bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing
Authors: Yang Bin , Borgeaud Alicia C , Buřičová Marcela , Aeschbach Lorène , Rodríguez-Lima Oscar , Ruiz Buendía Gustavo A , Cinesi Cinzia , Taylor Alysha S , Baubec Tuncay , Dion Vincent
Published: September 2021

Expanded CAG/CTG repeat disorders affect over 1 in 2500 individuals worldwide. Potential therapeutic avenues include gene silencing and modulation of repeat instability. However, there are major mechanistic gaps in our understanding of these processes, which prevent the rational design of an efficient treatment. To address this, we developed a novel system, ParB/ANCHOR-mediated Inducible Targeting (PInT), in which any protein can be recruited at will to a GFP reporter containing an expanded CAG/CTG repeat. Previous studies have implicated the histone deacetylase HDAC5 and the DNA methyltransferase DNMT1 as modulators of repeat instability via mechanisms that are not fully understood. Using PInT, we found no evidence that HDAC5 or DNMT1 modulate repeat instability upon targeting to the expanded repeat, suggesting that their effect is independent of local chromatin structure. Unexpectedly, we found that expanded CAG/CTG repeats reduce the effectiveness of gene silencing mediated by targeting HDAC5 and DNMT1. The repeat-length effect in gene silencing by HDAC5 was abolished by a small molecule inhibitor of HDAC3. Our results have important implications on the design of epigenome editing approaches for expanded CAG/CTG repeat disorders. PInT is a versatile synthetic system to study the effect of any sequence of interest on epigenome editing.
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease
Authors: Zheng Wen-Qiang , Pedersen Signe Vandal , Thompson Kyle , Bellacchio Emanuele , French Courtney E , Munro Benjamin , Pearson Toni S , Vogt Julie , Diodato Daria , Diemer Tue , Ernst Anja , Horvath Rita , Chitre Manali , Ek Jakob , Wibrand Flemming , Grange Dorothy K , Raymond Lucy , Zhou Xiao-Long , Taylor Robert W , Ostergaard Elsebet
Published: September 2021

TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.
A data harmonization pipeline to leverage external controls and boost power in GWAS
Authors: Chen Danfeng , Tashman Katherine , Palmer Duncan S , Neale Benjamin , Roeder Kathryn , Bloemendal Alex , Churchhouse Claire , Ke Zheng Tracy
Published: September 2021

The use of external controls in genome-wide association study (GWAS) can significantly increase the size and diversity of the control sample, enabling high-resolution ancestry matching and enhancing the power to detect association signals. However, the aggregation of controls from multiple sources is challenging due to batch effects, difficulty in identifying genotyping errors and the use of different genotyping platforms. These obstacles have impeded the use of external controls in GWAS and can lead to spurious results if not carefully addressed. We propose a unified data harmonization pipeline that includes an iterative approach to quality control and imputation, implemented before and after merging cohorts and arrays. We apply this harmonization pipeline to aggregate 27 517 European control samples from 16 collections within dbGaP. We leverage these harmonized controls to conduct a GWAS of Crohn’s disease. We demonstrate a boost in power over using the cohort samples alone, and that our procedure results in summary statistics free of any significant batch effects. This harmonization pipeline for aggregating genotype data from multiple sources can also serve other applications where individual level genotypes, rather than summary statistics, are required.
Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species
Authors: Carpentieri Giovanna , Leoni Chiara , Pietraforte Donatella , Cecchetti Serena , Iorio Egidio , Belardo Antonio , Pietrucci Daniele , Di Nottia Michela , Pajalunga Deborah , Megiorni Francesca , Mercurio Laura , Tatti Massimo , Camero Simona , Marchese Cinzia , Rizza Teresa , Tirelli Valentina , Onesimo Roberta , Carrozzo Rosalba , Rinalducci Sara , Chillemi Giovanni , Zampino Giuseppe , Tartaglia Marco , Flex Elisabetta
Published: September 2021

Germline-activating mutations in HRAS cause Costello syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. Concomitant inhibition of p38 and PI3K signaling by wortmannin was able to rescue both the dysregulated glucose intake and accelerated autophagic flux. Our findings provide a mechanistic link between upregulated HRAS function, defective growth and increased resting energetic expenditure in CS, and document that targeting p38 and PI3K signaling is able to revert this metabolic dysfunction.
Family Identity and Roles in the Context of Li-Fraumeni Syndrome: “No One’s Like Us Mutants”
Authors: Wilsnack Catherine , Young Jennifer L. , Merrill Shana L. , Groner Victoria , Loud Jennifer T. , Bremer Renee C. , Greene Mark H. , Khincha Payal P. , Werner-Lin Allison
Published: September 2021

