bluuebunny/crossref_metadata_2025 huggingface dataset:
Zinc isotopes in Late Pleistocene fossil teeth from a Southeast Asian cave setting preserve paleodietary information
Authors: Bourgon Nicolas , Jaouen Klervia , Bacon Anne-Marie , Jochum Klaus Peter , Dufour Elise , Duringer Philippe , Ponche Jean-Luc , Joannes-Boyau Renaud , Boesch Quentin , Antoine Pierre-Olivier , Hullot Manon , Weis Ulrike , Schulz-Kornas Ellen , Trost Manuel , Fiorillo Denis , Demeter Fabrice , Patole-Edoumba Elise , Shackelford Laura L. , Dunn Tyler E. , Zachwieja Alexandra , Duangthongchit Somoh , Sayavonkhamdy Thongsa , Sichanthongtip Phonephanh , Sihanam Daovee , Souksavatdy Viengkeo , Hublin Jean-Jacques , Tütken Thomas
Published: February 2020

Significance

Dietary habits, especially meat consumption, represent a key aspect in the behavior and evolution of fossil hominin species. Here, we explore zinc (Zn) isotope ratios in tooth enamel of fossil mammals. We show discrimination between different trophic levels and demonstrate that Zn isotopes could prove useful in paleodietary studies of fossil hominin, or other mammalian species, to assess their consumption of animal versus plant resources. We also demonstrate the high preservation potential of pristine diet-related Zn isotope ratios, even under tropical conditions with poor collagen preservation, such as the studied depositional context in Southeast Asia. However, assessing the preservation of original δ
66
Zn values is required for each fossil site as diagenesis may vary across and even within taphonomic settings.
Higher-rank zeta functions for elliptic curves
Authors: Weng Lin , Zagier Don
Published: February 2020

Significance

The Riemann zeta function and the Riemann hypothesis concerning its zeros are perhaps the most famous function and most famous conjecture in all of number theory. Almost 100 years ago, Artin defined an analog, the “Artin zeta function,” for a curve (one-dimensional variety) over a finite field. In 2005, L.W. found a whole series of zeta functions for curves over finite fields, including the original Artin zeta function. The analog of the (still unsolved) classical Riemann hypothesis was proved for the Artin
l
function by Andre Weil, but the corresponding statement for Weng’s higher zeta functions is still open. In this paper it is proved for the simplest nontrivial case, when the curve has genus one (elliptic curve).
Anatomy of a selectively coassembled β-sheet peptide nanofiber
Authors: Shao Qing , Wong Kong M. , Seroski Dillon T. , Wang Yiming , Liu Renjie , Paravastu Anant K. , Hudalla Gregory A. , Hall Carol K.
Published: February 2020

Peptide self-assembly, wherein molecule A associates with other A molecules to form fibrillar β-sheet structures, is common in nature and widely used to fabricate synthetic biomaterials. Selective coassembly of peptide pairs A and B with complementary partial charges is gaining interest due to its potential for expanding the form and function of biomaterials that can be realized. It has been hypothesized that charge-complementary peptides organize into alternating ABAB-type arrangements within assembled β-sheets, but no direct molecular-level evidence exists to support this interpretation. We report a computational and experimental approach to characterize molecular-level organization of the established peptide pair, CATCH. Discontinuous molecular dynamics simulations predict that CATCH(+) and CATCH(−) peptides coassemble but do not self-assemble. Two-layer β-sheet amyloid structures predominate, but off-pathway β-barrel oligomers are also predicted. At low concentration, transmission electron microscopy and dynamic light scattering identified nonfibrillar ∼20-nm oligomers, while at high concentrations elongated fibers predominated. Thioflavin T fluorimetry estimates rapid and near-stoichiometric coassembly of CATCH(+) and CATCH(−) at concentrations ≥100 μM. Natural abundance
13
C NMR and isotope-edited Fourier transform infrared spectroscopy indicate that CATCH(+) and CATCH(−) coassemble into two-component nanofibers instead of self-sorting. However,
13
C–
13
C dipolar recoupling solid-state NMR measurements also identify nonnegligible AA and BB interactions among a majority of AB pairs. Collectively, these results demonstrate that strictly alternating arrangements of β-strands predominate in coassembled CATCH structures, but deviations from perfect alternation occur. Off-pathway β-barrel oligomers are also suggested to occur in coassembled β-strand peptide systems.
Direct observation of ligand migration within human hemoglobin at work
Authors: Shibayama Naoya , Sato-Tomita Ayana , Ohki Mio , Ichiyanagi Kouhei , Park Sam-Yong
Published: February 2020

