bluuebunny/crossref_metadata_2025 huggingface dataset:
The hierarchical structure of galactic haloes: classification and characterization with halo-optics
Authors: Oliver William H , Elahi Pascal J , Lewis Geraint F , Power Chris
Published: December 2020

We build upon Ordering Points To Identify the Clustering Structure (optics ), a hierarchical clustering algorithm well known to be a robust data miner, in order to produce halo-optics , an algorithm designed for the automatic detection and extraction of all meaningful clusters between any two arbitrary sizes. We then apply halo-optics to the 3D spatial positions of halo particles within four separate synthetic Milky Way-type galaxies, classifying the stellar and dark matter structural hierarchies. Through visualization of the halo-optics output, we compare its structure identification to the state-of-the-art galaxy/(sub)halo finder VELOCIraptor , finding excellent agreement even though halo-optics does not consider kinematic information in this current implementation. We conclude that halo-optics is a robust hierarchical halo finder, although its determination of lower spatial-density features such as the tails of streams could be improved with the inclusion of extra localized information such as particle kinematics and stellar metallicity into its distance metric.
Correlations between supermassive black holes and hot gas atmospheres in IllustrisTNG and X-ray observations
Authors: Truong Nhut , Pillepich Annalisa , Werner Norbert
Published: December 2020

Recent X-ray observations have revealed remarkable correlations between the masses of central supermassive black holes (SMBHs) and the X-ray properties of the hot atmospheres permeating their host galaxies, thereby indicating the crucial role of the atmospheric gas in tracing SMBH growth in the high-mass regime. We examine this topic theoretically using the IllustrisTNG cosmological simulations and provide insights to the nature of this SMBH – gaseous halo connection. By carrying out a mock X-ray analysis for a mass-selected sample of TNG100 simulated galaxies at $z$ = 0, we inspect the relationship between the masses of SMBHs and the hot gas temperatures and luminosities at various spatial and halo scales – from galactic (∼Re) to group/cluster scales (∼R500c). We find strong SMBH-X-ray correlations mostly in quenched galaxies and find that the correlations become stronger and tighter at larger radii. Critically, the X-ray temperature (kBTX) at large radii (r ≳ 5Re) traces the SMBH mass with a remarkably small scatter (∼0.2 dex). The relations emerging from IllustrisTNG are broadly consistent with those obtained from recent X-ray observations. Overall, our analysis suggests that, within the framework of IllustrisTNG, the present-time MBH–kBTX correlations at the high-mass end (MBH ≳ 108M⊙) are fundamentally a reflection of the SMBH mass–halo mass relation, which at such high masses is set by the hierarchical assembly of structures. The exact form, locus, and scatter of those scaling relations are, however, sensitive to feedback processes such as those driven by star formation and SMBH activity.
A physico-chemical model to study the ion density distribution in the inner coma of comet C/2016 R2 (Pan-STARRS)
Authors: Raghuram Susarla , Bhardwaj Anil , Hutsemékers Damien , Opitom Cyrielle , Manfroid Jean , Jehin Emmanuel
Published: December 2020

The recent observations show that comet C/2016 R2 (Pan-Starrs) has a unique and peculiar composition when compared with several other comets observed at 2.8 au heliocentric distance. Assuming solar resonance fluorescence is the only excitation source, the observed ionic emission intensity ratios are used to constrain the corresponding neutral abundances in this comet. We developed a physico-chemical model to study the ion density distribution in the inner coma of this comet by accounting for photon and electron impact ionization of neutrals, charge exchange and proton transfer reactions between ions and neutrals, and electron–ion thermal recombination reactions. Our calculations show that CO2+ and CO+ are the major ions in the inner coma, and close to the surface of nucleus CH3OH+, CH3OH2+, and O2+ are also important ions. By considering various excitation sources, we also studied the emission mechanisms of different excited states of CO+, CO2+, N2+, and H2O+. We found that the photon and electron impact ionization and excitation of corresponding neutrals significantly contribute to the observed ionic emissions for radial distances smaller than 300 km and at larger distances, solar resonance fluorescence is the major excitation source. Our modelled ion emission intensity ratios are consistent with the ground-based observations. Based on the modelled emission processes, we suggest that the observed ion emission intensity ratios can be used to derive the neutral composition in the cometary coma only when the ion densities are significantly controlled by photon and photoelectron impact ionization of neutrals rather than by the ion–neutral chemistry.
Genetic Diversity and Distribution of Korean Isolates of Burkholderia glumae
Authors: Choi Okhee , Kim Seunghoe , Kang Byeongsam , Lee Yeyeong , Bae Juyoung , Kim Jinwoo
Published: December 2020