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome in which individuals have a significantly increased risk of developing multiple cancers throughout the life span. An LFS diagnosis may shift the individual’s sense of self and tolerance of cancer risk as they engage in cancer screening and cancer prevention activities. This study examined the impact of family identity on health decision making, communication, and role function. Forty-five families completed one or more interviews during an annual, protocol-specific cancer screening study. An interdisciplinary team analyzed 66 interviews using interpretive description and modified grounding theory. Thematically, identity emerged as an evolving construct regarding self and/or family, embedded in historical and ongoing experiences with LFS. Notions of individual and shared family identities guided decision making related to healthcare and influenced interpersonal communication and role function between supportive networks and families. Alignment between individual, family, and generational identities may shape engagement in genetic testing, risk management, and family life. Medical teams that are unequipped to address the psychosocial challenges that LFS populations face may include mental health professionals on interprofessional care teams to navigate risk management and consequential familial conflict.
Blastocyst formation is similar in obese and normal weight women: a morphokinetic study
Authors: Bellver José , Brandão Pedro , Alegre Lucía , Meseguer Marcos
Published: September 2021

STUDY QUESTION

Does the embryo cleavage pattern and rate of blastocyst formation differ between normal weight and obese women undergoing IVF?

SUMMARY ANSWER

Embryo morphokinetic development, final blastocyst formation rate and blastocyst morphology do not differ between obese and normal weight women.

WHAT IS KNOWN ALREADY

Female obesity has been related to impaired IVF outcomes. Although the mechanisms responsible for this detrimental effect are thought to include impaired oocyte and embryo quality and reduced endometrial receptivity, they are yet to be confirmed. Embryo quality has been commonly assessed using static morphological criteria. Only three studies have analysed the progress of embryos up to the blastocyst stage in women with elevated BMI, but they have used small samples of patients or have obtained contradictory results.

STUDY DESIGN, SIZE, DURATION

This retrospective, cohort study, was performed from January 2016 to May 2020. A total of 3316 ICSI cycles from 2822 women were included, of which 1251 cycles were part of a preimplantation genetic testing programme. In total, 17 848 embryos were analysed.

PARTICIPANTS/MATERIALS, SETTING, METHODS

This study reports on the IVF cycles of infertile women, with a known BMI, who underwent ICSI and whose embryos were grown until the fifth/sixth day of development in a time-lapse system. Patients were grouped as follows. Underweight was defined as a BMI <18.5 kg/m2; normal weight was a BMI of 18.5–24.9 kg/m2; overweight was a BMI of 25–29.9 kg/m2; and obesity was a BMI of ≥30 kg/m2. Embryo development was assessed on an external computer with analysis software.

MAIN RESULTS AND THE ROLE OF CHANCE

Despite an initial slower pattern of embryo development, the blastocyst formation rate on day 5 or on day 5 plus day 6 did not differ in obese women with respect to the other three BMI groups. Moreover, based on the evaluation of inner cell mass and the trophectoderm on both days of blastocyst development, embryo quality was similar across the BMI groups, as were the pattern of development and arrest up to blastocyst formation and the distribution of the categories of full, expanded and hatching blastocysts.

LIMITATIONS, REASONS FOR CAUTION

Limitations include the retrospective analysis of data, the use of BMI as the only parameter to define normal/abnormal female body weight, and the lack of complete information about clinical outcomes.

WIDER IMPLICATIONS OF THE FINDINGS

Blastocyst formation and embryo morphokinetics are not affected by female obesity, and the poorer IVF outcomes described for such women are probably due to deficient endometrial receptivity. The role of endometrial progesterone exposure on the day of embryo transfer should be analysed in future studies as a possible determining factor.

STUDY FUNDING/COMPETING INTEREST(S)

No external funding was used and there are no competing interests.

TRIAL REGISTRATION NUMBER

N/A.
Off the beaten path: what drives scientists’ entry into new fields?
Authors: Kelchtermans Stijn , Neicu Daniel , Veugelers Reinhilde
Published: September 2021

Given that venturing into unknown territory carries substantial risk, scientists do not take the decision to enter a new field lightly. This paper analyzes a broad set of factors associated with the risks and rewards from entry into new-to-the-researcher scientific fields, including individual capacities and preferences as well as incentives stemming from career progression and access to funding. Using a panel of researchers in biomedical sciences and science and engineering from a large European research university, we find that productivity affects new field entry as such but is not associated with entry into fields that are very distant to one’s current expertise. Scientists in more senior ranks, with larger co-author networks and collaborating with PhD students, are more likely to enter new fields, but these factors do not represent an additional push to enter very remote fields. Such “long jumps” are more likely to be made by above-average talented rather than merely productive researchers. Finally, accounting for its endogeneity, we find that funding does not make new field entry more likely.
Corporate governance and R&D investment: the role of debt financing
Authors: Muhammad Hussain , Migliori Stefania , Mohsni Sana
Published: September 2021

