bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell death and survival due to cytotoxic exposure modelled as a two-state Ising system
Authors: Arbabi Moghadam S. , Rezania V. , Tuszynski J. A.
Published: February 2020

Cancer chemotherapy agents are assessed for their therapeutic utility primarily by their ability to cause apoptosis of cancer cells and their potency is given by an IC50 value. Chemotherapy uses both target-specific and systemic-action drugs and drug combinations to treat cancer. It is important to judiciously choose a drug type, its dosage and schedule for optimized drug selection and administration. Consequently, the precise mathematical formulation of cancer cells' response to chemotherapy may assist in the selection process. In this paper, we propose a mathematical description of the cancer cell response to chemotherapeutic agent exposure based on a time-tested physical model of two-state multiple-component systems near criticality. We describe the Ising model methodology and apply it to a diverse panel of cytotoxic drugs administered against numerous cancer cell lines in a dose–response manner. The analysed dataset was generated by the Netherlands Translational Research Center B.V. (Oncolines). This approach allows for an accurate and consistent analysis of cytotoxic agents' effects on cancer cell lines and reveals the presence or absence of the bystander effect through the interaction constant. By calculating the susceptibility function, we see the value of IC50 coinciding with the peak of this measure of the system's sensitivity to external perturbations.
Metabolite identification, tissue distribution, excretion and preclinical pharmacokinetic studies of ET-26-HCl, a new analogue of etomidate
Authors: Yu Lu , Chen Xu , Zhang Wen Sheng , Zheng Liang , Xu Wen Wen , Xu Ming Yu , Jiang Xue Hua , Wang Ling
Published: February 2020

ET-26-HCl, a novel anaesthetic agent with promising pharmacological properties, lacks extensive studies on pharmacokinetics and disposition
in vitro
and
in vivo
. In this study, we investigated the metabolic stability, metabolite production and plasma protein binding (PPB) of ET-26-HCl along with its tissue distribution, excretion and pharmacokinetics in animals after intravenous administration. Ultra-high performance liquid chromatography–tandem quadrupole time-of-flight mass spectrometry identified a total of eight new metabolites after ET-26-HCl biotransformation in liver microsomes from different species. A hypothetical cytochrome P450-metabolic pathway including dehydrogenation, hydroxylation and demethylation was proposed. The PPB rate was highest in mouse and lowest in human. After intravenous administration, ET-26-HCl distributed rapidly to all tissues in rats and beagle dogs, with the highest concentrations in fat and liver. High concentrations of ET-26-acid, a major hydroxylation metabolite of ET-26-HCl, were found in liver, plasma and kidney. Almost complete clearance of ET-26-HCl from plasma occurred within 4 h after administration. Only a small fraction of the parent compound and its acid form were excreted via the urine and faeces. Taken together, the results added to a better understanding of the metabolic and pharmacokinetic properties of ET-26-HCl, which may contribute to the further development of this drug.
Urinary suPAR: a non-invasive biomarker of infection and tissue inflammation for use in studies of large free-ranging mammals
Authors: Higham James P. , Stahl-Hennig Christiane , Heistermann Michael
Published: February 2020

Studies of large free-ranging mammals incorporating physiological measurements typically require the collection of urine or faecal samples, due to ethical and practical concerns over trapping or darting animals. However, there is a dearth of validated biomarkers of immune activation and inflammation that can be measured non-invasively. We here evaluate the utility of urinary measurements of the soluble form of the urokinase plasminogen activator receptor (suPAR), for use as a health marker in studies of wild large mammals. We investigate how urinary suPAR concentrations change in response to viral infection and surgical trauma (inflammation), comparing it to the measurement of a marker of cellular immune activation, urinary neopterin (uNEO), in captive rhesus macaques. We then test the field utility of urinary suPAR, assessing the effects of soil and faecal contamination, sunlight, storage at different temperatures, freeze–thaw cycles, and lyophilization. We find that suPAR concentrations rise markedly in response to both infection and surgery-associated inflammation, unlike uNEO concentrations, which only rise in response to the former. Our field validation demonstrates that urinary suPAR is reasonably robust to many of the issues associated with field collection, sample processing, and storage, as long as samples can be stored in a freezer. Urinary suPAR is thus a promising biomarker applicable for monitoring various aspects of health in wild primates and potentially also other large mammals.
The hidden unstable orbits of maps with gaps
Authors: Jeffrey Mike R. , Webber Simon
Published: February 2020

Piecewise-continuous maps consist of smooth bran- ches separated by jumps, i.e. isolated discontinui- ties. They appear not to be constrained by the same rules that come with being continuous or differentiable, able to exhibit period incrementing and period adding bifurcations in which branches of attractors seem to appear ‘out of nowhere’, and able to break the rule that ‘period three implies chaos’. We will show here that piecewise maps are not actually so free of the rules governing their continuous cousins, once they are recognized as containing numerous unstable orbits that can only be found by explicitly including the ‘gap’ in the map’s definition. The addition of these ‘hidden’ orbits—which possess an iterate that lies on the discontinuity—bring the theory of piecewise-continuous maps closer to continuous maps. They restore the connections between branches of stable periodic orbits that are missing if the gap is not fully accounted for, showing that stability changes must occur in discontinuous maps via stability changes not so different to smooth maps, and bringing piecewise maps back under the powerful umbrella of Sharkovskii’s theorem. Hidden orbits are also vital for understanding what happens if the discontinuity is smoothed out to render the map continuous and/or differentiable.
A variational formulation for steady surface water waves on a Beltrami flow
Authors: Groves M. D. , Horn J.
Published: February 2020