Hemoglobin is one of the best-characterized proteins with respect to structure and function, but the internal ligand diffusion pathways remain obscure and controversial. Here we captured the CO migration processes in the tense (T), relaxed (R), and second relaxed (R2) quaternary structures of human hemoglobin by crystallography using a high-repetition pulsed laser technique at cryogenic temperatures. We found that in each quaternary structure, the photodissociated CO molecules migrate along distinct pathways in the α and β subunits by hopping between the internal cavities with correlated side chain motions of large nonpolar residues, such as α14Trp(A12), α105Leu(G12), β15Trp(A12), and β71Phe(E15). We also observe electron density evidence for the distal histidine [α58/β63His(E7)] swing-out motion regardless of the quaternary structure, although less evident in α subunits than in β subunits, suggesting that some CO molecules have escaped directly through the E7 gate. Remarkably, in T-state Fe(II)-Ni(II) hybrid hemoglobins in which either the α or β subunits contain Ni(II) heme that cannot bind CO, the photodissociated CO molecules not only dock at the cavities in the original Fe(II) subunit, but also escape from the protein matrix and enter the cavities in the adjacent Ni(II) subunit even at 95 K, demonstrating the high gas permeability and porosity of the hemoglobin molecule. Our results provide a comprehensive picture of ligand movements in hemoglobin and highlight the relevance of cavities, nonpolar residues, and distal histidines in facilitating the ligand migration.
Sons accelerate maternal aging in a wild mammal
Authors: Douhard Mathieu , Festa-Bianchet Marco , Pelletier Fanie
Published: February 2020

Aging, or senescence, is a progressive deterioration of physiological function with age. It leads to age-related declines in reproduction (reproductive senescence) and survival (actuarial senescence) in most organisms. However, senescence patterns can be highly variable across species, populations, and individuals, and the reasons for such variations remain poorly understood. Evolutionary theories predict that increases in reproductive effort in early life should be associated with accelerated senescence, but empirical tests have yielded mixed results. Although in sexually size-dimorphic species offspring of the larger sex (typically males) commonly require more parental resources, these sex differences are not currently incorporated into evolutionary theories of aging. Here, we show that female reproductive senescence varies with both the number and sex ratio of offspring weaned during early life, using data from a long-term study of bighorn sheep. For a given number of offspring, females that weaned more sons than daughters when aged between 2 and 7 y experienced faster senescence in offspring survival in old age. By contrast, analyses of actuarial senescence showed no cost of early-life reproduction. Our results unite two important topics in evolutionary biology: life history and sex allocation. Offspring sex ratio may help explain among-individual variation in senescence rates in other species, including humans.
GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone
Authors: Suh Joonho , Kim Na-Kyung , Lee Seung-Hoon , Eom Je-Hyun , Lee Youngkyun , Park Joo-Cheol , Woo Kyung Mi , Baek Jeong-Hwa , Kim Jung-Eun , Ryoo Hyun-Mo , Lee Se-Jin , Lee Yun-Sil
Published: February 2020

Significance

MSTN, a member of the TGF-β family, has been widely shown to suppress muscle growth, leading to an intense effort being directed at targeting MSTN to treat patients with muscle loss. GDF11 is another TGF-β family member closely related to MSTN, but its postnatal function is less clear. Using conditional knockout techniques, we show that GDF11 enhances bone mass in contrast to MSTN, emphasizing that MSTN/GDF11 inhibitors, such as FST, can induce adverse effects on bone through GDF11 inhibition. Because most MSTN inhibitors also inhibit GDF11 due to the high sequence similarity between MSTN and GDF11, our findings suggest that their opposing roles must be carefully considered when developing MSTN inhibitors for clinical applications.
Tunable and precise miniature lithium heater for point-of-care applications
Authors: Udugama Buddhisha , Kadhiresan Pranav , Chan Warren C. W.
Published: February 2020

Significance

Biochemical techniques are required for a variety of different point-of-care applications, from diagnosing illnesses to manufacturing vaccines. Many of these applications cannot be used in remote locations due to their reliance on electricity for temperature control. Here we have developed a miniature lithium heater, up to 8,000 times smaller than existing technologies, enabling the use of biochemical techniques at the point of care. By using these heaters in a model workflow that detects the presence of a virus, we demonstrate their applicability to a broad range of biochemical techniques that require precise temperature control. This technology may be broadly used, such as in disaster relief camps or mountain expeditions, for diagnostic and therapeutic applications.
β-Arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates
Authors: Woo Jung-A A. , Liu Tian , Fang Cenxiao C. , Castaño Maria A. , Kee Teresa , Yrigoin Ksenia , Yan Yan , Cazzaro Sara , Matlack Jenet , Wang Xinming , Zhao Xingyu , Kang David E. , Liggett Stephen B.
Published: February 2020

Significance

Frontotemporal lobar degeneration (FTLD) is second only to Alzheimer’s disease as a cause of dementia, and we find the scaffolding protein β-arrestin2 is elevated in human brains with this condition, and is responsible for accumulation of pathological tau tangles. Increased β-arrestin2 impairs tau clearance and promotes tau aggregation by impeding the autophagy cargo carrier p62/SQSTM1. Such activity requires β-arrestin2 in its oligomeric form, an assembly state that is not involved with receptor binding. Virus delivered gene therapy to the brain with dominant-negative mutant β-arrestin2s ablates pathologic tau in neurons of a mouse model of FTLD-tau, revealing a strategy to mitigate tauopathy by targeting β-arrestin2 oligomerization.
Microbial feedbacks optimize ocean iron availability
Authors: Lauderdale Jonathan Maitland , Braakman Rogier , Forget Gaël , Dutkiewicz Stephanie , Follows Michael J.
Published: February 2020