This paper examines the role of debt financing in the relationship between corporate governance and research and development (R&D) investment using a sample of publicly traded U.S. pharmaceutical firms from 2009 to 2018. The results show a positive and significant association between corporate governance mechanisms (such as board size, board independence, board gender diversity, and ownership concentration) and R&D investment and a negative and significant association between debt financing and R&D investment. In addition, we show that debt financing plays a moderating role and a partial mediating role in the relationship between corporate governance mechanisms and R&D investment. Specifically, debt financing attenuates the negative effect of board size on R&D investment and accentuates the positive effect of ownership concentration on R&D investment. Our study helps to shed light on a close and complex relationship existing between the firm’s choices of corporate governance, debt financing, and R&D investments, which the previous literature has so far examined in a partial and fragmented way. To ensure effective R&D investment, firms need to consider the effect of debt financing on corporate governance decisions.
Research, innovation, and bankruptcy: evidence from European manufacturing firms
Authors: Agostino Mariarosaria , Scalera Domenico , Succurro Marianna , Trivieri Francesco
Published: September 2021

This paper investigates the effects of R&D and innovation activities of firms on the risk of bankruptcy. The analysis is carried out on data drawn from the EU-EFIGE Survey and Amadeus Database (Bureau Van Dijk) on European manufacturing firms over the years 2009–2014. The empirical evidence shows that default probability is increasing in R&D investments and decreasing in innovation and productivity of research, measured by the ratio of innovation revenues to R&D outlays. In addition, to disentangle the influence of different innovation strategies (product, process, and patenting), 16 different firm profiles are compared. Firms carrying out R&D, adopting process innovation, and filing for patents are found to show the lowest probability of default. Sensitivity checks indicate that research and innovation do not affect the risk of financial distress events short of default (such as reorganization or application for insolvency procedure). Our findings are robust to potential endogeneity and hence allow for causal inference about the relationship between research and innovation and corporate bankruptcy.
Digital technologies, employment, and skills
Authors: Reljic Jelena , Evangelista Rinaldo , Pianta Mario
Published: September 2021

This article investigates the relationship between the diffusion of digital technologies, employment, and skills. The empirical analysis is carried out on industry-level data of six major European economies (Germany, France, Spain, Italy, the Netherlands, and the UK) over the 2009–2014 period. We analyze two dimensions of digitalization: industries’ consumption of intermediate inputs from digitally intensive sectors and investment in Information and Communication Technology (ICT) tangible and intangible assets, considering also patterns of demand, education, technological change, and offshoring. The results show that job creation in industries is positively associated with an increasing share of digital goods and services in total intermediate inputs and is negatively linked with processes of ICT capital deepening. We then explore how these two different patterns of digitalization are related to the evolution of four occupational groups—managers, clerks, craft, and Manual workers, defined on the basis of International Standard Classification of Occupations classes—finding a positive link between ICT consumption and managerial jobs, and negative ones between digital variables and mid-skill occupations.
External financing of innovative small and medium enterprises (SMEs): unpacking bank credit with respect to innovation typologies and combinations
Authors: Gregori Tullio , Montresor Sandro , Rossi Stefania Ps
Published: September 2021

We investigate the extent to which small and medium enterprises’ (SMEs) external financing varies with the innovation profiles they reveal in terms of introduced and combined innovation typologies. Using Survey on the Access to Finance of Enterprises data, we address this research issue with respect to 11 European countries over the 2014–2019 period and overcome the context specificity of previous analyses. Results suggest that the innovative profile of SMEs is responsible for several nuances in both their demand for and supply of bank loans. Being an innovator increases SMEs’ credit requests, but this demand increases also and above all with their involvement in specific innovation typologies and combinations. Having an innovative profile of nearly any type does not lead SMEs to refrain from demanding bank loans because of a fear of rejection, but a wide involvement in specific innovation types reduces the chance that their internal funds make them refrain from asking for credit. Innovative SMEs are significantly more likely to be credit-constrained than non-innovative ones, but the probability of not receiving bank loans increases only for firms that combine specific innovation typologies. An innovation status of SMEs makes banks more selective in their decision to completely fulfill a credit request, but the probability of this decision decreases only with respect to a few, multi-innovation profiles. The extent to which SMEs innovate in different domains, rather than the simple innovation intensity, appears to be a crucial dimension to consider in future research and in devising policies to attenuate financial constraints to innovation.
Phenological diversity of a prey species supports life-stage specific foraging opportunity for a mobile consumer
Authors: Chamberlin Joshua , Petrou Eleni , Duguid Will , Barsh Russel , Juanes Francis , Qualley Jessica , Hauser Lorenz
Published: September 2021