This paper considers steady surface waves ‘riding’ a Beltrami flow (a three-dimensional flow with parallel velocity and vorticity fields). It is demonstrated that the hydrodynamic problem can be formulated as two equations for two scalar functions of the horizontal spatial coordinates, namely the elevation
η
of the free surface and the potential
Φ
defining the gradient part (in the sense of the Hodge–Weyl decomposition) of the horizontal component of the tangential fluid velocity there. These equations are written in terms of a non-local operator
H
(
η
) mapping
Φ
to the normal fluid velocity at the free surface, and are shown to arise from a variational principle. In the irrotational limit, the equations reduce to the Zakharov–Craig–Sulem formulation of the classical three-dimensional steady water-wave problem, while
H
(
η
) reduces to the familiar Dirichlet–Neumann operator.
Beacon-referenced pursuit for collective motions in three dimensions
Authors: Galloway Kevin S. , Dey Biswadip
Published: February 2020

Motivated by real-world applications of unmanned aerial vehicles, this paper introduces a decentralized control mechanism to guide steering control of autonomous agents manoeuvring in the vicinity of multiple moving entities (e.g. other autonomous agents) and stationary entities (e.g. fixed beacons or points of reference) in a three-dimensional environment. The proposed control law, which can be perceived as a modification of the three-dimensional constant bearing (CB) pursuit law, provides a means to allocate simultaneous attention to multiple entities. We investigate the behaviour of the closed-loop dynamics for a system with one agent referencing two beacons, as well as a two-agentmutual pursuitsystem wherein each agent employs the beacon-referenced CB pursuit law with regards to the other agent and a stationary beacon. Under certain assumptions on the associated control parameters, we demonstrate that this problem admitscircling equilibriawith agents moving on circular orbits with a common radius, in planes perpendicular to a common axis passing through the beacons. As the common radius and distances from the beacon are determined by the choice of parameters in the pursuit law, this approach provides a means to engineer desired formations in a three-dimensional setting.
Reduced model for the surface dynamics of a generally anisotropic elastic half-space
Authors: Fu Yibin , Kaplunov Julius , Prikazchikov Danila
Published: February 2020

Near-surface resonance phenomena often arise in semi-infinite solids. For instance, when a moving load with a speed
v
close to the surface wave speed
v

R

is applied to the surface of an elastic half-space, it will give rise to a large-amplitude disturbance inversely proportional to
v
 − 
v

R

. The latter can be determined by a multiple-scale approach using an extra slow time variable. It has also been shown for isotropic elastic half-spaces that the reduced governing equation thus derived is capable of describing the surface wave contribution even for arbitrary dynamic loading. In this paper, we first derive the analogous evolution equation for a generally anisotropic elastic half-space, and then assess its applicability in the study of travelling waves in a half-space that is coated with a continuous array of spring-like vertical resonators or bonded to an elastic layer of different properties. Our results are validated by comparison with previously known results, and illustrative calculations are carried out for a fibre-reinforced half-space and a coated half-space that is subjected to a finite deformation.
Global reduction of
in situ
CO
2
transfer velocity by natural surfactants in the sea-surface microlayer
Authors: Mustaffa Nur Ili Hamizah , Ribas-Ribas Mariana , Banko-Kubis Hanne M. , Wurl Oliver
Published: February 2020

For decades, the effect of surfactants in the sea-surface microlayer (SML) on gas
transfer velocity (
k
) has been recognized; however, it has not
been quantified under natural conditions due to missing coherent data on
in situ k
of carbon dioxide (CO
2
) and
characterization of the SML. Moreover, a sea-surface phenomenon of
wave-dampening, known as slicks, has been observed frequently in the ocean and
potentially reduces the transfer of climate-relevant gases between the ocean and
atmosphere. Therefore, this study aims to quantify the effect of natural
surfactant and slicks on the
in situ k
of CO
2
. A
catamaran, Sea Surface Scanner (S
3
), was deployed to sample the SML
and corresponding underlying water, and a drifting buoy with a floating chamber
was deployed to measure the
in situ k
of CO
2
. We
found a significant 23% reduction of
k
above surfactant
concentrations of 200 µg Teq l
−1
,
which were common in the SML except for the Western Pacific. We conclude that an
error of approximately 20% in CO
2
fluxes for the Western
Pacific is induced by applying wind-based parametrization not developed in low
surfactant regimes. Furthermore, we observed an additional 62% reduction
in natural slicks, reducing global CO
2
fluxes by 19%
considering known frequency of slick coverage. From our observation, we
identified surfactant concentrations with two different end-members which lead
to an error in global CO
2
flux estimation if ignored.
Latitudinal directionality in ectotherm invasion success
Authors: Amarasekare Priyanga , Simon Margaret W.
Published: February 2020

