bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome-wide dynamics of extensive m6A mRNA methylation duringPlasmodium falciparumblood-stage development
Authors: Baumgarten Sebastian , Bryant Jessica M. , Sinha Ameya , Reyser Thibaud , Preiser Peter R. , Dedon Peter C. , Scherf Artur
Published: March 2019

Malaria pathogenesis results from the asexual replication ofPlasmodium falciparumwithin human red blood cells, which relies on a precisely timed cascade of gene expression over a 48-hour life cycle. Although substantial post-transcriptional regulation of this hardwired program has been observed, it remains unclear how these processes are mediated on a transcriptome-wide level. To this end, we identified mRNA modifications in theP. falciparumtranscriptome and performed a comprehensive characterization of N6-methyladenosine (m6A) over the course of blood stage development. Using mass spectrometry and m6A RNA sequencing, we demonstrate that m6A is highly developmentally regulated, exceeding m6A levels known in any other eukaryote. We identify an evolutionarily conserved m6A writer complex and show that knockdown of the putative m6A methyltransferase by CRISPR interference leads to increased levels of transcripts that normally contain m6A. In accordance, we find an inverse correlation between m6A status and mRNA stability or translational efficiency. Our data reveal the crucial role of extensive m6A mRNA methylation in dynamically fine-tuning the transcriptional program of a unicellular eukaryote as well as a new ‘epitranscriptomic’ layer of gene regulation in malaria parasites.
Looking for Therapeutic Antibodies in Next Generation Sequencing Repositories
Authors: Krawczyk Konrad , Raybould Matthew , Kovaltsuk Aleksandr , Deane Charlotte M.
Published: March 2019

Recently it has become possible to query the great diversity of natural antibody repertoires using Next Generation Sequencing (NGS). These methods are capable of producing millions of sequences in a single experiment. Here we compare Clinical Stage Therapeutic antibodies to the ∼1b sequences from 60 independent sequencing studies in the Observed Antibody Space Database. Of the 242 post Phase I antibodies, we find 16 with sequence identity matches of 95% or better for both heavy and light chains. There are also 54 perfect matches to therapeutic CDR-H3 regions in the NGS outputs, suggesting a nontrivial amount of convergence between naturally observed sequences and those developed artificially. This has potential implications for both the discovery of antibody therapeutics and the legal protection of commercial antibodies.
Cascaded-CNN: Deep Learning to Predict Protein Backbone Structure from High-Resolution Cryo-EM Density Maps
Authors: Moritz Spencer A. , Pfab Jonas , Wu Tianqi , Hou Jie , Cheng Jianlin , Cao Renzhi , Wang Liguo , Si Dong
Published: March 2019

Cryo-electron microscopy (cryo-EM) has become a leading technology for determining protein structures. Recent advances in this field have allowed for atomic resolution. However, predicting the backbone trace of a protein has remained a challenge on all but the most pristine density maps (< 2.5Å resolution). Here we introduce a deep learning model that uses a set of cascaded convolutional neural networks (CNNs) to predict Cα atoms along a protein’s backbone structure. The cascaded-CNN (C-CNN) is a novel deep learning architecture comprised of multiple CNNs, each predicting a specific aspect of a protein’s structure. This model predicts secondary structure elements (SSEs), backbone structure, and Cα atoms, combining the results of each to produce a complete prediction map. The cascaded-CNN is a semantic segmentation image classifier and was trained using thousands of simulated density maps. This method is largely automatic and only requires a recommended threshold value for each evaluated protein. A specialized tabu-search path walking algorithm was used to produce an initial backbone trace with Cα placements. A helix-refinement algorithm made further improvements to the α-helix SSEs of the backbone trace. Finally, a novel quality assessment-based combinatorial algorithm was used to effectively map Cα traces to obtain full-atom protein structures. This method was tested on 50 experimental maps between 2.6Å and 4.4Å resolution. It outperformed several state-of-the-art prediction methods including RosettaES, MAINMAST, and a Phenix based method by producing the most complete prediction models, as measured by percentage of found Cα atoms. This method accurately predicted 88.5% (mean) of the Cα atoms within 3Å of a protein’s backbone structure surpassing the 66.8% mark achieved by the leading alternate method (Phenix based fully automatic method) on the same set of density maps. The C-CNN also achieved an average RMSD of 1.23Å for all 50 experimental density maps which is similar to the Phenix based fully automatic method. The source code and demo of this research has been published athttps://github.com/DrDongSi/Ca-Backbone-Prediction.
Fine mapping using whole-genome sequencing confirms anti-Müllerian hormone as a major gene for sex determination in farmed Nile tilapia (Oreochromis niloticus L.)
Authors: Cáceres Giovanna , López María E. , Cadiz María I. , Yoshida Grazyella M. , Jedlicki Ana , Palma-Véjares Ricardo , Travisany Dante , Díaz-Domínguez Diego , Maass Alejandro , Lhorente Jean P. , Soto Jose , Salas Diego , Yáñez José M.
Published: March 2019