Dynamic prey resources influence foraging opportunities for consumers. In coastal food webs, forage fish abundance and seasonal reproduction mediate foraging opportunities for mobile consumers. Recent declines in Chinook salmon productivity have prompted efforts to determine whether poor marine survival is caused by limited feeding opportunities. To establish the importance of phenological diversity in Pacific herring for Chinook salmon, we used genetic stock identification to assign individual herring collected from the guts of juvenile and adult Chinook salmon to populations with distinct spawning phenologies. The majority of herring in the guts of adult Chinook salmon across seasons and geographic areas were dominated by the March–April herring spawn group, but juvenile Chinook salmon diets varied seasonally, with a higher proportion of January–February spawners in summer than in spring. Our results suggest that (1) population diversity of Pacific herring is used by juvenile Chinook salmon and thus contributes to their growth, and (2) stock-specific distribution of Pacific herring extends well beyond documented spawning grounds. Herring population diversity may therefore support foraging opportunities for Chinook salmon during a critical period and highlights the need for future research to quantify seasonal distribution and abundance of phenologically distinct groups of Pacific herring within Salish Sea.
Reconciling conflicting survey indices of abundance prior to stock assessment
Authors: Peterson Cassidy D , Courtney Dean L , Cortés Enric , Latour Robert J
Published: September 2021

Indices of relative abundance are one of the most important inputs into a stock assessment model. For many species, we must rely on several indices that routinely conflict with each other and which may result in biased and uncertain outputs. Here, we explored whether reconciled trends obtained from dynamic factor analysis (DFA) applied to conflicting indices can be used as a trend of relative abundance input into a stock assessment model. We simulated an age-structured population of two coastal shark species in the southeast United States to generate multiple disagreeing indices, reconciled the indices using DFA, and then inserted both the multiple conflicting survey indices and the simplified DFA-predicted trend into respective stock assessment models. We compared the results of each stock assessment model to simulated values to evaluate the relative performance of each approach. We found that the DFA-based assessment generally performed similarly to the conflicting index-based assessment and may be a useful assessment tool in situations where conflicting indices with different selectivities, catchabilities, variances, and missing data are present. DFA assessment results were more consistent across simulation scenarios and outperformed many conflicting index assessments when surveys underwent shifts in catchability and the underlying stock abundance exhibited contrast.
Identifying juvenile and sub-adult movements to inform recovery strategies for a high value fishery—European bass (Dicentrarchus labrax)
Authors: Stamp Thomas , Clarke David , Plenty Shaun , Robbins Tim , Stewart James E , West Elizabeth , Sheehan Emma
Published: September 2021

The European bass (Dicentrarchus labrax) support high value commercial and recreational fisheries, however the Spawning Stock Biomass (SSB) of the northern Atlantic stock (ICES divisions 4.b–c, 7.a, and 7.d–h) has rapidly declined to an unsustainable level. The decline in SSB has been attributed to high fishing pressure combined with poor recruitment. By tracking juvenile fish their spatial ecology can be identified, and appropriate fisheries management policies designed to boost recruitment can be implemented. Using acoustic telemetry 146 sub-adult European bass (25.2–60 cm fork length) were tracked for up to 370 d across three sites in the southwest of the UK. Tagged fish were detected 2 724 548 times (Range: 166–106 393 detections per fish). Linear modelling estimated tagged fish were resident within 2.4–20.1 km of the site where they were first caught for 42.9–75.5% of the year. Some fish were however resident throughout summer and winter. Individual fish were also tracked moving up to 317 km to other coastal sites, 81% of which returned to their original capture site. Fisheries management should account for the high site fidelity displayed by juveniles and sub-adults of this species and coastal nursery sites should be considered essential habitat.
Mesopelagic flesh shear viscosity estimation from in situ broadband backscattering measurements by a viscous–elastic model inversion
Authors: Khodabandeloo Babak , Agersted Mette Dalgaard , Klevjer Thor A , Pedersen Geir , Melle Webjørn
Published: September 2021

In fisheries acoustics, target strength (TS) is a key parameter in converting acoustic measurements to biological information such as biomass. Modelling is a versatile tool to estimate TS of marine organisms. For swimbladdered fish, flesh shear viscosity is one of the required parameters to correctly calculate TS around the resonance frequency, where the target scatters most strongly. Resonance of mesopelagic swimbladdered fish can occur over a range of frequencies and can be within commonly used frequencies (e.g. 18, 38, or 70 kHz). Since there is little information on flesh shear viscosity of fish, especially for mesopelagic species, their resonance can bias the biological information extracted from acoustic measurements. Here, first, the applicability of using a spherical model to estimate resonant backscattering of a generic swimbladder is investigated. Subsequently, a viscous–elastic spherical gas backscattering model is used to estimate the flesh shear viscosity of swimbladdered mesopelagic fish (most likely Cyclothone spp., Family: Gonostomatidae) from in situ broadband backscattering measurements. Finally, the effects of flesh shear viscosity on the TS of swimbladdered mesopelagic fish at 18, 38 (a widely used channel to study mesopelagic layers), and 70 kHz are examined.
Heterogeneity around CO2 vents obscures the effects of ocean acidification on shallow reef communities
Authors: Blain Caitlin O , Kulins Sara , Radford Craig A , Sewell Mary A , Shears Nick T
Published: September 2021

