bluuebunny/crossref_metadata_2025 huggingface dataset:
Same-Day Patient Consultation and Cochlear Implantation: Innovations in Patient-Centered Health Care Delivery
Authors: Nassiri Ashley M. , Yawn Robert J. , Gifford René H. , Holder Jourdan T. , Stimson C. J. , Eavey Roland D. , Haynes David S.
Published: October 2019

Objective:

To develop and implement a streamlined, patient-centered service delivery model for patients referred for cochlear implantation (CI) at a high-volume academic center.

Patients:

CI candidate adults.

Interventions:

CI, implementation of new CI delivery model.

Main Outcome Measures:

Referral-to-surgery time, patient travel burden.

Results:

Data from 206 adults that underwent CI were used to develop a process map of the initial operational state from referral date to day of surgery (referral-to-surgery time). The initial referral-to-surgery time was 136 days on average, yet the average total work time by all involved providers was 17.6 hours. Prolonged wait times were associated with the following preoperative tasks: appointment scheduling, insurance approval, device ordering and shipment, and surgical scheduling. Patients traveled to the institution on at least two occasions for appointments. A new bundled, patient-centered CI delivery model was developed to address prolonged wait times, travel burden, and process inefficiencies. The new model implemented an interactive electronic medical record, coordinated appointments with same-day surgery, and stocked device inventory to reduce the referral-to-surgery time to 24 days—an improvement of 112 days. In the new model, new patient consultation and surgery were completed in one day, reducing the patient travel burden to the institution.

Conclusions:

The new CI program demonstrates that delivery innovations can have a substantial impact on measures of patient convenience and experience, and that these results are achievable without new technologies or changes in medical management. With a focus on patient-centered design, health care delivery models can be augmented to increase value for patients.
Metastatic Nasopharyngeal Carcinoma Treated With Intraarterial Combined With Intravenous Peptide Receptor Radionuclide Therapy
Authors: Zhu Wenjia , Zhang Jingjing , Singh Aviral , Kulkarni Harshad R. , Baum Richard P.
Published: October 2019

Nasopharyngeal carcinoma may express somatostatin receptors (SSTR). We present a case with metastatic nasopharyngeal carcinoma in the liver, bone, and lymph nodes. The patient was in progression after chemotherapy, external beam radiation therapy (ERBT), atezolizumab, and cetuximab. Due to strong SSTR expression of the metastases, PRRT was applied. After 3 cycles of intravenous 177Lu-DOTATOC and 1 cycle of intraarterial 90Y-DOTATOC therapy, the hepatic and bone metastases showed excellent response after PRRT. No nephrotoxicity or myelotoxicity was observed.
Population genomic evidence that human and animal infections in Africa come from the same populations ofDracunculus medinensis
Authors: Durrant Caroline , Thiele Elizabeth A. , Holroyd Nancy , Doyle Stephen R , Sallé Guillaume , Tracey Alan , Sankaranaranayan Geetha , Lotkowska Magda E. , Bennett Hayley M. , Huckvale Thomas , Abdellah Zahra , Tchindebet Ouakou , Wossen Mesfin , Yibi Logora Makoy Samuel , Coulibaly Cheick Oumar , Weiss Adam , Schulte-Hostedde Albrecht I , Foster Jeremy , Cleveland Christopher A. , Yabsley Michael J. , Ruiz-Tiben Ernesto , Berriman Matthew , Eberhard Mark L. , Cotton James A.
Published: October 2019

Background

Guinea worm –Dracunculus medinensis– was historically one of the major parasites of humans and has been known since antiquity. Now, Guinea worm is on the brink of eradication, as efforts to interrupt transmission have reduced the annual burden of disease from millions of infections per year in the 1980s to only 30 human cases reported globally last year. Despite the enormous success of eradication efforts to date, one complication has arisen. Over the last few years, hundreds of dogs have been found infected with this previously apparently anthroponotic parasite, almost all in Chad. Moreover, the relative numbers of infections in humans and dogs suggests that dogs may be key in maintaining transmission in that country.

Results

In an effort to shed light on this peculiar epidemiology of Guinea worm in Chad, we have sequenced and compared the genomes of worms from dog, human and other animal infections. Confirming previous work with other molecular markers, we show that all of these worms areD. medinensis, and that the same population of worms are causing both infections, can confirm the suspected transmission between host species and detect signs of a population bottleneck due to the eradication efforts. The diversity of worms in Chad appears to exclude the possibility that there were no, or very few, worms present in the country during a 10-year absence of reported cases.

