bluuebunny/crossref_metadata_2025 huggingface dataset:
Active and weakening MJO events in the Maritime Continent
Authors: Barrett Bradford S. , Densmore Casey R. , Ray Pallav , Sanabia Elizabeth R.
Published: March 2021

To better understand the Madden–Julian Oscillation (MJO) in the Maritime Continent (MC), events from 1980 to 2019 were classified as active or weakening according to propagation characteristics and amplitude changes in two leading indices, the Real-time Multivariate MJO (RMM) index and Outgoing Longwave Radiation (OLR) MJO Index (OMI). Active MJO events had larger index amplitudes than weakening events, and those amplitude differences appeared at day − 3 in the RMM and day − 8 in the OMI and remained through day + 15 in both indices (day 0 marked the day an event entered the MC). Thus, active events were stronger than weakening events as they approached and crossed the MC. To understand differences in environments between these events, composites of OLR and specific humidity were compared for each. Active MJO events had consistently more negative OLR anomalies and greater specific humidity in both the boundary layer and free troposphere than weakening MJO events. Those differences persisted during both easterly and westerly phases of the Quasi-biennial Oscillation (QBO) and during La Niña and El Niño. Active MJO events during QBO westerly winds had more specific humidity than active events did during QBO easterly winds. Finally, both active and weakening MJO events featured a diurnal cycle of lower-tropospheric specific humidity over land areas of the MC, and the amount of atmospheric moisture available to active events was consistently greater than weakening ones. These results indicate that index amplitude, OLR, and tropospheric specific humidity can all be important tools in identifying active and weakening MJO events in the MC, including for different phases of the QBO and the El Niño-Southern Oscillation (ENSO).
Tear-drop technique in iliac screw placement: a technical analysis
Authors: Nowak Stephan , Müller Jonas , Weidemeier Martin E. , Schroeder Henry W. S. , Müller Jan-Uwe
Published: March 2021

Background

Instrumentation of the lumbosacral region is one of the more challenging regions due to the complex anatomical structures and biomechanical forces. Screw insertion can be done both navigated and based on X-ray verification. In this study, we demonstrate a fast and reliable open, low exposure X-ray-guided technique of iliac screw placement.

Methods

Between October 2016 and August 2019, 48 patients underwent sacropelvic fixation in tear-drop technique. Screw insertion was performed in open technique by using an X-ray converter angulated 25-30° in coronal and sagittal view. The anatomical insertion point was the posterior superior iliac spine. Verification of correct screw placement was done by intraoperative 3D scan.

Results

In total, 95 iliac screws were placed in tear-drop technique with a correct placement in 98.1%.

Conclusions

The tear-drop technique showed a proper screw position in the intraoperative 3D scan and therefore may be considered an alternative technique to the navigated screw placement.
Early Warning Signals for Rate-induced Critical Transitions in Salt Marsh Ecosystems
Authors: Neijnens Floris K. , Siteur Koen , van de Koppel Johan , Rietkerk Max
Published: March 2021

Intertidal ecosystems are important because of their function as coastal protection and ecological value. Sea level rise may lead to submergence of salt marshes worldwide. Salt marshes can exhibit critical transitions if the rate of sea level rise exceeds salt marsh sedimentation, leading to a positive feedback between reduced sedimentation and vegetation loss, drowning the marshes. However, a general framework to recognize such rate-induced critical transitions and predict salt marsh collapse through early warning signals is lacking. Therefore, we apply the novel concept of rate-induced critical transitions to salt marsh ecosystems. We reveal rate-induced critical transitions and new geomorphic early warning signals for upcoming salt marsh collapse in a spatial model. These include a decrease in marsh height, the ratio of marsh area to creek area, and creek cliff steepness, as well as an increase in creek depth. Furthermore, this research predicts that increasing sediment capture ability by vegetation would be an effective measure to increase the critical rate of sea level rise at which salt marshes collapse. The generic spatial model also applies to other intertidal ecosystems with similar dynamics, such as tidal flats and mangroves. Our findings facilitate better resilience assessment of intertidal ecosystems globally and identifying measures to protect these ecosystems.
Patterns of sexting and sexual behaviors in youth: A Latent Class Analysis
Authors: Mori Camille , Choi Hye Jeong , Temple Jeff R. , Madigan Sheri
Published: March 2021

Introduction

A sizable minority of youth are sexting; however there are likely large individual differences in sexting and sexual behaviors, yet to be captured. A Latent Class Analysis was used to identify subgroups of youth characterized by differential engagement in sexting and sexual behaviors.