Iron is the limiting factor for biological production over a large fraction of the surface ocean because free iron is rapidly scavenged or precipitated under aerobic conditions. Standing stocks of dissolved iron are maintained by association with organic molecules (ligands) produced by biological processes. We hypothesize a positive feedback between iron cycling, microbial activity, and ligand abundance: External iron input fuels microbial production, creating organic ligands that support more iron in seawater, leading to further macronutrient consumption until other microbial requirements such as macronutrients or light become limiting, and additional iron no longer increases productivity. This feedback emerges in numerical simulations of the coupled marine cycles of macronutrients and iron that resolve the dynamic microbial production and loss of iron-chelating ligands. The model solutions resemble modern nutrient distributions only over a finite range of prescribed ligand source/sink ratios where the model ocean is driven to global-scale colimitation by micronutrients and macronutrients and global production is maximized. We hypothesize that a global-scale selection for microbial ligand cycling may have occurred to maintain “just enough” iron in the ocean.
Natural variation in DNA methylation homeostasis and the emergence of epialleles
Authors: Zhang Yinwen , Wendte Jered M. , Ji Lexiang , Schmitz Robert J.
Published: February 2020

In plants and mammals, DNA methylation plays a critical role in transcriptional silencing by delineating heterochromatin from transcriptionally active euchromatin. A homeostatic balance between heterochromatin and euchromatin is essential to genomic stability. This is evident in many diseases and mutants for heterochromatin maintenance, which are characterized by global losses of DNA methylation coupled with localized ectopic gains of DNA methylation that alter transcription. Furthermore, we have shown that genome-wide methylation patterns in
Arabidopsis thaliana
are highly stable over generations, with the exception of rare epialleles. However, the extent to which natural variation in the robustness of targeting DNA methylation to heterochromatin exists, and the phenotypic consequences of such variation, remain to be fully explored. Here we describe the finding that heterochromatin and genic DNA methylation are highly variable among 725
A. thaliana
accessions. We found that genic DNA methylation is inversely correlated with that in heterochromatin, suggesting that certain methylation pathway(s) may be redirected to genes upon the loss of heterochromatin. This redistribution likely involves a feedback loop involving the DNA methyltransferase, CHROMOMETHYLASE 3 (CMT3), H3K9me2, and histone turnover, as highly expressed, long genes with a high density of CMT3-preferred CWG sites are more likely to be methylated. Importantly, although the presence of CG methylation in genes alone may not affect transcription, genes containing CG methylation are more likely to become methylated at non-CG sites and silenced. These findings are consistent with the hypothesis that natural variation in DNA methylation homeostasis may underlie the evolution of epialleles that alter phenotypes.
Divergent selection and genetic introgression shape the genome landscape of heterosis in hybrid rice
Authors: Lin Zechuan , Qin Peng , Zhang Xuanwen , Fu Chenjian , Deng Hanchao , Fu Xingxue , Huang Zhen , Jiang Shuqin , Li Chen , Tang Xiaoyan , Wang Xiangfeng , He Guangming , Yang Yuanzhu , He Hang , Deng Xing Wang
Published: February 2020

The successful application of heterosis in hybrid rice has dramatically improved rice productivity, but the genetic mechanism for heterosis in the hybrid rice remains unclear. In this study, we generated two populations of rice F
1
hybrids with present-day commercial hybrid parents, genotyped the parents with 50k SNP chip and genome resequencing, and recorded the phenotype of ∼2,000 hybrids at three field trials. By integrating these data with the collected genotypes of ∼4,200 rice landraces and improved varieties that were reported previously, we found that the male and female parents have different levels of genome introgressions from other rice subpopulations, including
indica
,
aus
, and
japonica
, therefore shaping heterotic loci in the hybrids. Among the introgressed exogenous genome, we found that heterotic loci, including
Ghd8
/
DTH8
,
Gn1a
, and
IPA1
existed in wild rice, but were significantly divergently selected among the rice subpopulations, suggesting these loci were subject to environmental adaptation. During modern rice hybrid breeding, heterotic loci were further selected by removing loci with negative effect and fixing loci with positive effect and pyramid breeding. Our results provide insight into the genetic basis underlying the heterosis of elite hybrid rice varieties, which could facilitate a better understanding of heterosis and rice hybrid breeding.
Functional lipid pairs as building blocks of phase-separated membranes
Authors: Soloviov Dmytro , Cai Yong Q. , Bolmatov Dima , Suvorov Alexey , Zhernenkov Kirill , Zav’yalov Dmitry , Bosak Alexey , Uchiyama Hiroshi , Zhernenkov Mikhail
Published: February 2020

Significance

Although it is believed that the raft formation in a cell membrane is governed by a selective interaction of different lipids and proteins, mechanisms driving and regulating the lateral membrane heterogeneity remain poorly understood. Here, using multicomponent lipid mixtures and inelastic X-ray scattering, we provide a spatial–temporal window to study lipid–lipid interactions. We show experimental evidence for the formation of dynamic lipid pairs, which are subnanometer in size and have a subnanosecond lifetime. These pairs form transient nanoscopic substructures in the liquid-ordered phase. The presented approach to study membrane heterogeneity is universal and can be applied to more realistic lipid mixtures, offering the possibility to discern differences between the structures of ordered and disordered phases in a cell membrane.
The grain boundary mobility tensor
Authors: Chen Kongtao , Han Jian , Pan Xiaoqing , Srolovitz David J.
Published: February 2020