Conclusions

This work reinforces the importance of adequate surveillance of both human and dog populations in the Guinea worm eradication campaign and suggests that control programs should stay aware of the possible emergence of unusual epidemiology as they approach elimination.
Mechanics of snake biting: Experiments and modelling
Authors: Kundanati Lakshminath , Guarino Roberto , Menegon Michele , Pugno Nicola M.
Published: October 2019

Among all the vertebrates, snakes possess the most sophisticated venom delivering system using their fangs. Fangs of many animals are well adapted to the mechanical loads experienced during the functions such as breaking the diet and puncturing the skin of the prey. Thus, investigation and modelling of puncturing mechanics of snakes is of importance to understand the form-function relationship of the fangs and tissue-fang interactions in detail. We have thus chosen fangs of two snake species i.e. viper (Bitis arietans) and burrowing snake (Atractaspis aterrima), with different shape and size and performed insertion experiments using tissue phantoms. Our results showed that both the species have similar mechanical properties but there was a difference in the insertion forces owing to the difference in shape of the fang. Also, our modelling of the fang-tissue interactions predicted some parameters close to the experimental values. Thus, our study can help in the development of bioinspired needles that can potentially have reduced insertion forces and less damage to the tissue.
High-phytate/low-calcium diet is a risk factor for crystal nephropathies, renal phosphate wasting, and bone loss
Authors: Kim Ok-Hee , Booth Carmen J. , Choi Han Seok , Lee Jinwook , Kang Jinku , Hur June , Choi Hyung Jin , Kim Hyeonjin , Auh Joong-Hyuck , Kim Jung-Wan , Cha Ji-Young , Lee Young Jae , Lee Cheol Soon , Choi Cheolsoo , Yang Jun-Young , Im Seung-Soon , Lee Dae Ho , Cho Sun Wook , Kim Young-Bum , Park Kyong Soo , Park Young Joo , Oh Byung-Chul
Published: October 2019

Phosphate overload contributes to mineral bone disorders associated with crystal nephropathies. Phytate, the major form of phosphorus in plant seeds, is known as an indigestible and negligible in humans. However, the mechanism and adverse effects of high-phytate intake on Ca2+and phosphate absorption and homeostasis are unknown. Here we show that excessive intake of phytate with a low-Ca2+diet fed to rats contributed to the development of crystal nephropathies, renal phosphate wasting, and bone loss through tubular dysfunction secondary to dysregulation of intestinal calcium and phosphate absorption. Moreover, Ca2+supplementation alleviated the detrimental effects of excess dietary phytate on bone and kidney through excretion of undigested Ca2+-phytate, which prevented a vicious cycle of intestinal phosphate overload and renal phosphate wasting while improving intestinal Ca2+bioavailability. Thus, we demonstrate that phytate is digestible without a high-Ca2+diet and a risk factor for phosphate overloading and developing crystal nephropathies and bone disease.
Intercellular transmission of a bacterial cytotoxic prion-like protein in mammalian cells
Authors: Revilla-García Aida , Fernández Cristina , Álamo María Moreno-del , de los Ríos Vivian , Vorberg Ina M. , Giraldo Rafael
Published: October 2019

RepA is a bacterial protein that builds intracellular amyloid oligomers acting as inhibitory complexes of plasmid DNA replication. When carrying a mutation enhancing its amyloidogenesis (A31V), the N-terminal domain (WH1) generates cytosolic amyloid particles that are inheritable within a bacterial lineage. Such amyloids trigger in bacteria a lethal cascade reminiscent to mitochondria impairment in human cells affected by neurodegeneration. To fulfil all the features of a prion-like protein, horizontal (intercellular) transmissibility remains to be demonstrated for RepA-WH1. Since this is experimentally intractable in bacteria, here we transiently expressed in a murine neuroblastoma cell line the soluble, barely cytotoxic RepA-WH1(WT) and assayed its response to co-incubation with in vitro assembled RepA-WH1(A31V) amyloid fibres. In parallel, cells releasing RepA-WH1(A31V) aggregates were co-cultured with human neuroblastoma cells expressing RepA-WH1(WT). Both the assembled fibres and the extracellular RepA-WH1(A31V) aggregates induce, in the cytosol of recipient cells, the formation of cytotoxic amyloid particles. Mass spectrometry analyses of the proteomes of both types of injured cells point to alterations in mitochondria, protein quality triage, signalling and intracellular traffic.

Summary blurb

The horizontal, cell-to-cell spread of a bacterial prion-like protein is shown for the first time in mammalian cells. Amyloid cross-aggregation of distinct variants, and their associated toxicities, follow the same trend found in bacteria, underlining the universality of prion biology.
Validation of a high-performance liquid chromatography-tandem mass spectrometry immunopeptidomics assay for the identification of HLA class I ligands suitable for pharmaceutical therapies
Authors: Ghosh Michael , Gauger Marion , Marcu Ana , Nelde Annika , Denk Monika , Schuster Heiko , Rammensee Hans-Georg , Stevanović Stefan
Published: October 2019

For more than two decades naturally presented, human leukocyte antigen (HLA)-restricted peptides (immunopeptidome) have been eluted and sequenced using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Since, identified disease-associated HLA ligands have been characterized and evaluated as potential active substances. Treatments based on HLA-presented peptides have shown promising results in clinical application as personalized T cell-based immunotherapy. Peptide vaccination cocktails are produced as investigational medicinal products under GMP conditions. In order to support clinical trials based on HLA-presented tumor-associated antigens, in this study the sensitive LC-MS/MS HLA class I antigen identification pipeline was fully validated for our technical equipment according to the current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines.