Methods

Participants were an ethnically diverse sample of 894 youth (55.8% female; Mage = 17.04, SD = 0.77) from a longitudinal survey study in southeast Texas. Latent classes were identified through participants’ responses to the following indicator variables: sending, receiving, and requesting sexts, sexual activity, contraception use, ≥ three partners, and substance use prior to sexual activity. Gender, ethnicity, impulsivity, and living situation were analyzed as predictors, and depressive symptoms as an outcome, of class membership.

Results

The analysis revealed four distinct classes: No sexting‐Low sex (42.2%), Sexting‐Low sex (4.5%), No sexting‐Moderately risky sex (28.3%), and Sexting‐Moderately risky sex (24.9%). Gender and ethnicity predicted class membership wherein females and ethnic minority youth were less likely to be in groups displaying higher rates of sexting. Impulsivity and living situation predicted class membership, such that youth reporting higher impulsivity and living in a situation other than with two biological parents were less likely to be in classes displaying low sexting and sexual behaviors. Group membership predicted depressive symptoms.

Conclusions

Results suggest that not all youth who are sexting are having sex, and not all youth who are having sex are sexting. Evidence of individual differences in youth sexual behaviors should inform educational initiatives aimed at teaching youth about sexual and online health.
MONSTROUS EMOTIONS IN SENECA'S MEDEA
Authors: Lima Paulo Alexandre
Published: March 2021

This article explores the phenomenon of the monstrous in Seneca's Medea by focusing on the emotions of its main character, in particular demonstrating that they are not merely an expression of Medea's inner psychological sphere but are intrinsically connected with her existential search for recognition in her surrounding world, a world especially marked by its social, cosmic, and mythical dimensions. The monstrous nature of Medea's emotions should be understood in the light of the wider phenomenon of the monstrous in this play, where it is a pervasive phenomenon, in the sense that it transcends the emotions of the main character and is present throughout the play as a tragic, mythically encoded enactment of the dissolution of social, religious, and cosmic boundaries. Other manifestations of the monstrous will be referred to in passing.
Art and Archaeology
Authors: Squire Michael
Published: March 2021

I am no doubt showing my prejudice, but I didn't expect a book on Greek acroteria to make for such exciting lockdown reading. Because of their position high up on temple buildings, extant sculpted materials tend to be fragmentary – and hence pushed to the literal and metaphorical corners of modern-day museums. Look to scholarly publications, moreover, and there is a tendency towards classificatory catalogues, markedly less in the way of theoretical discussion (whether about architectural and cultic framing, for example, historical aesthetics, or the intersection between ‘ornamental’ and ‘figurative’ representational modes).
Coarse alignment of marine strapdown inertial navigation system using the location of fitted parametric circle of gravity movement
Authors: Rahimi Hossein , Nikkhah Amir Ali
Published: March 2021

This paper presents a novel estimation method for coarse alignment of a marine strapdown inertial navigation system (SINS) under mooring conditions. The properties of gravitational motion are used to improve the accuracy of coarse alignment. The parametric motion of gravitational apparent is a circle that is on the surface of a sphere. The location of this parametric circle is dependent on the definition of the reference frames and the initial angles of SINS. In the method proposed here the initial direct cosine matrix is calculated only from the location of the gravity motion parametric circle. The novelty of this paper is to provide a new method for estimating the gravity motion trajectory in inertial frame, as well as direct extraction of the initial direct cosine matrix from this estimated trajectory. Simulation and testing show that the proposed method is suitable for coarse alignment in mooring conditions.
Changes in ultra-processed food consumption during the first Italian lockdown following the COVID-19 pandemic and major correlates: results from two population-based cohorts
Authors: Bonaccio Marialaura , Costanzo Simona , Ruggiero Emilia , Persichillo Mariarosaria , Esposito Simona , Olivieri Marco , Di Castelnuovo Augusto , Cerletti Chiara , Donati Maria Benedetta , de Gaetano Giovanni , Iacoviello Licia ,   for the Moli-LOCK Study Investigators
Published: March 2021

Objective:

To evaluate changes in ultra-processed food (UPF) intake and its major correlates during the first Italian lockdown (9 March–3 May 2020).

