bluuebunny/crossref_metadata_2025 huggingface dataset:
Who bears the burden of universal health coverage? An assessment of alternative financing policies using an overlapping-generations general equilibrium model
Authors: Abu-Zaineh Mohammad , Awawda Sameera , Ventelou Bruno
Published: April 2020

In their quest for universal health coverage (UHC), many developing countries use alternative financing strategies including general revenues to expand health coverage to the whole population. Unless a policy adjustment is undertaken, future generations may foot the bill of the UHC. This raises the important policy questions of who bears the burden of UHC and whether the UHC-fiscal stance is sustainable in the long term. These two questions are addressed using an overlapping generations model within a general equilibrium (OLG-CGE) framework applied to Palestine. We assess and compare alternative ways of financing the UHC-ridden deficit (viz. deferred-debt, current and phased-manner finance) and their implications on fiscal sustainability and intergenerational inequalities. The policy instruments examined include direct labour-income tax and indirect consumption taxes as well as health insurance contributions. Results show that in the absence of any policy adjustment, the implementation of UHC would explode the fiscal deficit and debt-GDP ratio. This indicates that the UHC-fiscal stance is rather unsustainable in the long term, thus, calling for a policy adjustment to service the UHC debt. Among the policies we examined, a current rather than deferred-debt finance through consumption taxation emerged to be preferred over other policies in terms of its implications for both fiscal sustainability and intergenerational inequality.
Reflection on modern methods: when is a stepped-wedge cluster randomized trial a good study design choice?
Authors: Hemming Karla , Taljaard Monica
Published: April 2020

The stepped-wedge cluster randomized trial (SW-CRT) involves the sequential transition of clusters (such as hospitals, public health units or communities) from control to intervention conditions in a randomized order. The use of the SW-CRT is growing rapidly. Yet the SW-CRT is at greater risks of bias compared with the conventional parallel cluster randomized trial (parallel-CRT). For this reason, the CONSORT extension for SW-CRTs requires that investigators provide a clear justification for the choice of study design. In this paper, we argue that all other things being equal, the SW-CRT is at greater risk of bias due to misspecification of the secular trends at the analysis stage. This is particularly problematic for studies randomizing a small number of heterogeneous clusters. We outline the potential conditions under which an SW-CRT might be an appropriate choice. Potentially appropriate and often overlapping justifications for conducting an SW-CRT include: (i) the SW-CRT provides a means to conduct a randomized evaluation which otherwise would not be possible; (ii) the SW-CRT facilitates cluster recruitment as it enhances the acceptability of a randomized evaluation either to cluster gatekeepers or other stakeholders; (iii) the SW-CRT is the only feasible design due to pragmatic and logistical constraints (for example the roll-out of a scare resource); and (iv) the SW-CRT has increased statistical power over other study designs (which will include situations with a limited number of clusters). As the number of arguments in favour of an SW-CRT increases, the likelihood that the benefits of using the SW-CRT, as opposed to a parallel-CRT, outweigh its risks also increases. We argue that the mere popularity and novelty of the SW-CRT should not be a factor in its adoption. In situations when a conventional parallel-CRT is feasible, it is likely to be the preferred design.
Determinant Expressions of Constraint Polynomials and the Spectrum of the Asymmetric Quantum Rabi Model
Authors: Kimoto Kazufumi , Reyes-Bustos Cid , Wakayama Masato
Published: April 2020

The purpose of this paper is to study the exceptional eigenvalues of the asymmetric quantum Rabi models (AQRMs), specifically, to determine the degeneracy of their eigenstates. Here, the Hamiltonian $H_{\textrm{Rabi}}^{\varepsilon }$ of the AQRM is defined by adding the fluctuation term $\varepsilon \sigma _x$, with $\sigma _x$ being the Pauli matrix, to the Hamiltonian of the quantum Rabi model, breaking its $\mathbb{Z}_{2}$-symmetry. The spectrum of $H_{\textrm{Rabi}}^{\varepsilon }$ contains a set of exceptional eigenvalues, considered to be remains of the eigenvalues of the uncoupled bosonic mode, which are further classified in two types: Juddian, associated with polynomial eigensolutions, and non-Juddian exceptional. We explicitly describe the constraint relations for allowing the model to have exceptional eigenvalues. By studying these relations we obtain the proof of the conjecture on constraint polynomials previously proposed by the third author. In fact we prove that the spectrum of the AQRM possesses degeneracies if and only if the parameter $\varepsilon $ is a halfinteger. Moreover, we show that non-Juddian exceptional eigenvalues do not contribute any degeneracy and we characterize exceptional eigenvalues by representations of $\mathfrak{s}\mathfrak{l}_2$. Upon these results, we draw the whole picture of the spectrum of the AQRM. Furthermore, generating functions of constraint polynomials from the viewpoint of confluent Heun equations are also discussed.
Meta-analysis of proton pump inhibitors induced risk of community-acquired pneumonia
Authors: Nguyen Phung Anh , Islam Mohaimenul , Galvin Cooper J , Chang Chih-Cheng , An Soo Yeon , Yang Hsuan-Chia , Huang Chih-Wei , Li Yu-Chuan (Jack) , Iqbal Usman
Published: April 2020

Purpose

Proton pump inhibitors (PPIs), one of the most widely used medications, are commonly used to suppress several acid-related upper gastrointestinal disorders. Acid-suppressing medication use could be associated with increased risk of community-acquired pneumonia (CAP), although the results of clinical studies have been conflicting.

