bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and Safety of Advanced Audiology-Led Triage in Pediatric Otolaryngology Services
Authors: Pokorny Michelle A. , Wilson Wayne J. , Whitfield Bernard C. S. , Thorne Peter R.
Published: February 2020

Objectives:

Expansion of the scopes of practice of allied health practitioners has the potential to improve the efficiency and cost-effectiveness of healthcare, given the identified shortages in medical personnel. Despite numerous examples in other allied health disciplines, this has yet to be applied to pediatric Audiology. This study aimed to investigate the effectiveness and safety of using audiologists with advanced training to independently triage children referred to otolaryngology (ORL) services, and compare the subsequent use of specialist resources, and postoperative grommet care to a standard medical ORL service.

Design:

One hundred twenty children consecutively referred to a large ORL outpatient service in Queensland, Australia, for middle ear and hearing concerns were prospectively allocated to either the ORL service or Advanced Audiology-led service. Demographic and clinical data were extracted from electronic medical records and compared between the two services. Clinical incidents and adverse events were recorded for the Advanced Audiology-led service.

Results:

Approximately half of all children referred to ORL for middle ear or hearing concerns were discharged without requiring any treatment, with the remaining half offered surgical treatment. The Advanced Audiology-led model increased the proportion of children assessed by ORL that proceeded to surgery from 57% to 82% compared with the standard medical ORL model. Children followed up by the audiologists after grommet insertion were more likely to be discharged independently and at the first postoperative review appointment compared with the standard medical ORL service. There were no reports of adverse events or long-term bilateral hearing loss after discharge by the Advanced Audiology-led service.

Conclusions:

These findings indicate that an Advanced Audiology-led service provides a safe and effective triaging model for the independent management of children not requiring treatment, and children requiring routine postoperative grommet review, and improves the effective use of specialist resource compared with the standard medical ORL service.
Simultaneous Determination of Dabigatran, Rivaroxaban, and Apixaban in Human Plasma by Liquid Chromatography/Tandem Mass Spectrometry
Authors: Zhang Mei , Moore Grant A. , Chin Paul K. L.
Published: February 2020

Background:

Pharmacokinetic studies and therapeutic drug monitoring of anticoagulants require a simple, rapid, and reliable analytical method for monitoring plasma concentrations. The aims of the current work were to develop and validate a liquid chromatography/tandem mass spectrometry method for the simultaneous determination of 3 direct oral anticoagulants (dabigatran, rivaroxaban, and apixaban) in human plasma that is suitable for pharmacokinetic studies and routine therapeutic drug monitoring in busy hospital laboratories.

Methods:

This method included a hydrolysis step to account for the active acylglucuronide metabolites of dabigatran that demonstrate an equivalent anticoagulant effect as dabigatran. After hydrolysis, a simple one-step protein precipitation was used for sample preparation. Total dabigatran (the sum of free dabigatran and the contribution from dabigatran acylglucuronides), rivaroxaban, and apixaban, and their corresponding isotopically labeled internal standards were resolved on a C18(2) column. All compounds were detected using electrospray ionization liquid chromatography/tandem mass spectrometry in the positive mode.

Results:

For all 3 anticoagulants, standard curves were linear over the concentration range of 1.0–1000 mcg/L (r > 0.99), bias was < ±10%, and intraday and interday coefficients of variation (imprecision) were <10%. The limit of quantification was 1.0 mcg/L. For all 3 anticoagulants and corresponding isotopically labeled internal standards, the absolute recoveries were similar and consistent, with mean values of 93%–102%. No significant matrix effects were observed.

Conclusions:

This method is simple, rapid, robust, and reliable and can be used to analyze the plasma concentrations of the drugs in patients on dabigatran or rivaroxaban therapy.
Effect of Vitamins and Dietary Supplements on Cardiovascular Health
Authors: Goudarzi Sogand , Memar Montazerin Sahar , Najafi Homa , Shojaei Fahimehalsadat , Chi Gerald
Published: February 2020

Cardiovascular disease marks the leading cause of mortality and morbidity in the United States. Pharmacological therapies have been developed to reduce the burden of cardiovascular diseases in the setting of large-scale randomized controlled trials. In contrast, vitamins and minerals have not undergone an equal level of scrutiny, and the evidence of cardiovascular benefit remains elusive. Multivitamins are the most popular over-the-counter supplements in the United States, despite the lack of clear benefit as a means of primary or secondary cardiovascular prevention. Recent studies indicate a potential role of multivitamins in secondary prevention when concomitantly administered with chelation therapy. Additionally, preclinical and observational studies have shown preliminary evidence of cardiovascular protection with dietary supplements such as carnitine, arginine, and coenzyme Q10. This review summarizes the currently available data about the effect of vitamins and other dietary supplements on the cardiovascular system.
Gonioscopy-assisted Transluminal Trabeculotomy (GATT) in Patients With Secondary Open-Angle Glaucoma Following Vitreoretinal Surgery
Authors: Quan Ann V. , Yannuzzi Nicolas A. , Chen Jenny , Wang Ye Elaine , Townsend Justin H. , Chang Ta Chen
Published: February 2020

Purpose:

To examine the short-term efficacy and safety of gonioscopy-assisted transluminal trabeculotomy (GATT) in a series of patients who developed glaucoma following vitreoretinal surgery.