A striking pattern, seen in both fossil and extant taxa, is that tropical ectotherms are better at invading temperate habitats than vice versa. This is puzzling because tropical ectotherms, being thermal specialists, face a harsher abiotic environmentandcompetition from temperate residents that are thermal generalists. We develop a mathematical framework to address this puzzle. We find that (i) tropical ectotherms can invade temperate habitats if they have higher consumption rates and lower mortality during warmer summers, (ii) stronger seasonal fluctuations at higher latitudes create more temporal niches, allowing coexistence of tropical invaders and temperate residents, and (iii) temperate ectotherms’ failure to invade tropical habitats is due to greater mortality rather than lower competitive ability. Our framework yields predictions about population-level outcomes of invasion success based solely on species’ trait responses to temperature. It provides a potential ecological explanation for why the tropics constitute both a cradle and a museum of biodiversity.
Application of High Resolution Melt analysis (HRM) for screening haplotype variation in non-model plants: a case study of Honeybush (CyclopiaVent.)
Authors: Galuszynski Nicholas C , Potts Alastair J
Published: February 2020

Aim

This study has three broad aims: a) to develop genus-specific primers for High Resolution Melt analysis (HRM) of members ofCyclopiaVent., b) test the haplotype discrimination of HRM compared to Sanger sequencing, and c) provide a case study using HRM to detect novel haplotype variation in wildC. subternataVogel. populations.

Location

The Cape Floristic Region (CFR), located along the southern Cape of South Africa.

Methods

Polymorphic loci were detected through a screening process of sequencing 12 non-coding chloroplast DNA regions across 14Cyclopiaspecies. Twelve genus-specific primer combinations were designed around variable cpDNA loci, four of which failed to amplify under PCR, the eight remaining were applied to test the specificity, sensitivity and accuracy of HRM. The three top performing HRM regions were then applied to detect novel haplotypes in wildC. subternatapopulations, and phylogeographic patterns ofC. subternatawere explored.

Results

We present a framework for applying HRM to non-model systems. HRM accuracy varied across the regions screened using the genus-specific primers developed, ranging between 56 and 100 %. The nucleotide variation failing to produce distinct melt curves is discussed. The top three performing regions, having 100 % specificity (i.e. different haplotypes were never grouped into the same cluster, no false negatives), were able to detect novel haplotypes in wildC. subternatapopulations with high accuracy (96%). Sensitivity below 100 % (i.e. a single haplotype being clustered into multiple unique groups during HRM curve analysis, false positives) was resolved through sequence confirmation of each cluster resulting in a final accuracy of 100 %. Phylogeographic analyses revealed that wildC. subternatapopulations tend to exhibit phylogeographic structuring across mountain ranges (accounting for 73.8 % of genetic variation base on an AMOVA), and genetic differentiation between populations increases with distance (p < 0.05 for IBD analyses).

Conclusions

After screening for regions with high HRM clustering specificity — akin to the screening process associated with most PCR based markers — the technology was found to be a high throughput tool for detecting genetic variation in non-model plants.
Beyond R0: Heterogeneity in secondary infections and probabilistic epidemic forecasting
Authors: Hébert-Dufresne Laurent , Althouse Benjamin M. , Scarpino Samuel V. , Allard Antoine
Published: February 2020

The basic reproductive number — R0 — is one of the most common and most commonly misapplied numbers in public health. Although often used to compare outbreaks and forecast pandemic risk, this single number belies the complexity that two different pathogens can exhibit, even when they have the same R0 [1–3]. Here, we show how to predict outbreak size using estimates of the distribution of secondary infections, leveraging both its average R0 and the underlying heterogeneity. To do so, we reformulate and extend a classic result from random network theory [4] that relies on contact tracing data to simultaneously determine the first moment (R0) and the higher moments (representing the heterogeneity) in the distribution of secondary infections. Further, we show the different ways in which this framework can be implemented in the data-scarce reality of emerging pathogens. Lastly, we demonstrate that without data on the heterogeneity in secondary infections for emerging infectious diseases like COVID-19, the uncertainty in outbreak size ranges dramatically. Taken together, our work highlights the critical need for contact tracing during emerging infectious disease outbreaks and the need to look beyond R0 when predicting epidemic size.
Ecotype Simulation 2: An improved algorithm for efficiently demarcating microbial species from large sequence datasets
Authors: Wood Jason M. , Becraft Eric D. , Krizanc Daniel , Cohan Frederick M. , Ward David M.
Published: February 2020

Background

Microbial systematists have used molecular cutoffs to classify the vast diversity present within a natural microbial community without invoking ecological theory. The use of ecological theory is needed to identify whether or not demarcated groups are the ecologically distinct, fundamental units (ecotypes), necessary for understanding the system. Ecotype Simulation, a Monte-Carlo approach to modeling the evolutionary dynamics of a microbial population based on the Stable Ecotype Model of microbial speciation, has proven useful for finding these fundamental units. For instance, predicted ecotypes ofSynechococcusforming microbial mats in Yellowstone National Park hot springs, which were previously considered to be a single species based on phenotype, have been shown to be ecologically distinct, with specialization to different temperature and light levels. Unfortunately, development of high-throughput DNA sequencing methods has outpaced the ability of the program to analyze all of the sequence data produced.