Data sources

A comprehensive search of MEDLINE, EMBASE and Cochrane library and Database of Systematic Reviews from the earliest available online year of indexing up to October 2018.

Study selection

We performed a systematic review and meta-analysis of observational studies to evaluate the risk of PPI use on CAP outcomes.

Data extraction

Included study location, design, population, the prevalence of CAP, comparison group and other confounders. We calculated pooled odds ratio (OR) using a random-effects meta-analysis.

Results of data synthesis

Of the 2577 studies screening, 11 papers were included in the systematic review and 7 studies with 65 590 CAP cases were included in the random-effects meta-analysis. In current PPI users, pooled OR for CAP was 1.86 (95% confidence interval (CI), 1.30–2.66), and in the case of recent users, OR for CAP was 1.66 (95% CI, 1.22–2.25). In the subgroup analysis of CAP, significance association is also observed in both high-dose and low-dose PPI therapy. When stratified by duration of exposure, 3–6 months PPIs users group was associated with increased risk of developing CAP (OR, 2.05; 95% CI, 1.22–3.45). There was a statistically significant association between the PPI users and the rate of hospitalization (OR, 2.59; 95% CI, 1.83–3.66).

Conclusion

We found possible evidence linking PPI use to an increased risk of CAP. More randomized controlled studies are warranted to clarify an understanding of the association between PPI use and risk of CAP because observational studies cannot clarify whether the observed epidemiologic association is a causal effect or a result of unmeasured/residual confounding.
Efficacy of dihydroartemisinin/piperaquine and artesunate monotherapy for the treatment of uncomplicated Plasmodium falciparum malaria in Central Vietnam
Authors: Rovira-Vallbona Eduard , Van Hong Nguyen , Kattenberg Johanna H , Huan Ro Mah , Hien Nguyen Thi Thu , Ngoc Nguyen Thi Hong , Guetens Pieter , Hieu Nguyen Luong , Mai Tran Tuyet , Duong Nguyen Thi Thuy , Duong Tran Thanh , Phuc Bui Quang , Xa Nguyen Xuan , Erhart Annette , Rosanas-Urgell Anna
Published: April 2020

Background

Artemisinin-based combination therapies (ACTs) have significantly contributed to reduce Plasmodium falciparum malaria burden in Vietnam, but their efficacy is challenged by treatment failure of dihydroartemisinin/piperaquine ACT in Southern provinces.

Objectives

To assess the efficacy of dihydroartemisinin/piperaquine for uncomplicated P. falciparum malaria in Gia Lai, Central Vietnam, and determine parasite resistance to artemisinin (ClinicalTrials.gov identifier NCT02604966).

Methods

Sixty patients received either dihydroartemisinin/piperaquine (4 mg/kg/day, 3 days; n = 33) or artesunate monotherapy (4 mg/kg/day, 3 days; n = 27) followed by dihydroartemisinin/piperaquine (AS + DHA/PPQ). Clinical phenotypes were determined during a 42 day follow-up and analysed together with ex vivo susceptibility to antimalarials and molecular markers of drug resistance.

Results

Day 3 positivity rate was significantly higher in the AS + DHA/PPQ arm compared with dihydroartemisinin/piperaquine (70.4% versus 39.4%, P = 0.016). Parasite clearance time was 95.2 h (AS + DHA/PPQ) versus 71.9 h (dihydroartemisinin/piperaquine, P = 0.063) and parasite clearance half-life was 7.4 h (AS + DHA/PPQ) versus 7.0 h (dihydroartemisinin/piperaquine, P = 0.140). Adequate clinical and parasitological response at Day 42 was 100% in both arms. By RT–qPCR, 36% (19/53) patients remained positive until Day 7. No recurrences were detected. kelch13 artemisinin resistance mutations were found in 87% (39/45) of isolates and 50% (20/40) were KEL1/C580Y. The piperaquine resistance marker plasmepsin-2 was duplicated in 10.4% (5/48). Isolates from Day 3-positive patients (n = 18) had higher ex vivo survival rates to artemisinin compounds (P < 0.048) and prevalence of kelch13 mutations (P = 0.005) than Day 3-negative patients (n = 5). The WHO definition of artemisinin resistance was fulfilled in 60% (24/40) of cases.

Conclusions

Although dihydroartemisinin/piperaquine remained effective to treat P. falciparum, the high Day 3 positivity rate and prevalence of KEL1 strains calls for continuous monitoring of dihydroartemisinin/piperaquine efficacy in Central Vietnam.
Explainable artificial intelligence models using real-world electronic health record data: a systematic scoping review
Authors: Payrovnaziri Seyedeh Neelufar , Chen Zhaoyi , Rengifo-Moreno Pablo , Miller Tim , Bian Jiang , Chen Jonathan H , Liu Xiuwen , He Zhe
Published: April 2020

Objective

To conduct a systematic scoping review of explainable artificial intelligence (XAI) models that use real-world electronic health record data, categorize these techniques according to different biomedical applications, identify gaps of current studies, and suggest future research directions.

Materials and Methods

We searched MEDLINE, IEEE Xplore, and the Association for Computing Machinery (ACM) Digital Library to identify relevant papers published between January 1, 2009 and May 1, 2019. We summarized these studies based on the year of publication, prediction tasks, machine learning algorithm, dataset(s) used to build the models, the scope, category, and evaluation of the XAI methods. We further assessed the reproducibility of the studies in terms of the availability of data and code and discussed open issues and challenges.