Significance

Defects and microstructures have a profound impact on material strength and ductility. Microstructure engineering can enhance/trade-off between these properties. One of the key parameters that dictates microstructure evolution is grain-boundary mobility. We demonstrate the fundamental nature of the mobility, reconciling a wide range of observations in a consistent model. We argue that the mobility is, in general, a tensor (classically, it is a scalar) and determine all of its components. We do this by combining molecular-dynamics simulations and the development of a statistical mechanics-based disconnection (line defects in grain boundaries) model. The tensor nature of the mobility explains which grain-boundary characteristics are materials properties and which are not and demonstrates that stress generation always slows grain growth.
Evidence that Criegee intermediates drive autoxidation in unsaturated lipids
Authors: Zeng Meirong , Heine Nadja , Wilson Kevin R.
Published: February 2020

Significance

Autoxidation leads to the slow persistent destruction of organic molecules causing oxidative stress and associated disease. The prevailing autoxidation mechanism of unsaturated lipids involves chain reactions initiated and propagated by H-atom abstraction, mediated by peroxy radicals and other reactive oxygen species. Here we report experimental evidence for an autoxidation mechanism initiated by OH, which is unanticipated and proceeds by OH addition followed by pathways involving Criegee intermediates (CIs). Although CIs are routinely encountered in atmospheric and synthetic organic chemistry, their role in autoxidation is unexpected. Our results suggest that in all likelihood these exotic species play a much more prominent and general role in the chemistry of cells, food, petrochemicals, and the environment beyond what is currently believed.
Bioinspired programmable wettability arrays for droplets manipulation
Authors: Sun Lingyu , Bian Feika , Wang Yu , Wang Yuetong , Zhang Xiaoxuan , Zhao Yuanjin
Published: February 2020

Significance

Droplet manipulation has received great attention and research for its potential applications in various fields. Wettability surfaces, especially tunable wettability surfaces, are efficient way to manipulate the pinning and sliding of droplets. However, these surfaces only demonstrate uniform wettability control behavior and thus were difficult to accurately manipulate droplets to a certain location or multiple locations. In this paper, inspired by the microstructure of stomata distributed on plants, we present programmable wettability arrays for droplets manipulation by using microfluidic emulsification templates. Based on the intelligent composite system, controllable droplet sliding on programmable wettability pathways and effective droplet transfer for printing with mask integration have been demonstrated.
A metaphorical map of subtitling
Authors: Labarta Postigo María
Published: February 2020

This study explores the metaphorical dimension of idioms in original filmic texts and their translations in
subtitles, in order to shed light on strategies used in the translation process. The research focuses on a corpus of 20 films
from the Library of Foreign Language Film Clips (LFLFC), at the Berkeley Language Center of the University of California,
Berkeley. More specifically, I analyze films in German and Spanish with English subtitles from a cognitive and contrastive
perspective. My goal is to explore how translation can affect understanding and reception by an audience with limited or no skills
in the original language. Results of the analysis show a tendency towards reduction of metaphorical expressions in translated
English subtitles, these varying according to the original language of the film. Contrastive analysis demonstrates that in
translation from Spanish, the explicit meaning strategy is far more frequent than in translation from German. The findings of this
study can be applied in foreign language teaching as a means of developing learners’ cultural awareness and language
comprehension, as well as in the field of audiovisual subtitling translation.
What the hands tell us about mathematical learning
Authors: Martinez-Lincoln Amanda , Tran Le M. , Powell Sarah R.
Published: February 2020

Mathematical achievement is an early predictor of students’ academic outcomes, and mathematics achievement continues to be important throughout life. Thus, it is essential to examine instructional methods that enhance mathematical learning. One method that may impact mathematical learning is the use of gestures, yet a comprehensive methodical review of the data has not been conducted. The current study examined the impact that gestures have on student learning when educators use gestures during mathematical instruction and educators’ perception of student mathematical knowledge when students use gestures. A systematic search was conducted to assemble research studies that evaluated the use of gestures in mathematical instruction with students in preschool to 12th grade. Empirical data from 35 research articles indicate that gestures used by students or educators that enhance verbal instruction can increase student mathematical performance and memory. Furthermore, it is practical to teach students and educators to use gestures effectively during mathematical learning.
Negation in San Juan Quiahije Chatino Sign Language
Authors: Mesh Kate , Hou Lynn
Published: February 2020

Sign languages do not arise from thin air: rather, they emerge in communities where conventions are already in place for using gesture. Little research has considered how these conventions are retained and/or adapted as gestures are integrated into emerging sign language lexicons. Here we describe a set of five gestures that are used to convey negative meanings by both speakers and signers in a single community: the San Juan Quiahije municipality in Oaxaca, Mexico. We show that all of the form-meaning mappings present for non-signers are retained by signers as they integrate the gestures into their lexicon. Interestingly, additional meanings are mapped to the gesture forms by signers – a phenomenon that appears to originate with deaf signers in particular. In light of this evidence, we argue that accounts of ‘wholesale borrowing’ of gestures into emerging sign languages is overly simplistic: signers evidently adapt gestures as they integrate them into their emerging lexicons.
Probing the subcellular distribution of phosphatidylinositol reveals a surprising lack at the plasma membrane
Authors: Zewe James P. , Miller April M. , Sangappa Sahana , Wills Rachel C. , Goulden Brady D. , Hammond Gerald R.V.
Published: February 2020