Design:

Retrospective observational study.

Setting:

Italy.

Participants:

We analysed 2992 subjects (mean age 57·9 ± 15·3 years, 40·4 % men). Individual participant data were pooled from two retrospective cohorts: (1) The Moli-LOCK cohort consists of 1501 adults, a portion of the larger Moli-sani study (n 24 325; 2005–2010) who were administered a phone-based questionnaire to assess lifestyles and psychological factors during confinement and (2) the Analysis of Long Term Risk of Covid-19 Emergency is a web-based survey of 1491 individuals distributed throughout Italy who self-responded to the same questionnaire by using Google forms.

UPF was defined according to NOVA classification based on degree of food processing. An UPF score was created by assigning 1 point to increased consumption, −1 to decreased and 0 point for unchanged intakes of nineteen food items, with higher values indicating an increase in UPF during confinement.

Results:

Overall, 37·5 % of the population reported some increase in UPF (UPF score ≥1). Adults were more likely to decrease UPF (multivariable regression coefficient β = −1·94; 95 % CI −2·72, −1·17 for individuals aged >75 years as compared with 18–39 years) as did individuals from southern Italian regions as compared with Northern inhabitants (β = −1·32; 95 % CI −1·80, −0·84), while UPF lowering associated with increased exercise (β = −0·90; 95 % CI −1·46, −0·35) and weight loss (β = −1·05; 95 % CI −1·51, −0·59) during confinement.

Conclusions:

During the first Italian lockdown, about 40 % of our population switched to unfavourable eating as reflected by increased UPF intake and this may have long-term effects for health.
Principles of Molecular Devices Operated by Electric Fields
Authors: Darwish N. , Foroutan-Nejad C. , Domulevicz L. , Hihath J. , Díez-Pérez I.
Published: March 2021

This chapter outlines the main device platforms that are available for harnessing electric field-induced reactivity in a confined nanoscale gap. The chapter begins with an introduction that describes the general architecture of the available experimental platforms for the design of electrically driven molecular devices. It then discusses recent literature that demonstrate the interplay between the built-in local electric field in molecular systems (D-LEF) and the oriented external electric field (OEEF) of the device. The chapter concludes by describing a molecular device designed to specifically enhance molecular spectroscopy by utilizing OEEFs.
Manipulation of Molecules by Combined Permanent and Induced Dipole Forces
Authors: Friedrich B.
Published: March 2021

This chapter describes a versatile technique to control molecular rotation and translation. The technique is based on the combined effect of external electric fields that act concurrently on the molecular permanent and induced dipole moments. This synergistic effect arises for any polar molecule, as only an anisotropic polarizability, along with a permanent dipole moment, is required. This is always available in polar molecules. The effect of the combined fields can be achieved either by superimposing an electrostatic and a far-off resonant optical field (i.e., one that supplies electric field strength but does not cause transitions) that act, respectively, on the molecule's permanent and induced electric dipole, or by making use of a unipolar electromagnetic pulse that seizes the permanent and induced dipole moments simultaneously. If the combined electric fields are homogeneous, only molecular rotation is affected, whereas inhomogeneous fields affect both molecular rotation and translation. As noted in the chapter, the ability to manipulate molecular rotation and translation has wide-ranging applications – in research areas as diverse as reaction dynamics, spectroscopy, higher harmonic generation and molecular orbital imaging, the focusing and trapping of molecules, as well as quantum simulation and computing.
Cavity-modified Chemistry: Towards Vacuum-field Catalysis
Authors: Climent C. , Garcia-Vidal F. J. , Feist J.
Published: March 2021