Nile tilapia (Oreochromis niloticus) is one of the most cultivated and economically important species in world aquaculture. Faster male development during grow-out phase is considered a major problem that generate heterogeneous sizes of fish at harvest. Identifying genomic regions associated with sex determination in Nile tilapia is a research topic of great interest. The objective of this study was to identify genomic variants associated with sex determination in three commercial populations of Nile tilapia. Whole-genome sequencing of 326 individuals was performed, and a total of 2.4 million high-quality bi-allelic single nucleotide polymorphisms (SNPs) were identified. A genome-wide association study (GWAS) was conducted to identify markers associated with the binary sexual trait (males = 0; females = 1). A mixed logistic regression GWAS model was fitted and a genome-wide significant signal comprising 36 SNPs, located on chromosome 23 spanning a genomic region of 536 kb, was identified. Ten out of these 36 genetic variants, intercept the anti-Müllerian hormone gene. Other significant SNPs were located in the neighboring Amh gene region. This gene has been strongly associated with sex determination in several vertebrate species, playing an essential role in the differentiation of male and female reproductive tissue in early stages of development. This finding provides useful information to better understand the genetic mechanisms underlying sex determination in Nile tilapia.
Maximum Likelihood Reconstruction of Ancestral Networks by Integer Linear Programming
Authors: Rajan Vaibhav , Kingsford Carl , Zhang Xiuwei
Published: March 2019

Motivation

The study of the evolutionary history of biological networks enables deep functional understanding of various bio-molecular processes. Network growth models, such as the Duplication-Mutation with Complementarity (DMC) model, provide a principled approach to characterizing the evolution of protein-protein interactions (PPI) based on duplication and divergence. Current methods for model-based ancestral network reconstruction primarily use greedy heuristics and yield sub-optimal solutions.

Results

We present a new Integer Linear Programming (ILP) solution for maximum likelihood reconstruction of ancestral PPI networks using the DMC model. We prove the correctness of our solution that is designed to find the optimal solution. It can also use efficient heuristics from general-purpose ILP solvers to obtain multiple optimal and near-optimal solutions that may be useful in many applications. Experiments on synthetic data show that our ILP obtains solutions with higher likelihood than those from previous methods, and is robust to noise and model mismatch. We evaluate our algorithm on two real PPI networks, with proteins from the families of bZIP transcription factors and the Commander complex. On both the networks, solutions from our ILP have higher likelihood and are in better agreement with independent biological evidence from other studies.

Availability

A Python implementation is available at https://bitbucket.org/cdal/.

Contact

vaibhav.rajan@nus.edu.sg
Bone morphogenetic protein 4 gene therapy in mice inhibits myeloma tumor growth, but has a negative impact on bone
Authors: Westhrin Marita , Holien Toril , Zahoor Muhammad , Moen Siv Helen , Buene Glenn , Størdal Berit , Hella Hanne , Yuan Huipin , de Bruijn Joost D , Martens Anton , Groen Richard WJ , Bosch Fatima , Smith Ulf , Sponaas Anne-Marit , Sundan Anders , Standal Therese
Published: March 2019

Multiple myeloma is characterized by accumulation of malignant plasma cells in the bone marrow. Most patients suffer from an osteolytic bone disease, caused by increased bone degradation and reduced bone formation. Bone morphogenetic protein 4 (BMP4) is important for both pre- and postnatal bone formation and induces growth arrest and apoptosis of myeloma cells. BMP4-treatment of myeloma patients could have the potential to reduce tumor growth and restore bone formation. We therefore explored BMP4 gene therapy in a human-mouse model of multiple myeloma where humanized bone scaffolds were implanted subcutaneously in RAG2−/−γC−/−mice. Mice were treated with adeno-associated virus serotype 8 BMP4 vectors (AAV8-BMP4) to express BMP4 in the liver. When mature BMP4 was detectable in the circulation, myeloma cells were injected into the scaffolds and tumor growth was examined by weekly imaging. Strikingly, the tumor burden was reduced in AAV8-BMP4 mice compared with the AAV8-CTRL mice, suggesting that increased circulating BMP4 reduced tumor growth. BMP4-treatment also prevented bone loss in the scaffolds, most likely due to reduced tumor load. To delineate the effects of BMP4 overexpression on bone per se, without direct influence from cancer cells, we examined the unaffected, non-myeloma femurs by μCT. Surprisingly, the AAV8-BMP4 mice had significantly reduced trabecular bone volume, trabecular numbers, as well as significantly increased trabecular separation compared with the AAV8-CTRL mice. There was no difference in cortical bone parameters between the two groups. Taken together, BMP4 gene therapy inhibited myeloma tumor growth, but also reduced the amount of trabecular bone in mice. Our data suggest that care should be taken when considering using BMP4 as a therapeutic agent.
The genetic architecture of sporadic and recurrent miscarriage
Authors: Laisk Triin , Soares Ana Luiza G , Ferreira Teresa , Painter Jodie N , Laber Samantha , Bacelis Jonas , Chen Chia-Yen , Lepamets Maarja , Lin Kuang , Liu Siyang , Millwood Iona Y , Ramu Avinash , Southcombe Jennifer , Andersen Marianne S , Yang Ling , Becker Christian M , Gordon Scott D , Bybjerg-Grauholm Jonas , Helgeland Øyvind , Hougaard David M , Jin Xin , Johansson Stefan , Juodakis Julius , Kartsonaki Christiana , Kukushkina Viktorija , Study Lifelines Cohort , Lind Penelope A , Metspalu Andres , Montgomery Grant W , Morris Andrew P , Mortensen Preben B , Njølstad Pål R , Nyholt Dale R , Lippincott Margaret , Seminara Stephanie , Salumets Andres , Snieder Harold , Zondervan Krina , Chen Zhengming , Conrad Donald F , Jacobsson Bo , Li Liming , Martin Nicholas G , Neale Benjamin M , Nielsen Rasmus , Walters Robin G , Granne Ingrid , Medland Sarah E , Mägi Reedik , Lawlor Deborah A , Lindgren Cecilia M
Published: March 2019

Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies1,2. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%,Pmeta=3.2×-8(CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located nearFGF9involved in pregnancy maintenance3and progesterone production4. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%,Pmeta=1.3×-8in controlling extravillous trophoblast motility5. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.
Cladocopium community divergence in two Acropora coral hosts across multiple spatial scales
Authors: Davies SW , Moreland K , Wham DC , Kanke MR , Matz MV
Published: March 2019

Many broadly-dispersing corals acquire their algal symbionts (Symbiodiniaceae) ‘horizontally’ from their environment upon recruitment. Horizontal transmission could promote coral fitness across diverse environments provided that corals can associate with divergent algae across their range and that these symbionts exhibit reduced dispersal potential. Here we quantified community divergence of Cladocopium algal symbionts in two coral host species (Acropora hyacinthus, Acropora digitifera) across two spatial scales (reefs on the same island, and between islands) across the Micronesian archipelago using microsatellites. We find that both hosts associated with two genetically distinct Cladocopium lineages (C40, C21), confirming that Acropora coral hosts associate with a range of Cladocopium symbionts across this region. Both C40 and C21 exhibited extensive clonality. Clones not only existed across host conspecifics living on the same reef, but also spanned host species, reef sites within islands, and even different islands. Both Cladocopium lineages exhibited moderate host specialization and divergence across islands. In addition, within every island, algal symbiont communities were significantly clustered by both host species and reef site, highlighting that coral-associated Cladocopium communities are structured across small spatial scales and within hosts on the same reef. This is in stark contrast to their coral hosts, which never exhibited significant genetic divergence between reefs on the same island. These results support the view that horizontal transmission could improve local fitness for broadly dispersing Acropora coral species.
A validated workflow for rapid taxonomic assignment and monitoring of a national fauna of bees (Apiformes) using high throughput barcoding
Authors: Creedy Thomas J. , Norman Hannah , Tang Cuong Q. , Chin Kai Qing , Andujar Carmelo , Arribas Paula , O’Connor Rory , Carvell Claire , Notton David G. , Vogler Alfried P.
Published: March 2019

Improved taxonomic methods are needed to quantify declining populations of insect pollinators. This study devises a high-throughput DNA barcoding protocol for a regional fauna (United Kingdom) of bees (Apiformes), consisting of reference library construction, a proof-of-concept monitoring scheme, and the deep barcoding of individuals to assess potential artefacts and organismal associations. A reference database of Cytochrome Oxidase subunit 1 (cox1) sequences including 92.4% of 278 bee species known from the UK showed high congruence with morphological taxon concepts, but molecular species delimitations resulted in numerous split and (fewer) lumped entities within the Linnaean species. Double tagging permitted deep illumina sequencing of 762 separate individuals of bees from a UK-wide survey. Extracting the target barcode from the amplicon mix required a new protocol employing read abundance and phylogenetic position, which revealed 180 molecular entities of Apiformes identifiable to species. An additional 72 entities were ascribed to mitochondrial pseudogenes based on patterns of read abundance and phylogenetic relatedness to the reference set. Clustering of reads revealed a range of secondary Operational Taxonomic Units (OTUs) in almost all samples, resulting from traces of insect species caught in the same traps, organisms associated with the insects including a known mite parasite of bees, and the common detection of human DNA, besides evidence for low-level cross-contamination in pan traps and laboratory steps. Custom scripts were generated to conduct critical steps of the bioinformatics protocol. The resources built here will greatly aid DNA-based monitoring to inform management and conservation policies for the protection of pollinators.
LTK is an ER-resident receptor tyrosine kinase that regulates secretion
Authors: Centonze Federica G. , Reiterer Veronika , Nalbach Karsten , Saito Kota , Pawlowski Krzysztof , Behrends Christian , Farhan Hesso
Published: March 2019