Burkholderia glumae causes panicle blight of rice (grain rot in Japan and Korea), and the severity of damage is increasing worldwide. During 2017 and 2018, 137 isolates of B. glumae were isolated from symptomatic grain rot of rice cultivated in paddy fields throughout South Korea. Genetic diversity of the isolates was determined using transposase-based PCR (Tnp-PCR) genomic fingerprinting. All 138 isolates, including the B. glumae BGR1 strain, produced toxoflavin in various amounts, and 17 isolates produced an unidentified purple or orange pigment on Luria-Bertani medium and casamino acid-peptone-glucose medium, respectively, at 28°C. Transposase-based PCR genomic fingerprinting was performed using a novel primer designed based on transposase (tnp) gene sequences located at the ends of the toxoflavin efflux transporter operon; this method provided reliable and reproducible results. Through Tnp-PCR genomic fingerprinting, the genetic groups of Korean B. glumae isolates were divided into 11 clusters and three divisions. The Korean B. glumae isolates were mainly grouped in division I (73%). Interestingly, most of the pigment-producing isolates were grouped in divisions II and III; of these, 10 were grouped in cluster VIII, which comprised 67% of this cluster. Results of a phylogenetic analysis based on tofI and hrpB gene sequences were consistent with classification by Tnp-PCR genomic fingerprinting. The BGR1 strain did not belong to any of the clusters, indicating that this strain does not exhibit the typical genetic representation of B. glumae. B. glumae isolates showed diversity in the use of carbon and nitrogen sources, but no correlation with genetic classification by PCR fingerprinting was found. This is the first study to analyze the geographical distribution and genetic diversity of Korean B. glumae isolates.
A Scoping Review of Implementation Science in Adult Critical Care Settings
Authors: McNett Molly , O’Mathúna Dónal , Tucker Sharon , Roberts Haley , Mion Lorraine C. , Balas Michele C.
Published: December 2020

Objectives:

The purpose of this scoping review is to provide a synthesis of the available literature on implementation science in critical care settings. Specifically, we aimed to identify the evidence-based practices selected for implementation, the frequency and type of implementation strategies used to foster change, and the process and clinical outcomes associated with implementation.

Data Sources:

A librarian-assisted search was performed using three electronic databases.

Study Selection:

Articles that reported outcomes aimed at disseminating, implementing, or sustaining an evidence-based intervention or practice, used established implementation strategies, and were conducted in a critical care unit were included.

Data Extraction:

Two reviewers independently screened titles, abstracts, and full text of articles to determine eligibility. Data extraction was performed using customized fields established a priori within a systematic review software system.

Data Synthesis:

Of 1,707 citations, 82 met eligibility criteria. Studies included prospective research investigations, quality improvement projects, and implementation science trials. The most common practices investigated were use of a ventilator-associated pneumonia bundle, nutritional support protocols, and the Awakening and Breathing Coordination, Delirium Monitoring/Management, and Early Exercise/Mobility bundle. A variety of implementation strategies were used to facilitate evidence adoption, most commonly educational meetings, auditing and feedback, developing tools, and use of local opinion leaders. The majority of studies (76/82, 93%) reported using more than one implementation strategy. Few studies specifically used implementation science designs and frameworks to systematically evaluate both implementation and clinical outcomes.

Conclusions:

The field of critical care has experienced slow but steady gains in the number of investigations specifically guided by implementation science. However, given the exponential growth of evidence-based practices and guidelines in this same period, much work remains to critically evaluate the most effective mechanisms to integrate and sustain these practices across diverse critical care settings and teams.
Multiscale and integrative single-cell Hi-C analysis with Higashi
Authors: Zhang Ruochi , Zhou Tianming , Ma Jian
Published: December 2020

The advent of single-cell Hi-C (scHi-C) technologies offers an unprecedented opportunity to unveil cell-to-cell variability of 3D genome organization. However, the development of computational methods that can effectively enhance scHi-C data quality and extract 3D genome features in single cells remains a major challenge. Here, we report Higashi, a new algorithm that achieves state-of-the-art analysis of scHi-C data based on hypergraph representation learning. Extensive evaluations demonstrate that Higashi significantly outperforms existing methods for embedding and imputation of scHi-C data. Higashi is uniquely able to identify multiscale 3D genome features (such as compartmentalization and TAD-like domain boundaries) in single cells, allowing markedly refined delineation of cell-to-cell variability of 3D genome features. By applying to a scHi-C dataset from human prefrontal cortex, Higashi reveals complex cell types as well as new connections between 3D genome features and cell type-specific gene regulation. Higashi provides an end-to-end solution to scHi-C data analysis and is applicable to studying single-cell 3D genomes in a wide range of biological contexts.
How inhibitory neurons increase information transmission under threshold modulation
Authors: Hsu Wei-Mien M. , Kastner David B. , Baccus Stephen A. , Sharpee Tatyana O.
Published: December 2020

Modulation of neuronal thresholds is ubiquitous in the brain. Phenomena such as figure-ground segmentation, motion detection, stimulus anticipation and shifts in attention all involve changes in a neuron’s threshold based on signals from larger scales than its primary inputs. However, this modulation reduces the accuracy with which neurons can represent their primary inputs, creating a mystery as to why threshold modulation is so widespread in the brain. We find that modulation is less detrimental than other forms of neuronal variability and that its negative effects can be nearly completely eliminated if modulation is applied selectively to sparsely responding neurons in a circuit by inhibitory neurons. We verify these predictions in the retina where we find that inhibitory amacrine cells selectively deliver modulation signals to sparsely responding ganglion cell types. Our findings elucidate the central role that inhibitory neurons play in maximizing information transmission under modulation.
STUB1 is an intracellular checkpoint for interferon gamma sensing
Authors: Ng Simon , Lim Shuhui , Sim Adrian Chong Nyi , Mangadu Ruban , Lau Ally , Zhang Chunsheng , Martinez Sarah Bollinger , Chandramohan Arun , Lim U-Ming , Ho Samantha Shu Wen , Chang Shih Chieh , Gopal Pooja , Hong Lewis Z. , Schwaid Adam , Fernandis Aaron Zefrin , Loboda Andrey , Li Cai , Phan Uyen , Henry Brian , Partridge Anthony W.
Published: December 2020

Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance.

Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNγ) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNγ response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition.

Furthermore, blockade of STUB1 protein function recapitulated theSTUB1-null phenotypes. Despite these encouragingin vitrodata and positive implications from clinical datasets, we did not observein vivobenefits of inactivatingStub1in mouse syngeneic tumour models – with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNγ sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.
Towards robust, unobtrusive sensing of respiration using ultra-wideband impulse radar for the care of people living with dementia
Authors: Chen Ziwei , Bannon Alan , Rapeaux Adrien , Constandinou Timothy G.
Published: December 2020

The unobtrusive monitoring of vital signals and behaviour can be used to gather intelligence to support the care of people living with dementia. This can provide insights into the persons wellbeing and the neurogenerative process, as well as enable them to continue to live safely at home, thereby improving their quality of life. Within this context, this study investigated the deployability of non-contact respiration rate (RR) measurement based on an Ultra-Wideband (UWB) radar System-on-Chip (SoC). An algorithm was developed to simultaneously and continuously extract the respiration signal, together with the confidence level of the respiration signal and the target position, without needing any prior calibration. The radar-measured RR results were compared to the RR results obtained from a ground truth measure based on the breathing sound, and the error rates were within 8% with a mean value of 2.4%. The target localisation results match to the radar-to-chest distances with a mean error rate of 5.4%. The tested measurement range was up to 5m. The results suggest that the algorithm could perform sufficiently well in non-contact stationary respiration rate detection.
Functional single-cell profiling identifies that exosomes are associated with increased immune cell infiltration in non-metastatic breast cancer
Authors: Fathi Mohsen , Joseph Robiya , Adolacion Jay R T. , Martinez-Paniagua Melisa , An Xingyue , Gabrusiewicz Konrad , Mani Sendurai A. , Varadarajan Navin
Published: December 2020

Exosomes mediate intercellular communication in health and disease. Conventional assays are limited in profiling exosomes secreted from large populations of cells and are unsuitable for studying the functional consequences of individual cells exhibiting varying propensity for exosome secretion. In cancer, since exosomes can support the development of the pre-metastatic niche, cells with varying abilities to secrete exosomes can directly impact tumorigenesis. Here, we developed a high throughput single-cell technique that enabled the mapping of exosome secretion dynamics. By utilizing clinically relevant models of breast cancer, we established that non-metastatic cancer cells secrete more exosomes than metastatic cancer cells. Single-cell RNA-sequencing confirmed that pathways related to exosome secretion were enriched in the non-metastatic cells compared to the metastatic cells. We established isogenic clonal cell lines from non-metastatic cells with differing propensities for exosome secretion and showed that exosome secretion is an inheritable property preserved during cell division. Combined in vitro and in vivo studies with these cell lines suggested that exosome secretion can impede tumor formation. In human non-metastatic breast tumors, tumors with higher secretion of exosomes have a better prognosis, higher immune cytolytic activity, and enrichment of pro-inflammatory macrophages compared to tumors with lower secretion of exosomes. Our single-cell methodology can become an essential tool that enables the direct integration of exosome secretion with multiple cellular functions.
Predicting recombination frequency from map distance
Authors: Kivikoski Mikko , Rastas Pasi , Löytynoja Ari , Merilä Juha
Published: December 2020

Map distance is one of the key measures in genetics and indicates the expected number of crossovers between two loci. Map distance is estimated from the observed recombination frequency using mapping functions, the most widely used of those, Haldane and Kosambi, being developed at the time when the number of markers was low and unobserved crossovers had a substantial effect on the recombination fractions. In contemporary high-density marker data, the probability of multiple crossovers between adjacent loci is negligible and different mapping functions yield the same result, that is, the recombination frequency between adjacent loci is equal to the map distance in Morgans. However, high-density linkage maps contain an interpretation problem: the map distance over a long interval is additive and its association with recombination frequency is not defined. Here, we demonstrate with high-density linkage maps from humans and stickleback fishes that the inverse of Haldane or Kosambi mapping functions fail to predict the recombination frequency from map distance, and show that this is because the expected number of crossovers is not sufficient to predict recombination frequency. We formulate a piecewise function to calculate the probability of no crossovers between the markers that yields more accurate predictions of recombination frequency from map distance. Our results demonstrate that the association between map distance and recombination frequency is context-dependent and no universal solution exists. We anticipate that our study will motivate further research on this subject to yield a more accurate mathematical description of map distance in the context of modern data.
Development of additional microsatellite primers for the mangrove tree speciesAvicennia germinans
Authors: Craig Hayley , Feller Ilka C. , Rowntree Jennifer K.
Published: December 2020

Objective

The objective of this study was to develop additional microsatellite primers for the mangrove tree speciesAvicennia germinansthat work in multiplex PCR panels to enable cost effective population analyses of this species at a finer scale.