The immunopeptidomes of JY cells with or without spiked-in, isotope labeled peptides, of peripheral blood mononuclear cells of healthy volunteers as well as a chronic lymphocytic leukemia and a bladder cancer sample were reliably identified using a data-dependent acquisition method. As the LC-MS/MS pipeline is used for identification purposes, the validation parameters include accuracy, precision, specificity, limit of detection and robustness.
RNA-spray-mediated silencing ofFusarium graminearum AGOandDCLgenes improve barley disease resistance
Authors: Werner B , Gaffar FY , Schuemann J , Biedenkopf D , Koch A
Published: October 2019

Over the last decade, several studies have revealed the enormous potential of RNA-silencing strategies as a potential alternative to conventional pesticides for plant protection. We have previously shown that targeted gene silencing mediated by anin plantaexpression of non-coding inhibitory double-stranded RNAs (dsRNAs) can protect host plants against various diseases with unprecedented efficiency. In addition to the generation of RNA-silencing (RNAi) signalsin planta, plants can be protected from pathogens and pests by spray-applied RNA-based biopesticides. Despite the striking efficiency of RNA-silencing-based technologies holds for agriculture, the molecular mechanisms underlying spray-induced gene silencing (SIGS) strategies are virtually unresolved, a requirement for successful future application in the field. Based on our previous work, we predict that the molecular mechanism of SIGS is controlled by the fungal-silencing machinery. In this study, we used SIGS to compare the silencing efficiencies of computationally-designed versus manually-designed dsRNA constructs targetingARGONAUTEandDICERgenes ofFusarium graminearum(Fg). We found that targeting key components of the fungal RNAi machinery via SIGS could protect barley leaves fromFginfection and that the manual design of dsRNAs resulted in higher gene-silencing efficiencies than the tool-based design. Moreover, our results indicate the possibility of cross-kingdom RNA silencing in theFg-barley interaction, a phenomenon in which sRNAs operate as effector molecules to induce gene silencing between species from different kingdoms, such as a plant host and their interacting pathogens.
Broadband Dynamics Rather than Frequency-Specific Rhythms Underlie Prediction Error in the Primate Auditory Cortex
Authors: Canales-Johnson Andrés , Teixeira Borges Ana Filipa , Komatsu Misako , Fujii Naotaka , Fahrenfort Johannes J. , Miller Kai J. , Noreika Valdas
Published: October 2019

Detection of statistical irregularities, measured as a prediction error response, is fundamental to the perceptual monitoring of the environment. We studied whether prediction error response is associated with neural oscillations or asynchronous broadband activity. Electrocorticography (ECoG) was carried out in three male monkeys, who passively listened to the auditory roving oddball stimuli. Local field potentials (LFP) recorded over the auditory cortex underwent spectral principal component analysis, which decoupled broadband and rhythmic components of the LFP signal. We found that the broadband component captured the prediction error response, whereas none of the rhythmic components were associated with statistical irregularities of sounds. The broadband component displayed more stochastic, asymmetrical multifractal properties than the rhythmic components, which revealed more self-similar dynamics. We thus conclude that the prediction error response is captured by neuronal populations generating asynchronous broadband activity, defined by irregular dynamical states which, unlike oscillatory rhythms, appear to enable the neural representation of auditory prediction error response.

Significance Statement

This study aimed to examine the contribution of oscillatory and asynchronous components of auditory local field potentials in the generation of prediction error responses to sensory irregularities, as this has not been directly addressed in the previous studies. Here, we show that mismatch negativity – an auditory prediction error response – is driven by the asynchronous broadband component of potentials recorded in the auditory cortex. This finding highlights the importance of non-oscillatory neural processes in the predictive monitoring of the environment. At a more general level, the study demonstrates that stochastic neural processes, which are often disregarded as neural noise, do have a functional role in the processing of sensory information.
Intrinsic dynamics enhance temporal stability of stimulus representation along rodent visual cortical hierarchies
Authors: Piasini Eugenio , Soltuzu Liviu , Muratore Paolo , Caramellino Riccardo , Vinken Kasper , de Beeck Hans Op , Balasubramanian Vijay , Zoccolan Davide
Published: October 2019

Along the ventral stream, cortical representations of brief, static stimuli become gradually more invariant to identity-preserving transformations. In the presence of long, temporally structured dynamic stimuli, higher invariance should imply temporally persistent representations at the top of this functional hierarchy. However, such stimuli could engage adaptive and predictive processes, whose impact on neural coding dynamics is unknown. By probing the rat analogue of the ventral stream with movies, we uncovered a hierarchy of temporal scales, with deeper areas encoding visual information more persistently. Furthermore, the impact of intrinsic dynamics on the stability of stimulus representations gradually grew along the hierarchy. Analysis of a large dataset of recordings from the mouse visual hierarchy yielded similar trends, revealing also their dependence on the behavioral state of the animal. Overall, these findings show that visual representations become progressively more stable along rodent visual processing hierarchies, with an important contribution provided by intrinsic processing.
ER transmembrane protein TMTC3 contributes to O-mannosylation of E-cadherin, Cellular Adherence and Embryonic Gastrulation
Authors: Graham Jill B. , Sunryd Johan C. , Mathavan Ketan , Weir Emma , Larsen Ida Signe Bohse , Halim Adnan , Clausen Henrik , Cousin Hélène , Alfandari Dominque , Hebert Daniel N.
Published: October 2019

