can involve many differential diagnoses and treatment options. This case report describes a 35-year-old active duty military man whose abdominal pain evaluation at a military treatment facility led to the diagnosis of epiploic appendagitis.
Care coordination for children with medical complexity
Authors: Cady Rhonda , Bushaw Andrea , Davis Heidi , Mills Julie , Thomasson Deana
Published: April 2020

Children with medical complexity have complex health management and care coordination needs. Care models that address these needs rely on interprofessional teams that include NPs. Understanding these care models allows NPs from all disciplines to support the care of this growing patient population in pediatric and adult settings.
Existential Contradictions in Living With End-Stage Renal Disease
Authors: Kristensen Ingrid Villadsen , Henriksen Jette , Birkelund Regner , Norlyk Annelise
Published: April 2020

A qualitative metasynthesis following Sandelowski and Barroso's method was conducted to explore what characterizes the existential experiences of individuals living with end-stage renal disease. The findings show that patients with end-stage renal disease live with several existential contradictions characterized by the following: perception of the body—oscillating between connection and separation, maintaining life—oscillating between freedom and captivity, uncertainty—oscillating between hope and despair, and enduring technology—oscillating between being perceived as an object and subject. Consequently, living with end-stage renal disease is challenging for patients; hence, the support of nurses is important to alleviate patients' vulnerability.
Anterior Vertebral Body Growth Modulation
Authors: Cobetto Nikita , Aubin Carl-Eric , Parent Stefan
Published: April 2020

Study Design.

Numerical planning and simulation of immediate and after 2 years growth modulation effects of anterior vertebral body growth modulation (AVBGM).

Objective.

The objective was to evaluate the planning tool predictive capability for immediate, 1-year, and 2-year postoperative correction and biomechanical effect on growth modulation over time.

Summary of Background Data.

AVBGM is used to treat pediatric scoliotic patients with remaining growth potential. A planning tool based on a finite element model (FEM) of pediatric scoliosis integrating growth was previously developed to simulate AVBGM installation and growth modulation effect.

Methods.

Forty-five patients to be instrumented with AVBGM were recruited. A patient-specific FEM was preoperatively generated using a 3D reconstruction obtained from biplanar radiographs. The FEM was used to assess different instrumentation configurations. The strategy offering the optimal 2-year postoperative correction was selected for surgery. Simulated 3D correction indices, as well as stresses applied on vertebral epiphyseal growth plates, intervertebral discs, and instrumentation, were computed.

Results.

On average, six configurations per case were tested. Immediate, 1-year, and 2-year postoperative 3D correction indices were predicted within 4° of that of actual results in coronal plane, whereas it was <0.8 cm (±2%) for spinal height. Immediate postoperative correction was of 40%, whereas an additional correction of respectively 13% and 3% occurred at 1- and 2 year postoperative. The convex/concave side computed forces difference at the apical level following AVBGM installation was decreased by 39% on growth plates and 46% on intervertebral discs.

Conclusion.

This study demonstrates the FEM clinical usefulness to rationalize surgical planning by providing clinically relevant correction predictions. The AVBGM biomechanical effect on growth modulation over time seemed to be maximized during the first year following the installation.

Level of Evidence: 3
Impact of High-intensity Zones on Their Corresponding Lumbar Spine Segments
Authors: Chen Xiao , Tamai Koji , Yang Jui-Jung , Shah Ishan D. , Paholpak Permsak , Wang Jeffrey C. , Buser Zorica
Published: April 2020

Study Design:

Retrospective radiographic study.

Objective:

The aim of this study was to compare disks with and without high-intensity zones (HIZ) to understand the impact of an HIZ on the stability of corresponding lumbar spinal segments.

Summary of Background Data:

Previous studies have established a relationship between back pain and the presence of HIZ on T2-weighted images of magnetic resonance imaging. These previous studies, however, used either plain radiographs or static (neutral position) magnetic resonance imaging to assess their chosen variables.

Materials and Methods:

We retrospectively reviewed 140 consecutive patients with MR images taken in weight-bearing neutral, flexion, and extension positions. We separated segments into those with HIZ and without HIZ and assessed the grade of disk degeneration for each segment. Subsequently, a matched control group was selected from the segments without HIZ. Multiple factors were compared in a univariate analysis. A multinomial logistic regression analysis was conducted to assess the association between angular range of motion (ROM) >10 degrees and translational motion >2 mm with multiple independent variables.

Results:

Upon assessment of the 700 lumbar segments, 70 (10%) segments had an HIZ and 68 patients had a single HIZ. On univariate analysis, the presence of an HIZ was not found to be significantly associated with degree of fatty muscle degeneration (P=0.969), muscle volume (P=0.646), degree of facet joint osteoarthritis (P=0.706), intervertebral disk height (P=0.077), Modic change (P=0.951), lower endplate shape (P=0.702), upper endplate shape (P=0.655), or degree of disk degeneration (P=0.607). Multifactorial analysis showed that none of the independent variables significantly correlated with angular ROM >10 degrees. For translational motion, the only significant correlation was the Goutallier classification (P=0.017).

Conclusions:

The presence of HIZ did not significantly affect spinal stability as measured by angular ROM and translational motion and was not associated with significant changes in several quantitative measurements of spine pathology.