The endoplasmic reticulum (ER) is a key regulator of cellular proteostasis because it controls folding, sorting and degradation of secretory proteins. Much has been learned about how environmentally triggered signaling pathways regulate ER function, but only little is known about local signaling at the ER. The identification of ER-resident signaling molecules will help gain a deeper understanding of the regulation of ER function and thus of proteostasis. Here, we show that leukocyte tyrosine kinase (LTK) is an ER-resident receptor tyrosine kinase. Depletion of LTK as well as its pharmacologic inhibition reduces the number of ER exit sites and slows ER-to-Golgi transport. Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module the potential to regulate proteostasis.
Dual activity of PNGM-1, a metallo-β-lactamase and tRNase Z, pinpoints the evolutionary origin of subclass B3 metallo-β-lactamases
Authors: Lee Jung Hun , Takahashi Masayuki , Jeon Jeong Ho , Kang Lin-Woo , Seki Mineaki , Park Kwang Seung , Hong Myoung-Ki , Park Yoon Sik , Kim Tae Yeong , Karim Asad Mustafa , Lee Jung-Hyun , Nashimoto Masayuki , Lee Sang Hee
Published: March 2019

Antibiotic resistance is a steadily increasing global problem which could lead to a fundamental upheaval in clinical care with the potential to return us to the pre-antibiotic era1-4. The production of β-lactamases, a group of enzymes that confer antibiotic resistance in Gram-negative bacteria, is now one of the major barriers in treating Gram-negative infections5. β-Lactamases are classified according to their catalytic mechanisms into serine β-lactamases and metallo-β-lactamases6,7. There are functional and structural similarities between serine β-lactamases and penicillin-binding proteins, and so serine β-lactamases are thought to have evolved from a penicillin-binding protein7,8. Given the functional and structural differences between serine β-lactamases and metallo-β-lactamases, metallo-β-lactamases are thought to have evolved from a protein other than a penicillin-binding protein, but to date this ancestor remains unknown8-11. We discovered PNGM-1, the first subclass B3 metallo-β-lactamase, in deep-sea sediments that predate the antibiotic era12. Here we discover the dual activity of PNGM-1, pinpointing the evolutionary origin of subclass B3 metallo-β-lactamases. Phylogenetic analysis suggested that PNGM-1 could yield insights into the evolutionary origin of subclass B3 metallo-β-lactamases. We reveal the structural similarities between tRNase Zs and PNGM-1, which prompted us to investigate their evolutionary relationship and the possibility of them possessing dual enzymatic activities. We demonstrate that PNGM-1 has dual activity with both true metallo-β-lactamase and tRNase Z activity, suggesting that PNGM-1 is thought to have evolved from a tRNase Z. We also show kinetic and structural comparisons between PNGM-1 and other proteins including subclass B3 metallo-β-lactamases and tRNase Zs. These comparisons revealed that the B3 metallo-β-lactamase activity of PNGM-1 is a promiscuous activity and subclass B3 metallo-β-lactamases are thought to have evolved through PNGM-1 activity. Our work provides a foundation for the evolution of tRNase Z into subclass B3 metallo-β-lactamases through the dual activity of PNGM-1.
CytoGPS: A Web-Enabled Karyotype Analysis Tool for Cytogenetics
Authors: Abrams Zachary B. , Zhang Lin , Abruzzo Lynne V. , Heerema Nyla A. , Li Suli , Dillon Tom , Rodriguez Ricky , Coombes Kevin R. , Payne Philip R. O.
Published: March 2019

Karyotype data are the most common form of genetic data that is regularly used clinically. They are collected as part of the standard of care in many diseases, particularly in pediatric and cancer medicine contexts. Karyotypes are represented in a unique text-based format, with a syntax defined by the International System for human Cytogenetic Nomenclature (ISCN). While human-readable, ISCN is not intrinsically machine-readable. This limitation has prevented the full use of complex karyotype data in discovery science use cases. To enhance the utility and value of karyotype data, we developed a tool named CytoGPS. CytoGPS first parses ISCN karyotypes into a machine-readable format. It then converts the ISCN karyotype into a binary Loss-Gain-Fusion (LGF) model, which represents all cytogenetic abnormalities as combinations of loss, gain, or fusion events, in a format that is analyzable using modern computational methods. Such data is then made available for comprehensive “downstream” analyses that previously were not feasible.

Availability and Implementation

Freely available at https://cytogps.org

Contact

prpayne@wustl.edu

Supplementary information

Not applicable
Biotic interactions affect fitness across latitudes, but only drive local adaptation in the tropics
Authors: Hargreaves Anna L. , Germain Rachel M. , Bontrager Megan , Persi Joshua , Angert Amy L.
Published: March 2019

Local adaptation to broad-scale environmental heterogeneity can increase species’ distributions and diversification, but which environmental components commonly drive local adaptation— particularly the importance of biotic interactions—is unclear. Biotic interactions should drive local adaptation when they impose consistent divergent selection; if this is common we expect experiments to detect more frequent and stronger local adaptation when biotic interactions are left intact. We tested this hypothesis using a meta-analysis of common-garden experiments from 138 studies (149 taxa). Across studies, local adaptation was common and biotic interactions affected fitness. Nevertheless, local adaptation was neither more common nor stronger when biotic interactions were left intact, either between experimental treatments within studies (control vs. biotic interactions experimentally manipulated) or between studies that used natural vs. biotically-altered transplant environments. However, tropical studies, which comprised only 7% of our data, found strong local adaptation in intact environments but not when negative biotic interactions were ameliorated, suggesting that interactions frequently drive local adaptation in the tropics. Our results suggest that biotic interactions often fail to drive local adaptation even though they affect fitness, perhaps because the temperate-zone biotic environment is less predictable at the spatiotemporal scales required for local adaptation.
Chrysin, but not flavone backbone, decreases anxiety-like behavior in animal screens
Authors: German-Ponciano León Jesús , Costa Bruna Patrícia Dutra , Feitosa Leonardo Miranda , dos Santos Campos Kimberly , da Silva Chaves Suianny Nayara , Cueto-Escobedo Jonathan , Lima-Maximino Monica , Rodríguez-Landa Juan Francisco , Maximino Caio
Published: March 2019