Protein glycosylation plays essential roles in protein structure, stability and activity such as cell adhesion. The cadherin superfamily of adhesion molecules carry O-linked mannose glycans at conserved sites and it was recently demonstrated that the TMTC1-4 genes contribute to the addition of these O-linked mannoses. Here, biochemical, cell biological and organismal analysis was used to determine that TMTC3 supports the O-mannosylation of E-cadherin, cellular adhesion and embryonic gastrulation. Using genetically engineered cells lacking all four TMTC genes, overexpression of TMTC3 rescued O-linked glycosylation of E-cadherin and cell adherence. The knockdown of the Tmtcs in Xenopus laevis embryos caused a delay in gastrulation that was rescued by the addition of human TMTC3. Mutations in TMTC3 have been linked to neuronal cell migration diseases including Cobblestone lissencephaly. Analysis of TMTC3 mutations associated with Cobblestone lissencephaly found that three of the variants exhibit reduced stability and missence mutations were unable to complement TMTC3 rescue of gastrulation in Xenopus embryo development. Our study demonstrates that TMTC3 regulates O-linked glycosylation and cadherin-mediated adherence, providing insight into its effect on cellular adherence and migration, as well the basis of TMTC3-associated Cobblestone lissencephaly.
Distinguishing Felsenstein zone from Farris zone using neural networks
Authors: Drucks Tamara , Leuchtenberger Alina F. , Burgstaller-Muehlbacher Sebastian , Crotty Stephen M. , Schmidt Heiko A. , von Haeseler Arndt
Published: October 2019

Maximum likelihood and maximum parsimony are two key methods for phylogenetic tree reconstruction. Under certain conditions, each of these two methods can perform more or less efficiently than the other. We show that a neural network can efficiently distinguish between four-taxon alignments that were evolved under conditions conducive to long-branch attraction, or long-branch repulsion. The feedback from the neural network can be used to select the most efficient tree reconstruction method yielding increased accuracy, when compared to a rigid choice of reconstruction methods. When applied to the contentious case of Strepsiptera evolution, our method agrees with the current scientific view.
Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers
Authors: Amin Ladan , Harris David A.
Published: October 2019

Oligomeric forms of amyloid-β (Aβ) peptide are known to be the primary neurotoxic species in Alzheimer’s disease (AD), but how they interact with neurons to produce their deleterious effects is unclear. Over ten different cell-surface receptors for Aβ have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating AD pathology have remained uncertain. In the present work, we have used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, the cellular prion protein, PrPC, specifically inhibits the polymerization Aβ fibrils via a unique mechanism in which it binds specifically to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other candidate Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. Taken together, our results suggest that neurotoxic signaling by several different receptors may be activated by common molecular interactions with both fibrillar and oligomeric Aβ ligands. Targeting such interactions with small molecules represents an attractive therapeutic strategy for treatment of AD.
A role for keratins in supporting mitochondrial organization and function in skin keratinocytes
Authors: Steen Kaylee , Chen Desu , Wang Fengrong , Chen Song , Kumar Surinder , Lombard David B. , Weigert Roberto , Zieman Abigail G. , Parent Carole A. , Coulombe Pierre A.
Published: October 2019

Mitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS) and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes fromKrt16null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5,Krt6a/Krt6bnull embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null forKrt6a/Krt6borKrt16exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders.
Firing Rate-dependent Phase Responses of Purkinje Cells Support Transient Oscillations
Authors: Zang Yunliang , Hong Sungho , De Schutter Erik
Published: October 2019

Both spike rate and timing can transmit information in the brain. Phase response curves (PRCs) quantify how a neuron transforms input to output by spike timing. They exhibit strong firing-rate adaptation, but its mechanism and relevance for network output are poorly understood. Using our Purkinje cell (PC) model we demonstrate that the rate adaptation is caused by rate-dependent subthreshold membrane potentials efficiently regulating the activation of Na+ channels. Then we use a realistic PC network model to examine how rate-dependent responses synchronize spikes in the scenario of reciprocal inhibition-caused high-frequency oscillations. The changes in PRC cause oscillations and spike correlations only at high firing rates. The causal role of the PRC is confirmed using a simpler coupled oscillator network model. This mechanism enables transient oscillations between fast-spiking neurons that thereby form PC assemblies. Our work demonstrates that rate adaptation of PRCs can spatio-temporally organize the PC input to cerebellar nuclei.
Index and biological spectrum of accessible DNA elements in the human genome
Authors: Meuleman Wouter , Muratov Alexander , Rynes Eric , Halow Jessica , Lee Kristen , Bates Daniel , Diegel Morgan , Dunn Douglass , Neri Fidencio , Teodosiadis Athanasios , Reynolds Alex , Haugen Eric , Nelson Jemma , Johnson Audra , Frerker Mark , Buckley Michael , Sandstrom Richard , Vierstra Jeff , Kaul Rajinder , Stamatoyannopoulos John
Published: October 2019

DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA and harbor disease- and phenotypic trait-associated genetic variation. We established high-precision maps of DNase I hypersensitive sites from 733 human biosamples encompassing 439 cell and tissue types and states, and integrated these to precisely delineate and numerically index ~3.6 million DHSs encoded within the human genome, providing a common coordinate system for regulatory DNA. Here we show that the expansive scale of cell and tissue states sampled exposes an unprecedented degree of stereotyped actuation of large sets of elements, signaling the operation of distinct genome-scale regulatory programs. We show further that the complex actuation patterns of individual elements can be captured comprehensively by a simple regulatory vocabulary reflecting their dominant cellular manifestation. This vocabulary, in turn, enables comprehensive and quantitative regulatory annotation of both protein-coding genes and the vast array of well-defined but poorly-characterized non-coding RNA genes. Finally, we show that the combination of high-precision DHSs and regulatory vocabularies markedly concentrate disease- and trait-associated non-coding genetic signals both along the genome and across cellular compartments. Taken together, our results provide a common and extensible coordinate system and vocabulary for human regulatory DNA, and a new global perspective on the architecture of human gene regulation.
Establishment of an eHAP1 Human Haploid Cell Line Hybrid Reference Genome Assembled from Short and Long Reads
Authors: Law William D. , Warren René L. , McCallion Andrew S.
Published: October 2019

Background

Haploid cell lines are a valuable research tool with broad applicability for genetic assays. As such the fully haploid human cell line, eHAP1, has been used in a wide array of studies. However, the absence of a corresponding reference genome sequence for this cell line has limited the potential for more widespread applications to experiments dependent on available sequence, like capture-clone methodologies.

Results

We generated ~15x coverage Nanopore long reads from ten GridION flowcells. We utilized this data to assemble a de novo draft genome using minimap and miniasm and subsequently polished using Racon. This assembly was further polished using previously generated, low-coverage, Illumina short reads with Pilon and ntEdit. This resulted in a hybrid eHAP1 assembly with >90% complete BUSCO scores. We further assessed the eHAP1 long read data for structural variants using Sniffles and identify a variety of rearrangements, including a previously established Philadelphia translocation. Finally, we demonstrate how some of these variants overlap open chromatin regions, potentially impacting regulatory regions.

Conclusions

By integrating both long and short reads, we generated a high-quality reference assembly for eHAP1 cells. We identify structural variants using long reads, including some that may impact putative regulatory elements. The union of long and short reads demonstrates the utility in combining sequencing platforms to generate a high-quality reference genome de novo solely from low coverage data. We expect the resulting eHAP1 genome assembly to provide a useful resource to enable novel experimental applications in this important model cell line.
Cerebellar lesions disrupt spatial and temporal visual attention
Authors: Craig B.T. , Morrill A. , Anderson B. , Danckert J. , Striemer C.L.
Published: October 2019

The current study represents the first comprehensive examination of spatial, temporal and sustained attention following cerebellar damage. Results indicated that, compared to controls, cerebellar damage resulted in a larger cueing effect at the longest SOA – possibly reflecting a slowed the onset of inhibition of return (IOR) during a reflexive covert attention task, and reduced the ability to detect successive targets during an attentional blink task. However, there was little evidence to support the notion that cerebellar damage disrupted voluntary covert attention or the sustained attention to response task (SART). Lesion overlay data and supplementary voxel-based lesion symptom mapping (VLSM) analyses indicated that impaired performance on the reflexive covert attention and attentional blink tasks were related to damage to Crus II of the left posterior cerebellum. In addition, subsequent analyses indicated our results are not due to either general motor impairments or to damage to the deep cerebellar nuclei. Collectively these data demonstrate, for the first time, that the same cerebellar regions may be involved in both spatial and temporal visual attention.
Assembling a corpus of phosphoproteomic annotations using ProtMapper to normalize site information from databases and text mining
Authors: Bachman John A. , Sorger Peter K. , Gyori Benjamin M.
Published: October 2019

