bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphorylated Lamin A/C in the nuclear interior binds active enhancers associated with abnormal transcription in progeria
Authors: Ikegami Kohta , Secchia Stefano , Almakki Omar , Lieb Jason D. , Moskowitz Ivan P.
Published: June 2019

LMNA encodes nuclear lamin A/C that tethers lamina-associated heterochromatin domains (LADs) to the nuclear periphery. Point mutations in LMNA cause degenerative disorders including the premature aging disorder Hutchinson-Gilford progeria, but the mechanisms are unknown. We report that Ser22-phosphorylated Lamin A/C (pS22-Lamin A/C) was localized to the interior of the nucleus in human fibroblasts throughout the cell cycle. pS22-Lamin A/C interacted with a specific subset of putative active enhancers, not LADs, primarily at locations co-bound by the transcriptional activator c-Jun. In progeria-patient fibroblasts, a subset of pS22-Lamin A/C-binding sites were lost whereas new pS22-Lamin A/C-binding sites emerged in normally quiescent loci. These new pS22-Lamin A/C-binding sites displayed increased histone acetylation and c-Jun binding, implying increased enhancer activity. The genes near these new binding sites, implicated in clinical components of progeria including carotid artery diseases, hypertension, and cardiomegaly, were upregulated in progeria. These results suggest that Lamin A/C regulates gene expression by direct enhancer binding in the nuclear interior. Disruption of the gene regulatory rather than LAD function of Lamin A/C presents a novel mechanism for disorders caused by LMNA mutations including progeria.

HIGHLIGHTS

pS22-Lamin A/C is present in the nuclear interior throughout interphase.

pS22-Lamin A/C associates with active enhancers, not lamina-associated domains.

pS22-Lamin A/C-genomic binding sites are co-bound by the transcriptional activator c-Jun.

New pS22-Lamin A/C binding in progeria accompanies upregulation of disease-related genes.
Expression reduction of biallelically transcribed X-linked genes during the human female preimplantation development
Authors: Reinius Björn , Sandberg Rickard
Published: June 2019

Our previous single-cell RNA-seq data from human preimplantation embryos showed that female X-chromosome mRNA levels become partly dose compensated during the timespan between zygotic genome activation (ZGA) and implantation. At the same time, XIST RNA is expressed from, and forms clouds in proximity to, both X-chromosome copies and biallelic expression of other X-linked genes persists. We proposed that X-chromosome transcription is transiently lowered on both alleles before X-chromosome inactivation (XCI) takes place. This notion was recently challenged in a reanalysis performed by Moreira de Mello et al, claiming to provide evidence against biallelic expression dampening and that instead proper XCI was responsible for the observed dosage compensation. Here we have addressed this reanalysis and highlighted methodological issues, and we conclude a current lack of evidence against biallelic X-chromosome dampening.
Broadly inhibiting anti-neuraminidase monoclonal antibodies induced by trivalent influenza vaccine and H7N9 infection in humans
Authors: Rijal Pramila , Wang Bei Bei , Tan Tiong Kit , Schimanski Lisa , Janesch Philipp , Dong Tao , McCauley John W. , Daniels Rodney S. , Townsend Alain R. , Huang Kuan-Ying A.
Published: June 2019

The majority of antibodies induced by influenza neuraminidase (NA), like those against hemagglutinin (HA), are relatively specific to viruses isolated within a limited time-window as seen in serological studies and the analysis of many murine monoclonal antibodies. We report three broadly reactive human monoclonal antibodies (mAbs) targeting N1 NA. Two were isolated from a young adult vaccinated with trivalent influenza vaccine (TIV), which inhibited N1 NA from viruses isolated from human over a period of a hundred years. The third antibody isolated from a child with acute mild H7N9 infection inhibited both group 1 N1 and group 2 N9 NAs. In addition, the antibodies cross-inhibited the N1 NAs of highly pathogenic avian H5N1 influenza viruses. These antibodies are protective in prophylaxis against seasonal H1N1 viruses in mice. This study demonstrates that human antibodies to N1 NA with exceptional cross-reactivity can be recalled by vaccination and highlights the importance of standardizing the NA antigen in seasonal vaccines to offer optimal protection.

Importance

Antibodies to the influenza NA can provide protection against influenza disease. Analysis of human antibodies to NA lags behind that for HA. We show that human monoclonal antibodies against NA induced by vaccination and infection can be very broadly reactive and able to inhibit a wide spectrum of N1 NAs between 1918 and 2018. This suggests that antibodies to NA may be a useful therapy, and that efficacy of influenza vaccines could be enhanced by ensuring appropriate content of NA antigen.