Patients and Methods:

Retrospective case series of consecutive patients aged above 18 years with secondary open-angle glaucoma following vitreoretinal surgery who had undergone GATT between January 2015 and June 2019. Eyes were excluded if there is<1 month of follow-up or glaucoma before vitreoretinal surgery.

Results:

Eight eyes of 8 patients were included, with age range 18 to 72 years (median 43.5 y). Mean pretreatment intraocular pressure (IOP) was 32.7±5.1 mm Hg with a mean of 4.8±0.9 medications. Following GATT, mean IOP improved to 13.6±1.8 mm Hg (P<0.001) with a reduction to 1.6±1.4 medications after a mean follow-up of 8.6 months (range 1 to 25 mo). Five of the 8 eye (62.5%) had silicone oil in the vitreous cavity during GATT, none of which had concurrent oil removal.

Conclusions:

GATT is a safe and effective procedure for eyes with secondary open-angle glaucoma following vitreoretinal surgery. Further studies are needed to elucidate long-term benefits of angle surgery on eyes with high pressure following vitreoretinal surgery.
Short-term cane use in subacute stroke patients affects the nonparetic upper extremity nerves
Authors: Jeong Yong Sung , Kim Jong Keun , Bae Jin Seok , Park Hyo Sik , Park Shin Who , Lim Jong Youb
Published: February 2020

Overuse of the nonparetic upper extremity can lead to entrapment neuropathies in chronic stroke patients. However, little is known about the effects of cane use in subacute stage of stroke. The aim of this study was to investigate the short-term effects of cane use on the upper extremity nerves in subacute stroke patients recovering from a bedridden state. Thirty subacute hemiparetic stroke patients who were initially bedridden participated when they were able to walk with a cane. Symptoms and signs related to the median or ulnar nerves were checked, and nerve conduction studies were performed. The largest cross-sectional area (CSA) of these nerves from the wrist to elbow was measured with ultrasound. After 3 weeks of cane use, electrophysiologic and ultrasonographic reevaluation was performed. Nerve conduction studies and CSA of the nerves at the nonparetic upper extremity showed significant changes, whereas those of the hemiparetic upper extremity did not. Walking with a cane for a short period can induce the enlargement of the median and ulnar nerves at the nonparetic extremity of subacute hemiparetic stroke patients. Attention should be placed on correct cane usage from the beginning of rehabilitation.
A series of dual-reporter vectors for ratiometric analysis of protein abundance in plants
Authors: Khosla Aashima , Rodriguez-Furlan Cecilia , Kapoor Suraj , Van Norman Jaimie M. , Nelson David C.
Published: February 2020

Ratiometric reporter systems enable comparisons of the abundance of a protein of interest, or “target,” relative to a reference protein. Both proteins are encoded on a single transcript but are separated during translation. This arrangement bypasses the potential for discordant expression that can arise when the target and reference proteins are encoded by separate genes. We generated a set of 18 Gateway-compatible vectors termed pRATIO that combine a variety of promoters, fluorescent and bioluminescent reporters, and 2A “self-cleaving” peptides. These constructs are easily modified to produce additional combinations or introduce new reporter proteins. We found that mScarlet-I provides the best signal-to-noise ratio among several fluorescent reporter proteins during transient expression experiments inNicotiana benthamiana. Firefly and Gaussia luciferase also produce high signal-to-noise inN. benthamiana. As proof of concept, we used this system to investigate whether degradation of the receptor KAI2 after karrikin treatment is influenced by its subcellular localization. KAI2 is normally found in the cytoplasm and the nucleus of plant cells. InN. benthamiana, karrikin-induced degradation of KAI2 was only observed when it was retained in the nucleus. These vectors are tools to easily monitorin vivothe abundance of a protein that is transiently expressed in plants, and will be particularly useful for investigating protein turnover in response to different stimuli.
Single mosquito metatranscriptomics identifies vectors, emerging pathogens and reservoirs in one assay
Authors: Batson Joshua , Dudas Gytis , Haas-Stapleton Eric , Kistler Amy L. , Li Lucy M. , Logan Phoenix , Ratnasiri Kalani , Retallack Hanna
Published: February 2020

Mosquitoes are major infectious disease-carrying vectors. Assessment of current and future risks associated with the mosquito population requires knowledge of the full repertoire of pathogens they carry, including novel viruses, as well as their blood meal sources. Unbiased metatranscriptomic sequencing of individual mosquitoes offers a straightforward, rapid and quantitative means to acquire this information. Here, we profile 148 diverse wild-caught mosquitoes collected in California and detect sequences from eukaryotes, prokaryotes, 24 known and 46 novel viral species. Importantly, sequencing individuals greatly enhanced the value of the biological information obtained. It allowed us to a) speciate host mosquito, b) compute the prevalence of each microbe and recognize a high frequency of viral co-infections, c) associate animal pathogens with specific blood meal sources, and d) apply simple co-occurrence methods to recover previously undetected components of highly prevalent segmented viruses. In the context of emerging diseases, where knowledge about vectors, pathogens, and reservoirs is lacking, the approaches described here can provide actionable information for public health surveillance and intervention decisions.
A Cretaceous bug with exaggerated antennae might be a double-edged sword in evolution
Authors: Du Bao-Jie , Chen Rui , Tao Wen-Tao , Shi Hong-Liang , Bu Wen-Jun , Liu Ye , Ma Shuai , Ni Meng-Ya , Kong Fan-Li , Xiao Jin-Hua , Huang Da-Wei
Published: February 2020