Protein phosphorylation regulates numerous cellular processes and is highly studied in biology.However, the analysis of phosphoproteomic datasets remains challenging due to limited information on upstream regulators of phosphosites, which is fragmented across multiple curated databases and unstructured literature. When aggregating information on phosphosites from six databases and three text mining systems, we found that a substantial proportion of phosphosites were mentioned at residue positions not matching the reference sequence. These errors were often attributable to the use of residue numbers from non-canonical protein isoforms, mouse or rat proteins, or post-translationally processed proteins. Non-canonical site numbering is also prevalent in mass spectrometry datasets from large-scale efforts such as the Clinical Proteomic Tumor Analysis Consortium (CPTAC). To address these issues, we developed ProtMapper, an open-source Python tool that automatically normalizes site positions to human protein reference sequences. We used ProtMapper coupled with the INDRA knowledge assembly system to create a corpus of 37,028 regulatory annotations for 16,332 sites – to our knowledge, the most comprehensive corpus of literature-derived information about phosphosite regulation currently available. This work highlights how automated phosphosite normalization coupled to text mining and knowledge assembly allows researchers to leverage phosphosite information that exists within the scientific literature.
A comparative analysis among ADAR mutant mice reveals site-specific regulation of RNA editing
Authors: Cruz Pedro Henrique Costa , Kato Yuki , Nakahama Taisuke , Shibuya Toshiharu , Kawahara Yukio
Published: October 2019

Adenosine-to-inosine RNA editing is an essential posttranscriptional modification catalyzed by adenosine deaminase acting on RNA (ADAR)1 and ADAR2 in mammals. For numerous sites in coding sequences (CDS) and microRNAs (miRNAs), editing is highly conserved and has significant biological consequences, for example, by altering amino acid residues and target recognition. However, technical limitations have prevented a comprehensive and quantitative study to determine how specific ADARs contribute to each site. Here, we developed a simple method in which each RNA region with an editing site was amplified separately and combined for deep sequencing. Using this method, we compared the editing ratios of all sites that were either definitely or possibly conserved in CDS and miRNAs in the cerebral cortex and spleen of wild-type mice, Adar1E861A/E861AIfih−/− mice expressing inactive ADAR1 (Adar1 KI) and Adar2−/−Gria2R/R (Adar2 KO) mice. We found that the editing ratio was frequently upregulated in either Adar mutant mouse strain. In contrast, we found that the presence of both ADAR1 and ADAR2 was required for the efficient editing of specific sites. In addition, some sites, such as miR-3099-3p, showed no preference for either ADAR. We further created double mutant Adar1 KI Adar2 KO mice and observed viable and fertile animals with complete absence of editing, suggesting that ADAR1 and ADAR2 are the sole enzymes responsible for all editing sites in vivo. Collectively, these findings indicate that editing is regulated in a site-specific manner by the different interplay between ADAR1 and ADAR2.
Refined mechanism ofMycoplasma mobilegliding based on structure, ATPase activity, and sialic acid binding of machinery
Authors: Nishikawa Miyuki S , Nakane Daisuke , Toyonaga Takuma , Kawamoto Akihiro , Kato Takayuki , Namba Keiichi , Miyata Makoto
Published: October 2019

Mycoplasma mobile, a fish pathogen, glides on solid surfaces by repeated catch, pull, and release of sialylated oligosaccharides by a unique mechanism based on ATP energy. The gliding machinery is composed of huge surface proteins and an internal jellyfish -like structure. Here, we elucidated the detailed three-dimensional structures of the machinery by electron cryotomography. The internal tentacle -like structure hydrolyzed ATP, which was consistent with the fact that the paralogs of the α- and β-subunits of F1-ATPase are at the tentacle structure. The electron microscopy suggested conformational changes of the tentacle structure depending on the presence of ATP analogs. The gliding machinery was isolated and shown that the binding activity to sialylated oligosaccharide was higher in the presence of ADP than in the presence of ATP. Based on these results, we proposed a model to explain the mechanism ofM. mobilegliding.

IMPORTANCE

The genusMycoplasmais made up of the smallest parasitic and sometimes commensal bacteria;Mycoplasma pneumoniae, which causes human walking pneumonia, is representative. More than tenMycoplasmaspecies glide on host tissues by novel mechanisms always in the direction of the distal side of the machinery.Mycoplasma mobile, the fastest species in the genus, catches, pulls, and releases sialylated oligosaccharides (SOs), the carbohydrate molecules also targeted by influenza viruses, by means of a specific receptor and using ATP hydrolysis for energy. Here, the architecture of the gliding machinery was visualized three-dimensionally by electron cryotomography (ECT), and changes in the structure and binding activity coupled to ATP hydrolysis were discovered. Based on the results, a refined mechanism was proposed for this unique motility.
Species richness increases fitness differences, but does not affect niche differences
Authors: Spaak Jurg W. , Carpentier Camille , De Laender Frederik
Published: October 2019

A key question in ecology is what limits species richness. Modern coexistence theory presents the persistence of species as a balance between niche differences and fitness differences that favor and hamper coexistence, respectively. With most applications focusing on species pairs, however, we know little about if and how this balance changes with species richness. Here, we present the first mathematical proof that the average fitness difference among species increases with richness, while the average niche difference stays constant. Extensive simulations with more complex models and analyses of empirical data confirmed these mathematical results. Taken together, our work suggests that, as species accumulate in ecosystems, ever-increasing fitness differences will at some point exceed constant niche differences, limiting species richness. Our results contribute to the expansion of modern coexistence theory towards multi-species communities.
Genetic analysis ofAedes aegypticaptured in two international airports serving to the Greater Tokyo Area during 2012—2015
Authors: Itokawa Kentaro , Hu Jinping , Sukehiro Nayu , Tsuda Yoshio , Komagata Osamu , Kasai Shinji , Tomita Takashi , Minakawa Noboru , Sawabe Kyoko
Published: October 2019