Studies that use CO2 vents as natural laboratories to investigate the impacts of ocean acidification (OA) typically employ control-impact designs or local-scale gradients in pH or pCO2, where impacted sites are compared to reference sites. While these strategies can accurately represent well-defined and stable vent systems in relatively homogenous environments, it may not adequately encompass the natural variability of heterogeneous coastal environments where many CO2 vents exist. Here, we assess the influence of spatial heterogeneity on the perceived impacts of OA at a vent system well established in the OA literature. Specifically, we use a multi-scale approach to investigate and map the spatial variability in seawater pH and benthic communities surrounding vents at Whakaari-White Island, New Zealand to better understand the scale and complexity of ecological impacts of an acidified environment. We found a network of vents embedded in complex topography throughout the study area, and spatially variable pH and pCO2 levels. The distribution of habitats (i.e. macroalgal forests and turfing algae) was most strongly related to substratum type and sea urchin densities, rather than pH. Epifaunal communities within turfing algae differed with sampling distance from vents, but this pattern was driven by higher abundances of a number of taxa immediately adjacent to vents, where pH and temperature gradients are steep and white bacterial mats are prevalent. Our results contrast with previous studies at White Island that have used a control-impact design and suggested significant impacts of elevated CO2 on benthic communities. Instead, we demonstrate a highly heterogeneous reef where it is difficult to separate effects of reduced pH from spatial variation in reef communities. We urge that future research carefully considers and quantifies the biological and physical complexity of venting environments, and suggest that in dynamic systems, such as White Island, the use of control-impact designs can oversimplify and potentially overestimate the future impacts of OA.
A ruptured giant mediastinal mature teratoma mimicking an encapsulated empyema
Authors: Zhang Junjie , Zhu Xiaobo , Jiang Minyan , Lv Yajun
Published: September 2021

A female patient with a right-sided encapsulated pleural effusion was misdiagnosed preoperatively as having an encapsulated empyema. However, a giant mass in the anterior mediastinum was found via thoracoscopy, and a mature teratoma was detected based on the pathological result. Herein we report this case and provide lessons for cardiothoracic surgeons.
The Effectiveness of LDOCE Definitions for Concrete and Abstract Nouns in Headword- and Picture-Identification Tasks
Authors: Kamiński Mariusz , Bilynsky Michael , Szymańska-Czaplak Elżbieta , Kamińska Małgorzata
Published: September 2021

LDOCE uses a defining vocabulary to make their definitions intelligible to the user. Critics claim this policy may result in imprecise definitions, something especially noticeable in certain concrete and abstract words that are difficult to define by a definition only. This paper examines to what extent LDOCE definitions of such words help learners identify the objects and words being defined. In our experiment on 381 learners of English as a foreign language, three groups of participants viewed different definition types: simplified definitions of LDOCE, unsimplified definitions of MWC, and definitions written in the learners’ mother tongue (UDPL/TR). The results show that the LDOCE definitions proved significantly more useful in the identification tasks than the definitions in MWC, and slightly more useful than in UDPL/TR. Learners with a limited receptive vocabulary size (RVS) did not benefit from LDOCE as much as high-RVS users.
Robust recovery of sparse non-negative weights from mixtures of positive-semi-definite matrices
Authors: Jaensch Fabian , Jung Peter
Published: September 2021

We consider a structured estimation problem where an observed matrix is assumed to be generated as an $s$-sparse linear combination of $N$ given $n\times n$ positive-semi-definite matrices. Recovering the unknown $N$-dimensional and $s$-sparse weights from noisy observations is an important problem in various fields of signal processing and also a relevant preprocessing step in covariance estimation. We will present related recovery guarantees and focus on the case of non-negative weights. The problem is formulated as a convex program and can be solved without further tuning. Such robust, non-Bayesian and parameter-free approaches are important for applications where prior distributions and further model parameters are unknown. Motivated by explicit applications in wireless communication, we will consider the particular rank-one case, where the known matrices are outer products of iid. zero-mean sub-Gaussian $n$-dimensional complex vectors. We show that, for given $n$ and $N$, one can recover non-negative $s$-sparse weights with a parameter-free convex program once $s\leq O(n^2 / \log ^2(N/n^2)$. Our error estimate scales linearly in the instantaneous noise power whereby the convex algorithm does not need prior bounds on the noise. Such estimates are important if the magnitude of the additive distortion depends on the unknown itself.
Quasi feedback forms for differential-algebraic systems
Authors: Berger Thomas , Ilchmann Achim , Trenn Stephan
Published: September 2021