Chrysin (5,7-dihydroxyflavone), a nutraceutical flavonoid present in diverse plants, has a backbone structure shared with the flavone backbone, with additional hydroxyl groups that confers its antioxidant properties and effects at the GABAA receptor complex. However, whether these effects are due to the hydroxyl groups is unknown. Here we report the effects of chrysin or the flavone backbone (1 mg/kg) in rats subjected to the elevated plus-maze and the locomotor activity test, as well as in the zebrafish evaluated in light/dark model. Chrysin, but not flavone, increased entries and time in the open arms of the elevated plus-maze, as well as time on white compartment of the light/dark model in zebrafish. These effects were comparable to diazepam, and were devoid of motor effects in both tests, as well as in the locomotor activity test. On the other hand, flavone decreased risk assessment in the light/dark test but increased rearing in the locomotor activity test in rats, suggesting effects threat information gathering; important species differences suggest new avenues of research. It is suggested that the specific effects of chrysin in relation to flavone include more of a mechanism of action in which in addition to its action at the GABAA/benzodiazepine receptor complex also could be involved its free radical scavenging abilities, which require specific research.

Preprint

https://doi.org/10.1101/575514;

Data and scripts

https://github.com/lanec-unifesspa/chrysin
Single-base mapping of m6A by an antibody-independent method
Authors: Zhang Zhang , Chen Li-Qian , Zhao Yu-Li , Yang Cai-Guang , Roundtree Ian A , Zhang Zijie , Ren Jian , Xie Wei , He Chuan , Luo Guan-Zheng
Published: March 2019

N6-methyladenosine (m6A) is one of the most abundant mRNA modifications in eukaryotes, involved in various pivotal processes of RNA metabolism. The most popular high-throughput m6A identification method depends on the anti-m6A antibody but suffers from poor reproducibility and limited resolution. Exact location information is of great value for understanding the dynamics, machinery and functions of m6A. Here we developed a precise and high-throughput antibody-independent m6A identification method based on the m6A-sensitive RNA endoribonuclease (m6A-sensitive RNA-Endoribonuclease-Facilitated sequencing or m6A-REF-seq). Whole-transcriptomic, single-base m6A maps generated by m6A-REF-seq quantitatively displayed an explicit distribution pattern with enrichment on stop codons. Independent methods were used to validate the methylation status and abundance of individual m6A sites, confirming the high reliability and accuracy of m6A-REF-seq. We applied this method on five tissues from human, mouse and rat, showing that m6A sites were conserved with single nucleotide specificity and tend to cluster among species.
Btbd6-dependent Plzf recruitment to Cul3 E3 ligase complexes through BTB domain heterodimerization
Authors: Ismail Mohamed , Martin Stephen R. , Ball Neil J. , Taylor Ian A. , Howell Steven , Wilkinson David G. , Smerdon Stephen J.
Published: March 2019

The Cul3 adaptor Btbd6 plays crucial roles in neural development by driving the ubiquitin-dependent degradation of promyelocytic zinc finger transcription factor (Plzf). Btbd6 has conserved motifs, BTB-BACK-PHR, and by analogy with other BTB-BACK adaptors, might be expected to bind to Cul3 through the BTB-BACK domain, and to substrate through the PHR domain. However, we now present a mode of adaptor-substrate interaction through heterodimerisation between the normally homodimeric BTB domains of Btbd6 and Plzf. This heterodimerization appears to occur through monomer exchange that is detected only at or near physiological concentrations. The Btbd6-Plzf heterodimer thus formed assembles into a ternary complex with Cul3. In addition we show that the BTB and PHR domains of Btbd6 promote localisation in the nucleus and that the BACK domain contains a nuclear export signal. Our findings support a model whereby Btbd6 moves into and out of the nucleus, iteratively ‘sweeping’ Plzf into the cytoplasm and enabling complex formation with Cul3 that presents Plzf for ubiquitination.