Results

We developed an improved version of the program called Ecotype Simulation 2, which can rapidly analyze alignments of very large sequence datasets. For instance, while the older version takes days to analyze 200 sequences, the new version can analyze 1.92 × 105sequences in about six hours. The faster simulation identified similar ecotypes as found with the slower version, but from larger amounts of sequence data.

Conclusions

Based on ecological theory, Ecotype Simulation 2 provides a much-needed approach that will help guide microbial ecologists and systematists to the natural, fundamental units of bacterial diversity.
Measuring protected-area outcomes with leech iDNA: large-scale quantification of vertebrate biodiversity in Ailaoshan nature reserve
Authors: Baker Christopher CM , Ji Yinqiu , Popescu Viorel D , Wang Jiaxin , Wu Chunying , Wang Zhengyang , Li Yuanheng , Wang Lin , Hua Chaolang , Yang Zhongxing , Yang Chunyan , Xu Charles CY , Diana Alex , Wen Qingzhong , Pierce Naomi E , Yu Douglas W
Published: February 2020

1

Protected areas are central to meeting biodiversity conservation goals, but measuring their effectiveness is challenging. We address this challenge by using DNA from leech-ingested bloodmeals to estimate vertebrate occupancies across the 677 km2Ailaoshan reserve in Yunnan, China. 163 park rangers collected 30,468 leeches from 172 patrol areas. We identified 86 vertebrate species, including amphibians, mammals, birds, and squamates. Multi-species occupancy modelling showed that species richness increased with elevation and distance to reserve edge, including the distributions of most of the large mammals (e.g. sambar, black bear, serow, tufted deer). The exceptions were the three domestic mammal species (cows, sheep, goats) and muntjak deer, which were more common at lower elevations. eDNA-estimated vertebrate occupancies areGranular, Repeatable, Auditable, Direct, Efficient, andSimple-to-understandmeasures that can be used to assess conservation effectiveness and thus to improve the contributions that protected areas make to achieving global biodiversity goals.
Intron retention as a new pre-symptomatic marker of aging and its recovery to the normal state by a traditional Japanese multi-herbal medicine
Authors: Okada Norihiro , Oshima Kenshiro , Iwasaki Yuki , Maruko Akiko , Matsumura Kenya , Iioka Erica , Vu Trieu-Duc , Fujitsuka Naoki , Nishi Akinori , Sugiyama Aiko , Nishiyama Mitsue , Kaneko Atsushi , Mizoguchi Kazushige , Yamamoto Masahiro , Nishimura Susumu
Published: February 2020

Intron retention (IR) is an important regulatory mechanism that affects gene expression and protein functions. Using klotho mice at the pre-symptomatic state, we discovered that retained-introns accumulated in several organs including the liver and that among these retained introns in the liver a subset was recovered to the normal state by a Japanese traditional herbal medicine. This is the first report of IR recovery by a medicine. IR-recovered genes fell into two categories: those involved in liver-specific metabolism and in splicing. Metabolome analysis of the liver showed that the klotho mice were under starvation stress. In addition, our differentially expressed gene analysis showed that liver metabolism was actually recovered by the herbal medicine at the transcriptional level. By analogy with the widespread accumulation of intron-retained pre-mRNAs induced by heat shock stress, we propose a model in which retained-introns in klotho mice were induced by an aging stress and in which this medicine-related IR recovery is indicative of the actual recovery of liver-specific metabolic function to the healthy state. Accumulation of retained-introns was also observed at the pre-symptomatic state of aging in wild-type mice and may be an excellent marker for this state in general.
Predictive features of gene expression variation reveal a mechanistic link between expression variation and differential expression
Authors: Sigalova Olga M. , Shaeiri Amirreza , Forneris Mattia , Furlong Eileen E.M. , Zaugg Judith B
Published: February 2020

For most biological processes, organisms must respond to extrinsic cues, while maintaining essential gene expression programs. Although studied extensively in single cells, it is still unclear how variation is controlled in multicellular organisms. Here, we used a machine-learning approach to identify genomic features that are predictive of genes with high versus low variation in their expression across individuals, using bulk data to remove stochastic cell-to-cell variation. Using embryonic gene expression across 75Drosophilaisogenic lines, we identify features predictive of expression variation, while controlling for expression level. Genes with low variation fall into two classes, indicating they employ different mechanisms to maintain a robust expression. In contrast, genes with high variation seem to lack both types of stabilizing mechanisms. Applying the framework to human tissues from GTEx revealed similar predictive features, indicating that promoter architecture is an ancient mechanism to control expression variation. Remarkably, expression variation features could also predict differential expression upon stress in bothDrosophilaand human. Differential gene expression signatures may therefore be partially explained by genetically encoded gene-specific features, unrelated to the studied treatment.
Biogeochemical variability in the California Current System
Authors: Deutsch Curtis , Frenzel Hartmut , McWilliams James C. , Renault Lionel , Kessouri Faycal , Howard Evan , Liang Jun-Hong , Bianchi Daniele , Yang Simon
Published: February 2020