We investigate feedback forms for linear time-invariant systems described by differential-algebraic equations. Feedback forms are representatives of certain equivalence classes. For example, state space transformations, invertible transformations from the left and proportional state feedback constitute an equivalence relation. The representative of such an equivalence class, which we call proportional feedback form for the above example, allows to read off relevant system theoretic properties. Our main contribution is to derive a quasi proportional feedback form. This form is advantageous since it provides some geometric insight and is simple to compute, but still allows to read off the relevant structural properties of the control system. We also derive a quasi proportional and derivative feedback form. Similar advantages hold.
A mathematical model of cardiovascular dynamics for the diagnosis and prognosis of hemorrhagic shock
Authors: D’Orsi Laura , Curcio Luciano , Cibella Fabio , Borri Alessandro , Gavish Lilach , Eisenkraft Arik , De Gaetano Andrea
Published: September 2021

A variety of mathematical models of the cardiovascular system have been suggested over several years in order to describe the time-course of a series of physiological variables (i.e. heart rate, cardiac output, arterial pressure) relevant for the compensation mechanisms to perturbations, such as severe haemorrhage. The current study provides a simple but realistic mathematical description of cardiovascular dynamics that may be useful in the assessment and prognosis of hemorrhagic shock. The present work proposes a first version of a differential-algebraic equations model, the model dynamical ODE model for haemorrhage (dODEg). The model consists of 10 differential and 14 algebraic equations, incorporating 61 model parameters. This model is capable of replicating the changes in heart rate, mean arterial pressure and cardiac output after the onset of bleeding observed in four experimental animal preparations and fits well to the experimental data. By predicting the time-course of the physiological response after haemorrhage, the dODEg model presented here may be of significant value for the quantitative assessment of conventional or novel therapeutic regimens. The model may be applied to the prediction of survivability and to the determination of the urgency of evacuation towards definitive surgical treatment in the operational setting.
Lumped parameter models for two-ventricle and healthy and failing extracardiac Fontan circulations
Authors: Doyle Matthew G , Chugunova Marina , Roche S Lucy , Keener James P
Published: September 2021

Fontan circulations are surgical strategies to treat infants born with single ventricle physiology. Clinical and mathematical definitions of Fontan failure are lacking, and understanding is needed of parameters indicative of declining physiologies. Our objective is to develop lumped parameter models of two-ventricle and single-ventricle circulations. These models, their mathematical formulations and a proof of existence of periodic solutions are presented. Sensitivity analyses are performed to identify key parameters. Systemic venous and systolic left ventricular compliances and systemic capillary and pulmonary venous resistances are identified as key parameters. Our models serve as a framework to study the differences between two-ventricle and single-ventricle physiologies and healthy and failing Fontan circulations.
Curvature Estimates and Gap Theorems for Expanding Ricci Solitons
Authors: Chan Pak-Yeung
Published: September 2021

We derive a sharp lower bound for the scalar curvature of non-flat and non-compact expanding gradient Ricci soliton provided that the scalar curvature is non-negative and the potential function is proper. Upper bound for the scalar curvature of expander with nonpositive Ricci curvature will also be given. Furthermore, we provide a sufficient condition for the scalar curvature of expanding soliton being non-negative. Curvature estimates of expanding solitons in dimensions three and four will also be established. As an application, we prove a gap theorem on 3D gradient expander.
On the Defocusing Semilinear Wave Equations in Three Space Dimension with Small Power
Authors: Wei Dongyi , Yang Shiwu
Published: September 2021

By introducing new weighted vector fields as multipliers, we derive quantitative pointwise estimates for solutions of defocusing semilinear wave equation in $\mathbb {R}^{1+3}$ with pure power nonlinearity for all $1<p\leq 2$. Consequently, the solution vanishes on the future null infinity and decays in time polynomially for all $\sqrt {2}<p\leq 2$. This improves the uniform boundedness result of the 2nd author when $\frac {3}{2}<p\leq 2$.
Hyperbolic Equivariants of Rational Maps
Authors: Jacobs Kenneth
Published: September 2021

Let $K$ denote either ${\mathbb{R}}$ or ${\mathbb{C}}$. In this article, we study two new equivariants and a new invariant attached to a rational map $f\in K(z)$ under the action of conjugation by ${\operatorname{SL}}_2(K)$. The 1st two equivariants naturally live on real hyperbolic $[K:{\mathbb{Q}}]+1$ space and carry information about the action of $f$ on ${\mathbb{P}}^1(K)$. When $K={\mathbb{C}}$, we study how these objects behave as the map $f$ is iterated; the limits that arise are related to Douady and Earle’s construction of conformal barycenters of measures on $S^2$. We end by giving a description of these objects for maps of degree $d=1$.
The Koopman Representation and Positive Rokhlin Entropy
Authors: Seward Brandon
Published: September 2021