Results

Primer sets were identified from whole genome sequencing data and combined into multiplex PCR panels. Five multiplex reactions containing 20 novel primer sets with trinucleotide repeats were successfully developed. Fifteen of the microsatellite loci were polymorphic in the samples tested, with 1-4 alleles per locus.
Effects of Ca2+on encystment and growth inScrippsiella trochoidea
Authors: Wang Zhifu , Feng Weihua , Cao Jing , Zhang Haifeng , Zhang Dongrong , Qian Jian , Xu Heng Tao , Hao Zhe
Published: December 2020

Cysts serve as a seed source for the initiation and recurrence of a harmful algal bloom (HAB) caused by dinoflagellates. And the influence of calcium on cyst formation has been relatively understudied. In the present study, we investigated the effects of calcium (Ca2+) on the growth and encystment ofScrippsiella trochoidea.We incubatedS. trochoideain modified f/2 media in flasks which were divided into five groups and treated with different Ca2+concentrations (0, 0.2, 0.4, 0.6, and 0.8 g·L−1). We revealed that cell density increased with increasing Ca2+concentrations; however, cell density was reduced when Ca2+concentrations exceeded 0.2 g·mL−1. Additionally, the number of cysts and the cyst formation rate similarly increased as Ca2+concentrations increased, but these were reduced when Ca2+concentrations exceeded 0.4 g·mL−1. Lastly,S. trochoideaabsorbed Ca2+from the water when cysts were formed and under high Ca2+concentrations, more calcareous thorn cysts formed.
Juvenile exposure to acute traumatic stress leads to long-lasting alterations in grey matter myelination in adult female but not male rats
Authors: Breton Jocelyn M. , Barraza Matthew , Hu Kelsey Y. , Frias Samantha Joy , Long Kimberly L.P. , Kaufer Daniela
Published: December 2020

Stress early in life can have a major impact on brain development, and there is increasing evidence that childhood stress confers vulnerability for later developing psychiatric disorders. In particular, during peri-adolescence, brain regions crucial for emotional regulation, such as the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HPC), are still developing and are highly sensitive to stress. Changes in myelin levels have been implicated in mental illnesses and stress effects on myelin and oligodendrocytes (OLs) are beginning to be explored as a novel and underappreciated mechanism underlying psychopathologies. Yet there is little research on the effects of acute stress on myelin during peri-adolescence, and even less work exploring sex-differences. Here, we used a rodent model to test the hypothesis that exposure to acute traumatic stress as a juvenile would induce changes in OLs and myelin content across limbic brain regions. Male and female juvenile rats underwent three hours of restraint stress with exposure to a predator odor on postnatal day (p) 28. Acute stress induced a physiological response, increasing corticosterone release and reducing weight gain in stress-exposed animals. Brain sections containing the PFC, AMY and HPC were taken either in adolescence (p40), or in adulthood (p95) and stained for markers of OLs and myelin. We found that acute stress induced sex-specific changes in grey matter (GM) myelination and OLs in both the short- and long-term. Exposure to a single stressor as a juvenile increased GM myelin content in the AMY and HPC in p40 males, compared to the respective control group. At p40, corticosterone release during stress exposure was also positively correlated with GM myelin content in the AMY of male rats. Single exposure to juvenile stress also led to long-term effects exclusively in female rats. Compared to controls, stress-exposed females showed reduced GM myelin content in all three brain regions. Acute stress exposure decreased PFC and HPC OL density in p40 females, perhaps contributing towards this observed long-term decrease in myelin content. Overall, our findings suggest that the juvenile brain is vulnerable to exposure to a brief severe stressor. Exposure to a single short traumatic event during peri-adolescence produces long-lasting changes in GM myelin content in the adult brain of female, but not male, rats. These findings highlight myelin plasticity as a potential contributor to sex-specific sensitivity to perturbation during a critical window of development.
Highly contiguous assemblies of 101 drosophilid genomes
Authors: Kim Bernard Y. , Wang Jeremy R. , Miller Danny E. , Barmina Olga , Delaney Emily , Thompson Ammon , Comeault Aaron A. , Peede David , D’Agostino Emmanuel R. R. , Pelaez Julianne , Aguilar Jessica M. , Haji Diler , Matsunaga Teruyuki , Armstrong Ellie E. , Zych Molly , Ogawa Yoshitaka , Stamenković-Radak Marina , Jelić Mihailo , Savić Veselinović Marija , Tanasković Marija , Erić Pavle , Gao Jian-jun , Katoh Takehiro K. , Toda Masanori J. , Watabe Hideaki , Watada Masayoshi , Davis Jeremy S. , Moyle Leonie C. , Manoli Giulia , Bertolini Enrico , Košťál Vladimír , Hawley R. Scott , Takahashi Aya , Jones Corbin D. , Price Donald K. , Whiteman Noah , Kopp Artyom , Matute Daniel R. , Petrov Dmitri A.
Published: December 2020