The polyphosphoinositides (PPIn) are central regulatory lipids that direct membrane function in eukaryotic cells. Understanding how their synthesis is regulated is crucial to revealing these lipids’ role in health and disease. PPIn are derived from the major structural lipid, phosphatidylinositol (PI). However, although the distribution of most PPIn has been characterized, the subcellular localization of PI available for PPIn synthesis is not known. Here, we used several orthogonal approaches to map the subcellular distribution of PI, including localizing exogenous fluorescent PI, as well as detecting lipid conversion products of endogenous PI after acute chemogenetic activation of PI-specific phospholipase and 4-kinase. We report that PI is broadly distributed throughout intracellular membrane compartments. However, there is a surprising lack of PI in the plasma membrane compared with the PPIn. These experiments implicate regulation of PI supply to the plasma membrane, as opposed to regulation of PPIn-kinases, as crucial to the control of PPIn synthesis and function at the PM.
Heparan sulfate is a clearance receptor for aberrant extracellular proteins
Authors: Itakura Eisuke , Chiba Momoka , Murata Takeshi , Matsuura Akira
Published: February 2020

The accumulation of aberrant proteins leads to various neurodegenerative disorders. Mammalian cells contain several intracellular protein degradation systems, including autophagy and proteasomal systems, that selectively remove aberrant intracellular proteins. Although mammals contain not only intracellular but also extracellular proteins, the mechanism underlying the quality control of aberrant extracellular proteins is poorly understood. Here, using a novel quantitative fluorescence assay and genome-wide CRISPR screening, we identified the receptor-mediated degradation pathway by which misfolded extracellular proteins are selectively captured by the extracellular chaperone Clusterin and undergo endocytosis via the cell surface heparan sulfate (HS) receptor. Biochemical analyses revealed that positively charged residues on Clusterin electrostatically interact with negatively charged HS. Furthermore, the Clusterin–HS pathway facilitates the degradation of amyloid β peptide and diverse leaked cytosolic proteins in extracellular space. Our results identify a novel protein quality control system for preserving extracellular proteostasis and highlight its role in preventing diseases associated with aberrant extracellular proteins.
Generating synthetic magnetism via Floquet engineering auxiliary qubits in phonon-cavity-based lattice
Authors: Wang Xin , Li Hong-Rong , Li Fu-Li
Published: February 2020

Gauge magnetic fields have a close relation to breaking time-reversal symmetry in condensed matter. In the presence of the gauge fields, we might observe nonreciprocal and topological transport. Inspired by these, there is a growing effort to realize exotic transport phenomena in optical and acoustic systems. However, due to charge neutrality, realizing analog magnetic flux for phonons in nanoscale systems is still challenging in both theoretical and experimental studies. Here we propose a novel mechanism to generate synthetic magnetic field for phonon lattice by Floquet engineering auxiliary qubits. We find that, a longitudinal Floquet drive on the qubit will produce a resonant coupling between two detuned acoustic cavities. Specially, the phase encoded into the longitudinal drive can exactly be transformed into the phonon–phonon hopping. Our proposal is general and can be realized in various types of artificial hybrid quantum systems. Moreover, by taking surface-acoustic-wave (SAW) cavities for example, we propose how to generate synthetic magnetic flux for phonon transport. In the presence of synthetic magnetic flux, the time-reversal symmetry will be broken, which allows one to realize the circulator transport and analog Aharonov–Bohm effects for acoustic waves. Last, we demonstrate that our proposal can be scaled to simulate topological states of matter in quantum acoustodynamics system.
Protein–ligand binding residue prediction enhancement through hybrid deep heterogeneous learning of sequence and structure data
Authors: Xia Chun-Qiu , Pan Xiaoyong , Shen Hong-Bin
Published: February 2020

Motivation

Knowledge of protein–ligand binding residues is important for understanding the functions of proteins and their interaction mechanisms. From experimentally solved protein structures, how to accurately identify its potential binding sites of a specific ligand on the protein is still a challenging problem. Compared with structure-alignment-based methods, machine learning algorithms provide an alternative flexible solution which is less dependent on annotated homogeneous protein structures. Several factors are important for an efficient protein–ligand prediction model, e.g. discriminative feature representation and effective learning architecture to deal with both the large-scale and severely imbalanced data.

Results

In this study, we propose a novel deep-learning-based method called DELIA for protein–ligand binding residue prediction. In DELIA, a hybrid deep neural network is designed to integrate 1D sequence-based features with 2D structure-based amino acid distance matrices. To overcome the problem of severe data imbalance between the binding and nonbinding residues, strategies of oversampling in mini-batch, random undersampling and stacking ensemble are designed to enhance the model. Experimental results on five benchmark datasets demonstrate the effectiveness of proposed DELIA pipeline.