In the preceding chapters, electric field effects on chemical reactivity have been extensively discussed, focusing on STM setups and enzyme catalysis among many others. Here we will focus on a rather different and only recently explored approach to manipulate chemical reactions with electric fields. With the use of resonant cavity modes hosted in Fabry–Pérot cavities for instance, as well as plasmonic modes, very recent investigations have shown modifications of chemical reactivity and dynamics, including thermal reactions and photochemistry, as well as manipulation of materials properties and non-adiabatic processes. All these works have given birth to a new field termed polaritonic chemistry due to the fact that in the so-called strong-coupling regime, polaritons become the new eigenstates of the system. These are hybrid states of light and matter that inherit properties from both constituents, providing new means to modify chemical phenomena. The aim of this chapter is two-fold: on one side, we aim to provide a general background on confined light modes and strong coupling for the non-specialised reader, and on the other, we aim to review the recent achievements of the field, paying special attention to modifications in ground-state reactivity. To this end, the chapter is organised as follows. After an introduction to settle basic concepts, we review the most relevant experimental and theoretical work in which modified chemical reactivity has been reported and conclude with the challenges faced by the field.
An ab initio investigation of the electronic and magnetic properties of graphite and nickel-doped graphite
Authors: Sellam Abdellah , Hlil El Kebir , Heyd Rodolphe , Koumina Abdelaziz
Published: March 2021

In this paper, the KKR (Korringa, Kohn, and Rostoker) is presented with coherent potential approximation methods which is used to investigate the electronic and magnetic properties of allotropic graphite forms of carbon and nickel-doped graphite. The density of states (DOS), band structure, total energy, and the magnetic moments of atoms are computed. The crystallographic structure optimization is carried out by evaluating the total energy as a function of unit lattice parameters. The DOS analysis reveals a partially metallic behavior of the compound. The magnetism vs the Ni-doping content in C1−xNix is also investigated by computing moments induced on atoms; the sensitivity of the magnetism to Ni-doping is also analyzed.
Journal d’un bébé résilient
Authors: Pelloux Anne-Sylvie , Bezeaud Amélie
Published: March 2021

Les auteurs présentent un suivi en consultation parent-bébé qui débute avant l’épidémie et se poursuit durant le confinement. L’aménagement des liens intrafamiliaux et thérapeutique, la parentalité, interpellent les consultants durant la première période et leur font redouter une détérioration de la situation à l’arrêt du suivi en présentiel. Pour autant, le lien est préservé avec les téléconsultations et la famille montre des ressources et une résilience, inattendues.
A comparative study of the structural and mechanical properties of avian eggshells among hosts of obligate brood parasitic cowbirds (genusMolothrus)
Authors: López Analía V , Reboreda Juan C , Fiorini Vanina D , Gerschenson Lía N , Hauber Mark E
Published: March 2021

Obligate avian brood parasites depend on hosts for parental care, which in turn suffer fitness losses as a result of parasitism. Mechanisms by which brood parasitic cowbirds (Molothrus spp.) reduce host breeding success include the puncture (M. rufoaxillaris and M. bonariensis) or removal (M. ater) of the eggs of the host. Our working hypothesis is that the host eggs’ mechanical strength and their size and shape in species with higher frequency of parasitism covaries with the cowbird’s strategy to reduce host clutch size. Our results, obtained through phylogenetic analyses based on egg 2D geometric morphometry and eggshell mechanical and ultrastructural measurements, suggest that egg-puncturer behaviour has led to an increase in the strength of the host’s eggshell, which might make them more difficult to be pierced. We also characterized larger, more rounded and asymmetrical eggs in frequent hosts of M. ater, which might be more difficult to be removed. These interspecific host egg and shell traits were also positively affected by the frequency of parasitism, indicating that species-specific patterns of parasitic costs select for respective anti-parasitic defences in hosts.
Decolonizing the British Army: a preliminary response
Authors: King Anthony
Published: March 2021

Following the death of George Floyd in Minneapolis on 25 May 2020, anti-racist protests occurred across America and Europe. As a result, public institutions in the UK have begun to re-examine their cultures and practices to ensure not only that they are non-discriminatory, but also that they are actively anti-racist. The Army will not be immune to this process. Indeed, senior commanders including the Chief of the Defence Staff have already embraced the ‘decolonizing’ programme. Since 2000, the Army has incorporated significant numbers of Black, Asian and minority ethnic (BAME) soldiers; just over 10 per cent of the Army is now BAME. This article examines the integration of minority soldiers over the last two decades in order to assess the prospects of ‘de-colonization’ in the Army today. Despite the apparent success of the Army's integration policy, this article identifies three obstacles which still obstruct minority integration and are likely to impede de-colonization. Firstly, the majority of the Army's BAME soldiers are not British citizens, but foreign and Commonwealth nationals. Secondly, the young age of the majority of British soldiers generates interactional dynamics in barracks and training which often accidentally excludes foreign minority soldiers. Thirdly, the military ideal of the British Army remains understandably Anglo-Saxon. This article considers the tensions inherent in the Army's multicultural project and lays out suggestions about how they might be overcome to pursue a de-colonizing agenda.
The alignment of interstellar dust grains: thermal flipping and the Davis–Greenstein mechanism
Authors: Weingartner Joseph C , Kolasi Erald , Woods Cameron
Published: March 2021