Over 100 years of studies inDrosophila melanogasterand related species in the genusDrosophilahave facilitated key discoveries in genetics, genomics, and evolution. While high-quality genome assemblies exist for several species in this group, they only encompass a small fraction of the genus. Recent advances in long read sequencing allow high quality genome assemblies for tens or even hundreds of species to be generated. Here, we utilize Oxford Nanopore sequencing to build an open community resource of high-quality assemblies for 101 lines of 95 drosophilid species encompassing 14 species groups and 35 sub-groups with an average contig N50 of 10.5 Mb and greater than 97% BUSCO completeness in 97/101 assemblies. These assemblies, along with detailed wet lab protocol and assembly pipelines, are released as a public resource and will serve as a starting point for addressing broad questions of genetics, ecology, and evolution within this key group.
Distinguishing the behavioral potencies of α-pyrrolidino-phenone cathinone stimulants
Authors: Taffe Michael A. , Nguyen Jacques D. , Vandewater Sophia A. , Grant Yanabel , Dickerson Tobin J.
Published: December 2020

The α-pyrrolidino-phenone cathinone stimulants first came to widespread attention because of bizarre behavior consequent to the use of α-pyrrolidinopentiophenone (α-PVP, “flakka”) reported in the popular press. As with other designer drugs, diversification of cathiones has been driven by desireable subjective effects, but also by attempts to stay ahead of legal controls of specific molecules. The α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinopropiophenone (α-PPP) compounds have been relatively under-investigated relative to α-PVP and provide a key opportunity to also investigate structure-activity relationships, i.e., how the extension of the alpha carbon chain may affect potency or efficacy. Male and female rats were used to contrast the effects of α-PHP and α-PPP with those of α-PVP in altering wheel activity and effects on spontaneous locomotion and body temperature were assessed in female rats. The α-PHP and α-PVP compounds (5, 10 mg/kg, i.p.) suppressed wheel activity in female and male rats, whereas α-PPP was only effective in female rats. Inhalation of α-PHP or α-PVP by female rats suppressed wheel activity for an abbreviated duration, compared with the injection route. Spontaneous activity was increased in a dose-dependent manner by all three compounds in female rats, and a small decrements in body temperature were observed after the highest dose of all three compounds. These data show that all three of the α-pyrrolidino-phenone cathinones exhibit significant stimulant-like activity in both male and female rats. Differences were minor and were mostly in potency and the duration of activity. Abuse liability is therefore likely to be equivalent for all three pyrrolidino-phenones.
Genomic diversity analysis of SARS-CoV-2 genomes in Rwanda
Authors: Nzungize Lambert , Ndishimye Pacifique , Zakham Fathiah
Published: December 2020

COVID-19 (Coronavirus disease 2019) is an emerging pneumonia-like respiratory disease of humans and is recently spreading across the globe.

Objective

To analyze the genome sequence of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) isolated from Rwanda with other viral strains from African countries.

Methods

We downloaded 75 genomes sequences of clinical SARS-CoV-2 from the GISAID (global initiative on sharing all influenza data) database and we comprehensively analyzed these SARS-CoV-2 genomes sequences alongside with Wuhan SARS-CoV-2 sequences as the reference strains.

Results

We analyzed 75 genomes sequences of SARS-CoV-2 isolated in different African countries including 10 samples of SARS-CoV-2 isolated in Rwanda between July and August 2020. The phylogenetic analysis of the genome sequence of SARS-CoV-2 revealed a strong identity with reference strains between 90-95%. We identified a missense mutation in four proteins including orf1ab polyprotein, NSP2, 2’-O-ribose methyltransferase and orf1a polyprotein. The most common changes in the base are C > T. We also found that all clinically SARS-CoV-2 isolated from Rwanda had genomes belonging to clade G and lineage B.1.

Conclusions

Tracking the genetic evolution of SARS-CoV-2 over time is important to understand viral evolution pathogenesis. These findings may help to implement public health measures in curbing COVID-19 in Rwanda.
CD137-stimulated cytotoxic T lymphocytes exert superior tumour control due to an enhanced antimitotic effect on tumour cells
Authors: Beck Richard J , Weigelin Bettina , Beltman Joost B
Published: December 2020

Several immunotherapeutic strategies for the treatment of cancer are under development. Two prominent strategies are adoptive cell transfer (ACT) of cytotoxic T lymphocytes (CTLs) and modulation of CTL function with immune checkpoint inhibitors or with costimulatory antibodies. Despite some success with these approaches, there remains a lack of detailed and quantitative descriptions of the events following CTL transfer and the impact of immunomodulation.

Here, we have applied ordinary differential equation models to two photon imaging data derived from a B16F10 murine melanoma. Models were parameterised with data from two different treatment conditions: either ACT-only, or ACT with intratumoural costimulation using a CD137 targeted antibody. Model dynamics and best fitting parameters were compared, in order to assess the mode of action of the CTLs and examine how the CD137 antibody influenced their activities.