Highlights of the paper

Antibodies that inhibit influenza viruses with N1 neuraminidase (NA), with broad reactivity for viruses isolated between 1918-2018, can be isolated from human recipients of seasonal influenza vaccine

Antibodies targeting N1 NA of human seasonal H1N1 viruses can cross-react with a variety of avian N1 neuraminidases

Acute H7N9 infection can recall memory B cells to N1 NA and elicit cross-reactive antibodies to the group 1 N1 and group 2 N9 NAs

Antibodies to N1 NA with this broad reactivity protect against lethal virus challenge
The Lid/KDM5 histone demethylase complex activates a critical effector of the oocyte-to-zygote transition
Authors: Torres-Campana Daniela , Kimura Shuhei , Orsi Guillermo A. , Horard Béatrice , Benoit Gérard , Loppin Benjamin
Published: June 2019

Following fertilization of a mature oocyte, the formation of a diploid zygote involves a series of coordinated cellular events that ends with the first embryonic mitosis. In animals, this complex developmental transition is almost entirely controlled by maternal gene products. How such a crucial transcriptional program is established during oogenesis remains poorly understood. Here, we have performed an shRNA-based genetic screen inDrosophilato identify genes required to form a diploid zygote. We found that the Lid/KDM5 histone demethylase and its partner, the Sin3A-HDAC1 deacetylase complex, are necessary for sperm nuclear decompaction and karyogamy. Surprisingly, transcriptomic analyses revealed that these histone modifiers are required for the massive transcriptional activation ofdeadhead(dhd), which encodes a maternal thioredoxin involved in sperm chromatin remodeling. Unexpectedly, whilelidknock-down tends to slightly favor the accumulation of its target, H3K4me3, on the genome, this mark was lost at thedhdlocus. We propose that Lid/KDM5 and Sin3A cooperate to establish a local chromatin environment facilitating the unusually high expression ofdhd, a key effector of the oocyte-to-zygote transition.
Enhancing the biological relevance of Gene Co-expression Networks: A plant mitochondrial case study
Authors: Law Simon R. , Kellgren Therese G. , Björk Rafael , Ryden Patrik , Keech Olivier
Published: June 2019

Gene Co-expression Networks (GCNs) are obtained by a variety of mathematical of models commonly derived on data sampled from diverse developmental processes, tissue types, pathologies, mutant backgrounds, and stress conditions. These networks aim to identify genes with similar expression dynamics, but are prone to introduce false-positive and -negative relations, especially in the instance of large and highly complex datasets. With the aim of optimizing the relevance of edges in GCNs and enhancing global biological insight, we propose a novel approach that involves a data-centering step performed simultaneously per gene and per sub-experiment, called centralisation within sub-experiments (CSE).

Using a gene set encoding for the plant mitochondrial proteome as a case study, our results show that CSE-based GCNs had significantly more edges within the majority of the considered functional sub-networks, such as the mitochondrial electron transport chain and its sub-complexes, than GCNs not using CSE; thus demonstrating that the CSE-based GCNs are efficient at predicting those canonical functions and associated pathways, also referred to as the “core network”. Furthermore, we show that CSE, in conjunction with conventional correlation analyses can be used to fine-tune the prediction of the function for uncharacterised genes; while in combination with analyses based on non-centralised data can augment those conventional stress analyses with the innate connections underpinning the dynamic system examined.

Therefore, CSE appears as an alternative method to conventional batch correction approaches. The method is easy to implement into a pre-existing GCN analysis pipeline and can provide accentuated biological relevance to conventional GCNs by allowing users to delineate a “core” gene network.

Author Summary

Gene Co-expression networks (GCNs) are the product of a variety of mathematical models that identify causal relationships in gene expression dynamics, but are prone to the misdiagnoses of false-positives and -negatives, especially in the instance of large and highly complex datasets. In light of the burgeoning output of next generation sequencing projects performed on any species, under different developmental or clinical conditions, the statistical power and complexity of these networks will undoubtedly increase, while their biological relevance will be fiercely challenged. Here, we propose a novel approach to primarily generate a “core” GCN with augmented biological relevance. Our method, which involves data-centering steps and thus effectively removes all primary treatment / tissue /patient effects, is simple to employ and can be easily implemented into pre-existing GCN analysis pipelines. The gained biological relevance of such an approach was validated using a subcellular gene set encoding for the plant mitochondrial proteome, and by applying numerous steps to challenge its application.
Expression of normal levels of the Pumilio domain protein PUF3 is required for optimal growth of Trypanosoma brucei
Authors: Marucha Kevin Kamanyi , Clayton Christine
Published: June 2019

The Trypanosoma brucei pumilio domain protein PUF3 is a cytosolic mRNA-binding protein that suppresses expression when tethered to a reporter mRNA. An induced reduction of PUF3 in bloodstream forms caused a slight growth defect and slightly delayed differentiation to the procyclic form, but the cells lost both defects upon prolonged cultivation. Both PUF3 genes could also be deleted in bloodstream-form and procyclic-form trypanosomes, suggesting that in vitro, at least, these life-cycle stages do not require PUF3. Procyclic forms without PUF3 grew somewhat slower than wild-type, but were able to transform to bloodstream forms after induced expression of the bloodstream-form RNA-binding protein RBP10. In contrast, ectopic expression of C-terminally tagged PUF3 in procyclic forms impaired viability. There was little evidence for specific binding of PUF3 to bloodstream-form mRNAs and RNAi had no significant effect on the transcriptome. Moreover, mass spectrometry revealed no PUF3 binding partners that might explain its suppressive activity. Since PUF3 is conserved in all Kinetoplastids, we suggest that it might be required within the invertebrate host, or perhaps implicated in fine-tuning gene expression.
Serial protein crystallography in an electron microscope
Authors: Bücker Robert , Hogan-Lamarre Pascal , Mehrabi Pedram , Schulz Eike C. , Bultema Lindsey A. , Gevorkov Yaroslav , Brehm Wolfgang , Yefanov Oleksandr , Oberthür Dominik , Kassier Günther H. , Miller R. J. Dwayne
Published: June 2019