Results

Forty-two articles were included in this review. We reported the research trend and most-studied diseases. We grouped XAI methods into 5 categories: knowledge distillation and rule extraction (N = 13), intrinsically interpretable models (N = 9), data dimensionality reduction (N = 8), attention mechanism (N = 7), and feature interaction and importance (N = 5).

Discussion

XAI evaluation is an open issue that requires a deeper focus in the case of medical applications. We also discuss the importance of reproducibility of research work in this field, as well as the challenges and opportunities of XAI from 2 medical professionals’ point of view.

Conclusion

Based on our review, we found that XAI evaluation in medicine has not been adequately and formally practiced. Reproducibility remains a critical concern. Ample opportunities exist to advance XAI research in medicine.
Overcoming barriers to the adoption and implementation of predictive modeling and machine learning in clinical care: what can we learn from US academic medical centers?
Authors: Watson Joshua , Hutyra Carolyn A , Clancy Shayna M , Chandiramani Anisha , Bedoya Armando , Ilangovan Kumar , Nderitu Nancy , Poon Eric G
Published: April 2020

There is little known about how academic medical centers (AMCs) in the US develop, implement, and maintain predictive modeling and machine learning (PM and ML) models. We conducted semi-structured interviews with leaders from AMCs to assess their use of PM and ML in clinical care, understand associated challenges, and determine recommended best practices. Each transcribed interview was iteratively coded and reconciled by a minimum of 2 investigators to identify key barriers to and facilitators of PM and ML adoption and implementation in clinical care. Interviews were conducted with 33 individuals from 19 AMCs nationally. AMCs varied greatly in the use of PM and ML within clinical care, from some just beginning to explore their utility to others with multiple models integrated into clinical care. Informants identified 5 key barriers to the adoption and implementation of PM and ML in clinical care: (1) culture and personnel, (2) clinical utility of the PM and ML tool, (3) financing, (4) technology, and (5) data. Recommendation to the informatics community to overcome these barriers included: (1) development of robust evaluation methodologies, (2) partnership with vendors, and (3) development and dissemination of best practices. For institutions developing clinical PM and ML applications, they are advised to: (1) develop appropriate governance, (2) strengthen data access, integrity, and provenance, and (3) adhere to the 5 rights of clinical decision support. This article highlights key challenges of implementing PM and ML in clinical care at AMCs and suggests best practices for development, implementation, and maintenance at these institutions.
Goal Conflict Encourages Work and Discourages Leisure
Authors: Etkin Jordan , Memmi Sarah A
Published: April 2020

Leisure is desirable and beneficial, yet consumers frequently forgo leisure in favor of other activities—namely, work. Why? We propose that goal conflict plays an important role. Seven experiments demonstrate that perceiving greater goal conflict shapes how consumers allocate time to work and leisure—even when those activities are unrelated to the conflicting goals. This occurs because goal conflict increases reliance on salient justifications, influencing how much time people spend on subsequent, unrelated activities. Because work tends to be easier to justify and leisure harder to justify, goal conflict increases time spent on work and decreases time spent on leisure. Thus, despite the conflicting goals being independent of the specific work and leisure activities considered (i.e., despite goal conflict being “incidental”), perceiving greater goal conflict encourages work and discourages leisure. The findings further understanding of how consumers allocate time to work and leisure, incidental effects of goal conflict on decision-making, and the role of justification in consumer choice. They also have implications for the use of “time-saving” technologies and the marketing of leisure activities.
Multinational enterprises, industrial relatedness and employment in European regions
Authors: Cortinovis Nicola , Crescenzi Riccardo , van Oort Frank
Published: April 2020

This article investigates the link between multinational enterprises (MNEs) and employment in their host regions by cross-fertilising the literature on MNE externalities with the emerging body of research on industrial relatedness. The link between employment and MNE presence in the same and related industries is tested for European regions. The results suggest that cross-sectoral MNE spillovers are mediated through industrial relatedness and that they are positively and significantly associated with higher employment levels, independently of input–output relations. Our results indicate that regions characterised by lower factor prices are likely to benefit the most from the presence of multinationals in terms of employment, but these benefits are concentrated in high knowledge-intensive sectors, potentially fostering inequalities within less-developed economies.
Diffuse γ-ray emission from the vicinity of young massive star cluster RSGC 1
Authors: Sun Xiao-Na , Yang Rui-Zhi , Wang Xiang-Yu
Published: April 2020

We report the Fermi Large Area Telescope (Fermi-LAT) detection of the γ-ray emission towards the young massive star cluster RSGC 1. Using the latest source catalogue and diffuse background models, we found that the diffuse γ-ray emission in this region can be resolved into three different components. The GeV γ-ray emission from the region HESS J1837-069 has a photon index of 1.83 ± 0.08. Combining with the HESS and MAGIC data, we argue that the γ-ray emission in this region likely originates from a pulsar wind nebula. The γ-ray emission from the north-west part (region A) can be modelled by an ellipse with the semimajor and semiminor axes of 0.5° and 0.25°, respectively. The GeV emission has a hard spectrum with a photon index of about −2 and partially coincides with the TeV source MAGIC J1835-069. The possible origin of the γ-ray emission in this region is the interaction of the cosmic rays (CRs) accelerated by SNR G24.7+0.6 or/and the OB cluster G25.18+0.26 with the surrounding gas clouds. The GeV γ-ray emission from the south-east region (region B) can be modelled as an ellipse with the semimajor and semiminor axes of 0.9° and 0.5°, respectively, and also reveals a hard γ-ray spectrum. We argue that the most probable origin is the interaction of the accelerated protons in the young massive star cluster RSGC 1 with ambient gas clouds, and the total CR proton energy is estimated to be as high as ${\sim}1\times 10^{50}\ \rm erg$.
Time-dependent high-energy gamma-ray signal from accelerated particles in core-collapse supernovae: the case of SN 1993J
Authors: Cristofari P , Renaud M , Marcowith A , Dwarkadas V V , Tatischeff V
Published: April 2020