Highlights

A general mechanism for recruitment of BTB domain-containing substrates by BTBdomain adaptors for the Cul3 E3 ligase complex

Nuclear export of the Plzf/Btbd6 complex mediated by a NES within the Btbd6 BACK domain

Cul3-dependent Plzf ubiquitylation through heterodimerisation of BTB domains on adaptor and substrate by monomer exchang
Watered-down biodiversity? A comparison of metabarcoding results from DNA extracted from matched water and bulk tissue biomonitoring samples
Authors: Hajibabaei Mehrdad , Porter Teresita M. , Robinson Chloe V. , Baird Donald J. , Shokralla Shadi , Wright Michael
Published: March 2019

Biomonitoring programs have evolved beyond the sole use of morphological identification to determine the composition of invertebrate species assemblages in an array of ecosystems. The application of DNA metabarcoding in freshwater systems for assessing benthic invertebrate communities is now being employed to generate biological information for environmental monitoring and assessment. A possible shift from the extraction of DNA from net-collected bulk benthic samples to its extraction directly from water samples for metabarcoding has generated considerable interest based on the assumption that taxon detectability is comparable when using either method. To test this, we studied paired water and benthos samples from a taxon-rich wetland complex, to investigate differences in the detection of taxa from each sample type. We demonstrate that metabarcoding of DNA extracted directly from water samples is a poor surrogate for DNA extracted from bulk benthic samples, focusing on key bioindicator groups. Our results continue to support the use of bulk benthic samples as a basis for metabarcoding-based biomonitoring, with nearly three times greater total richness in benthic samples compared to water samples. We also demonstrated that few arthropod taxa are shared between collection methods, with a notable lack of key bioindicator EPTO taxa in the water samples. Although species coverage in water could likely be improved through increased sample replication and/or increased sequencing depth, benthic samples remain the most representative, cost-effective method of generating aquatic compositional information via metabarcoding.
Refinement of the primate corticospinal pathway during prenatal development
Authors: Ribeiro Gomes Ana Rita , Olivier Etienne , Killackey Herbert P. , Giroud Pascale , Berland Michel , Knoblauch Kenneth , Dehay Colette , Kennedy Henry
Published: March 2019

Perturbation of the developmental refinement of the corticospinal pathway leads to motor disorders. In non-primates developmental refinement is well documented, however in primates invasive investigations of the developing corticospinal pathway have been confined to neonatal and postnatal stages when refinement is relatively modest.

Here, we investigated the developmental changes in the distribution of corticospinal projection neurons in cynomolgus monkey. Injections of retrograde tracer at the cervical levels of the spinal cord at embryonic day (E) 95 and E105 show that (i) areal distribution of back-labeled neurons is more extensive than in the neonate and dense labeling is found in prefrontal, limbic, temporal and occipital cortex; (ii) distributions of contra- and ipsilateral projecting corticospinal neurons are comparable in terms of location and numbers of labeled neurons, in contrast to the adult where the contralateral projection is an order of magnitude higher than the ipsilateral projection. Findings from one largely restricted injection suggest a hitherto unsuspected early innervation of the gray matter.

In the fetus there was in addition dense labeling in the central nucleus of the amygdala, the hypothalamus, the subthalamic nucleus and the adjacent region of the zona incerta, subcortical structures with only minor projections in the adult control.
SurfaceGenie: a web-based application for prioritizing cell-type specific marker candidates
Authors: Waas Matthew , Snarrenberg Shana T. , Littrell Jack , Jones Lipinski Rachel A. , Hansen Polly A. , Corbett John A. , Gundry Rebekah L.
Published: March 2019

Motivation

Cell-type specific surface proteins can be exploited as valuable markers for a range of applications including immunophenotyping live cells, targeted drug delivery, and in vivo imaging. Despite their utility and relevance, the unique combination of molecules present at the cell surface are not yet described for most cell types. A significant challenge in analyzing ‘omic’ discovery datasets is the selection of candidate markers that are most applicable for downstream applications.

Results

Here, we developed GenieScore, a prioritization metric that integrates a consensus-based prediction of cell surface localization with user-input data to rank-order candidate cell-type specific surface markers. In this report, we demonstrate the utility of GenieScore for analyzing human and rodent data from proteomic and transcriptomic experiments in the areas of cancer, stem cell, and islet biology. We also demonstrate that permutations of GenieScore, termed IsoGenieScore and OmniGenieScore, can efficiently prioritize co-expressed and intracellular cell-type specific markers, respectively.

Availability and Implementation

Calculation of GenieScores and lookup of SPC scores is made freely accessible via the SurfaceGenie web-application: www.cellsurfer.net/surfacegenie.
Population dynamics and age-dependent mortality processes in tropical reptiles
Authors: Cayuela Hugo , Akani Godfrey C. , Hema Emmanuel M. , Eniang Edem A. , Amadi Nioking , Ajong Stephanie N. , Dendi Daniele , Petrozzi Fabio , Luiselli Luca
Published: March 2019