Serial X-ray crystallography at free-electron lasers allows to solve biomolecular structures from sub-micron-sized crystals. However, beam time at these facilities is scarce, and involved sample delivery techniques are required. On the other hand, rotation electron diffraction (MicroED) has shown great potential as an alternative means for protein nano-crystallography. Here, we present a method for serial electron diffraction of protein nanocrystals combining the benefits of both approaches. In a scanning transmission electron microscope, crystals randomly dispersed on a sample grid are automatically mapped, and a diffraction pattern at fixed orientation is recorded from each at a high acquisition rate. Dose fractionation ensures minimal radiation damage effects. We demonstrate the method by solving the structure of granulovirus occlusion bodies and lysozyme to resolutions of 1.55 Å and 1.80 Å, respectively. Our method promises to provide rapid structure determination for many classes of materials with minimal sample consumption, using readily available instrumentation.
The mitogenome of Norway spruce and a reappraisal of mitochondrial recombination in plants
Authors: Sullivan Alexis R. , Eldfjell Yrin , Schiffthaler Bastian , Delhomme Nicolas , Asp Torben , Hebelstrup Kim H. , Keech Olivier , Öberg Lisa , Møller Ian Max , Arvestad Lars , Street Nathaniel R. , Wang Xiao-Ru
Published: June 2019

Plant mitogenomes can be difficult to assemble because they are structurally dynamic and prone to intergenomic DNA transfers, leading to the unusual situation where an organelle genome is far outnumbered by its nuclear counterparts. As a result, comparative mitogenome studies are in their infancy and some key aspects of genome evolution are still known mainly from pre-genome, qualitative methods. To help address these limitations, we combined machine learning andin silicoenrichment of mitochondrial-like long reads to assemble the bacterial-sized mitogenome of Norway spruce (Pinaceae:Picea abies). We conducted comparative analyses of repeat abundance, intergenomic transfers, substitution and rearrangement rates, and estimated repeat-by-repeat homologous recombination rates. Prompted by our discovery of highly recombinogenic small repeats inP. abies, we assessed the genomic support for the prevailing hypothesis that intramolecular recombination is predominantly driven by repeat length, with larger repeats facilitating DNA exchange more readily. Overall, we found mixed support for this view: recombination dynamics were heterogeneous across vascular plants and highly active small repeats (ca. 200 bp) were present in about a third of studied mitogenomes. As in previous studies, we did not observe any robust relationships among commonly-studied genome attributes, but we identify variation in recombination rates as a underinvestigated source of plant mitogenome diversity.
Validating Paired-end Read Alignments in Sequence Graphs
Authors: Jain Chirag , Zhang Haowen , Dilthey Alexander , Aluru Srinivas
Published: June 2019

Graph based non-linear reference structures such as variation graphs and colored de Bruijn graphs enable incorporation of full genomic diversity within a population. However, transitioning from a simple string-based reference to graphs requires addressing many computational challenges, one of which concerns accurately mapping sequencing read sets to graphs. Paired-end Illumina sequencing is a commonly used sequencing platform in genomics, where the paired-end distance constraints allow disambiguation of repeats. Many recent works have explored provably good index-based and alignment-based strategies for mapping individual reads to graphs. However, validating distance constraints efficiently over graphs is not trivial, and existing sequence to graph mappers rely on heuristics. We introduce a mathematical formulation of the problem, and provide a new algorithm to solve it exactly. We take advantage of the high sparsity of reference graphs, and use sparse matrix-matrix multiplications (SpGEMM) to build an index which can be queried efficiently by a mapping algorithm for validating the distance constraints. Effectiveness of the algorithm is demonstrated using real reference graphs, including a human MHC variation graph, and a pan-genome de-Bruijn graph built using genomes of 20 B. anthracis strains. While the one-time indexing time can vary from a few minutes to a few hours using our algorithm, answering a million distance queries takes less than a second.

2012 ACM Subject Classification

Mathematics of computing → Paths and connectivity problems; Applied computing → Computational genomics
High conservation priority of range-edge plant populations not matched by habitat protection or research effort
Authors: Caissy P. , Klemet-N’Guessan S. , Jackiw R. , Eckert C.G. , Hargreaves A. L.
Published: June 2019