Some core-collapse supernovae are likely to be efficient cosmic ray accelerators up to the PeV range, and therefore, to potentially play an important role in the overall Galactic cosmic ray population. The TeV gamma-ray domain can be used to study particle acceleration in the multi-TeV and PeV range. This motivates the study of the detectability of such supernovae by current and future gamma-ray facilities. The gamma-ray emission of core-collapse supernovae strongly depends on the level of the two-photon annihilation process: high-energy gamma-ray photons emitted at the expanding shock wave following the supernova explosion can interact with soft photons from the supernova photosphere through the pair production channel, thereby strongly suppressing the flux of gamma-rays leaving the system. In the case of SN 1993J, whose photospheric and shock-related parameters are well measured, we calculate the temporal evolution of the expected gamma-ray attenuation by accounting for the temporal and geometrical effects. We find the attenuation to be of about 10 orders of magnitude in the first few days after the supernova explosion. The probability of detection of a supernova similar to SN 1993J with the Cherenkov Telescope Array is highest if observations are performed either earlier than 1 d, or later than 10 d after the explosion, when the gamma-ray attenuation decreases to about two orders of magnitude.
Life-Course Monitoring of Endogenous Phytohormone Levels under Field Conditions Reveals Diversity of Physiological States among Barley Accessions
Authors: Hirayama Takashi , Saisho Daisuke , Matsuura Takakazu , Okada Satoshi , Takahagi Kotaro , Kanatani Asaka , Ito Jun , Tsuji Hiroyuki , Ikeda Yoko , Mochida Keiichi
Published: April 2020

Agronomically important traits often develop during the later stages of crop growth as consequences of various plant–environment interactions. Therefore, the temporal physiological states that change and accumulate during the crop’s life course can significantly affect the eventual phenotypic differences in agronomic traits among crop varieties. Thus, to improve productivity, it is important to elucidate the associations between temporal physiological responses during the growth of different crop varieties and their agronomic traits. However, data representing the dynamics and diversity of physiological states in plants grown under field conditions are sparse. In this study, we quantified the endogenous levels of five phytohormones — auxin, cytokinins (CKs), ABA, jasmonate and salicylic acid — in the leaves of eight diverse barley (Hordeum vulgare) accessions grown under field conditions sampled weekly over their life course to assess the ongoing fluctuations in hormone levels in the different accessions under field growth conditions. Notably, we observed enormous changes over time in the development-related plant hormones, such as auxin and CKs. Using 3′ RNA-seq-based transcriptome data from the same samples, we investigated the expression of barley genes orthologous to known hormone-related genes of Arabidopsis throughout the life course. These data illustrated the dynamics and diversity of the physiological states of these field-grown barley accessions. Together, our findings provide new insights into plant–environment interactions, highlighting that there is cultivar diversity in physiological responses during growth under field conditions.
Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility
Authors: Aue Arman , Szelinski Franziska , Weißenberg Sarah Y , Wiedemann Annika , Rose Thomas , Lino Andreia C , Dörner Thomas
Published: April 2020

Objectives

SLE is characterized by two pathogenic key signatures, type I IFN and B-cell abnormalities. How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT). JAK-STAT inhibition is an attractive therapeutic possibility for SLE. We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared with other autoimmune diseases and healthy controls (HD) and related it to disease activity.

Methods

Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T cells of 21 HD, 10 rheumatoid arthritis (RA), seven primary Sjögren’s (pSS) and 22 SLE patients was analysed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs (peripheral blood mononuclear cells) of SLE patients and HD after IFNα and IFNγ incubation were further investigated.

Results

SLE patients showed substantially higher STAT1 but not pSTAT1 in B- and T-cell subsets. Increased STAT1 expression in B-cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker. STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.

Conclusion

Enhanced expression of STAT1 by B-cell candidates as a key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold a promise to block STAT1 expression and control plasmablast induction in SLE.
TO USE OR NOT USE PATIENT SHIELDING ON PREGNANT WOMEN UNDERGOING CT PULMONARY ANGIOGRAPHY: A PHANTOM STUDY
Authors: Begano Dino , Söderberg Marcus , Bolejko Anetta
Published: April 2020