Introduction of exotic diseases vectors into a new habitat can drastically change the local epidemiological situation. During 2012—2015, larvae and an adult of the yellow-fever mosquito,Aedes aegypti, were captured alive in two international airports serving to the Greater Tokyo Area, Japan. Because this species does not naturally distribute in this country, those mosquitoes were considered to be introduced from overseaviaair-transportation. To infer the places of origin of those mosquitoes, we genotyped 12 microsatellite loci for which the most comprehensive population genetic reference is available. Although clustering by Bayesian and multivariate methods both suggested all those airport mosquitoes belong to Asia/Pacific population, they were not clustered into a single population. Also, there was variation in mitochondrialCox1haplotypes among mosquitoes collected in different incidents of discovery which indicated the existence of multiple maternal origins. Whereas we conclude there is little evidence to support overwintering ofAe. aegyptiin the airports in this study, special attention is still desired to prevent the invasion of this prominent arbovirus vector.
Integrating Transposable Elements in the 3D Genome
Authors: Bousios Alexandros , Nuetzmann Hans-Wilhelm , Buck Dorothy , Michieletto Davide
Published: October 2019

Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Here, we propose a new predictive modelling framework for the study of the integration patterns of TEs based on extensions of widely employed polymer models for genome organisation. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, we now show that it can also offer orthogonal and generic insights into the integration and distribution profiles (or “topography”) of TEs across organisms. Here, we present polymer physics arguments and molecular dynamics simulations on TEs inserting into heterogeneously flexible polymers and show with a simple model that polymer folding and local flexibility affects TE integration patterns. The preliminary discussion presented herein lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome.
Phenotypic diversity of Methylobacterium associated with rice landraces in Northeast India
Authors: Sanjenbam Pratibha , Buddidathi Radhika , Venkatesan Radhika , Shivaprasad P V , Agashe Deepa
Published: October 2019

The ecology and distribution of many bacteria is strongly associated with specific eukaryotic hosts. However, the impact of such host association on bacterial ecology and evolution is not well understood. Bacteria from the genus Methylobacterium consume plant-derived methanol, and are some of the most abundant and widespread plant-associated bacteria. In addition, many of these species impact plant fitness. To determine the ecology and distribution of Methylobacterium in nature, we sampled bacteria from 36 distinct rice landraces, traditionally grown in geographically isolated locations in North-East (NE) India. These landraces have been selected for diverse phenotypic traits by local communities, and we expected that the divergent selection on hosts may have also generated divergence in associated Methylobacterium strains. We determined the ability of 91 distinct rice-associated Methylobacterium isolates to use a panel of carbon sources, finding substantial variability in carbon use profiles. Consistent with our expectation, across spatial scales this phenotypic variation was largely explained by host landrace identity rather than geographical factors or bacterial taxonomy. However, variation in carbon utilisation was not correlated with sugar exudates on leaf surfaces, suggesting that bacterial carbon use profiles do not directly determine bacterial colonization across landraces. Finally, experiments showed that at least some rice landraces gain an early growth advantage from their specific phyllosphere-colonizing Methylobacterium strains. Together, our results suggest that landrace-specific host-microbial relationships may contribute to spatial structure in rice-associated Methylobacterium in a natural ecosystem. In turn, association with specific bacteria may provide new ways to preserve and understand diversity in one of the most important food crops of the world.
Relationship between True Digestibility of dietary Phosphorus and Gastrointestinal Bacteria of Goats
Authors: Wang Lizhi , Shah Ali Mujtaba , Liu Yuehui , Jin Lei , Wang Zhisheng , Xue Bai , Peng Quanhui
Published: October 2019

The present research was conducted to evaluate the connection between the true digestibility of Phosphorus (TDP) in diet and bacterial community structure in the gastrointestinal tract (GIT) of goats. Twenty-eight Nubian goats were chosen and metabolic experiment was conducted to analyze TDP of research animals. Eight goats were grouped into the high digestibility of phosphorus (HP) phenotype, and another 8 were grouped into the low digestibility of phosphorus (LP) phenotype. And from the rumen, abomasum, jejunim, cecum and colon content of the goats, bacterial 16S rRNA gene amplicons were sequenced. In the rumen 239 genera belonging to 23 phyla, in abomasum 319 genera belonging to 30 phyla, in jejunum 248 genera belonging to 36,in colon 248 genera belonging to 25 phyla and in cecum 246 genera belonging to 23 phyla were noticed. In addition, there was a significant correlation between the TDP and the abundance of Ruminococcaceae_UCG-010, Ruminococcus_2, Ruminococcaceae_UCG-014, Selenomonas_1 and Prevotella in the rumen, Lachnospiraceae_ND3007_group, Saccharofermentans, Ruminococcus_1, Ruminococcaceae_UCG-014, Lachnospiraceae_XPB1014_group and Desulfovibrio in the abomasum, Prevotella, Clostridium_sensu_stricto_1, Fibrobacter, Desulfovibrio and Ruminococcus_2 in the jejunum, Ruminococcaceae_UCG-014 in the colon, and Desulfovibrio in the cecum. Present research trial recommended that the community of gastrointestinal microbiota is a factor affecting TDP in goats.
Dynamic-ultrastructural cell volume (3D) correlative microscopy facilitated by intracellular fluorescent nanodiamonds as multi-modal probes
Authors: Prabhakar Neeraj , Belevich Ilya , Peurla Markus , Heiligenstein Xavier , Chang Huan-Cheng , Sahlgren Cecilia , Jokitalo Eija , Rosenholm Jessica M.
Published: October 2019