In the competition for the opposite sex, sexual selection can favor production of exaggerated features, but the high cost of such features in terms of energy consumption and enemy avoidance makes them go to extinction under the influence of natural selection. However, to our knowledge, fossil on exaggerated traits that are conducive to attracting opposite sex are very rare. Here, we report the exaggerated leaf-like expansion antennae ofMagnusantenna wuaeDu & Chen gen. et sp. nov. (Hemiptera: Coreidae) with more abundant sensory hairs from a new nymph coreid preserved in a Cretaceous Myanmar amber. The antennae are the largest among species of coreid and one of the largest known insects. Such bizarre antennae indicate that sensitive and delicate sensory system and magnificent appearance in Hemiptera have been already well established in mid-Cretaceous. Our findings provide evidence for Darwin’s view that sensory organs play an important role in sexual selection. This nymph with the leaf-like antennae may also represents a new camouflage pattern for defense. However, the oversized antennae are costly to develop and maintain, increasing the risks from predators. Such unparalleled expanded antennae might be the key factor for the evolutionary fate of this Myanmar amber coreid species.

Significance

Darwin proposed the importance of sensory organs in sexual selection, but it was greatly ignored compared with weapons and other common ornaments. Here, we report a new type of insect antennae, the multiple segments leaf-like expansion antennae from a new nymph coreid preserved in a Cretaceous Myanmar amber. Our finding provides evidence for the prominent role of sensory organs in sexual selection and thus supports Darwin’s viewpoint. This discovery demonstrates that high-efficiency antennae were present in Coreidae 99 million years ago. In addition, the exaggerated antennae might represent a new evolutionary innovation for defensive behavior. This is a case in which the high benefits and high costs brought by the exaggerated antennae jointly determine the direction of species evolution.
Drivers of vascular plant species area relationships in British broadleaved woodlands and their effects on the species area curve
Authors: Guy Petra , Smart Simon , Prentice Colin
Published: February 2020

The loss of plant biodiversity in Great Britain is a major concern, with a fifth of species endangered or vulnerable according to the latest IUCN Red List. The Government’s 25 Year Plan for the environment aims to halt this loss and build new habitats, including new woodlands. To ensure that biodiversity loss is halted in existing woodlands and gain is maximised in new ones, we need to better understand which drivers have been most influential in controlling biodiversity. Here we focus on vascular plant species’ richness.

Previous attempts to explain plant species richness have mainly focussed on alpha diversity in a consistent, fixed unit area. Here, we additionally undertake a novel analysis of the effects of environmental heterogeneity and abiotic factors on species-area relationships derived from 16 randomly placed quadrats in each of 103 semi-natural, broad-leaved woodlands across Britain. Species-area relationships were examined at two scales (4m2to 200m2and 200m2to 3200m2) to explore the relationship between the drivers of species richness and the exponent z, of the canonical species-area curve, S = cAz. We also explore the use of a new metric ζr, based on zeta diversity to quantify heterogeneity. Zeta diversity quantifies the number of species shared between multiple combinations of plots.

Habitat heterogeneity increased species richness, as did the proximity of the woodlands to surrounding natural habitats. Higher levels of soil organic matter and the progression of woodlands to later successional stages, decreased species richness. Richness was also seen to have a unimodal response to soil acidity with a peak around pH 6. At the smaller scale, heterogeneity elements in the woodland such as riparian zones or coppicing led to an increase in the value of the exponent of the species area curve. At the larger scale, species turnover led to an increase in the exponent of the curves while succession led to a decrease. At both scales, soil organic matter content had a negative effect. ζrwas found to be a significant and important variable and to affect both species richness and the slope of the species accumulation curves at larger scales.

Synthesis

Habitat heterogeneity measures included the presence of coppicing, open areas such as rides and riparian zones and the difference between species assemblages in different plots in the woodland. Results suggest that to maximize vascular plant diversity, woodlands should be managed for heterogeneity. In addition, the increase in richness with exposure to surrounding natural habitats suggests that woodlands benefit from being embedded in more benign habitats and further, that land management surrounding woodlands has a clear role to play in supporting biodiversity within woodlands. This is an area were Agri-environment schemes have an important role.
Common Vetch: a drought tolerant, high protein neglected leguminous crop with potential as a sustainable food source
Authors: Nguyen Vy , Riley Samuel , Nagel Stuart , Fisk Ian , Searle Iain R.
Published: February 2020