Pregnancy increases the risk of pulmonary embolism. Computed tomography pulmonary angiography (CTPA) is used for diagnosis. CT generates ionising radiation, and thus, abdominal shielding may be used. This phantom study investigated the effects of patient shielding and scan length reduction on the fetal and maternal ionising radiation dose from CTPA. The absorbed dose to the fetus was measured using thermoluminescent dosemeters. Estimated effective doses to the pregnant patient were based on the dose-length products. Shielding increased both the effective dose to the patient by 47% and the mean absorbed dose to the fetus (0.10 vs. 0.12 mGy; p < 0.001) compared with unshielded standard CTPA, as it affected the automatic exposure control. Shielded short CTPA marginally lowered only the mean fetal absorbed dose (0.03 vs. 0.02 mGy; p = 0.018). Shortening the scan reduced the fetal absorbed dose most effectively by 70% (0.10 vs. 0.03 mGy; p = 0.006), compared with the standard unshielded scan. Shielding modestly reduces fetal radiation dose but may compromise automatic exposure control, possibly increasing the maternal and fetal radiation dose. Shortening the scan is beneficial, assuming anatomical coverage is secured.
Impact of a fumaric acid and palm oil additive on beef cattle performance and carcass characteristics in diets containing increasing concentrations of corn silage1
Authors: Wilson Hannah Carissa , Hilscher Fred H , McPhillips Levi J , Boyd Bradley M , Watson Andrea K , Erickson Galen E , MacDonald Jim C
Published: April 2020

A feedlot study was conducted comparing a natural feed additive at varying corn silage (CS) inclusions on receiving and finishing cattle performance. The study utilized 480 crossbred steers (initial shrunk body weight [BW] = 296 kg; SD = 24.1 kg) in 48 pens with 10 steers/pen and 8 pens per treatment. Treatments were designed as a 2 × 3 factorial with 3 inclusions of CS (14%, 47%, 80%; dry matter [DM] basis) with or without (+, −) the inclusion of a feed additive containing fumaric acid and palm oil (FAPO). All treatment diets contained 16% modified distillers grains plus solubles and 4% supplement with dry-rolled corn replacing CS on a DM basis. All steers were fed the 80 CS diet and adapted to 47% and 14% CS over a 10- and 24-d period, respectively. Cattle fed 80 CS were fed for 238 days, 47 CS for 195 days, and 14% CS were fed for 168 days to a common backfat of 1.28 cm (P ≥ 0.59). There were no interactions for CS inclusion and the inclusion of FAPO on final body weight (FBW), DMI, ADG, G:F, hot carcass weight (HCW), LM area, marbling, or calculated yield grade (CYG; P ≥ 0.15). There was no significant difference for FBW, DMI, ADG, G:F, HCW, marbling, or CYG for cattle fed with or without FAPO (P ≥ 0.13). However, there was a quadratic response for FBW, ADG, G:F, HCW, marbling, and CYG with increased inclusion of CS (P ≤ 0.04). Inclusion of FAPO had no effect on performance. Feeding CS at greater inclusions decreased daily gain and feed efficiency but increased FBW when fed to an equal fat endpoint. CS gave greater returns ($/animal) when fed at 80% of diet DM. Feeding greater amounts of CS can be an economical way to finish cattle. In this study, FAPO did not affect animal performance, carcass characteristics, or economic return.
Changes in the coordination between respiration and swallowing from suckling through weaning
Authors: Bond Laura E. , Mayerl Christopher J. , Stricklen Bethany M. , German Rebecca Z. , Gould Francois D. H.
Published: April 2020

All mammals undergo weaning from milk to solid food. This process requires substantial changes to mammalian oropharyngeal function. The coordination of swallowing and respiration is a crucial component of maintaining airway function throughout feeding and matures over infant development. However, how this coordination is affected by weaning is unknown. In this study, we ask how changes in posture, neural maturation and food properties associated with the weaning affect coordination of respiration and swallowing in a validated infant pig model. We recorded seven piglets feeding before and during the weaning age with liquid milk in a bottle and in a bowl, and solid feed in a bowl. Using videofluoroscopy synchronized with respiration, we found (i) the delay in the onset of inspiration after swallowing does not change with head position, (ii) the delay is different between solid food and bowl drinking at the same age and (iii) the delay increases over time when bottle feeding, suggesting a maturational effect. Significant changes in aerodigestive coordination occur prior to and post-weaning, resulting in distinctive patterns for liquid and solid food. The interplay of maturational timelines of oropharyngeal function at weaning may serve as a locus for behavioural and life-history plasticity.
High-Arctic family planning: earlier spring onset advances age at first reproduction in barnacle geese
Authors: Fjelldal Mari Aas , Layton-Matthews Kate , Lee Aline Magdalena , Grøtan Vidar , Loonen Maarten J. J. E. , Hansen Brage Bremset
Published: April 2020

Quantifying how key life-history traits respond to climatic change is fundamental in understanding and predicting long-term population prospects
.
Age at first reproduction (AFR), which affects fitness and population dynamics, may be influenced by environmental stochasticity but has rarely been directly linked to climate change
.
Here, we use a case study from the highly seasonal and stochastic environment in High-Arctic Svalbard, with strong temporal trends in breeding conditions, to test whether rapid climate warming may induce changes in AFR in barnacle geese,
Branta leucopsis
. Using long-term mark–recapture and reproductive data (1991–2017)
,
we developed a multi-event model to estimate individual AFR (i.e. when goslings are produced). The annual probability of reproducing for the first time was negatively affected by population density but only for 2 year olds, the earliest age of maturity. Furthermore, advanced spring onset (SO) positively influenced the probability of reproducing and even more strongly the probability of reproducing for the first time. Thus, because climate warming has advanced SO by two weeks, this likely led to an earlier AFR by more than doubling the probability of reproducing at 2 years of age. This may, in turn, impact important life-history trade-offs and long-term population trajectories.
Roseovarius bejariae sp. nov., a moderately halophilic bacterium isolated from a hypersaline steep-sided river bed
Authors: Castro David J. , Gomez-Altuve Andreina , Reina José Carlos , Rodríguez Miguel , Sampedro Inmaculada , Llamas Inmaculada , Martínez-Checa Fernando
Published: April 2020