Understanding age-dependent mortality processes is a critical challenge for population biologists. Actuarial senescence appears to be a common process across the tree of life. Senescence patterns are highly variable in pluricellular organisms: senescence can be gradual or sharp and its onset may be early or delayed. By contrast, studies revealed that organisms may also not experience senescence at all while others display a “negative senescence”; i.e. a decrease of mortality rate with age. To date, studies on senescence have largely focused on human and other endotherm vertebrates, limiting our understanding of senescence in amniotes as a whole. By contrast, few have examined the diversity of senescence patterns in ectotherm vertebrates as reptiles. Here, we examined population dynamics and age-dependent mortality patterns in three tropical tortoises (Kinixys erosa, Kinixys homeana, Kinixys nogueyi) and snakes (Bitis gabonica, Bitis nasicornis, Causus maculatus). Our study revealed that tortoises ofKinixysgenus had a higher survival and a lower recruitment than snakes of the generaBitisandCausus, indicating that they have a slower life history. Furthermore, we showed that survival more slowly decreased with age in tortoises than in snakes. In addition, we highlighted contrasted patterns of age-dependent mortality in the three genera. InKinixys, the relationship between mortality rate and age was positive and linear, suggesting gradual senescence over tortoise lifetime. By contrast, the relationship between mortality rate and age was negative and sharp inBitisandCausus, possibly due to a “negative senescence” starting early in life. Our study highlighted various age-dependent mortality patterns in tropical reptiles. It also contributed to extend our knowledge of senescence in ectotherm vertebrates whose the demography is still poorly understood. In addition, while negative senescence has never been reported in endotherm vertebrates, our results showed that it can be common phenomenon in ectotherms.
Cancer avatars derived from genetically engineered pluripotent stem cells allow for longitudinal assessment of tumor development
Authors: Koga Tomoyuki , Chaim Isaac A. , Benitez Jorge A. , Markmiller Sebastian , Parisian Alison D. , Hevner Robert F. , Turner Kristen M. , Hessenauer Florian M. , D’Antonio Matteo , Nguyen Nam-phuong D. , Saberi Shahram , Ma Jianhui , Miki Shunichiro , Boyer Antonia D. , Ravits John , Frazer Kelly A. , Bafna Vineet , Chen Clark C. , Mischel Paul S. , Yeo Gene W. , Furnari Frank B.
Published: March 2019

Many current cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a new cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that capture authentic cancer pathobiology. Orthotopic engraftment of neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) result in formation of high-grade gliomas. As observed in GBM patient samples, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, and intra-tumor heterogeneity. Further, re-engraftment of primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. Thus, these cancer avatar models provide a platform for a comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.
Intrinsic Cell-type Selectivity and Inter-neuronal Connectivity Alteration by Transcranial Focused Ultrasound
Authors: Yu Kai , Niu Xiaodan , Krook-Magnuson Esther , He Bin
Published: March 2019

Transcranial focused ultrasound (tFUS) is a promising neuromodulation technique, but its mechanisms remain unclear. We investigate the effect of tFUS stimulation on different neuron types and synaptic connectivity in in vivo anesthetized rodent brains. Single units were separated into regular-spiking and fast-spiking units based on their extracellular spike shapes, further validated in transgenic optogenetic mice models of light-excitable excitatory and inhibitory neurons. For the first time, we show that excitatory neurons are significantly less responsive to low ultrasound pulse repetition frequencies (UPRFs), whereas the spike rates of inhibitory neurons do not change significantly across all UPRF levels. Our results suggest that we can preferentially target specific neuron types noninvasively by altering the tFUS UPRF. We also report in vivo observation of long-term synaptic connectivity changes induced by noninvasive tFUS in rats. This finding suggests tFUS can be used to encode temporally dependent stimulation paradigms into neural circuits and non-invasively elicit long-term changes in synaptic connectivity.
Rapid recalibration of temporal order judgements: Response bias accounts for contradictory results
Authors: Keane Brendan , Bland Nicholas S. , Matthews Natasha , Carroll Timothy J , Wallis Guy
Published: March 2019

Recent findings indicate that timing perception is systematically changed after only a single presentation of temporal asynchrony. This effect is known as rapid recalibration. In the synchrony judgement task, similar timing relationships in consecutive trials seem more synchronous (positive rapid recalibration; Van der Burg et al., 2013, 2015). Interestingly, the direction of this effect is reversed for temporal order judgements (negative rapid recalibration; Roseboom, 2019). We aimed to determine whether negative rapid recalibration of temporal order judgements (TOJs) reflects genuine rapid temporal recalibration, or a choice-repetition bias unrelated to timing perception. In our first experiment we found no evidence of rapid recalibration of TOJs, but positive rapid recalibration of associated confidence. This suggests that timing perception had rapidly recalibrated, but that this was undetectable in TOJs, plausibly because the positive recalibration effect was obfuscated by a large negative bias effect. In our second experiment, we dissociated participants’ previous TOJ from the most recently presented timing relationship, mitigating the choice-repetition bias effect, and found evidence of positive rapid recalibration of TOJs. We therefore conclude that timing perception is rapidly recalibrated positively for both synchrony and temporal order judgements. It remains unclear whether rapid recalibration occurs at the level of sensory processing, leading to similar effects in all subsequent judgements, or reflects a generalised decision-making strategy.
Effect of Interpopulation Spike-Timing-Dependent Plasticity on Synchronized Rhythms in Neuronal Networks with Inhibitory and Excitatory Populations
Authors: Kim Sang-Yoon , Lim Woochang
Published: March 2019