Global demand for protein is predicted to increase by 50% by 2050. To meet the increasing demand whilst ensuring sustainability, protein sources that generate low-greenhouse gas emissions are required and protein-rich legume seeds have the potential to make a significant contribution. Legumes like common vetch (Vicia sativa) that grow in marginal cropping zones and are drought tolerant and resilient to changeable annual weather patterns, will be in high demand as the climate changes. In common vetch, the inability to eliminate the γ-glutamyl-β-cyano-alanine (GBCA) toxin present in the seed has hindered its utility as a human and animal food for many decades, leaving this highly resilient species an “orphan” legume. However, the availability of the vetch genome and transcriptome data together with the application of CRISPR-Cas genome editing technologies lay the foundations to eliminate the GBCA toxin constraint. In the near future, we anticipate that a zero-toxin vetch variety will become a significant contributor to global protein demand.
Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization
Authors: Perrin Florian , Papadopoulos Nicolas , Opsomer Rémi , Vadukul Devkee M. , Vrancx Céline , Pierrot Nathalie , Smith Steven O. , Vertommen Didier , Kienlen-Campard Pascal , Constantinescu Stefan N.
Published: February 2020

Amyloid precursor protein (APP) cleavage by the β secretase produces the C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric C99 TM orientations regulate the precise cleavage lines by γ-secretase. Of all possible dimeric orientations imposed by a coiled coil to the C99 TM-cytosolic domain, the dimer (cc-del7) containing33Gly-x-x-x-Gly37in the interface promoted Aβ42processing line and AICD (APP Intracellular Domain)-dependent gene transcription, including BACE1 mRNA induction, enhancing amyloidogenic signaling. Another orientation exhibiting25Gly-x-x-x-Gly29in the interface (cc-del6) favored processing to Aβ43/40, induced significantly less gene transcription, while promoting formation of SDS-resistant “Aβ-like” oligomers, reminiscent of Aβ peptide oligomers. These required both Val24 of a pro-β motif and the25Gly-x-x-x-Gly29interface. Thus, crossing angles imposed by dimeric orientations give access to γ-secretase at Aβ48or Aβ49,linking the former to enhanced signaling and Aβ42. We discuss avenues of blocking amyloidogenic processing.
Emergence of stealth polymorphs that escape α-synuclein amyloid monitoring, take over and acutely spread in neurons
Authors: De Giorgi Francesca , Laferrière Florent , Zinghirino Federica , Faggiani Emilie , Lends Alons , Bertoni Mathilde , Yu Xuan , Grélard Axelle , Morvan Estelle , Habenstein Birgit , Dutheil Nathalie , Doudnikoff Evelyne , Daniel Jonathan , Claverol Stéphane , Qin Chuan , Loquet Antoine , Bezard Erwan , Ichas François
Published: February 2020

The conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is possibly at the origin of the different clinical presentations of synucleinopathies. Experimentally, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe Thioflavin T (ThT). We report here that besides classical ThT positive products, fibrillization in saline simultaneously gives rise to competing fibril polymorphs that are invisible to ThT (stealth polymorphs), and that can take over. Due to competition, spontaneous generation of such stealth polymorphs bears on the apparent fibrillization kinetics and on the final plateau values. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. Compared to their ThT-positive counterparts, and as judged from their chemical shift resonances fingerprint, these new stealth polymorphs present a yet undescribed atomic organization and show an exacerbated propensity (approx. 20-fold) towards self-replication in cortical neurons. They also trigger a long distance synucleinopathic spread along nigro-striatal projectionsin vivo. In order to rapidly screen fibrillization products for the presence of such stealth polymorphs, we designed a simple multiplexed assay that can be easily and rapidly operated. This assay allows us to demonstrate the sustainability of the conformational replication of these novel and particularly invasive strains. It should also be of help to avoid erroneous upstream interpretations of fibrillization rates based on sole ThT, and to expedite further structural and functional characterization of stealth amyloid assemblies.

One Sentence Summary

stealth α-synuclein fibrils take over
Fibronectin-Based Nanomechanical Biosensors to Map 3D Strains in Live Cells and Tissues
Authors: Shiwarski Daniel J. , Tashman Joshua W. , Tsamis Alkiviadis , Bliley Jacqueline M. , Blundon Malachi A. , Aranda-Michel Edgar , Jallerat Quentin , Szymanski John M. , McCartney Brooke M. , Feinberg Adam. W.
Published: February 2020

Mechanical forces are integral to a wide range of cellular processes including migration, differentiation and tissue morphogenesis; however, it has proved challenging to directly measure strain at high spatial resolution and with minimal tissue perturbation. Here, we fabricated, calibrated, and tested a fibronectin (FN)-based nanomechanical biosensor (NMBS) that can be applied to cells and tissues to measure the magnitude, direction, and dynamics of strain from subcellular to tissue length-scales. The NMBS is a fluorescently-labeled, ultrathin square lattice FN mesh with spatial resolution tailored by adjusting the width and spacing of the lattice fibers from 2-100 µm. Time-lapse 3D confocal imaging of the NMBS demonstrated strain tracking in 2D and 3D following mechanical deformation of known materials and was validated with finite element modeling. Imaging and 3D analysis of the NMBS applied to single cells, cell monolayers, and Drosophila ovarioles demonstrated the ability to dynamically track microscopic tensile and compressive strains in various biological applications with minimal tissue perturbation. This fabrication and analysis platform serves as a novel tool for studying cells, tissues, and more complex systems where forces guide structure and function.
TheLanatatrichome mutation increases stomatal conductance and reduces leaf temperature in tomato
Authors: Gasparini Karla , Souto Ana Carolina R. , da Silva Mateus F. , Costa Lucas C. , Figueiredo Cássia Regina Fernandes , Martins Samuel C. V. , Peres Lázaro E. P. , Zsögön Agustin
Published: February 2020