Availability and implementation

The web server of DELIA is available at www.csbio.sjtu.edu.cn/bioinf/delia/.

Supplementary information

Supplementary data are available at Bioinformatics online.
MUM&Co: accurate detection of all SV types through whole-genome alignment
Authors: O’Donnell Samuel , Fischer Gilles
Published: February 2020

MUM&Co is a single bash script to detect structural variations (SVs) utilizing whole-genome alignment (WGA). Using MUMmer’s nucmer alignment, MUM&Co can detect insertions, deletions, tandem duplications, inversions and translocations greater than 50 bp. Its versatility depends upon the WGA and therefore benefits from contiguous de-novo assemblies generated by third generation sequencing technologies. Benchmarked against five WGA SV-calling tools, MUM&Co outperforms all tools on simulated SVs in yeast, plant and human genomes and performs similarly in two real human datasets. Additionally, MUM&Co is particularly unique in its ability to find inversions in both simulated and real datasets. Lastly, MUM&Co’s primary output is an intuitive tabulated file containing a list of SVs with only necessary genomic details.

Availability and implementation

https://github.com/SAMtoBAM/MUMandCo.

Supplementary information

Supplementary data are available at Bioinformatics online.
High-throughput and efficient multilocus genome-wide association study on longitudinal outcomes
Authors: Xu Huang , Li Xiang , Yang Yaning , Li Yi , Pinheiro Jose , Sasser Kate , Hamadeh Hisham , Steven Xu , Yuan Min ,   and for the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2020

Motivation

With the emerging of high-dimensional genomic data, genetic analysis such as genome-wide association studies (GWAS) have played an important role in identifying disease-related genetic variants and novel treatments. Complex longitudinal phenotypes are commonly collected in medical studies. However, since limited analytical approaches are available for longitudinal traits, these data are often underutilized. In this article, we develop a high-throughput machine learning approach for multilocus GWAS using longitudinal traits by coupling Empirical Bayesian Estimates from mixed-effects modeling with a novel ℓ0-norm algorithm.

Results

Extensive simulations demonstrated that the proposed approach not only provided accurate selection of single nucleotide polymorphisms (SNPs) with comparable or higher power but also robust control of false positives. More importantly, this novel approach is highly scalable and could be approximately >1000 times faster than recently published approaches, making genome-wide multilocus analysis of longitudinal traits possible. In addition, our proposed approach can simultaneously analyze millions of SNPs if the computer memory allows, thereby potentially allowing a true multilocus analysis for high-dimensional genomic data. With application to the data from Alzheimer's Disease Neuroimaging Initiative, we confirmed that our approach can identify well-known SNPs associated with AD and were much faster than recently published approaches (≥6000 times).

Availability and implementation

The source code and the testing datasets are available at https://github.com/Myuan2019/EBE_APML0.

Supplementary information

Supplementary data are available at Bioinformatics online.
Estimation and inference for the indirect effect in high-dimensional linear mediation models
Authors: Zhou Ruixuan Rachel , Wang Liewei , Zhao Sihai Dave
Published: February 2020

Mediation analysis is difficult when the number of potential mediators is larger than the sample size. In this paper we propose new inference procedures for the indirect effect in the presence of high-dimensional mediators for linear mediation models. We develop methods for both incomplete mediation, where a direct effect may exist, and complete mediation, where the direct effect is known to be absent. We prove consistency and asymptotic normality of our indirect effect estimators. Under complete mediation, where the indirect effect is equivalent to the total effect, we further prove that our approach gives a more powerful test compared to directly testing for the total effect. We confirm our theoretical results in simulations, as well as in an integrative analysis of gene expression and genotype data from a pharmacogenomic study of drug response. We present a novel analysis of gene sets to understand the molecular mechanisms of drug response, and also identify a genome-wide significant noncoding genetic variant that cannot be detected using standard analysis methods.
Antibiotic Prescribing Choices and Their Comparative C. Difficile Infection Risks: A Longitudinal Case-Cohort Study
Authors: Brown Kevin Antoine , Langford Bradley , Schwartz Kevin L , Diong Christina , Garber Gary , Daneman Nick
Published: February 2020

Background

Antibiotic use is the strongest modifiable risk factor for the development of Clostridioides difficile infection, but prescribers lack quantitative information on comparative risks of specific antibiotic courses. Our objective was to estimate risks of C. difficile infection associated with receipt of specific antibiotic courses.

Methods

We conducted a longitudinal case-cohort analysis representing over 90% of Ontario nursing home residents, between 2012 and 2017. Our primary exposure was days of antibiotic receipt in the prior 90 days. Adjustment covariates included: age, sex, prior emergency department or acute care stay, Charlson comorbidity index, prior C. difficile infection, acid suppressant use, device use, and functional status. We examined incident C. difficile infection, including cases identified within the nursing home, and those identified during subsequent hospital admissions. Adjusted and unadjusted regression models were used to measure risk associated with 5- to 14-day courses of 18 different antibiotics.