Interstellar dust grains are non-spherical and, in some environments, partially aligned along the direction of the interstellar magnetic field. Numerous alignment theories have been proposed, all of which examine the grain rotational dynamics. In 1999, Lazarian & Draine introduced the important concept of thermal flipping, in which internal relaxation processes induce the grain body to flip while its angular momentum remains fixed. Through detailed numerical simulations, we study the role of thermal flipping on the grain dynamics during periods of relatively slow rotation, known as ‘crossovers’, for the special case of a spheroidal grain with a non-uniform mass distribution. Lazarian & Draine proposed that rapid flipping during a crossover would lead to ‘thermal trapping’, in which a systematic torque, fixed relative to the grain body, would time average to zero, delaying spin-up to larger rotational speeds. We find that the time-averaged systematic torque is not zero during the crossover and that thermal trapping is not prevalent. As an application, we examine whether the classic Davis–Greenstein alignment mechanism is viable, for grains residing in the cold neutral medium and lacking superparamagnetic inclusions. We find that Davis–Greenstein alignment is not hindered by thermal trapping, but argue that it is, nevertheless, too inefficient to yield the alignment of large grains responsible for optical and infrared starlight polarization. Davis–Greenstein alignment of small grains could potentially contribute to the observed ultraviolet polarization. The theoretical and computational tools developed here can also be applied to analyses of alignment via radiative torques and rotational disruption of grains.
Genome sequencing and analysis of an emergent SARS-CoV-2 variant characterized by multiple spike protein mutations detected from the Central Visayas Region of the Philippines
Authors: Tablizo Francis A. , Kim Kenneth M. , Lapid Carlo M. , Castro Marc Jerrone R. , Yangzon Maria Sofia L. , Maralit Benedict A. , Ayes Marc Edsel C. , Cutiongco-de la Paz Eva Maria , De Guzman Alethea R. , Yap Jan Michael C. , Llames Jo-Hannah S. , Araiza Shiela Mae M. , Punayan Kris P. , Asin Irish Coleen A. , Tambaoan Candice Francheska B. , Chong Asia Louisa U. , Padilla Karol Sophia Agape R. , Cruz Rianna Patricia S. , Morado El King D. , Dizon Joshua Gregor A. , Hao Razel Nikka M. , Zamora Arianne A. , Pacial Devon Ray , Magalang Juan Antonio R. , Alejandria Marissa , Carlos Celia , Ong-Lim Anna , Salvaña Edsel Maurice , Wong John Q. , Montoya Jaime C. , Singh-Vergeire Maria Rosario , Saloma Cynthia P.
Published: March 2021

The emergence of SARS-CoV-2 variants of concern such as the B.1.1.7, B.1.351 and the P.1 have prompted calls for governments worldwide to increase their genomic biosurveillance efforts. Globally, quarantine and outbreak management measures have been implemented to stem the introduction of these variants and to monitor any emerging variants of potential clinical significance domestically. Here, we describe the emergence of a new SARS-CoV-2 lineage, mainly from the Central Visayas region of the Philippines. This emergent variant is characterized by 13 lineage-defining mutations, including the co-occurrence of the E484K, N501Y, and P681H mutations at the spike protein region, as well as three additional radical amino acid replacements towards the C-terminal end of the said protein. A three-amino acid deletion at positions 141 to 143 (LGV141_143del) in the spike protein was likewise seen in a region preceding the 144Y deletion found in the B.1.1.7 variant. A single amino acid replacement, K2Q, at the N-terminus of ORF8 was also shared by all 33 samples sequenced. The mutation profile of this new virus variant warrants closer investigation due to its potential public health implications. The current distribution of this emergent variant in the Philippines and its transmission are being monitored and addressed by relevant public health agencies to stem its spread in nearby islands and regions in the country.
Quantitative estimates of deciduousness in woody species from a seasonally dry tropical forest are related to leaf functional traits and the timing of leaf flush
Authors: Chakrabarty Souparna , Sharma Sheetal , Ganguly Shatarupa , Jezeera Asmi , Mohanbabu Neha , Barua Deepak
Published: March 2021