Background and aims

Trichomes are epidermal structures with an enormous variety of ecological functions and economic applications. Glandular trichomes produce a rich repertoire of secondary metabolites, whereas non-glandular trichomes create a physical barrier against biotic and abiotic stressors. Intense research is underway to understand trichome development and function and enable breeding of more resilient crops. However, little is known on how enhanced trichome density would impinge on leaf photosynthesis, gas exchange and energy balance.

Methods

Previous work has compared multiple species differing in trichome density, instead here we analyzed monogenic trichome mutants in a single tomato genetic background (cv. Micro-Tom). We determined growth parameters, leaf spectral properties, gas exchange and leaf temperature in thehairs absent(h),Lanata(Ln) andWoolly(Wo) trichome mutants.

Key results

Shoot dry mass, leaf area, leaf spectral properties and cuticular conductance were not affected by the mutations. However, theLnmutant showed increased carbon assimilation (A) possibly associated with higher stomatal conductance (gs), since there were no differences in stomatal density or stomatal index between genotypes. Leaf temperature was furthermore reduced inLnin the early hours of the afternoon.

Conclusions

We show that a single monogenic mutation can increase glandular trichome density, a desirable trait for crop breeding, whilst concomitantly improving leaf gas exchange and reducing leaf temperature.

HIGHLIGHT

A monogenic mutation in tomato increases trichome density and optimizes gas exchange and leaf temperature
The FUSED LEAVES1/ADHERENT1Regulatory Module Is Required For Maize Cuticle Development And Organ Separation
Authors: Liu Xue , Bourgault Richard , Strable Josh , Galli Mary , Chen Zongliang , Dong Jiaqiang , Molina Isabel , Gallavotti Andrea
Published: February 2020

In land plants all aerial epidermal cells are covered by the cuticle, an extracellular hydrophobic layer. The cuticle represents a primary barrier between cells and the external environment, provides protection against abiotic and biotic stresses, and prevents organ fusion during development. Here we report the cloning and characterization of a classic mutant of maize calledadherent1(ad1), first described a century ago, and we show thatAD1encodes a 3-KETOACYL-CoA SYNTHASE involved in the deposition of cuticular wax on the epidermis of leaves and inflorescences.ad1mutants show decreased amounts of various wax components as well as a range of organ fusion defects during vegetative and reproductive development. Accordingly, we find thatAD1is strongly expressed in the epidermis of various developing organs where it is directly regulated by the MYB transcription factor FUSED LEAVES1 (FDL1), which in turn controls a series of additional genes involved in cuticle formation. Altogether, our results identify a major pathway of cuticle biosynthesis essential for the development of maize plants, and a key regulatory module that is conserved across monocot and eudicot species.

One sentence summary

The classic maize mutantadherent1, first isolated a century ago, is affected in an enzyme responsible for cuticle formation that is regulated by the MYB transcription factor FUSED LEAVES1.
scTenifoldNet: a machine learning workflow for constructing and comparing transcriptome-wide gene regulatory networks from single-cell data
Authors: Osorio Daniel , Zhong Yan , Li Guanxun , Huang Jianhua Z. , Cai James J.
Published: February 2020

Constructing and comparing gene regulatory networks (GRNs) from single-cell RNA sequencing (scRNAseq) data has the potential to reveal critical components in the underlying regulatory networks regulating different cellular transcriptional activities. Here, we present a robust and powerful machine learning workflow—scTenifoldNet—for comparative GRN analysis of single cells. The scTenifoldNet workflow, consisting of principal component regression, low-rank tensor approximation, and manifold alignment, constructs and compares transcriptome-wide single-cell GRNs (scGRNs) from different samples to identify gene expression signatures shifting with cellular activity changes such as those associated with pathophysiological processes and responses to environmental perturbations. We used simulated data to benchmark scTenifoldNet’s performance, and then applied scTenifoldNet to several real data sets. In real-data applications, scTenifoldNet identified highly specific changes in gene regulation in response to acute morphine treatment, an antibody anticancer drug, gene knockout, double-stranded RNA stimulus, and amyloid-beta plaques in various types of mouse and human cells. We anticipate that scTenifoldNet can help achieve breakthroughs through constructing and comparing scGRNs in poorly characterized biological systems, by deciphering the full cellular and molecular complexity of the data.

Highlights

scTenifoldNet is a machine learning workflow built upon principal component regression, low-rank tensor approximation, and manifold alignment

scTenifoldNet uses single-cell RNA sequencing (scRNAseq) data to construct single-cell gene regulatory networks (scGRNs)

scTenifoldNet compares scGRNs of different samples to identify differentially regulated genes

Real-data applications demonstrate that scTenifoldNet accurately detects specific signatures of gene expression relevant to the cellular systems tested.