In this paper, we study connections between positive entropy phenomena and the Koopman representation for actions of general countable groups. Following the line of work initiated by Hayes for sofic entropy, we show in a certain precise manner that all positive entropy must come from portions of the Koopman representation that embed into the left-regular representation. We conclude that for actions having completely positive outer entropy, the Koopman representation must be isomorphic to the countable direct sum of the left-regular representation. This generalizes a theorem of Dooley–Golodets for countable amenable groups. As a final consequence, we observe that actions with completely positive outer entropy must be mixing, and when the group is non-amenable they must be strongly ergodic and have spectral gap.
A Density Theorem for the Difference Galois Groups of Regular Singular Mahler Equations
Authors: Poulet Marina
Published: September 2021

The difference Galois theory of Mahler equations is an active research area. The present paper aims at developing the analytic aspects of this theory. We first attach a pair of connection matrices to any regular singular Mahler equation. We then show that these connection matrices can be used to produce a Zariski-dense subgroup of the difference Galois group of any regular singular Mahler equation.
Clinicoepidemiological Observations of Enteric Fever in Infants: Experiences From a Tertiary Care Pediatric Hospital in North India
Authors: Saigal Karnika , Gupta Deepika , Saikia Diganta
Published: September 2021

Background

There is a lack of evident data to explain the true scenario of age-specific enteric fever in India. The current study aimed to evaluate the burden and disease pattern of enteric fever among infants in a tertiary care pediatric hospital.

Methods

A prospective laboratory-based surveillance was conducted from April 2018 to January 2020 at a children’s hospital in North India, under the Surveillance for Enteric Fever in India study. The study included children <1 year of age in whom Salmonella serovar Typhi/Salmonella serovar Paratyphi grew in cultures from blood or sterile body fluid. The key outcome measures included disease spectrum and clinical presentation.

Results

Of the 10 737 blood cultures from infants, 26 were positive for S. Typhi or S. Paratyphi. The majority of cases occurred in infants aged 6–12 months, with the youngest being 1 month old. Fever with abdominal pain and diarrhea were the common symptoms, with 46% of infants requiring inpatient care. All of the isolates were susceptible to ceftriaxone. Third-generation cephalosporins were used as the first-line therapy for hospitalized infants. The average duration of fever was 8.6 days. The overall case-fatality rate among infants with enteric fever was 7.4%.

Conclusions

Enteric fever is a major contributor to disease and death among children. Robust surveillance studies are required to understand the true disease burden.
Group 2 innate lymphoid cells in bone marrow regulate osteoclastogenesis in a reciprocal manner via RANKL, GM-CSF and IL-13
Authors: Momiuchi Yoshiki , Motomura Yasutaka , Suga Emiko , Mizuno Hiroki , Kikuta Junichi , Morimoto Akito , Mochizuki Miho , Otaki Natsuko , Ishii Masaru , Moro Kazuyo
Published: September 2021

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells that play different roles in different organs by sensing surrounding environmental factors. Initially, it was thought that ILC2s in bone marrow (BM) are progenitors for systemic ILC2s, which migrate to other organs and acquire effector functions. However, accumulating evidence that ILC2s differentiate in peripheral tissues suggests that BM ILC2s may play a specific role in the BM as a unique effector per se. Here, we demonstrate that BM ILC2s highly express the receptor activator of nuclear factor κB ligand (RANKL), a robust cytokine for osteoclast differentiation and activation, and RANKL expression on ILC2s is up-regulated by interleukin (IL)-2, IL-7 and all-trans retinoic acid (ATRA). BM ILC2s co-cultured with BM-derived monocyte/macrophage lineage cells (BMMs) in the presence of IL-7 induce the differentiation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in a RANKL-dependent manner. In contrast, BM ILC2s stimulated with IL-33 down-regulate RANKL expression and convert BMMs differentiation into M2 macrophage-like cells rather than osteoclasts by granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-13 production. Intravital imaging using two-photon microscopy revealed that a depletion of ILC2s prominently impaired in vivo osteoclast activity in an IL-7 plus ATRA-induced bone loss mouse model. These results suggest that ILC2s regulate osteoclast activation and contribute to bone homeostasis in both steady state and IL-33-induced inflammation.
The discovery of group 2 innate lymphoid cells has changed the concept of type 2 immune diseases
Authors: Kobayashi Tetsuro , Motomura Yasutaka , Moro Kazuyo
Published: September 2021

Group 2 innate lymphoid cells (ILC2s), discovered in 2010, have been recognized as immune cells with unique functions and their involvement in various diseases has been clarified. Before 2010, the antigen-specific response was a primary focus of immunology research, and immune responses were considered almost equivalent to biological responses to foreign antigens. However, with the emergence of ILC2s, the importance of ‘antigen-independent responses’ was confirmed, and this concept has permeated basic and clinical research as well as drug development. When ILC2s were discovered, their function in the acute phase of diseases garnered attention because of their rapid and potent type 2 immune response. However, several studies have revealed that the main role of ILC2s is more closely related to the chronicity of diseases, such as allergy and fibrosis, than to the induction of diseases. In this review, we discuss how ILC2 research has affected the concept of ‘Taishitsu’, a Japanese term describing the overall nature of an individual as determined by the interaction of genetic and acquired predisposition.
Creative Agency as Executive Agency: Grounding the Artistic Significance of Automatic Images
Authors: Anscomb Claire
Published: September 2021