Leaf phenology based classification of woody species into discrete evergreen and deciduous categories is widely used in ecology, but these categories hide important variation in leaf phenological behaviour. Few studies have examined the continuous nature of deciduousness and our understanding of variation in quantitative estimates of leaf shedding behaviour and the causes and consequences of this is limited. In this study we monitored leaf phenology in 75 woody species from a seasonally dry tropical forest to quantify three quantitative measures of deciduousness, namely: maximum canopy loss, duration of deciduousness, and average canopy loss. Based on proposed drought tolerance and drought avoidance strategies of evergreen and deciduous species, respectively, we tested whether the quantitative measures of deciduousness were related to leaf functional traits. Additionally, to understand the functional consequences of variation in deciduousness we examined relationships with the timing of leaf flushing and senescing. We found wide and continuous variation in quantitative measures of deciduousness in these coexisting species. Variation in deciduousness was related to leaf function traits, and the timing of leaf flushing. Along a continuous axis ranging from evergreen to deciduous species, increasing deciduousness was associated with more acquisitive leaf functional traits, with lower leaf mass per area and leaf dry matter content, and greater leaf nitrogen content. These results indicate that the continuous nature of deciduousness is an important component of resource acquisition strategies in woody species from seasonally dry forests.
Organelle genome assembly uncovers the dynamic genome reorganization and cytoplasmic male sterility associated genes in tomato
Authors: Kuwabara Kosuke , Harada Issei , Matsuzawa Yuma , Ariizumi Tohru , Shirasawa Kenta
Published: March 2021

To identify cytoplasmic male sterility (CMS)-associated genes in tomato, we determined the genome sequences of mitochondria and chloroplasts in three CMS tomato lines derived from independent asymmetric cell fusions, their nuclear and cytoplasmic donors, and male fertile weedy cultivated tomato and wild relatives. The structures of the CMS mitochondrial genomes were highly divergent from those of the nuclear and cytoplasmic donors, and genes of the donors were mixed up in these genomes. On the other hand, the structures of CMS chloroplast genomes were moderately conserved across the donors, but CMS chloroplast genes were unexpectedly likely derived from the nuclear donors. Comparative analysis of the structures and contents of organelle genes and transcriptome analysis identified three genes that were uniquely present in the CMS lines, but not in the donor or fertile lines. RNA sequencing analysis indicated that these three genes transcriptionally expressed in anther, two of which were also expressed in pollen. They could be potential candidates for CMS-associated genes. This study suggests that organelle reorganization mechanisms after cell fusion events differ between mitochondria and chloroplasts, and provides insight into the development of new F1 hybrid breeding programs employing the CMS system in tomato.
The analysis of epigenomic evolution
Authors: Sahm Arne , Koch Philipp , Horvath Steve , Hoffmann Steve
Published: March 2021

While the investigation of the epigenome becomes increasingly important, still little is known about the long-term evolution of epigenetic marks and systematic investigation strategies are still withstanding. Here, we systematically demonstrate the transfer of classic phylogenetic methods such as maximum likelihood based on substitution models, parsimony, and distance-based to interval-scaled epigenetic data (available atGithub). Using a great apes blood data set, we demonstrate that DNA methylation is evolutionarily conserved at the level of individual CpGs in promotors, enhancers and genic regions. Our analysis also reveals that this epigenomic conservation is significantly correlated with its transcription factor binding density. Binding sites for transcription factors involved in neuron differentiation and components of AP-1 evolve at a significantly higher rate at methylation than at nucleotide level. Moreover, our models suggest an accelerated epigenomic evolution at binding sites of BRCA1, CBX2, and factors of the polycomb repressor 2 complex in humans. For most genomic regions, the methylation-based reconstruction of phylogenetic trees is at par with sequence-based reconstruction. Most strikingly, phylogenetic reconstruction using methylation rates in enhancer regions was ineffective independently of the chosen model. We identify a set of phylogenetically uninformative CpG sites enriching in enhancers controlling immune-related genes.
Accounting for B cell behaviour and sampling bias yields a superior predictor of anti-PD-L1 response in bladder cancer
Authors: Dyugay I.A. , Lukyanov D.K. , Turchaninova M.A. , Zaretsky A.R. , Khalmurzaev O. , Matveev V.B. , Shugay M. , Shelyakin P.V. , Chudakov D.M.
Published: March 2021