High-latitude countries tend to contain the polar range-edge of many species that are nationally rare but globally common. This can focus national conservation efforts toward range-edge populations, whose conservation needs and value are disputed. Using plants in Canada as a case study, we ask whether national species-conservation rankings prioritize range-edge populations, and whether conservation priority is matched by habitat protection and research effort. We found that >75% of federally-protected plants only occur in Canada peripherally, at the northernmost 20% or less of their total range, and that the most imperilled taxa had the smallest percentage of their range in Canada (endangered plants: median=1.0%). Occurring peripherally in Canada was associated with higher threat even after accounting for range area, potentially because range-edge taxa experienced 85% higher human population densities in their Canadian range than non-peripheral taxa. High conservation priority was not matched by habitat protection, as more imperilled and more peripheral taxa had smaller fractions of their Canadian range in protected areas. Finally, peer-reviewed research on plants at-risk in Canada was low. Only 42% of plants considered at-risk in Canada had been studied in Canada, and only 11% of species with large distributions outside Canada had been studied in the context of their wider geographic range—information that is critical to establishing their relative conservation value. Our results illustrate that plant conservation in Canada is fundamentally linked to conserving range-edge populations, yet edge populations themselves are understudied, a research gap we must close to improve evidence-based conservation.
A hydrogen dependent geochemical analogue of primordial carbon and energy metabolism
Authors: Preiner Martina , Igarashi Kensuke , Muchowska Kamila B. , Yu Mingquan , Varma Sreejith J. , Kleinermanns Karl , Nobu Masaru K. , Kamagata Yoichi , Tüysüz Harun , Moran Joseph , Martin William F.
Published: June 2019

Hydrogen gas, H2, is generated in alkaline hydrothermal vents from reactions of iron containing minerals with water during a geological process called serpentinization. It has been a source of electrons and energy since there was liquid water on the early Earth, and it fuelled early anaerobic ecosystems in the Earth’s crust1–3. H2is the electron donor for the most ancient route of biological CO2fixation, the acetyl-CoA (or Wood-Ljungdahl) pathway, which unlike any other autotrophic pathway simultaneously supplies three key requirements for life: reduced carbon in the form of acetyl groups, electrons in the form of reduced ferredoxin, and ion gradients for energy conservation in the form of ATP4,5. The pathway is linear, not cyclic, it releases energy rather than requiring energy input, its enzymes are replete with primordial metal cofactors6,7, it traces to the last universal common ancestor8and abiotic, geochemical organic syntheses resembling segments of the pathway occur in hydrothermal vents today9,10. Laboratory simulations of the acetyl-CoA pathway’s reactions include the nonenzymatic synthesis of thioesters from CO and methylsulfide11, the synthesis of acetate12and pyruvate13from CO2using native iron or external electrochemical potentials14as the electron source. However, a full abiotic analogue of the acetyl-CoA pathway from H2and CO2as it occurs in life has not been reported to date. Here we show that three hydrothermal minerals — awaruite (Ni3Fe), magnetite (Fe3O4) and greigite (Fe3S4) — catalyse the fixation of CO2with H2at 100 °C under alkaline aqueous conditions. The product spectrum includes formate (100 mM), acetate (100 μM), pyruvate (10 μM), methanol (100 μM), and methane. With these simple catalysts, the overall exergonic reaction of the acetyl-CoA pathway is facile, shedding light on both the geochemical origin of microbial metabolism and on the nature of abiotic formate and methane synthesis in modern hydrothermal vents.
Calcium buffers and L-type calcium channels as modulators of cardiac subcellular alternans
Authors: Lai Yi Ming , Coombes Stephen , Thul Rüdiger
Published: June 2019

In cardiac myocytes, calcium cycling links the dynamics of the membrane potential to the activation of the contractile filaments. Perturbations of the calcium signalling toolkit have been demonstrated to disrupt this connection and lead to numerous pathologies including cardiac alternans. This rhythm disturbance is characterised by alternations in the membrane potential and the intracellular calcium concentration, which in turn can lead to sudden cardiac death. In the present computational study, we make further inroads into understanding this severe condition by investigating the impact of calcium buffers and L-type calcium channels on the formation of subcellular calcium alternans when calcium diffusion in the sarcoplasmic reticulum is strong. Through numerical simulations of a two dimensional network of calcium release units, we show that increasing calcium entry is proarrhythmogenic and that this is modulated by the calcium-dependent inactivation of the L-type calcium channel. We also find that while calcium buffers can exert a stabilising force and abolish subcellular Ca2+alternans, they can significantly shape the spatial patterning of subcellular calcium alternans. Taken together, our results demonstrate that subcellular calcium alternans can emerge via various routes and that calcium diffusion in the sarcoplasmic reticulum critically determines their spatial patterns.
Cerebral dopamine neurotrophic factor (CDNF) reduces myocardial ischemia/reperfusion injuries by the activation of PI3K-AKT via KDEL-receptor binding
Authors: Maciel Leonardo , de Oliveira Dahienne Ferreira , Mesquita Fernanda , da Silva Souza Hercules Antônio , Oliveira Leandro , Palhano Fernando L. , de Carvalho Antônio Carlos Campos , Matheus Nascimento José Hamilton , Foguel Debora
Published: June 2019

CDNF (Cerebral Dopamine Neurotrophic Factor) belongs to a new family of NF, which presents several beneficial activities beyond the brain. Little is known about CDNF in the cardiac context. Herein we investigate CDNF effects in cardiomyocytes under endoplasmic reticulum (ER)-stress and in whole rat hearts subjected to ischemia/reperfusion (I/R). We showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated hearts subjected to I/R. CDNF protects human and mouse cardiomyocytes against ER-stress by restoring the calcium transient, and isolated heart against I/R injuries by reducing the infarct area and avoiding mitochondrial impairment. This protection is abrogated by wortmannin (PI3K-inhibitor) or by heptapeptides containing KDEL sequence, which block KDEL-receptor. These data suggest that CDNF induces cardioprotection via KDEL receptor binding and PI3K/AKT activation. This is the first study to propose CDNF as a cardiomyokine and to unravel the receptor and signaling pathway for this interesting family of NF.
Sequential Operations Revealed by Serendipitous Feature Selectivity in Frontal Eye Field
Authors: Lowe Kaleb A. , Schall Jeffrey D.
Published: June 2019