Results

We identified 1708 cases of C. difficile infection (1.27 per 100 000 resident-days). Longer antibiotic duration was associated with increased risk: 10- and 14-day courses incurred 12% (adjusted relative risk [ARR] = 1.12, 95% confidence interval [CI]: 1.09, 1.14) and 27% (ARR = 1.27, 95% CI: 1.21,1.30) more risk compared to 7-day courses. Among 7-day courses with similar indications: moxifloxacin resulted in 121% more risk than amoxicillin (ARR = 2.21, 95% CI: 1.67, 3.08), ciprofloxacin engendered 89% more risk than nitrofurantoin (ARR = 1.89, 95% CI: 1.45, 2.68), and clindamycin resulted in 112% (ARR = 2.12, 95% CI: 1.32, 3.78) more risk than cloxacillin.

Conclusions

C. difficile infection risk increases with antibiotic duration, and there are wide disparities in risks associated with antibiotic courses used for similar indications.
Plasma S100A8/A9 Concentrations and Clinical Outcomes of Ischemic Stroke in 2 Independent Multicenter Cohorts
Authors: Guo Daoxia , Zhu Zhengbao , Xu Tan , Zhong Chongke , Wang Aili , Xie Xuewei , Peng Yanbo , Peng Hao , Li Qunwei , Ju Zhong , Geng Deqin , Chen Jing , Liu Liping , Wang Yilong , Zhang Yonghong , He Jiang
Published: February 2020

Background

S100A8/A9 is implicated in inflammation mechanisms related to atherosclerosis and plaque vulnerability, but it remains unclear whether S100A8/A9 is associated with the prognosis of ischemic stroke. The aim of this study was to investigate these associations in 2 independent multicenter cohorts.

Methods

Plasma S100A8/A9 concentrations at baseline were measured among 4785 patients with ischemic stroke from 2 independent cohorts: Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke (IIPAIS) and China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a composite outcome of death or major disability at 3 months after ischemic stroke. Secondary outcomes were major disability, death, and a composite outcome of death or vascular events.

Results

Among the combined participants of IIPAIS and CATIS, the adjusted odds ratios associated with the highest quartile of plasma S100A8/A9 were 2.11 (95% CI, 1.66–2.68) for the primary outcome and 1.62 (95% CI, 1.27–2.07) for the secondary outcome of major disability; adjusted hazard ratios were 4.14 (95% CI, 2.10–8.15) for the secondary outcome of death and 2.08 (95% CI, 1.38–3.13) for the composite outcome of death or vascular events. Each SD increase of log-transformed S100A8/A9 was associated with 28% (95% CI, 18%–39%; P < 0.001) increased risk of the primary outcome. Multivariable-adjusted spline regression analyses showed a linear association between plasma S100A8/A9 concentrations and primary outcome (P < 0.001 for linearity). Subgroup analyses further confirmed these associations.

Conclusions

High plasma S100A8/A9 concentrations at baseline were independently associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that S100A8/A9 might have a role as a prognostic marker of ischemic stroke.
Teacher interaction strategies and situated willingness to communicate
Authors: Peng Jian-E
Published: February 2020

This study explores variation in willingness to communicate (WTC) in English between whole-class interaction and dyadic and group interaction, and teacher interaction strategies identified to sustain students’ WTC in whole-class interaction that primarily followed the initiation–response–feedback (IRF) pattern. Data were collected from a regular English class at a university in China through audio-recording of a lesson, classroom observation, self-rating of WTC by 23 students, and stimulated recall interviews with four focal students. The results indicate that WTC in whole-class interaction did not significantly differ from WTC in dyadic and group interaction. Teacher interaction strategies, including the use of open or referential questions in the I-move and F-move, manipulation of wait time following prompts, and monitoring private speech and contextual or multimodal clues of students’ WTC, functioned to sustain classroom WTC. Implications for adopting teacher interaction strategies in line with lesson plans within the framework of IRF pedagogic discourse are discussed.
Constraining landslide characteristics with Bayesian inversion of field and seismic data
Authors: Moretti L , Mangeney A , Walter F , Capdeville Y , Bodin T , Stutzmann E , Le Friant A
Published: February 2020

Using a fully nonlinear Bayesian approach based on forward modelling of granular flow, we invert for landslide parameters (volume, release geometry and rheology) from different kinds of observations. Synthetic tests show that the runout distance and the deposit area by themselves do not constrain landslide parameters. Better constraints on landslide parameters are obtained from the thickness distribution of the landslide deposits, as well as from the force history applied by the landslide to the ground, which contains information on the landslide dynamics. Therefore, inverting force histories calculated from seismic broad-band records is an important alternative to inverting thickness distributions of landslide deposits, which are usually difficult to obtain. We test the method on the 1997 Boxing Day debris avalanche on Montserrat Island, which involved 40 − 50 Mm3. The Bayesian inversion and granular flow model provide good estimates for volume, release geometry and effective friction coefficient. This study thus underlines the value of broad-band seismic records as observations to monitor landslides and validation for their numerical flow models.
Co-participation in physical activity: perspectives from Australian parents of pre-schoolers
Authors: Hnatiuk Jill A , Dwyer Genevieve , George Emma S , Bennie Andrew
Published: February 2020