Three-dimensional correlative light and electron microscopy (3D CLEM) are attaining popularity as a potential technique to explore the functional aspects of a cell together with high-resolution ultrastructural details across the cell volume. In order to perform such a 3D CLEM experiment, there is an imperative requirement for multi-modal probes that are both fluorescent and electron-dense. These multi-modal probes will serve as landmarks in matching up the large full cell volume datasets acquired by different imaging modalities. Fluorescent nanodiamonds (FNDs) are a unique nanosized, fluorescent, and electron-dense material from the nanocarbon family. We hereby propose a novel and straightforward method for executing 3D CLEM using FNDs as multi-modal landmarks. We demonstrate that FNDs is biocompatible and easily identified both in living cell fluorescence imaging and in serial block-face scanning electron microscopy (SB-EM). We illustrate the 3D CLEM method by registering multi-modal datasets.
PopInf: An approach for reproducibly visualizing and assigning population affiliation in genomic samples of uncertain origin
Authors: Taravella Oill Angela M. , Deshpande Anagha J. , Natri Heini M. , Wilson Melissa A.
Published: October 2019

Germline genetic variation contributes to cancer etiology, but self-reported race is not always consistent with genetic ancestry, and samples may not have identifying ancestry information. Here we describe a flexible computational pipeline, PopInf, to visualize principal components analysis output and assign ancestry to samples with unknown genetic ancestry, given a reference population panel of known origins. PopInf is implemented as a reproducible workflow in Snakemake with a tutorial on GitHub. We provide a pre-processed reference population panel that can be quickly and efficiently implemented in cancer genetics studies. We ran PopInf on TCGA liver cancer data and identify discrepancies between reported race and inferred genetic ancestry.

Significance

The PopInf pipeline facilitates visualization and identification of genetic ancestry across samples, so that this ancestry can be accounted for in studies of disease risk. All code and a tutorial are available on Github: https://github.com/SexChrLab/PopInf.
Molecular principles of Piezo1 activation by increased membrane tension
Authors: De Vecchis Dario , Beech David J , Kalli Antreas C
Published: October 2019

SUMMARY PARAGRAPH

Piezo1 is a mechanosensitive channel involved in many cellular functions and responsible for sensing shear-stress and pressure forces in cells1–3. Piezo1 plays a critical role in the circulatory system and tissue development. Mutations on Piezo1 are linked to human diseases such as lymphedema2,4 or hematological disorders such as hemolytic anaemia5 and resistance to malaria6. Hypotheses for Piezo1 gating include the “force-from-lipids” principle7,8 that suggests that Piezo1 senses mechanical forces through the bilayer1,9 and a direct involvement of the cytoskeleton as well as the extracellular matrix in Piezo1 activation10,11. However, the molecular and structural changes underpinning the Piezo1 gating mechanism and how the channel senses forces in the membrane remain unknown. Here we reveal the activation mechanism of Piezo1 and the structural rearrangements that occur when Piezo1 moves from a closed to an open state when mechanical tension is applied to the cell membrane. Our results show that Piezo1’s curved shape is stable in a native-like model membrane without tension creating a membrane indentation with a trilobed topology. Upon stretching Piezo1 adapts to the stretched bilayer by flattening and expansion of its blade region. In our simulations Piezo1 expands up to a planar circular area of ∼680 nm2 comparable with previous structural data and hypotheses12–14. Piezo1 flattening and expansion results in changes in the beam helix tilt angle. These movements result in the tilting and lateral movement of the pore lining TM37 and TM38 helices. This leads to the opening of the channel and to the movement of lipids that occupy Piezo1 pore region outside of this region, revealing for the first time the structural changes that happen during Piezo1 mechanical activation. The changes in the blade region are transmitted to helices TM37 and 38 via hydrophobic interactions and by interactions of neighbouring subunits via the elbow region. The flat structure of Piezo1 identified in this study exposes the C-terminal extracellular domain (CED) that in the closed state is hidden in the membrane and presumably from shear stress. Our results provide new structural data for different states of Piezo1 and suggest the molecular principles by which mechanical force opens the Piezo1 channel, thus coupling force to physiological effect via ion permeation.