The biological productivity and diversity of the California Current System (CCS) is at the leading edge of major emerging climate trends, including hypoxia and acidification. We present results from a hindcast simulation (reanalysis) of an eddy-resolving oceanic physical-biogeochemical model of the CCS, to characterize its mean state and its patterns and drivers of variability in marine biogeochemical and ecosystem processes from 1995-2010. This is a companion paper to a physical analysis in Renault et al. (2021). The model reproduces long-term mean distributions of key ecosystem metrics, including surface nutrients and productivity and subsurface O2 and carbonate undersaturation. The spatial patterns of Net Primary Productivity (NPP) are broadly consistent with measured and remotely sensed rates, and they reflect a predominant limitation by nitrogen, with seasonal and episodic limitation by Fe nearshore in the central CCS, and in the open ocean northern CCS. The vertical distribution of NPP is governed by the trade-off between nutrient and light limitation, a balance that reproduces and explains the observed spatial variations in the depth of the deep Chl maximum. The seasonal to interannual variability of biogeochemical properties and rates is also well captured by model simulations. Because of the prevailing nutrient limitation, fluctuations in the depth of the pycnocline and associated nutricline are the leading single factor explaining interannual variability in the interior biogeochemical state, and the relationships between density and biogeochemical rates and tracers are consistent between model and observations. The magnitude and relationship between density structure and biogeochemical processes is illustrated by the 1997-98 El Niño event, which faithfully reproduces the single largest deviation from the mean state in the simulated period. A slower decadal shoaling of the pycnocline also accounts for the concomitant trends in hypoxic and corrosive conditions on the shelf. The resulting variability is key to understanding the vulnerability of marine species to oceanic change, and to the detection of such changes, soon projected to exceed the range of conditions in the past century.
Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics
Authors: Patel Gaurang , Fury Wen , Yang Hua , Gomez-Caraballo Maria , Bai Yu , Yang Tao , Adler Christina , Wei Yi , Ni Min , Hu Ying , Yancopoulos George , Stamer W. Daniel , Romano Carmelo
Published: February 2020

The conventional outflow pathway is a complex tissue responsible for maintaining intraocular pressure (IOP) homeostasis. The coordinated effort of multiple cells with differing responsibilities ensure healthy outflow function and IOP maintenance. Dysfunction of one or more resident cell type results in ocular hypertension and risk for glaucoma, a leading cause of blindness. In this study, single cell RNA sequencing was performed to generate a comprehensive cell atlas of human conventional outflow tissues. We obtained 17757 genes expression profiles from 8758 cells from eight eyes of four donors representing the outflow cell transcriptome. Upon clustering analysis, 12 distinct cell types were identified, and region-specific expression of candidate genes were mapped in human tissues. Significantly, we identified two distinct expression patterns (myofibroblast and fibroblast) from cells located in the trabecular meshwork (TM), the primary structural component of the conventional outflow pathway. We also located neuron and macrophage signatures in the TM. The second primary component structure, Schlemm’s canal displayed a unique combination of lymphatic/blood vascular gene expression. Other expression clusters corresponded to cells from neighboring tissues, predominantly in the ciliary muscle/scleral spur, which together correspond to the uveoscleral outflow path. Importantly, the utility of our atlas was demonstrated by mapping glaucoma-relevant genes to outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of conventional and unconventional outflow pathway structures responsible for IOP homeostasis.

Significance statement

Ocular hypertension is the primary, and only modifiable risk factor for glaucoma, the leading cause of irreversible blindness. Intraocular pressure is regulated homeostatically by resistance to aqueous humor outflow through an architecturally complex tissue, the conventional/trabecular pathway. In this study, we generated a comprehensive cell atlas of the human trabecular meshwork and neighboring tissues using single cell, RNA sequencing. We identified 12 distinct cell types, and mapped region-specific expression of candidate genes. The utility of our atlas was demonstrated by mapping glaucoma-relevant genes to conventional outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of tissue structures responsible for intraocular pressure homeostasis in health, and dysregulation in disease.
Agreement between ranking metrics in network meta-analysis: an empirical study
Authors: Chiocchia Virginia , Nikolakopoulou Adriani , Papakonstantinou Theodoros , Egger Matthias , Salanti Georgia
Published: February 2020

Objective

To empirically explore the level of agreement of the treatment hierarchies from different ranking metrics in network meta-analysis (NMA) and to investigate how network characteristics influence the agreement.

Design

Empirical evaluation from re-analysis of network meta-analyses.

Data

232 networks of four or more interventions from randomised controlled trials, published between 1999 and 2015.

Methods

We calculated treatment hierarchies from several ranking metrics: relative treatment effects, probability of producing the best value (pBV) and the surface under the cumulative ranking curve (SUCRA). We estimated the level of agreement between the treatment hierarchies using different measures: Kendall’sτand Spearman’sρcorrelation; and the YilmazτAPand Average Overlap, to give more weight to the top of the rankings. Finally, we assessed how the amount of the information present in a network affects the agreement between treatment hierarchies, using the average variance, the relative range of variance, and the total sample size over the number of interventions of a network.

Results

Overall, the pairwise agreement was high for all treatment hierarchies obtained by the different ranking metrics. The highest agreement was observed between SUCRA and the relative treatment effect for both correlation and top-weighted measures whose medians were all equal to one. The agreement between rankings decreased for networks with less precise estimates and the hierarchies obtained frompBVappeared to be the most sensitive to large differences in the variance estimates. However, such large differences were rare.