Co-participation in physical activity may be important for helping families with young children meet physical activity recommendations. Yet, little is known about what families perceive to be the benefits, barriers and facilitators of co-participation. This study explored (i) parents’ perceptions about physical activity and possible benefits of family-based co-participation in physical activity, (ii) their perceived facilitators and barriers to co-participation and (iii) their recommendations for improving co-participation within their community. Fifteen parents (14 mothers, 1 father) of 2- to 4-year-old children residing in Western Sydney, Australia, participated in one-on-one interviews between September 2016 and January 2017. Interviews were audio-recorded and transcribed verbatim. Four main themes and seven sub-themes emerged from the thematic analysis of the interview data. When parents were asked to reflect on their understanding of physical activity, they discussed a range of well-known activities (e.g. active play, active transport) and also reported ‘anything but screen time’. The major benefits parents reported about co-participation were spending quality time together, improving children’s general health and well-being and the development of physical skills. Social (e.g. social networks, negative stereotypes) and environmental (e.g. home space, neighbourhood design, shading) facilitators and barriers were identified, yet their impact on co-participation often varied depending on the presence (or lack thereof) of other factors in the physical or social environment. Key recommendations suggested by parents included improvements to home outdoor spaces, neighbourhood design and play spaces and community services.
Study of the time-relationship of the mechano-electrical interaction in an animal model of tetralogy of Fallot: implications for the risk assessment of ventricular arrhythmias
Authors: Bove Thierry , Alipour Symakani Rahi , Verbeke Jonas , Vral Anne , El Haddad Milad , De Wilde Hans , Stroobandt Roland , De Pooter Jan
Published: February 2020

OBJECTIVES

The long-term outcome of tetralogy of Fallot (TOF) is determined by progressive right ventricular (RV) dysfunction through pulmonary regurgitation (PR) and the risk of malignant arrhythmia. Although mechano-electrical coupling in TOF is well-known, its time effect on the inducibility of arrhythmia remains ill-defined. The goal of this study was to investigate the mechano-electrical properties at different times in animals with chronic PR.

METHODS

PR was induced by a transannular patch with limited RV scarring in infant pigs. Haemodynamic assessment included biventricular pressure–volume loops after 3 (n = 8) and 6 months (n = 7) compared to controls (n = 5). The electrophysiological study included endocardial monophasic action potential registration, intraventricular conduction velocity and induction of ventricular arrhythmia by burst pacing.

RESULTS

Progressive RV dilation was achieved at 6 months (RV end-diastolic volume 143 ± 13 ml/m2—RV end-systolic volume 96 ± 7 ml/m2; P < 0.001), in association with depressed RV contractility (preload recruitable stroke work-slope: 19 ± 1 and 11 ± 3 Mw.ml−1.s−1 for control and 6 m; P < 0.001) and left ventricular contractility (preload recruitable stroke work-slope: 60 ± 13 and 40 ± 11 Mw.ml−1.s−1 for control and 6 m; P = 0.005). Concomitant to QRS prolongation, monophasic action potential90-duration and dispersion at the RV and left ventricle were increased at 6 months. Intraventricular conduction was delayed only in the RV at 6 months (1.8 ± 0.2 and 2.4 ± 0.6 m/s for group 6M and the control group; P = 0.035). Sustained ventricular arrhythmias were not inducible.

CONCLUSIONS

In animals yielding the sequelae of a contemporary operation for TOF, mechano-electrical alterations are progressive and affect predominantly the RV after midterm exposure of PR. Because ventricular arrhythmias were not inducible despite significant RV dilation, the data suggest that the haemodynamic RV deterioration effectively precedes the risk of inducing sustained arrhythmia after TOF repair and opens a window for renewed stratification of contemporary risk factors of ventricular arrhythmias in patients operated on with currently used pulmonary valve- and RV-related techniques.
Treat bronchopleural fistula after right lower lobectomy by extra right middle lobectomy—a neglected approach
Authors: Wang Yan-Qing , Zhuang Wei
Published: February 2020

OBJECTIVES

Bronchopleural fistula (BPF) after right lower lobectomy (RLL), although uncommon, is associated with high mortality rates. This study was aimed at evaluating the therapeutic effect of extra right middle lobectomy (ERML) in the management of BPF after RLL.

METHODS

We investigated 12 consecutive patients who were treated at our hospital for BPF occurring after RLL. The diagnosis of BPF was established by bronchoscopy in all cases and BPFs were treated by ERML. All patients were followed up for at least 1 year after ERML to assess treatment outcomes.

RESULTS

The severity of infection and malnutrition after BPF was different for different patients. All patients agreed to undergo ERML. The procedure was uneventful in all cases, and there were no cases of perioperative complications or death. The median duration of hospitalization after ERML was 10.5 (range 6–21) days. Postoperative pathological examination showed the presence of hyperaemia and oedema in the BPF stump, and inflammatory cell infiltration in the stroma. The fresh stump of the bronchus intermedius was well structured. Patients were followed up for a median duration of 27 (range 12–41) months. The BPFs were successfully treated in all patients, and a new BPF did not develop in the new fresh stump in any of the cases.

CONCLUSIONS

ERML aimed at creating a fresh stump for quick healing could be alternative for treating BPF after RLL.