Neurons in macaque frontal eye field contribute to spatial but typically not feature selection during visual search. Using an innovative visual search task, we report a serendipitous discovery that some frontal eye field neurons can develop rapid selectivity for stimulus orientation that is used to guide gaze during a visual search task with pro-saccade and anti-saccade responses. This feature selectivity occurs simultaneously at multiple locations for all objects sharing that feature and coincides with when neurons select the singleton of a search array. This feature selectivity also reveals the distinct, subsequent operation of selecting the endpoint of the saccade in pro-saccade as well as anti-saccade trials. These results demonstrate that target selection preceding saccade preparation is composed of multiple operations. We conjecture that singleton selection indexes the allocation of attention, which can be divided, to conspicuous items. Consequently, endpoint selection indexes the focused allocation of attention to the endpoint of the saccade. These results demonstrate that saccade target selection is not a unitary process.

SIGNIFICANCE STATEMENT

Frontal eye field is well known to contribute to spatial selection for attention and eye movements. We discovered that some frontal eye field neurons can acquire selectivity for stimulus orientation when it guides visual search. The chronometry of neurons with and without feature selectivity reveal distinct operations accomplishing visual search.
Quantifying within-host diversity of H5N1 influenza viruses in humans and poultry in Cambodia
Authors: Moncla Louise H. , Bedford Trevor , Dussart Philippe , Horm Srey Viseth , Rith Sareth , Buchy Philippe , Karlsson Erik A , Li Lifeng , Liu Yongmei , Zhu Huachen , Guan Yi , Friedrich Thomas C. , Horwood Paul F.
Published: June 2019

Avian influenza viruses (AIVs) periodically cross species barriers and infect humans. The likelihood that an AIV will evolve mammalian transmissibility depends on acquiring and selecting mutations during spillover, but data from natural infection is limited. We analyze deep sequencing data from infected humans and domestic ducks in Cambodia to examine how H5N1 viruses evolve during spillover. Overall, viral populations in both species are predominated by low-frequency (<10%) variation shaped by purifying selection and genetic drift, and half of the variants detected within-host are never detected on the H5N1 virus phylogeny. However, we do detect a subset of mutations linked to human receptor binding and replication (PB2 E627K, HA A150V, and HA Q238L) that arose in multiple, independent humans. PB2 E627K and HA A150V were also enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adaptive. Our data show that H5N1 viruses generate putative human-adapting mutations during natural spillover infection, many of which are detected at >5% frequency within-host. However, short infection times, genetic drift, and purifying selection likely restrict their ability to evolve extensively during a single infection. Applying evolutionary methods to sequence data, we reveal a detailed view of H5N1 virus adaptive potential, and develop a foundation for studying host-adaptation in other zoonotic viruses.

Author summary

H5N1 avian influenza viruses can cross species barriers and cause severe disease in humans. H5N1 viruses currently cannot replicate and transmit efficiently among humans, but animal infection studies and modeling experiments have suggested that human adaptation may require only a few mutations. However, data from natural spillover infection has been limited, posing a challenge for risk assessment. Here, we analyze a unique dataset of deep sequence data from H5N1 virus-infected humans and domestic ducks in Cambodia. We find that well-known markers of human receptor binding and replication arise in multiple, independent humans. We also find that 3 mutations detected within-host are enriched along phylogenetic branches leading to human infections, suggesting that they are likely human-adapting. However, we also show that within-host evolution in both humans and ducks are shaped heavily by purifying selection and genetic drift, and that a large fraction of within-host variation is never detected on the H5N1 phylogeny. Taken together, our data show that H5N1 viruses do generate human-adapting mutations during natural infection. However, short infection times, purifying selection, and genetic drift may severely limit how much H5N1 viruses can evolve during the course of a single infection.
An individual interneuron participates in many kinds of inhibition and innervates much of the mouse visual thalamus
Authors: Morgan Josh L. , Lichtman Jeff W.
Published: June 2019

One way to assess a neuron’s function is to describe all its inputs and outputs. With this goal in mind, we used serial section electron microscopy to map 899 synaptic inputs and 623 outputs in one inhibitory interneuron in a large volume of the mouse visual thalamus. This neuron innervated 256 thalamocortical cells spread across functionally distinct subregions of the visual thalamus. All but one of its neurites were bifunctional, innervating thalamocortical and local interneurons while also receiving synapses from the retina. We observed a wide variety of local synaptic motifs. While this neuron innervated many cells weakly, with single en passant synapses, it also deployed specialized branches that climbed along other dendrites to form strong multi-synaptic connections with a subset of partners. This neuron’s diverse range of synaptic relationships allows it to participate in a mix of global and local processing but defies assigning it a single circuit function.
Corticotrophin-Releasing Hormone neurons of Barrington’s nucleus: Probabilistic, spinally-gated control of bladder pressure and micturition
Authors: Ito H. , Sales A.C. , Fry C.H. , Kanai A.J. , Drake M.J. , Pickering A.E.
Published: June 2019