This article examines the artistic potential of forms of image-making that involve registering the features of real objects using mind-independent processes. According to skeptics, these processes limit an agent’s intentional control over the features of the resultant “automatic images,” which in turn limits the artistic potential of the work, and the form as a whole. I argue that this is true only if intentional control is understood to mean that an agent produces the features of the work by their own bodily movements alone. Not only is this an unrealistic standard to uphold, but I show that a definition of intentional control based on the skeptic’s position does not prohibit an agent from realizing the features of an image by means beyond their own actions. An agent can exercise intentional control over the features of an image if they successfully anticipate the effect that the remote consequences of their actions will have on these. This, I argue, entails that to exert intentional control over the features of an image is to exercise “creative agency,” which is a species of executive agency. Consequently, I defend the idea that the origin of automatic images in creative agency grounds their artistic significance.
Embodied Metaphor: Playing with Gender in South Asian Sufism
Authors: Ewing Katherine Pratt
Published: September 2021

This paper brings the life and social world of a cross-dressing Sufi in rural Pakistan into relationship with the Sufi textual tradition to demonstrate that living gendered practices of sexual difference may serve as a form of what I call embodied metaphor that carries multiple layers of significance. Such embodied metaphors are not mere expressions or negotiations of identity but go beyond gender to point to other desires and realities. Drawing on a Lacanian interpretation of metaphor and metonymy, I argue that gender play allows confrontation with an aporia of sexual difference that unsettles the speaking subject. I demonstrate the rich intertextuality of the Sufi body as metaphor while also addressing how the metaphorical possibilities of the Sufi body have been affected by the recent development of a legal discourse of the third gender in Pakistan and the intensification of efforts to reform or purify Islam.
Spread of ESC-, carbapenem- and colistin-resistant Escherichia coli clones and plasmids within and between food workers in Lebanon
Authors: Al-Mir Hiba , Osman Marwan , Drapeau Antoine , Hamze Monzer , Madec Jean-Yves , Haenni Marisa
Published: September 2021

Objectives

Knowledge on the dynamic of MDR Escherichia coli in the human community is still limited, especially in low- and middle-income countries. Our goal was to decipher the dynamics of E. coli lineages and plasmids resistant to ESC, carbapenem and colistin within and between food workers in Lebanon using genomic-based approaches.

Methods

Eighty-four healthy adults working in three bakeries were sampled twice at a 6 monthly interval. E. coli resistant to ESC (ESC-E), carbapenem (CP-E) and colistin (CO-E) were collected on selective plates. Non-duplicate isolates were whole-genome sequenced using the Illumina technology and plasmid transmission was assessed by long-read sequencing. Data were analysed using bioinformatics tools and SNP-based phylogeny.

Results

ESC-E carriage rate reached 34.5% (t0) and 52.9% (t6), and 15 workers were positive at both t0 and t6. Carbapenem resistance (blaOXA-181, blaOXA-204, blaNDM-5) was found in five workers at t0 and two at t6, while colistin resistance (mcr-1.1) was found in five workers at t0 and one at t6. Forty-seven different STs were identified, of which three STs were predominant (ST131, n = 9; ST10, n = 5; ST69, n = 5). One worker presented the same ESC-E clone at t0 and t6. Twelve different events of clonal transmission among individuals were exemplified while plasmid transmission was only shown once.

Conclusions

Our study revealed a high carriage rate of MDR E. coli (60.7%) and the emergence of CP and colistin resistance in the Lebanese community. Incidental and long-term ESC-E carriage was observed in 41.7% and 17.9% of the workers, respectively. The high clonal diversity suggests an important dynamic of acquisition and loss of MDR E. coli and limited plasmid spread.
Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment
Authors: Gelé Thibaut , Chéret Antoine , Castro Gordon Alicia , Nkam Lionelle , Furlan Valérie , Pallier Coralie , Becker Pierre-Hadrien , Catalan Pilartxo , Goujard Cécile , Taburet Anne-Marie , Gasnault Jacques , Gouget Hélène , Barrail-Tran Aurélie
Published: September 2021

Objectives

The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study.

Methods

Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range).

Results

Twenty-four patients (nine women) were enrolled. The age was 45 (26–68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6–9.6), 84.4 (28.6–337.4) and 1.6 (0.7–4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%–82%) versus 0.33% (0.11%–0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir).

Conclusions

We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age.