We found that the cytolytic activity of the transferred CTLs was minimal without CD137 costimulation, and that the CD137 targeted antibody did not enhance the per-capita killing ability of the transferred CTLs. Instead, the results of our modelling study suggest that an antiproliferative effect of CTLs exerted upon the tumour likely accounted for the majority of the reduction in tumour growth after CTL transfer. We found that CD137 most likely improved tumour control via enhancement of this antiproliferative effect, as well as prolonging the period in which CTLs were inside the tumour, leading to a sustained duration of their antitumour effects following CD137 stimulation.

Significance

CTLs play an important role in controlling tumours, and improved understanding of how they accomplish this will benefit immunotherapeutic cancer treatment strategies. Stimulation of CTLs by targeting their CD137 receptor is a strategy currently under investigation for enhancing responses against tumours, yet so far only limited quantitative knowledge regarding the effects of such stimulation upon CTLs has been obtained. Here, we develop mathematical models to describe dynamicin vivotwo-photon imaging of tumour infiltrating CTLs, to characterise differences in their function either in the presence or absence of a CD137 agonist antibody. We showed that an increased antiproliferative effect and a more sustained presence of CTLs within the tumour were the most significant effects associated with anti-CD137 treatment.
Scaling of Internal Organs duringDrosophilaEmbryonic Development
Authors: Tiwari P. , Rengarajan H. , Saunders T. E.
Published: December 2020

Many species show a diverse range of sizes; for example, domestic dogs have large variation in body mass. Yet, the internal structure of the organism remains similar,i.e. the system scales to organism size.Drosophila melanogasterhas been a powerful model system for exploring scaling mechanisms. In the early embryo, gene expression boundaries scale very precisely to embryo length. Later in development, the adult wings grow with remarkable symmetry and scale well with animal size. Yet, our knowledge of whether internal organs initially scale to embryo size remains largely unknown. Here, we utilise artificially smallDrosophilaembryos to explore how three critical internal organs – the heart, hindgut and ventral nerve cord (VNC) – adapt to changes in embryo morphology. We find that the heart scales precisely with embryo length. Intriguingly, reduction in cardiac cell length, rather than number, appears to be important in controlling heart length. The hindgut – which is the first chiral organ to form – displays scaling with embryo size under large-scale changes in the artificially smaller embryos but shows few hallmarks of scaling within wild-type size variation. Finally, the VNC only displays weak scaling behaviour; even large changes in embryo geometry result in only small shifts in VNC length. This suggests that the VNC may have an intrinsic minimal length, which is largely independent of embryo length. Overall, our work shows that internal organs can adapt to embryo size changes inDrosophila. but the extent to which they scale varies significantly between organs.
Reassessing associations between white matter and behaviour with multimodal microstructural imaging
Authors: Lazari Alberto , Salvan Piergiorgio , Cottaar Michiel , Papp Daniel , van der Werf Olof Jens , Johnstone Ainslie , Sanders Zeena-Britt , Sampaio-Baptista Cassandra , Eichert Nicole , Miyamoto Kentaro , Winkler Anderson , Callaghan Martina F. , Nichols Thomas E. , Stagg Charlotte J , Rushworth Matthew , Verhagen Lennart , Johansen-Berg Heidi
Published: December 2020

Several studies have established specific relationships between White Matter (WM) and behaviour. However, these studies have typically focussed on fractional anisotropy (FA), a neuroimaging metric that is sensitive to multiple tissue properties, making it difficult to identify what biological aspects of WM may drive such relationships. Here, we carry out a pre-registered assessment of WM-behaviour relationships in 50 healthy individuals across multiple behavioural and anatomical domains, and complementing FA with myelin-sensitive quantitative MR modalities (MT, R1, R2*).

Surprisingly, we only find support for predicted relationships between FA and behaviour in one of three pre-registered tests. For one behavioural domain, where we failed to detect an FA-behaviour correlation, we instead find evidence for a correlation between behaviour and R1. This hints that multimodal approaches are able to identify a wider range of WM-behaviour relationships than focusing on FA alone.

To test whether a common biological substrate such as myelin underlies WM-behaviour relationships, we then ran joint multimodal analyses, combining across all MRI parameters considered. No significant multimodal signatures were found and power analyses suggested that sample sizes of 40 to 200 may be required to detect such joint multimodal effects, depending on the task being considered.

These results demonstrate that FA-behaviour relationships from the literature can be replicated, but may not be easily generalisable across domains. Instead, multimodal microstructural imaging may be best placed to detect a wider range of WM-behaviour relationships, as different MRI modalities provide distinct biological sensitivities. Our findings highlight a broad heterogeneity in WM’s relationship with behaviour, suggesting that variable biological effects may be shaping their interaction.

Highlights

Pre-registered testing of microstructural imaging across modalities (FA, MT, R1, R2*) to test WM-behaviour relationships.

Partial support for FA-behaviour relationships hypothesised based on previous literature.

Multimodal approaches can help detect WM-behaviour relationships that are not detected with FA alone.

Sample sizes of 40 to 200 may be needed to detect myelin-behaviour relationships in joint multimodal analyses.