Micturition, the co-ordinated process of expulsion of urine from the bladder, requires precise control of bladder and urethral sphincter via parasympathetic, sympathetic and somatic motoneurons. In adult mammals this involves a spinobulbospinal control circuit incorporating Barrington’s nucleus in the pons (Barr). The largest Barr cell population is comprised of pontospinal glutamatergic neurons that express corticotrophin-releasing hormone. There is evidence that BarrCRH neurons can generate bladder contractions but it is unknown whether they act as a simple switch or a high-fidelity pre-parasympathetic motor drive and whether their activation can actually trigger voids. Combined opto- and chemo-genetic manipulations along with recordings in mice shows that BarrCRH neurons provide a probabilistic drive that generates co-ordinated voids or non-voiding contractions depending on the phase of the micturition cycle. These findings inform a new inferential model of micturition and emphasise the importance of the state of the spinal gating circuit in the generation of voiding.
A Consensus Framework Unifies Multi-Drug Synergy Metrics
Authors: Wooten David J. , Meyer Christian T. , Quaranta Vito , Lopez Carlos
Published: June 2019

Drug combination discovery depends on reliable synergy metrics; however, no consensus exists on the appropriate synergy model to prioritize lead candidates. The fragmented state of the field confounds analysis, reproducibility, and clinical translation of combinations. Here we present a mass-action based formalism to accurately measure the synergy of drug combinations. In this work, we clarify the relationship between the dominant drug synergy principles and show how biases emerge due to intrinsic assumptions which hinder their broad applicability. We further present a mapping of commonly used frameworks onto a unified synergy landscape, which identifies fundamental issues impacting the interpretation of synergy in discovery efforts. Specifically, we infer how traditional metrics mask consequential synergistic interactions, and contain biases dependent on the Hill-slope and maximal effect of single-drugs. We show how these biases systematically impact the classification of synergy in large combination screens misleading discovery efforts. The proposed approach has potential to accelerate the translatability and reproducibility of drug-synergy studies, by bridging the gap between the curative potential of drug mixtures and the complexity in their study.
Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo
Authors: Qiu Rongde , Zhang Jun , Xiang Xin
Published: June 2019

Deficiency of the LIS1 protein causes lissencephaly, a brain developmental disorder. Although LIS1 binds the microtubule motor cytoplasmic dynein and has been linked to dynein function in many experimental systems, its mechanism of action remains unclear. Here we revealed the function of LIS1 in cargo-adapter-mediated dynein activation in the model organism Aspergillus nidulans. Specifically, we found that overexpressed cargo adapter HookA (Hook in A. nidulans) missing its cargo-binding domain (ΔC-HookA) causes dynein and its regulator dynactin to relocate from the microtubule plus ends to the minus ends, and this dramatic relocation requires LIS1 and its binding protein NudE. Astonishingly, the requirement for LIS1 or NudE can be bypassed to a significant extent by specific mutations that open the auto-inhibited “phi-dynein” in which the motor domains of the dynein dimer are held close together. Our results suggest a novel mechanism of LIS1 action: it promotes the switch of dynein from the auto-inhibited state to an open state to facilitate dynein activation.

This study reveals the role of Lissencephaly 1 (LIS1) in cargo-adapter-mediated dynein activation. Furthermore, it discovers a novel mechanism of LIS1 action involving a switch of dynein from an auto-inhibited state to an active state.
Exploring the Relationship between Geomagnetic Activity and Human Heart Rate Variability
Authors: Mattoni Matthew , Ahn Sangtae , Fröhlich Carla , Fröhlich Flavio
Published: June 2019

Both geomagnetic and solar activity fluctuate over time and have been proposed to affect human physiology. One physiological measurement that has been previously investigated in this context, heart rate variability (HRV), has substantial health implications regarding the ability to adapt to stressors and has been shown to be altered in many cardiovascular and neurological disorders. Intriguingly, previous work found significant, strong correlations between HRV and geomagnetic/solar activity. In an attempt to replicate these findings, we simultaneously measured HRV from 20 healthy participants during a thirty-day period. In agreement with previous work, we found several significant correlations between HRV and geophysical time-series. However, after correction for autocorrelation, which is inherent in time-series, the only significant results were an increase in very low frequency during higher local geomagnetic activity and a geomagnetic anticipatory decrease in heart rate a day before higher global geomagnetic activity. Both correlations were very low. The loss of most significant effects after this correction suggests that previous findings may be a result of autocorrelation. A further note of caution is required since our and the previous studies in the field do not correct for multiple comparisons given the exploratory analysis strategy. We thus conclude that the effects of geomagnetic and solar activity are (if present) most likely of very small effect size and question the validity of the previous studies given the methodological concerns we have uncovered in our work.
Tensor decomposition-Based Unsupervised Feature Extraction Applied to Single-Cell Gene Expression Analysis
Authors: Taguchi Y-h. , Turki Turki
Published: June 2019