An aerobic, Gram-stain-negative ovoid, designated as strain A21T, was isolated using the dilution-to-extinction method from a soil sample taken from Rambla Salada, an athalassohaline habitat located in Murcia (south-eastern Spain). Strain A21T is non-motile, has a respiratory metabolism and grows at NaCl concentrations within the range 0.5–15 % (w/v) [optimum, 5 % (w/v)], at 5–35 °C (optimum, 28 °C) and at pH 6–8 (optimum, pH 7.0). This strain is positive for catalase activity, oxidase activity and nitrate reduction. The 16S rRNA gene sequence indicates that it belongs to the genus

Roseovarius

in the class

Alphaproteobacteria

. The most closely related species are Roseovarius pacificus and Roseovarius halotolerans to which the strain A21T shows 16S rRNA gene sequence similarity values of 98.06 and 97.7 %, respectively. The average nucleotide identity in blast and digital DNA–DNA hybridization values between strain A21T and

R. pacificus

LMG 24575T are 76.8 and 21 %, respectively. The DNA G+C content based on the genome is 61.28 mol%. The major fatty acids (>5 % of the total fatty acids) of strain A21T are C18 : 1 ω7c/C18 : 1 ω6c and C16 : 0. The only detected isoprenoid quinone in strain A21T is ubiquinone 10 (Q-10). The polar lipid profile contains phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and three unidentified polar lipids. Based on the phylogenetic, genotypic, phenotypic and chemotaxonomic data, the strain represents a novel species of the genus

Roseovarius

, for which the name Roseovarius bejariae sp. nov. is proposed. Strain A21T (=CECT 9817T=LMG 31311T) is the type strain.
Validation of a Lysis Buffer Containing 4 M Guanidinium Thiocyanate (GITC)/ Triton X-100 for Extraction of SARS-CoV-2 RNA for COVID-19 Testing: Comparison of Formulated Lysis Buffers Containing 4 to 6 M GITC, Roche External Lysis Buffer and Qiagen RTL Lysis Buffer
Authors: Scallan Martina F. , Dempsey Catherine , MacSharry John , O’Callaghan Isabelle , O’Connor Paula M. , Horgan Conor P. , Durack Edel , Cotter Paul D. , Hudson Sarah , Moynihan Humphrey A. , Lucey Brigid
Published: April 2020

The COVID-19 pandemic has resulted in increased need for diagnostic testing using reverse transcriptase real-time PCR (RT-PCR). An exponential increase in demand has resulted in a shortage of numerous reagents in particular those associated with the lysis buffer required to extract the viral RNA. Herein, we describe a rapid collective effort by hospital laboratory scientists, academic researchers and the biopharma industry to generate a validated lysis buffer. We have formulated a 4M Guanidinium thiocyanate (GITC)/ Triton X-100 Lysis buffer which provides comparable results with the recommended reagents. This buffer will ease the burden on hospital labs in their heroic efforts to diagnose a large population of patients.
LAMP-Seq: Population-Scale COVID-19 Diagnostics Using Combinatorial Barcoding
Authors: Schmid-Burgk Jonathan L. , Schmithausen Ricarda M. , Li David , Hollstein Ronja , Ben-Shmuel Amir , Israeli Ofir , Weiss Shay , Paran Nir , Wilbring Gero , Liebing Jana , Feldman David , Słabicki Mikołaj , Lippke Bärbel , Sib Esther , Borrajo Jacob , Strecker Jonathan , Reinhardt Julia , Hoffmann Per , Cleary Brian , Hölzel Michael , Nöthen Markus M. , Exner Martin , Ludwig Kerstin U. , Regev Aviv , Zhang Feng
Published: April 2020

The ongoing SARS-CoV-2 pandemic has already caused devastating losses. Exponential spread can be slowed by social distancing and population-wide isolation measures, but those place a tremendous burden on society, and, once lifted, exponential spread can re-emerge. Regular population-scale testing, combined with contact tracing and case isolation, should help break the cycle of transmission, but current detection strategies are not capable of such large-scale processing. Here we present a protocol for LAMP-Seq, a barcoded Reverse-Transcription Loop-mediated Isothermal Amplification (RT-LAMP) method that is highly scalable. Individual samples are stabilized, inactivated, and amplified in three isothermal heat steps, generating barcoded amplicons that can be pooled and analyzeden masseby sequencing. Using unique barcode combinations per sample from a compressed barcode space enables extensive pooling, potentially further reducing cost and simplifying logistics. We validated LAMP-Seq on 28 clinical samples, empirically optimized the protocol and barcode design, and performed initial safety evaluation. Relying on world-wide infrastructure for next-generation sequencing, and in the context of population-wide sample collection, LAMP-Seq could be scaled to analyze millions of samples per day.
Derivation of the effective reproduction number ℛ for COVID-19 in relation to mobility restrictions and confinement
Authors: Arenas Alex , Cota Wesley , Gómez-Gardeñes Jesús , Gómez Sergio , Granell Clara , Matamalas Joan T. , Soriano-Paños David , Steinegger Benjamin
Published: April 2020