We consider a two-population network consisting of both inhibitory (I) interneurons and excitatory (E) pyramidal cells. This I-E neuronal network has adaptive dynamic I to E and E to I interpopulation synaptic strengths, governed by interpopulation spike-timing-dependent plasticity (STDP). In previous works without STDPs, fast sparsely synchronized rhythms, related to diverse cognitive functions, were found to appear in a range of noise intensityDfor static synaptic strengths. Here, by varyingD, we investigate the effect of interpopulation STDPs on fast sparsely synchronized rhythms that emerge in both the I- and the E-populations. Depending on values ofD, long-term potentiation (LTP) and long-term depression (LTD) for population-averaged values of saturated interpopulation synaptic strengths are found to occur. Then, the degree of fast sparse synchronization varies due to effects of LTP and LTD. In a broad region of intermediateD, the degree of good synchronization (with higher synchronization degree) becomes decreased, while in a region of largeD, the degree of bad synchronization (with lower synchronization degree) gets increased. Consequently, in each I- or E-population, the synchronization degree becomes nearly the same in a wide range ofD(including both the intermediate and the largeDregions). This kind of “equalization effect” is found to occur via cooperative interplay between the average occupation and pacing degrees of spikes (i.e., the average fraction of firing neurons and the average degree of phase coherence between spikes in each synchronized stripe of spikes in the raster plot of spikes) in fast sparsely synchronized rhythms. Finally, emergences of LTP and LTD of interpopulation synaptic strengths (leading to occurrence of equalization effect) are intensively investigated via a microscopic method based on the distributions of time delays between the pre- and the post-synaptic spike times.

PACS numbers

87.19.lw, 87.19.lm, 87.19.lc
Towards a real-world brain-computer interface for image retrieval
Authors: McCartney Ben , Martinez-del-Rincon Jesus , Devereux Barry , Murphy Brian
Published: March 2019

Brain decoding — the process of inferring a person’s momentary cognitive state from their brain activity — has enormous potential in the field of human-computer interaction. In this study we propose a zero-shot EEG-to-image brain decoding approach which makes use of state-of-the-art EEG preprocessing and feature selection methods, and which maps EEG activity to biologically inspired computer vision and linguistic models. We apply this approach to solve the problem of identifying viewed images from recorded brain activity in a reliable and scalable way. We demonstrate competitive decoding accuracies across two EEG datasets, using a zero-shot learning framework more applicable to real-world image retrieval than traditional classification techniques.
Ice formation and solvent nanoconfinement in protein crystals
Authors: Moreau David W. , Atakisi Hakan , Thorne Robert E.
Published: March 2019

Ice formation within protein crystals is a major obstacle to the cryocrystallographic study of protein structure, and has limited studies of how the structural ensemble of a protein evolves with temperature in the biophysically interesting range from ∼260 K to the protein–solvent glass transition near 200 K. Using protein crystals with solvent cavities as large as ∼70 Å, time-resolved X-ray diffraction was used to study the response of protein and internal solvent during rapid cooling. Solvent nanoconfinement suppresses freezing temperatures and ice-nucleation rates so that ice-free, low-mosaicity diffraction data can be reliably collected down to 200 K without the use of cryoprotectants. Hexagonal ice (Ih) forms in external solvent, but internal crystal solvent forms stacking-disordered ice (Isd) with a near-random stacking of cubic and hexagonal planes. Analysis of powder diffraction from internal ice and single-crystal diffraction from the host protein structure shows that the maximum crystallizable solvent fraction decreases with decreasing crystal solvent-cavity size, and that an ∼6 Å thick layer of solvent adjacent to the protein surface cannot crystallize. These results establish protein crystals as excellent model systems for the study of nanoconfined solvent. By combining fast cooling, intense X-ray beams and fast X-ray detectors, complete structural data sets for high-value targets, including membrane proteins and large complexes, may be collected at ∼220–240 K that have much lower mosaicities and comparableBfactors, and that may allow more confident identification of ligand binding than in current cryocrystallographic practice.
The salt–cocrystal spectrum in salicylic acid–adenine: the influence of crystal structure on proton-transfer balance
Authors: Sedghiniya Sima , Soleimannejad Janet , Janczak Jan
Published: March 2019

At one extreme of the proton-transfer spectrum in cocrystals, proton transfer is absent, whilst at the opposite extreme, in salts, the proton-transfer process is complete. However, for acid–base pairs with a small ΔpK
a (pK
a of base − pK
a of acid), prediction of the extent of proton transfer is not possible as there is a continuum between the salt and cocrystal ends. In this context, we attempt to illustrate that in these systems, in addition to ΔpK
a, the crystalline environment could change the extent of proton transfer. To this end, two compounds of salicylic acid (SaH) and adenine (Ad) have been prepared. Despite the same small ΔpK
a value (≈1.2), different ionization states are found. Both crystals, namely adeninium salicylate monohydrate, C5H6N5
+·C7H5O3
−·H2O, I, and adeninium salicylate–adenine–salicylic acid–water (1/2/1/2), C5H6N5
+·C7H5O3
−·2C5H5N5·C7H6O3·2H2O, II, have been characterized by single-crystal X-ray diffraction, IR spectroscopy and elemental analysis (C, H and N) techniques. In addition, the intermolecular hydrogen-bonding interactions of compounds I and II have been investigated and quantified in detail on the basis of Hirshfeld surface analysis and fingerprint plots. Throughout the study, we use crystal engineering, which is based on modifications of the intermolecular interactions, thus offering a more comprehensive screening of the salt–cocrystal continuum in comparison with pure pK
a analysis.