Although single cell RNA sequencing (scRNA-seq) technology is newly invented and promising one, because of lack of enough information that labels individual cells, it is hard to interpret the obtained gene expression of each cell. Because of this insufficient information available, unsupervised clustering, e.g., t-Distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection, is usually employed to obtain low dimensional embedding that can help to understand cell-cell relationship. One possible drawback of this strategy is that the outcome is highly dependent upon genes selected for the usage of clustering. In order to fulfill this requirement, there are many methods that performed unsupervised gene selection. In this study, a tensor decomposition (TD) based unsupervised feature extraction (FE) was applied to the integration of two scRNA-seq expression profiles that measure human and mouse midbrain development. TD based unsupervised FE could not only select coincident genes between human and mouse, but also biologically reliable genes. Coincidence between two species as well as biological reliability of selected genes is increased compared with principal component analysis (PCA) based FE applied to the same data set in the previous study. Since PCA based unsupervised FE outperformed other three popular unsupervised gene selection methods, highly variable genes, bimodal genes and dpFeature, TD based unsupervised FE can do so as well. In addition to this, ten transcription factors (TFs) that might regulate selected genes and might contribute to midbrain development are identified. These ten TFs, BHLHE40, EGR1, GABPA, IRF3, PPARG, REST, RFX5, STAT3, TCF7L2, and ZBTB33, were previously reported to be related to brain functions and diseases. TD based unsupervised FE is a promising method to integrate two scRNA-seq profiles effectively.
Increased nuclear factor I/B expression in prostate cancer correlates with AR expression
Authors: Nanda Jagpreet S. , Awadallah Wisam N. , Kohrt Sarah E. , Popovics Petra , Cates Justin M. M. , Mirosevich Janni , Clark Peter E. , Giannico Giovanna A. , Grabowska Magdalena M.
Published: June 2019

Background

Most prostate cancers express androgen receptor (AR), and our previous studies have focused on identifying transcription factors that modify AR function. We have shown that nuclear factor I/B (NFIB) regulates AR activity in androgen-dependent prostate cancer cellsin vitro. However, the status of NFIB in prostate cancer was unknown.

Methods

We immunostained a tissue microarray including normal, hyperplastic, prostatic intraepithelial neoplasia, primary prostatic adenocarcinoma, and castration-resistant prostate cancer tissue samples for NFIB, AR, and synaptophysin, a marker of neuroendocrine differentiation. We interrogated publically available data sets in cBioPortal to correlateNFIBexpression and AR and neuroendocrine prostate cancer (NEPCa) activity scores. We analyzed prostate cancer cell lines for NFIB expression via Western blotting and used nuclear and cytoplasmic fractionation to assess where NFIB is localized. We performed coimmunoprecipitation studies to determine if NFIB and AR interact.

Results

NFIB increased in the nucleus and cytoplasm of prostate cancer samples versus matched normal controls, independent of Gleason score. Similarly, cytoplasmic AR and synaptophysin increased in primary prostate cancer. We observed strong NFIB staining in primary small cell prostate cancer. The ratio of cytoplasmic-to-nuclear NFIB staining was predictive of earlier biochemical recurrence in prostate cancer, once adjusted for tumor margin status. Cytoplasmic AR was an independent predictor of biochemical recurrence. There was no statistically significant difference between NFIB and synaptophysin expression in primary and castration-resistant prostate cancer, but cytoplasmic AR expression was increased in castrationresistant samples. In primary prostate cancer, nuclear NFIB expression correlated with cytoplasmic NFIB and nuclear AR, while cytoplasmic NFIB correlated with synaptophysin, and nuclear and cytoplasmic AR. In castration-resistant prostate cancer samples,NFIBexpression correlated positively with an AR activity score, and negatively with the NEPCa score. In prostate cancer cell lines, NFIB exists in several isoforms. We observed NFIB predominantly in the nuclear fraction of prostate cancer cells with increased cytoplasmic expression seen in castration-resistant cell lines. We observed an interaction between AR and NFIB through coimmunoprecipitation experiments.

Conclusion

We have described the expression pattern of NFIB in primary and castrationresistant prostate cancer and its positive correlation with AR. We have also demonstrated AR interacts with NFIB.
ShadowCaster: compositional methods under the shadow of phylogenetic models for the detection of horizontal gene transfer events in prokaryotes
Authors: Sánchez-Soto Daniela , Agüero-Chapin Guillermin , Armijos-Jaramillo Vinicio , Perez-Castillo Yunierkis , Tejera Eduardo , Antunes Agostinho , Sánchez-Rodríguez Aminael
Published: June 2019

Horizontal gene transfer (HGT) plays an important role in the evolution of many organisms, especially in prokaryotes where commonly occurs. Microbial communities can improve survival due to the evolutionary innovations induced by HGT events. Thus, several computational approaches have arisen to identify such events in recipient genomes. However, this has been proven to be a complex task due to the generation of a great number of false positives and the prediction disagreement among the existing methods. Phylogenetic reconstruction methods turned out to be the most reliable but they are not extensible to all genes/species and are computationally demanding when dealing with large datasets. On the other hand, the so-called surrogate methods that use heuristic solutions either based on nucleotide composition patterns or phyletic distribution of BLAST hits can be applied easily to genomic scale, however, they fail in identifying common HGT events. Here, we present ShadowCaster, a hybrid approach that sequentially combines compositional features under the shadow of phylogenetic models independent of tree reconstruction to improve the detection of HTG events in prokaryotes. ShadowCaster predicted successfully close and distant HTG events in both artificial and bacterial genomes. It detected HGT related to heavy metal resistance in the genome of Rhodanobacter denitrificans with higher accuracy than the most popular state-of-the-art computational approaches. ShadowCaster’s predictions showed the highest agreement among those obtained with other assayed methods. ShadowCaster is released as an open-source software under the GPLv3 license. Source code is hosted at https://github.com/dani2s/ShadowCaster and documentation at https://shadowcaster.readthedocs.io/en/latest/.
A non-canonical unfolded protein response pathway and mitochondrial dynamics control the number of ER-mitochondria contact sites
Authors: Kojima Rieko , Kakimoto Yuriko , Shinmyo Manatsu , Kurokawa Kazuo , Nakano Akihiko , Endo Toshiya , Tamura Yasushi
Published: June 2019