The spread of COVID-19 is posing an unprecedented threat to health systems worldwide1. The fast propagation of the disease combined with the existence of covert contagions by asymptomatic individuals make the controlling of this disease particularly challenging. The key parameter to track the progression of the epidemics is the effective reproduction number ℛ, defined as the number of secondary infections generated by an infected individual2. The suppression of the epidemics is directly related to this value, and is attained when ℛ < 1. Here, we find an analytical expression for ℛ as a function of mobility restrictions and confinement measures, using an epidemic model tailored for COVID-19. This expression for ℛ is an extremely useful tool to design containment policies that are able to suppress the epidemics. We applied our epidemic model for the case of Spain, successfully forecasting both the observed incidence in each region and the overload of the health system. The expression for ℛ allowed us to determine the precise reduction of mobility κ0 needed to bend the curve of epidemic incidence, which turned out to be κ0 ∼ 0.7. This value, for the case of Spain, translates to a total lockdown with the exception of the mobility associated to essential services, a policy that was finally enforced on March 28.
Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors
Authors: Lavaert Marieke , Liang Kai Ling , Vandamme Niels , Park Jong-Eun , Roels Juliette , Kowalczyk Monica S. , Li Bo , Ashenberg Orr , Tabaka Marcin , Dionne Danielle , Tickle Timothy L. , Slyper Michal , Rozenblatt-Rosen Orit , Vandekerckhove Bart , Leclercq Georges , Regev Aviv , Van Vlierberghe Pieter , Guilliams Martin , Teichmann Sarah A. , Saeys Yvan , Taghon Tom
Published: April 2020

During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone marrow derived hematopoietic progenitors that migrate through the bloodstream. In human, the nature of these thymus immigrants has remained unclear. Here, we employ single-cell RNA sequencing on approximately 70.000 CD34+thymocytes to unravel the heterogeneity of the human immature postnatal thymocytes. Integration of bone marrow and peripheral blood precursors datasets identifies several putative thymus seeding precursors that display heterogeneity for currently used surface markers as revealed by CITEseq. Besides T cell precursors, we discover branches of intrathymic developing dendritic cells with predominantly plasmacytoid DCs. Trough trajectory inference, we delineate the transcriptional dynamics underlying early human T-lineage development from which we predict transcription factor modules that drive stage-specific steps of human T cell development. Thus, our work resolves the heterogeneity of thymus seeding precursors in human and reveals the molecular mechanisms that drive theirin vivocell fate.
Adaptive mitochondrial regulation of the proteasome
Authors: Meul Thomas , Berschneider Korbinian , Schmitt Sabine , Mayr Christoph H. , Mattner Laura F. , Schiller Herbert B. , Yazgili Ayse , Wang Xinyuan , Lukas Christina , Prehn Cornelia , Adamski Jerzy , Graf Elisabeth , Schwarzmayr Thomas , Perocchi Fabiana , Kukat Alexandra , Trifunovic Aleksandra , Kremer Laura , Prokisch Holger , Popper Bastian , von Toerne Christine , Hauck Stefanie M. , Zischka Hans , Meiners Silke
Published: April 2020

The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Regulation of proteasome function by mitochondrial metabolism, however, is unknown.

Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome in the absence of oxidative stress. Impaired respiratory complex I function leads to metabolic reprogramming of the Krebs cycle and deficiency in aspartate. Aspartate supplementation activates assembly and activity of 26S proteasomes via transcriptional activation of the proteasome assembly factors p28 and Rpn6. This metabolic adaptation of 26S proteasome function involves sensing of aspartate via the mTORC1 pathway. Metformin treatment of primary human cells similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, respiratory dysfunction conferred resistance towards the proteasome inhibitor Bortezomib.

Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications.
Transcription-coupled repair inDrosophila melanogasteris independent of the mismatch repair pathway
Authors: Törmä Lauri , Burny Claire , Nolte Viola , Senti Kirsten-André , Schlötterer Christian
Published: April 2020

Transcription-coupled repair (TCR) removes base damage on the transcribed strand of a gene to ensure a quick resumption of transcription. Based on the absence of key enzymes for TCR and empirical evidence, TCR was thought to be missing inDrosophila melanogaster. The recent demonstration of TCR in S2 cells raises the question about the involved genes. Since the mismatch repair (MMR) pathway serves a central role in TCR, at least inEscherichia coli, we studied the mutational signatures in flies with a deletion of the MMR genespellchecker1(spel1), a MutS homolog. Whole-genome sequencing of mutation accumulation (MA) lines obtained 7,345 new single nucleotide variants (SNVs) and 5,672 short indel mutations, the largest data set from an MA study inD. melanogaster. Based on the observed mutational strand-asymmetries, we conclude that TCR is still active withoutspel1. The operation of TCR is further confirmed by a negative association between mutation rate and gene expression. Surprisingly, the TCR signatures are detected for introns, but not for exons. We propose that an additional exon-specific repair pathway is masking the signature of TCR. This study presents the first step towards understanding the molecular basis of TCR inDrosophila melanogaster.
Sensory coding and contrast invariance emerge from the control of plastic inhibition over emergent selectivity
Authors: Larisch René , Gönner Lorenz , Teichmann Michael , Hamker Fred H.
Published: April 2020