Conclusions

Different ranking metrics address different treatment hierarchy problems, however they produced similar rankings in the published networks. Researchers reporting NMA results can use the ranking metric they prefer, unless there are imprecise estimates or large imbalances in the variance estimates. In this case treatment hierarchies based on both probabilistic and non-probabilistic ranking metrics should be presented.

STRENGTH AND LIMITATIONS OF THIS STUDY

To our knowledge, this is the first empirical study exploring the level of agreement of the treatment hierarchies from different ranking metrics in network meta-analysis (NMA).

The study also explores how agreement is influenced by network characteristics.

More than 200 published NMAs were re-analysed and three different ranking metrics calculated using both frequentist and Bayesian approaches.

Other potential factors not investigated in this study could influence the agreement between hierarchies.
Ophthalmologic evidence against the interpersonal transmission of 2019 novel coronavirus through conjunctiva
Authors: Zhou Yunyun , Zeng Yuyang , Tong Yongqing , Chen Changzheng
Published: February 2020

Background

The emerging 2019 novel coronavirus (2019-nCoV) has pushed several countries into state of emergency all over the world. The possible transmission of 2019-nCoV by conjunctiva is controversial and has substantial public health implications.

Methods

A retrospective cohort study was initiated to investigate the possible transmission of 2019-nCoV through aerosol contact with conjunctiva. We enrolled 67 cases of confirmed or suspected cases of novel coronavirus pneumonia (NCP) during 17–28 Jan 2020. Nasopharyngeal and conjunctival swabs were collected for real time RT-PCR analysis to detect 2019-nCoV.

Results

63 patients were identified as laboratory-confirmed NCP and the remaining four were suspected NCP. Conjunctival swab samples from one NCP patient yielded positive PCR results and two NCP patients yielded probable positive PCR results. None of the three patients had ocular symptoms. The only one NCP patient with conjunctivitis as the first symptom had negative conjunctival sac 2019-nCoV test. Conjunctival swab samples from the four suspected cases of NCIP were negative.

Conclusion

2019-nCoV can be detected in the conjunctival sac of patients with NCP. Through clinical analysis, viral transmission via the conjunctival route was not supported by the data. Good clinical protection can effectively cut off the transmission path.
Healthcare-resource-adjusted vulnerabilities towards the 2019-nCoV epidemic across China
Authors: Zhou Hanchu , Yang Jiannan , Tang Kaicheng , Zhang Qingpeng , Cao Zhidong , Pfeiffer Dirk , Zeng Daniel Dajun
Published: February 2020

We integrate the human movement and healthcare resource data to identify cities with high vulnerability towards the 2019-nCoV epidemic with respect to available health resources. The results inform public health responses in multiple ways.
TheSeminavis robustagenome provides insights into the evolutionary adaptations of benthic diatoms
Authors: Osuna-Cruz Cristina Maria , Bilcke Gust , Vancaester Emmelien , De Decker Sam , Poulsen Nicole , Bulankova Petra , Verhelst Bram , Audoor Sien , Stojanovova Darja , Pargana Aikaterini , Russo Monia , Stock Frederike , Cirri Emilio , Brembu Tore , Pohnert Georg , Winge Per , Bones Atle M. , Piganeu Gwenael , Ferrante Maria Immacolata , Mock Thomas , Sterck Lieven , Sabbe Koen , De Veylder Lieven , Vyverman Wim , Vandepoele Klaas
Published: February 2020

Benthic diatoms are the main primary producers in shallow freshwater and coastal environments, fulfilling important ecological functions such as nutrient cycling and sediment stabilization. However, little is known about their evolutionary adaptations to these highly structured but heterogeneous environments. Here, we report a reference genome for the marine biofilm-forming diatomSeminavis robusta, showing that gene family expansions are responsible for a quarter of all 36,254 protein-coding genes. Tandem duplications play a key role in extending the repertoire of specific gene functions, including light and oxygen sensing, which are probably central for its adaptation to benthic habitats. Genes differentially expressed during interactions with bacteria are strongly conserved in other benthic diatoms while many species-specific genes are strongly upregulated during sexual reproduction. Combined with re-sequencing data from 48 strains, our results offer new insights on the genetic diversity and gene functions in benthic diatoms.
Aerial attack strategies of bat-hunting hawks, and the dilution effect of swarming
Authors: Brighton Caroline H. , Zusi Lillias , McGowan Kathryn , Kinniry Morgan , Kloepper Laura N. , Taylor Graham K.
Published: February 2020

Aggregation behaviors can often reduce predation risk, whether through dilution, confusion, or vigilance effects, but these effects are challenging to measure under natural conditions, involving strong interactions between the behaviors of predators and prey. Here we study aerial predation of massive swarms of Brazilian free-tailed batsTadarida brasiliensisby Swainson’s hawksButeo swainsoni, testing how the behavioral strategies of predator and prey influence catch success and predation risk. The hawks achieved high overall catch success, but they were no more successful against lone bats than against bats flying in column formation. There was therefore no evidence of any net vigilance or confusion effect, and hawks attacking the column benefitted from the opportunity to make several attempted grabs. Even so, the bats’ overall risk of predation was an order of magnitude higher when flying alone. Attacks on lone bats (∼10% of attacks) were greatly overrepresented relative to the proportion of bats classified as flying alone (∼0.2%), so dilution is both necessary and sufficient to explain the higher survival rates of bats flying in the column. From the hawks’ perspective, their odds of catching a bat more than trebled if the attack involved a stoop rather than level flight, or a rolling rather than pitching grab maneuver. These behavioral tactics were independently deployed in nearly three-quarters of all attacks. Hence, whereas the survival rate of a bat depends principally on whether it flies alone or in a group, the catch success of a hawk depends principally on how it maneuvers to attack.