Short abstract

We present scTenifoldNet—a machine learning workflow built upon principal component regression, low-rank tensor approximation, and manifold alignment—for constructing and comparing single-cell gene regulatory networks (scGRNs) using data from single-cell RNA sequencing (scRNAseq). scTenifoldNet reveals regulatory changes in gene expression between samples by comparing the constructed scGRNs. With real data, scTenifoldNet identifies specific gene expression programs associated with different biological processes, providing critical insights into the underlying mechanism of regulatory networks governing cellular transcriptional activities.
Oomycete metabolism is highly dynamic and reflects lifestyle adaptations
Authors: Rodenburg Sander Y.A. , de Ridder Dick , Govers Francine , Seidl Michael F.
Published: February 2020

Pathogen-host symbiosis drives metabolic adaptations. Animal and plant pathogenic oomycetes are thought to adapt their metabolism to facilitate interactions with their hosts. Here, we performed a large-scale comparison of oomycete metabolism and uncovered considerable variation in oomycete metabolism that could be linked to differences in lifestyle. Pathway comparisons revealed that plant pathogenic oomycetes can be divided in two parts; a conserved part and an accessory part. The accessory part could be associated with the degradation of plant compounds produced during defence responses. Obligate biotrophic oomycetes have smaller metabolic networks, and this group displays converged evolution by repeated gene losses affecting the same metabolic pathways. A comparison of the metabolic networks of obligate biotrophic oomycetes with those of plant pathogenic oomycetes as a whole revealed that the losses of metabolic enzymes in biotrophs are not random and that the network of biotrophs contracts from the periphery inwards. Our analyses represent the first metabolism-focused comparison of oomycetes at this scale and will contribute to a better understanding of the evolution and relationship between metabolism and lifestyle adaptation.

ORIGINALITY & SIGNFICANCE STATEMENT

The intimate interaction between pathogens and their hosts exerts strong selection pressure leading to rapid adaptation. How this shapes the metabolism of pathogens is largely unknown. Here, we used comparative genomics to systematically characterize the metabolisms of animal and plant pathogenic oomycetes, a group of eukaryotes comprising many important animal and plant pathogens with significant economic and ecological impact. Core- and pan-genome as well as metabolic network analyses of distantly related oomycetes and their non-pathogenic relatives revealed considerable lifestyle- and lineage-specific adaptations. Extreme lifestyle adaptation could be observed in the metabolism of obligate biotrophic oomycetes – a group of pathogens that require a living host for proliferation. The metabolic networks of obligate biotrophic oomycetes reflect profound patterns of reductive evolution, converging to a loss the same metabolic enzymes during acquisition of an obligate parasitic lifestyle. These findings contribute to a be better understanding of oomycete evolution and the relationship between metabolism and lifestyle adaptation.
Emergence of ribozyme and tRNA-like structures from mineral-rich muddy pools on prebiotic earth
Authors: Roy Suvam , Bapat Niraja V. , Derr Julien , Rajamani Sudha , Sengupta Supratim
Published: February 2020

Abstract

The RNA world hypothesis, although a viable one regarding the origin of life on earth, has so far failed to provide a compelling explanation for the synthesis of RNA molecules with catalytic functions, from free nucleotides via abiotic processes. To tackle this long-standing problem, we develop a realistic model for the onset of the RNA world, using experimentally determined rates for polymerization reactions. We start with minimal assumptions about the initial state that only requires the presence of short oligomers or just free nucleotides and consider the effects of environmental cycling by dividing a day into a dry, semi-wet and wet phases that are distinguished by the nature of reactions they support. Long polymers, with maximum lengths sometimes exceeding 100 nucleotides, spontaneously emerge due to a combination of non-enzymatic, non-templated polymer extension and template-directed primer extension processes. The former helps in increasing the lengths of RNA strands, whereas the later helps in producing complementary copies of the strands. Strands also undergo hydrolysis in a structure-dependent manner that favour breaking of bonds connecting unpaired nucleotides. We identify the most favourable conditions needed for the emergence of ribozyme and tRNA-like structures and double stranded RNA molecules, classify all RNA strands on the basis of their secondary structures and determine their abundance in the population. Our results indicate that under suitable environmental conditions, non-enzymatic processes would have been sufficient to lead to the emergence of a variety of ribozyme-like molecules with complex secondary structures and potential catalytic functions.
MPRAudit Quantifies the Fraction of Variance Described by Unknown Features in Massively Parallel Reporter Assays
Authors: Siegel David A. , Le Tonqueze Olivier , Biton Anne , Erle David J. , Zaitlen Noah
Published: February 2020