Visual stimuli are represented by a highly efficient code in the primary visual cortex, but the development of this code is still unclear. Two distinct factors control coding efficiency: Representational efficiency, which is determined by neuronal tuning diversity, and metabolic efficiency, which is influenced by neuronal gain. How these determinants of coding efficiency are shaped during development, supported by excitatory and inhibitory plasticity, is only partially understood. We investigate a fully plastic spiking network of the primary visual cortex, building on phenomenological plasticity rules. Our results suggest that inhibitory plasticity is key to the emergence of tuning diversity and accurate input encoding. We show that inhibitory feedback (random and specific) increases the metabolic efficiency by implementing a gain control mechanism. Interestingly, this led to the spontaneous emergence of contrast-invariant tuning curves. Our findings highlight that (1) interneuron plasticity is key to the development of tuning diversity and (2) that efficient sensory representations are an emergent property of the resulting network.
Population connectivity predicts vulnerability to white-nose syndrome in the Chilean myotis (Myotis chiloensis) - a genomics approach
Authors: Lilley Thomas M. , Sävilammi TM Tiina M. , Ossa Gonzalo , Blomberg Anna S , Vasemägi Anti , Yung Veronica , Vendrami David L.J. , Johnson Joseph S
Published: April 2020

Despite its peculiar distribution, the biology of the southernmost bat species in the world, the Chilean myotis (Myotis chiloensis), has garnered little attention so far. The species has a north-south distribution of c. 2800 km, mostly on the eastern side of the Andes mountain range. Use of extended torpor occurs in the southernmost portion of the range, putting the species at risk of bat white-nose syndrome (WNS), a fungal disease responsible for massive population declines in North American bats. Here, we examined how geographic distance and topology would be reflected in the population structure ofM. chiloensisalong the majority of its range using a double digestion RAD-tag method. We sampled 66 individuals across the species range and discovered pronounced isolation-by-distance. Furthermore, and surprisingly, we found higher degrees of heterozygosity in the southernmost populations compared to the north. A coalescence analysis revealed that our populations may still not have reached secondary contact after the Last Glacial Maximum. As for the potential spread of pathogens, such as the fungus causing WNS, connectivity among populations was noticeably low, especially between the southern hibernatory populations in the Magallanes and Tierra del Fuego, and more northerly populations. This suggests the probability of geographic spread of the disease from the north through bat-to-bat contact to susceptible populations is low. The study presents a rare case of defined population structure in a bat species and warrants further research on the underlying factors contributing to this.
Comparison among the first representative chloroplast genomes ofOrontium, Lasia, Zamioculcas, andStylochaetonof the plant family Araceae: inverted repeat dynamics are not linked to phylogenetic signaling
Authors: Abdullah  , Henriquez Claudia L. , Mehmood Furrukh , Shahzadi Iram , Ali Zain , Waheed Mohammad Tahir , Croat Thomas B. , Poczai Peter , Ahmed Ibrar
Published: April 2020

The chloroplast genome provides insight into the evolution of plant species. Wede novoassembled and annotated chloroplast genomes of the first representatives of four genera representing three subfamilies:Lasia spinosa(Lasioideae),Stylochaeton bogneri, Zamioculcas zamiifolia(Zamioculcadoideae), andOrontium aquaticum(Orontioideae), and performed comparative genomics using the plastomes. The size of the chloroplast genomes ranged from 163,770–169,982 bp. These genomes comprise 114 unique genes, including 80 protein-coding, 4 rRNA, and 30 tRNA genes. These genomes exhibited high similarities in codon usage, amino acid frequency, RNA editing sites, and microsatellites. The junctions JSB (IRb/SSC) and JSA (SSC/IRa) are highly variable, as is oligonucleotide repeats content among the genomes. The patterns of inverted repeats contraction and expansion were shown to be homoplasious and therefore unsuitable for phylogenetic analyses. Signatures of positive selection were shown for several genes inS. bogneri. This study is a valuable addition to the evolutionary history of chloroplast genome structure in Araceae.
Structural basis for the binding of SNAREs to the multisubunit tethering complex Dsl1
Authors: Travis Sophie M. , DAmico Kevin , Yu I-Mei , Hamid Safraz , Ramirez-Arellano Gabriel , Jeffrey Philip D. , Hughson Frederick M.
Published: April 2020

Multisubunit tethering complexes (MTCs) are large (250 to >750 kDa), conserved macromolecular machines that are essential for SNARE-mediated membrane fusion in all eukaryotes. MTCs are thought to function as organizers of membrane trafficking, mediating the initial, long-range interaction between a vesicle and its target membrane and promoting the formation of membrane-bridging SNARE complexes. Previously, we reported the structure of the Dsl1 complex, the simplest known MTC, which is essential for COPI-mediated transport from the Golgi to the endoplasmic reticulum (ER). This structure suggested how the Dsl1 complex might function to tether a vesicle to its target membrane by binding at one end to the COPI coat and at the other end to ER SNAREs. Here, we use x-ray crystallography to investigate these Dsl1-SNARE interactions in greater detail. The Dsl1 complex comprises three subunits that together form a two-legged structure with a central hinge. Our results show that distal regions of each leg bind N-terminal Habc domains of the ER SNAREs Sec20 (a Qb-SNARE) and Use1 (a Qc-SNARE). The observed binding modes appear to anchor the Dsl1 complex to the ER target membrane while simultaneously ensuring that both SNAREs are in open conformations with their SNARE motifs available for assembly. The proximity of the two SNARE motifs, and therefore their ability to enter the same SNARE complex, depends on the relative orientation of the two Dsl1 legs.