Lay summary

Bats emerging by daylight from a massive desert roost are able to minimise their predation risk by maintaining tight column formation, because the hawks that attack them target stragglers disproportionately often. Whereas the predation risk of a bat therefore depends on how it maintains its position within the swarm, the catch success of a hawk depends on how it maneuvers to attack. Catch success is maximised by executing a stooping dive or a rolling grab.
Structural insights into secretory immunoglobulin A and its interaction with a pneumococcal adhesin
Authors: Wang Yuxin , Wang Guopeng , Li Yaxin , Shen Hao , Chu Huarui , Gao Ning , Xiao Junyu
Published: February 2020

Secretory Immunoglobulin A (SIgA) is the most abundant antibody at the mucosal surface. SIgA possesses two additional subunits besides IgA: the joining chain (J-chain) and secretory component (SC). SC is the ectodomain of the polymeric immunoglobulin receptor (pIgR), which functions to transport IgA to the mucosa. The underlying mechanism of how the J-chain and pIgR/SC facilitates the assembly and secretion of SIgA remains to be understood. During the infection ofStreptococcus pneumoniae, a pneumococcal adhesin SpsA hijacks SIgA and unliganded pIgR/SC to evade host defense and gain entry to human cells. How SpsA specifically targets SIgA and pIgR/SC also remains unclear. Here we report a cryo-electron microscopy structure of the Fc region of human IgA1 (Fcα) in complex with J-chain and SC (Fcα-J-SC), which reveals the organization principle of SIgA. We also present the structure of Fcα-J-SC in complex with SpsA, which uncovers the specific interaction between SpsA and human pIgR/SC. These results advance the molecular understanding of SIgA and shed light on the pathogenesis ofS. pneumoniae.
Replicative aging is associated with loss of genetic heterogeneity from extrachromosomal circular DNA inSaccharomyces cerevisiae
Authors: Prada-Luengo Iñigo , Møller Henrik D. , Henriksen Rasmus A. , Gao Qian , Larsen Camilla E. , Alizadeh Sefa , Maretty Lasse , Houseley Jonathan , Regenberg Birgitte
Published: February 2020

Circular DNA of chromosomal origin form from all parts of eukaryotic genomes. In yeast, circular rDNA accumulates as cells divide, contributing to replicative aging. However, little is known about how other chromosome-deri ved circles segregate and contribute to geneticvariation as cells age. We identified circular DNA across the genome of youngS. cerevisiaepopulations and their aged descendants. Young cells had highly diverse circular DNA populations, but lost 94% of the different circular DNA after 20 divisions. Circles present in both young and old cells were characterized by replication origins and included circles from unique regions of the genome, rDNA circles and telomericY’circles. The loss in genetic heterogeneity in aged cells was accompanied by massive accumulation of rDNA circles >95% of all circular DNA. We discovered circles had flexible inherence patterns. Glucose limited conditions selected for cells with glucose-transporter gene circles, [HXT6/7circle], and up to 50% of cells in a population carried them. [HXT6/7circle] cells were eventually substituted by cells carrying stable chromosomalHXT6 HXT6/7 HXT7amplifications, suggesting circular DNA were intermediates in chromosomal amplifications. In conclusion, DNA circles can offer a flexible adaptive solution but cells lose genetic heterogeneity from circular DNA as they undergo replicative aging.
To improve the predictions of binding residues with DNA, RNA, carbohydrate, and peptide via multiple-task deep neural networks
Authors: Sun Zhe , Zheng Shuangjia , Zhao Huiying , Niu Zhangming , Lu Yutong , Pan Yi , Yang Yuedong
Published: February 2020

Motivation

The interactions of proteins with DNA, RNA, peptide, and carbohydrate play key roles in various biological processes. The studies of uncharacterized protein–molecules interactions could be aided by accurate predictions of residues that bind with partner molecules. However, the existing methods for predicting binding residues on proteins remain of relatively low accuracies due to the limited number of complex structures in databases. As different types of molecules partially share chemical mechanisms, the predictions for each molecular type should benefit from the binding information with other molecules types.

Results

In this study, we employed a multiple task deep learning strategy to develop a new sequence-based method for simultaneously predicting binding residues/sites with multiple important molecule types named MTDsite. By combining four training sets for DNA, RNA, peptide, and carbohydrate-binding proteins, our method yielded accurate and robust predictions with AUC values of 0.852, 0836, 0.758, and 0.776 on their respective independent test sets, which are 0.52 to 6.6% better than other state-of-the-art methods. More importantly, this study provides a new strategy to improve predictions by combining multiple similar tasks.