Transformative advances in molecular technologies, such as massively parallel reporter assays (MPRAs) and CRISPR screens, can efficiently characterize the effects of genetic and genomic variation on cellular phenotypes. Analysis approaches to date have focused on identifying individual genomic regions or genetic variants that perturb a phenotype of interest. In this work, we develop a wholistic framework (MPRAudit) to determine the global contribution of sequence to phenotypic variation across subsets of the entire experiment, opening the door to myriad novel analyses. For example, MPRAudit can reliably estimate the upper limit of predictive performance, the fraction of variation attributed to specific biological categories, and the total contribution of experimental noise. We demonstrate through simulation and application to several types of real MPRA data sets how MPRAudit can lead to an improved understanding of experimental quality, molecular biology, and guide future research. Applying MPRAudit to real MPRA data, we observe that sequence variation is the primary driver of outcome variability, but that known biological categories explain only a fraction of this variance. We conclude that our understanding of how sequence variation impacts phenotype, even at the level of MPRAs, remains open to further scientific discovery.
A critical period terminates the differentiation of olfactory sensory neurons
Authors: Jafari Shadi , Alenius Mattias
Published: February 2020

Development generates a vast number of neuron types and classes. When and how neuronal differentiation end is poorly understood. Here, we show thatDrosophilaolfactory sensory neurons (OSNs) matures during a critical period and reveal that the differentiation termination mechanism is similar to the mammalian odorant receptor (OR) choice mechanism. We first showed that initiation ofDrosophilaOR expression required heterochromatin opening and a H3K9me3 demethylase,Kdm4b. Further genetic studies demonstrated thatLsd1andsu(var)3-9, similar to mouse, were required to balance heterochromatin in order to stabilize OR expression. Expression analysis showed thatLsd1, su(var)3-9increased andKdm4bdecreased during the first two days after eclosion. We further showed that environment changes during the period, but not after, caused permanent transformed Lsd1, su(var)3-9 and Kdm4b expression and altered OR gene regulation. These results together suggest the last step in OSN terminal differentiation to be a gene regulatory critical period.
Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva
Authors: Saitou Marie , Gaylord Eliza , Xu Erica , May Alison , Neznanova Lubov , Nathan Sara , Grawe Anissa , Chang Jolie , Ryan William , Ruhl Stefan , Knox Sarah M. , Gokcumen Omer
Published: February 2020

Salivary proteins are essential for maintaining health in the oral cavity and proximal digestive tract and serve as a diagnostic window into human disease. However, their precise organ origins remain unclear. Through transcriptomic analysis of major adult and fetal salivary glands, and integration with the saliva proteome and transcriptomes of 28+ organs, we linked human saliva proteins to their source, identified salivary gland-specific genes, and uncovered fetal- and adult-specific gene repertoires. Our results also provide new insights into the degree of gene retention during maturation and suggest that functional diversity between adult gland-types is driven by specific dosage combinations of hundreds of transcriptional regulators rather than a few gland-specific factors. Finally, we demonstrate the hitherto unrecognized heterogeneity of the human acinar cell lineage. Our results pave the way for future investigations into glandular biology and pathology, as well as saliva’s use as a diagnostic fluid.
Suppression of canonical TGF-β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis
Authors: Riching Andrew S. , Danis Etienne , Zhao Yuanbiao , Cao Yingqiong , Chi Congwu , Bagchi Rushita A. , Klein Brianna J. , Xu Hongyan , Kutateladze Tatiana G. , McKinsey Timothy A. , Buttrick Peter M. , Song Kunhua
Published: February 2020

Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression ofGATA4,HAND2,MEF2C,TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGF-β) inhibition efficiently promotes reprogramming. However, the mechanisms by which TGF-β blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3) – demethylase JMJD3, the SWI/SNF remodeling complex subunit BRG1, and cardiac transcription factors. Furthermore, canonical TGF-β signaling regulates the interaction between GATA4 and JMJD3. TGF-β activation impairs the ability of GATA4 to bind target genes and prevents demethylation of H3K27 at cardiac gene promoters during cardiac reprogramming. Finally, a mutation inGATA4(V267M) exhibits reduced binding to JMJD3 and impaired cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGF-β pathway activation impairs cardiac gene programming by interfering with GATA4-JMJD3 interactions.
Nanoscale Molecular Characterisation of Hair Cuticles using Integrated AFM-IR
Authors: Fellows A. P. , Casford M. T. L. , Davies P. B.
Published: February 2020

The nanometre-scale topography and chemical structure of hair cuticles has been investigated by vibrational spectroscopy and imaging in two spectral regions. The combination of Atomic Force Microscopy with a tuneable infrared laser (AFM-IR) circumvents the diffraction limit that has impaired traditional infrared spectroscopy, facilitating surface spectroscopy at ultra-spatial resolution. The variation in protein and lipid content of the cuticle cell surface approaching its edge, as well as the exposed layered structure of the cell at the edge itself, was investigated. Furthermore, the contribution of cystine-related products to the cuticle layers was determined. The variation of protein, lipid and cystine composition in the observed layers, as well as the measured dimensions of each, correspond closely to that of the epicuticle, A-layer, exocuticle and endocuticle layers of the cuticle cell sub-structure.