Variable biological effects may be shaping WM-behaviour relationships.
Predicting which genes will respond to perturbations of a TF: TF-independent properties of genes are major determinants of their responsiveness
Authors: Kang Yiming , Brent Michael R.
Published: December 2020

Background

The ability to predict which genes will respond to perturbation of a TF’s activity serves as a benchmark for our systems-level understanding of transcriptional regulatory networks. In previous work, machine learning models have been trained to predict static gene expressionlevelsin a given sample by using data from the same or similar conditions, including data on TF binding locations, histone marks, or DNA sequence. We report on a different challenge – training machine learning models that can predict which genes will respond to perturbation of a TFwithout using any data from the perturbed cells.

Results

Existing TF location data (ChIP-Seq) from human K562 cells have no detectable utility for predicting which genes will respond to perturbation of the TF, but data obtained by newer methods in yeast cells are useful. TF-independent features of genes, including their pre-perturbation expression level and expression variation, are very useful for predicting responses to TF perturbations. This shows that some genes are poised to respond to TF perturbations and others are resistant, shedding significant light on why it has been so difficult to predict responses from binding locations. Certain histone marks (HMs), including H3K4me1 and H3K4me3, have some predictive power, especially when downstream of the transcription start site. In human, the predictive power of HMs is much less than that of gene expression level and variation. Code is available athttps://github.com/yiming-kang/TFPertRespExplainer.

Conclusions

Sequence-based or epigenetic properties of genes strongly influence their tendency to respond to direct TF perturbations, partially explaining the oft-noted difficulty of predicting responsiveness from TF binding location data. These molecular features are largely reflected in and summarized by the gene’s expression level and expression variation.
Unsupervised logic-based mechanism inference for network-driven biological processes
Authors: Prugger Martina , Einkemmer Lukas , Beik Samantha P. , Harris Leonard A. , Lopez Carlos F.
Published: December 2020

Modern analytical techniques enable researchers to collect data about cellular states, before and after perturbations. These states can be characterized using analytical techniques, but the inference of regulatory interactions that explain and predict changes in these states remains a challenge. Here we present a generalizable unsupervised approach to generate parameter-free, logic-based mechanistic hypotheses of cellular processes, described by multiple discrete states. Our algorithm employs a Hamming-distance based approach to formulate, test, and identify, the best mechanism that links two states. Our approach comprises two steps. First, a model with no prior knowledge except for the mapping between initial and attractor states is built. Second, we employ biological constraints to improve model fidelity. Our algorithm automatically recovers the relevant dynamics for the explored models and recapitulates all aspects of the original models biochemical species concentration dynamics. We then conclude by placing our results in the context of ongoing work in the field and discuss how our approach could be used to infer mechanisms of signaling, gene-regulatory, and any other input-output processes describable by logic-based mechanisms.
Shoot-root interaction in control of camalexin exudation in Arabidopsis
Authors: Koprivova Anna , Volz Vanessa , Kopriva Stanislav
Published: December 2020

Plants exude secondary metabolites from the roots to shape the composition and function of their microbiome. Many of these compounds are known for their anti-microbial activity and are part of the plant immunity, such as the indole-derived phytoalexin camalexin. Here we studied the dynamics of camalexin synthesis and exudation upon induction ofArabidopsis thalianawith a plant growth promotion bacteriaPseudomonas sp. CH267 or a bacterial pathogenBurkholderia glumaePG1. We show that while the camalexin accumulation and exudation is more rapidly but transiently induced upon interaction with the growth promoting strain, the pathogen induces a higher and more stable camalexin levels. The concentration of camalexin in shoots, roots and exudates is well correlated, triggering a question on the origin of the exuded camalexin. By combination of experiments with cut shoots and roots and grafting of wild type plant with mutants in camalexin synthesis we showed that while camalexin can be produced and released by both organs, in intact plant the exuded camalexin originates in the shoots. We show that camalexin synthesis in response toB. glumaePG1 is dependent on cooperation of four CYP71 genes and a loss of function of any of them reduces camalexin synthesis. In conclusion, camalexin synthesis seems to be controlled on a whole plant level and coordinated between shoots and roots.
ViralRecall – A Flexible Command-Line Tool for the Detection of Giant Virus Signatures in ‘Omic Data
Authors: Aylward Frank O. , Moniruzzaman Mohammad
Published: December 2020

Giant viruses are widespread in the biosphere and play important roles in biogeochemical cycling and host genome evolution. Also known as Nucleo-Cytoplasmic Large DNA Viruses (NCLDV), these eukaryotic viruses harbor the largest and most complex viral genomes known. Recent studies have shown that NCLDV are frequently abundant in metagenomic datasets, and that sequences derived from these viruses can also be found endogenized in diverse eukaryotic genomes. The accurate detection of sequences derived from NCLDV is therefore of great importance, but this task is challenging owing to both the high level of sequence divergence between NCLDV families and the extraordinarily high diversity of genes encoded in their genomes, including some encoding for metabolic or translation-related functions that are typically found only in cellular lineages. Here we present ViralRecall, a bioinformatic tool for the identification of NCLDV signatures in ‘omic data. This tool leverages a library of Giant Virus Orthologous Groups (GVOGs) to identify sequences that bear signatures of NCLDV. We demonstrate that this tool can effectively identify NCLDV sequences with high sensitivity and specificity. Moreover, we show that it can be useful both for removing contaminating sequences in metagenome-assembled viral genomes as well as the identification of eukaryotic genomic loci that derived from NCLDV. ViralRecall is written in Python 3.5 and is freely available on GitHub:https://github.com/faylward/viralrecall.
DAF-16/FoxO and DAF-12/VDR control cellular plasticity both cell-autonomously and via interorgan signaling
Authors: Aghayeva Ulkar , Bhattacharya Abhishek , Sural Surojit , Jaeger Eliza , Churgin Matthew , Fang-Yen Christopher , Hobert Oliver
Published: December 2020