Availability

http://biomed.nscc-gz.cn/server/MTDsite/

Contact

yangyd25@mail.sysu.edu.cn
Expression ofdlxgenes in the normal and regenerating brain of adult zebrafish
Authors: Weinschutz Mendes Hellen , Taktek Mariam , Duret Thomas , Ekker Marc
Published: February 2020

Dysfunctions in the GABAergic system lead to various pathological conditions and impaired inhibitory function is one of the causes behind neuropathies characterized by neuronal hyper excitability. TheDlxhomeobox genes are involved in the development of nervous system, neural crest, brachial arches and developing appendages.Dlxgenes also take part in neuronal migration and differentiation during development, more precisely, in the migration and differentiation of GABAergic neurons. Functional analysis ofdlxgenes has mainly been carried out in developing zebrafish embryos and larvae; however information regarding the expression and roles of these genes in the adult zebrafish brain is still lacking. The extensive neurogenesis that takes place in the brain of adult zebrafish makes them a good model for the visualization of mechanisms involvingdlxgenes during adulthood in physiological conditions and during regeneration of the nervous system. We have identified the adult brain regions where transcripts ofdlx1a, dlx2a, dlx5aanddlx6agenes are normally found and have confirmed that within telencephalic domains, there is high overlapping expression of the fourdlxparalogs with a marker for GABAergic neurons. Co-localization analyses carried with the Tg(dlx6a-1.4kbdlx5a/dlx6a:GFP) reporter line have also shown that in some areas of the diencephalon, cells expressing thedlx5a/6abigene may have a neural stem cell identity by co-localizing with a Sox2 antibody. Furthermore, investigations in a response to stab wound lesions, have demonstrated a possible participation of thedlx5a/6abigene, most likely, ofdlx5aduring the regeneration of the adult zebrafish brain. These data suggest a possible participation ofdlx-expressing cells during brain regeneration in adult zebrafish and also provide information on the role ofdlxgenes under normal physiological conditions in adults.
Site wind right: Identifying low-impact wind development areas in the Central United States
Authors: Hise Chris , Obermeyer Brian , Ahlering Marissa , Wilkinson Jessica , Fargione Joseph
Published: February 2020

To help avoid the most catastrophic effects of climate change, society needs to achieve net-zero greenhouse gas emissions by mid-century. Wind energy provides a clean, renewable source of electricity; however, improperly sited wind facilities pose known threats to wildlife populations and contribute to degradation of natural habitats. To support a rapid transition to low-carbon energy while protecting imperiled species, we identified potential low-impact areas for wind development in a 17-state region of the central U.S. By combining maps of sensitive habitats and species with wind speed and land use information, we demonstrate that there is significant potential to develop wind energy in the Great Plains while avoiding significant negative impacts to wildlife. These low-impact areas have the potential to yield approximately 1,099-1,832 GW of wind capacity. This is equivalent to 10-18 times current U.S. installed wind capacity. Our analysis demonstrates that ambitious low-carbon energy goals are achievable on sites with minimal risk of wildlife conflict.
Correlation between the immuno-virological response and the nutritional profile of treatment-experienced HIV-infected patients in the East region of Cameroon
Authors: Aissatou Abba , Fokam Joseph , Kamgaing Rachel Simo , Yimga Junie Flore , Ka’e Aude Christelle , Nka Alex Durand , Tommo Tchouaket Michel Carlos , Chenwi Ambe Collins , Jagni Semengue Ezechiel Ngoufack , Ndjolo Alexis , Sosso Samuel Martin
Published: February 2020

Background

HIV management remains concerning and even more challenging in the frame of comorbidities like malnutrition that favors disease progression and mortality in resource-limited settings (RLS).

Objective

To evaluate the correlation between immuno-virological responses and the nutritional profile of HIV-infected individuals receiving antiretroviral therapy (ART).

Methods

A cross-sectional study was conducted from October to December 2018 among 146 consenting participants enrolled in two health facilities of the East-Region of Cameroon. Socio-demographic data, basic clinical information and treatment history were collected; blood samples were collected by venipuncture for laboratory analysis (HIV-1 viral load, CD4-CD8 Tcells measurement and biochemical analysis) performed at the “Chantal Biya” International Reference Center”, Yaounde, Cameroon. Nutritional profile was evaluated using anthropometric and biochemical parameters. Data were analyzed using Excel 2016, Graph pad prism version 6 and R.version3.5.0; Spearman correlation was used; with p<0.05 considered statistically significant.

Results

Median [IQR] age was 42 [33-51] years, 76.0% (111/146) were female and median [IQR] duration on ART was 54 [28-86] months. Of these participants, 11.6% (17/146) were underweight based on the body mass index and 4.7% (7/146) were at the stage of advanced weight loss. According to immunovirological responses, 44.5% (65/146) were immunocompromised (CD4<500 cell/µl) and 75.3% (110/146) had an undetectable viremia (<40 copies/mL). CD4 count inversely correlated with total protein concentration (r=-0.18, p=0.030) and viremia was inversely correlated with total cholesterol (r=-0.65; p=0.001), and positively correlated with total protein (r=0.28; p<0.001) and seemingly with triglycerides (r=0.27; p=0.070) concentrations.

Conclusion

In this RLS with patients having about five years of ART-experience, half are immunocompromised while the majority have achieved good virological response. Interestingly, one out of eight patients might be experiencing malnutrition. Specifically, increasing CD4 may favour hypo-proteinemia while increasing viral load may prone hyper-proteinemia and hypo-cholesterolemia. Further studies are needed in RLS with high burden of HIV-infection.