Statement of Significance

Using AFM-IR to analyse the nanoscale cuticle features is both significant and novel in the field. Thus far, the great majority of work on the chemical investigation of the structure of hair has been limited to bulk measurements, or subject to the diffraction limit associated with traditional IR spectroscopies and microscopies. AFM-IR circumvents this diffraction limit and allows nanometre-scale, localised chemical investigation with high surface selectivity. While non-chemical investigations, e.g. those using Transmission Election Microscopy, have previously shown cuticles to have a layered substructure, AFM-IR sheds light on significant chemical variations of protein and lipid compositions within such layers, enabling their quantification.
Microtubule instability driven by longitudinal and lateral strain propagation
Authors: Igaev Maxim , Grubmüller Helmut
Published: February 2020

Tubulin dimers associate longitudinally and laterally to form metastable microtubules (MTs). MT disassembly is preceded by subtle structural changes in tubulin fueled by GTP hydrolysis. These changes render the MT lattice unstable, but it is unclear exactly how they affect lattice energetics and strain. We performed long-time atomistic simulations to interrogate the impacts of GTP hydrolysis on tubulin lattice conformation, lateral inter-dimer interactions, and (non-)local lateral coordination of dimer motions. The simulations suggest that most of the hydrolysis energy is stored in the lattice in the form of longitudinal strain. While not significantly affecting lateral bond stability, the stored elastic energy results in more strongly confined and correlated dynamics of GDP-tubulins, thereby entropically destabilizing the MT lattice.
Nanoscale pattern extraction from relative positions of sparse 3D localisations
Authors: Curd Alistair P. , Leng Joanna , Hughes Ruth E. , Cleasby Alexa J. , Rogers Brendan , Trinh Chi , Baird Michelle A. , Takagi Yasuharu , Tiede Christian , Sieben Christian , Manley Suliana , Schlichthaerle Thomas , Jungmann Ralf , Ries Jonas , Shroff Hari , Peckham Michelle
Published: February 2020

We present a method for extracting high-resolution ordered features from localisation microscopy data by analysis of relative molecular positions in 2D or 3D. This approach allows pattern recognition at sub-1% protein detection efficiencies, in large and heterogeneous samples, and in 2D and 3D datasets. We used this method to infer ultrastructure of the nuclear pore, the cardiomyocyte Z-disk, DNA origami structures and the centriole.
COVID-19 in a Designated Infectious Diseases HospitalOutside Hubei Province,China
Authors: Cai Qingxian , Huang Deliang , Ou Pengcheng , Yu Hong , Zhu Zhibin , Xia Zhang , Su Yinan , Ma Zhenghua , Zhang Yiming , Li Zhiwei , He Qing , Liu Lei , Fu Yang , Chen Jun
Published: February 2020

Background

A new type of novel coronavirus infection (COVID-19) occurred in Wuhan, Hubei Province. Previous investigations reported patients in Wuhan city often progressed into severe or critical and had a high mortality rate.The clinical characteristics of affected patients outside the epicenter of Hubei province are less well understood.

Methods

All confirmed COVID-19 case treated in the Third People’s Hospital of Shenzhen,from January 11, 2020 to February 6, 2020, were included in this study. We analyzed the epidemiological and clinical features of these cases to better inform patient management in normal hospital settings.

Results

Among the 298 confirmed cases, 233(81.5%) had been to Hubei while 42(14%) had not clear epidemiological history. Only 192(64%) cases presented with fever as initial symptom. The lymphocyte count decreased in 38% patients after admission. The number (percent) of cases classified as non-severe and severe was 240(80.6%) and 58(19.4%) respectively. Thirty-two patients (10.7%) needed ICU care. Compared to the non-severe cases, severe cases were associated with older age, underlying diseases, as well as higher levels of CRP, IL-6 and ESR. The median (IRQ) duration of positive viral test were 14(10-19). Slower clearance of virus was associated with higher risk of progression to severe clinical condition. As of February 14, 2020, 66(22.1%) patients were discharged and the overall mortality rate remains 0.

Conclusions

In a designated hospital outside the Hubei Province, COVID-19 patients were mainly characterized by mild symptoms and could be effectively manage by properly using the existing hospital system.
Playing around with MP, a tool for the analysis of pseudosymmetry: recurrent appearance of local pseudo-space groups in the asymmetric unit of Z′ = 4 structures
Authors: Baggio Ricardo
Published: February 2020

A systematic application of the MP procedure [Baggio (2019). Acta Cryst. C75, 837–850] to a subset of Z′ = 4 structures in the literature revealed a number of suggestive properties in many of the cases analysed, which allowed us to conclude that: (i) very few of those structures showed no pseudosymmetry (PS) whatsoever linking any of the possible moiety pairs in the asymmetric unit (AU), the vast majority disclosing, instead, at least two (and frequently more) molecules linked by these PS operations; (ii) on occasion, two pairs of molecules were related, each by the same PS element, enabling the resulting pair of dimers to be viewed locally as a Z′ = 2 rather than a Z′ = 4 case; (iii) sometimes all four moieties in the AU appeared interrelated by PS relationships, closely suggesting a distribution of symmetry operations as found in real space groups; (iv) in many cases, this resemblance was of a superior quality, leading to surprising local replicas of real space groups in the reduced realm of the AU, thus locally reducing the description to a Z′ = 1 one. Through a systematic application of the MP procedure, we analyze in this article a number of these latter cases, which proved to be surprisingly common, far beyond any original expectation, and leaving open the question about the eventual reasons for the phenomenon, which would certainly merit appropriate theoretical attention.