Mitochondria maintain their morphology and functions through the optimized balance between the mitochondrial fusion and division. Here we report a novel role of mitochondrial dynamics in controlling the number of ER-mitochondria encounter structure (ERMES) clusters in a yeast cell. Loss of mitochondrial fusion or division caused the increased or decreased number, respectively, of ERMES foci observed in cells. ERMES complexes, therefore, appear to cluster with each other and mitochondrial division may inhibit undesired ERMES hyper-clustering. Furthermore, our microscopic analyses suggest that ER stress induces dissociation of ERMES clusters, increasing the number of ERMES foci even in the absence of Ire1 and Hac1, which are essential factors for the UPR response. Interestingly, we found that ER stress leads to expansion of both the ER and mitochondrial membranes in an ERMES function-dependent manner. These findings imply that a cell is equipped with two independent regulatory mechanisms controlling the number of ER-mitochondria contact sites to meet the cellular as well as environmental demands.
Synthesis, crystal structure and biological properties of Cd and Zn coordination polymers based on a flexible tripodal ligand
Authors: Wang Xia , Ling Ning , Li Hanbing , Xiao Xiaohe , Zhang Yawen
Published: June 2019

Two new coordination polymers, namely poly[[hexathiocyanatotetrakis{μ3-2,4,6-trimethyl-1,3,5-tris[(triazol-1-yl)methyl]benzene}tricadmium(II)] 3.5-hydrate], {[Cd3(SCN)6(C18H21N9)4]·3.5H2O}
n
(1), and poly[[hexathiocyanatotetrakis{μ3-2,4,6-trimethyl-1,3,5-tris[(triazol-1-yl)methyl]benzene}trizinc(II)] 3.5-hydrate], {[Zn3(SCN)6(C18H21N9)4]·3.5H2O}
n
(2), have been synthesized under hydrothermal conditions and characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction analysis. From the X-ray analysis, it is noteworthy that polymers 1 and 2 are isostructural, with their three-dimensional structures composed of three kinds of four-connection metal ions and two kinds of three-connection 2,4,6-trimethyl-1,3,5-tris[(triazol-1-yl)methyl]benzene (TTTMB) ligand nodes. Each metal ion is six-coordinated in a slightly distorted octahedral geometry. The antioxidant activity against DPPH (2,2-diphenyl-1-picrylhydrazyl) and the antidiabetic activity against α-amylase of the synthesized compounds were evaluated in vitro. The results of the DPPH free-radical scavenging assay showed that polymers 1 and 2 exhibited strong antioxidant effects, with IC50 values of 3.81 and 2.56 mg ml−1, respectively. The IC50 value in the antidiabetic studies of polymer 1 was 3.94 mg ml−1, while polymer 2 exhibited no antidiabetic activity. Polymers 1 and 2 revealed different inhibitory activities on DPPH and α-amylase, which indicated that the metal ions play important roles in the biological activity of coordination polymers. In addition, the solid-state photoluminescence properties and thermal stability of 1 and 2 have been investigated.
An MBD based framework for relative position accuracy measurement in digital assembly of large-scale component
Authors: Duan Guijiang , Shen Zhibang , Liu Rui
Published: June 2019

Purpose

This paper aims to promote the integration of the relative position accuracy (RPA) measurement and evaluation in digital assembly process by adopting the model-based method. An integrated framework for RPA measurement is proposed based on a model-based definition (MBD) data set. The study also aims to promote the efficiency of inspection planning of RPA measurement by improving the reusability and configurability of the inspection planning.

Design/methodology/approach

The works have been carried out on three layers. In the data layer, an extended MBD data set is constructed to describe the objects and data for defining RPA measurement items; In definition layer, a model based and hierarchical structure for RPA item definition is constructed to support quick definition for RPA measurement items. In function layer, a toolset consisting three modules is constructed in a sequence from measurement planning to RPA value solving to visualized displaying again. Based on this framework, a prototype system is developed.

Findings

The paper provides an identified practice of model-based inspection. It suggests that MBD is valuable in promoting both the integration and efficiency of digital inspection.

Research limitations/implications

The templates and constructed geometry objects given in this paper are still limited in a scenario of aircraft assembly. The integrity and universality of them still need follow-up works.

Practical implications

The paper includes implications for the model based digital inspection, the digital assembly and the extended application of MBD.

Originality/value

This paper expands the application of MBD in inspection and fulfils the need to promote the integration and efficiency of digital inspection in large-scale component assembly.