Many cell types display the remarkable ability to alter their cellular phenotype in response to specific external or internal signals. Such phenotypic plasticity is apparent in the nematodeC. eleganswhen adverse environmental conditions trigger entry into the dauer diapause stage. This entry is accompanied by structural, molecular and functional remodeling of a number of distinct tissue types of the animal, including its nervous system. The transcription factor effectors of three different hormonal signaling systems, the insulin-responsive DAF-16/FoxO transcription factor, the TGFβ-responsive DAF-3/SMAD transcription factor and the steroid nuclear hormone receptor, DAF-12/VDR, a homolog of the vitamin D receptor, were previously shown to be required for entering the dauer arrest stage, but their cellular and temporal focus of action for the underlying cellular remodeling processes remained incompletely understood. Through the generation of conditional alleles that allowed us to spatially and temporally control gene activity, we show here that all three transcription factors are not only required to initiate tissue remodeling upon entry into the dauer stage, as shown before, but are also continuously required to maintain the remodeled state. We show that DAF-3/SMAD is required in sensory neurons to promote and then maintain animal-wide tissue remodeling events. In contrast, DAF-16/FoxO or DAF-12/VDR act cell autonomously to control anatomical, molecular and behavioral remodeling events in specific cell types. Intriguingly, we also uncover non-cell autonomous function of DAF-16/FoxO and DAF-12/VDR in nervous system remodeling, indicating the presence of several insulin-dependent inter-organ signaling axes. Our findings provide novel perspectives on how hormonal systems control tissue remodeling.
Zfp36l1 and Zfp36l2 balances proliferation and differentiation in the developing retina
Authors: Wu Fuguo , Kaczynski Tadeusz , Matheson Louise S. , Liu Tao , Wang Jie , Turner Martin , Mu Xiuqian
Published: December 2020

Both transcriptional and post-transcriptional regulation of gene expression play significant roles in diverse biological processes, but little is known about how post-transcriptional regulation impacts retinal development. Here we report our study of the function of two members of the TTP (tristetraprolin) mRNA binding protein family, Zfp36l1 and Zfp36l2, in the developing retina. TTP proteins are highly conserved CCCH zinc finger proteins, which carry out their functions by promoting target mRNA decay and modulating translation. We found that Zfp36l1 and Zfp36l2 were expressed in retinal progenitor cells (RPCs) during development and Müller glial cells and photoreceptors in the mature retina. Our analysis of the mutant retinas showed that, whereas the single knockout retinas were largely normal, the double knockout (DKO) retina showed decreased RPC proliferation and increased differentiation of multiple retinal cell types. RNA-seq analysis confirmed the imbalance of proliferation and differentiation in the DKO retina. Gene ontology and in silico target gene analysis indicates that Zfp36l1 and Zfp36l2 exert their function by directly regulating multiple classes of proteins, including components of multiple signaling pathways such as the sonic hedgehog pathway and the Notch pathway, cell cycle regulators, and most interestingly transcription factors directly involved in retinal differentiation. These results reveal a new tier of gene regulation controlling retinal development.
Silver thiosulfate and Benzyladenine in combination with pruning additively feminizes cassava flowers and modulates transcriptome
Authors: Deborah Oluwasanya , Olayemisi Esan , Peter Hyde , Peter Kulakow , Tim Setter
Published: December 2020

Cassava, a tropical storage-root crop, is a major source of food security for millions in the tropics. Cassava breeding however is hindered by the poor development of flowers and female flowers in particular, since flower development is strongly skewed towards male flowers. Our objectives were to test plant growth regulator and pruning treatments for their effectiveness in field conditions in improving flower production and fruit set in cassava. Pruning the fork type branches that arise at the shoot apex immediately below newly formed inflorescences stimulated inflorescence and floral development. The anti-ethylene silver thiosulfate (STS) also increased flower abundance. Both pruning and STS increased flower numbers without influencing sex ratios. In contrast, the cytokinin benzyladenine (BA) feminized flowers without increasing flower abundance. Combining pruning and STS treatments led to an additive increase in flower abundance; with the addition of BA, over 80% of flowers were females. This three-way treatment combination of pruning+STS+BA also led to an increase in fruit development. Transcriptomic analysis of gene expression in tissues of the apical region and developing inflorescence revealed that the enhancement of female flower development by STS+BA was accompanied by the downregulation in of several genes associated with repression of flowering, including Tempranillo 1 (TEM1), GA receptor GID1b, and ABA signaling genes ABI1 and PP2CA. We conclude that treatments with pruning, STS and BA create widespread changes on the network of hormone signaling and regulatory factors beyond ethylene and cytokinin.