Tumor-infiltrating B cells and intratumorally-produced immunoglobulins (IG) play important roles in the tumor microenvironment and response to immunotherapy1–5. IgG antibodies produced by intratumoral B cells may drive antibody-dependent cellular cytotoxicity (ADCC) and enhance antigen presentation by dendritic cells6–8. Furthermore, B cells are efficient antigen-specific antigen presenters that can essentially modulate the behaviour of helper T cells9–11.

Here we investigated the role of intratumoral IG isotype and clonality in bladder cancer. Our results show that the IgG1/IgA ratio offers a strong and independent prognostic indicator for theBasal squamousmolecular subtype and for the whole ImVigor210 cohort in anti-PD-L1 immunotherapy. Our findings also indicate that effector B cell functions, rather than clonally-produced antibodies, are involved in the antitumor response. High IgG1/IgA ratio was associated with relative abundance of cytotoxic genes and prominence of the IL-21/IL-21R axis suggesting importance of T cell/B cell interaction.

We integrated the B, NK, and T cell components, employing immFocus-like normalization to account for the stochastic nature of tumor tissue sampling. Using a random forest model with nested cross-validation, we developed a tumor RNA-Seq-based predictor of anti-PD-L1 therapy response in muscle-invasive urothelial carcinoma. The resulting PRIMUS (PRedIctive MolecUlar Signature) predictor achieves superior sensitivity compared to PD-L1 expression scores or existing gene signatures, allowing for reliable identification of responders even within thedesertpatient subcohort analyzed as a hold out set.
Barcode Sequencing and a High-throughput Assay for Chronological Lifespan
Uncover Ageing-associated Genes in Fission Yeast
Authors: Romila Catalina A. , Townsend StJohn , Malecki Michal , Kamrad Stephan , Rodríguez-López María , Hillson Olivia , Cotobal Cristina , Ralser Markus , Bähler Jürg
Published: March 2021

Ageing-related processes are largely conserved, with simple organisms
remaining the main platform to discover and dissect new ageing-associated genes.
Yeasts provide potent model systems to study cellular ageing owing their
amenability to systematic functional assays under controlled conditions. Even
with yeast cells, however, ageing assays can be laborious and
resource-intensive. Here we present improved experimental and computational
methods to study chronological lifespan in Schizosaccharomyces
pombe. We decoded the barcodes for 3206 mutants of the latest
gene-deletion library, enabling the parallel profiling of ∼700 additional
mutants compared to previous screens. We then applied a refined method of
barcode sequencing (Bar-seq), addressing technical and statistical issues raised
by persisting DNA in dead cells and sampling bottlenecks in aged cultures, to
screen for mutants showing altered lifespan during stationary phase. This screen
identified 341 long-lived mutants and 1246 short-lived mutants which point to
many previously unknown ageing-associated genes, including 51 conserved but
entirely uncharacterized genes. The ageing-associated genes showed coherent
enrichments in processes also associated with human ageing, particularly with
respect to ageing in non-proliferative brain cells. We also developed an
automated colony-forming unit assay for chronological lifespan to facilitate
medium- to high-throughput ageing studies by saving time and resources compared
to the traditional assay. Results from the Bar-seq screen showed good agreement
with this new assay, validating 33 genes not previously associated with cellular
ageing. This study provides an effective methodological platform and identifies
many new ageing-associated genes as a framework for analysing cellular ageing in
yeast and beyond.
Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma
Authors: Ohmura Shunya , Marchetto Aruna , Orth Martin F. , Li Jing , Jabar Susanne , Ranft Andreas , Vinca Endrit , Ceranski Katharina , Carreño-Gonzalez Martha J. , Romero-Pérez Laura , Wehweck Fabienne S. , Musa Julian , Bestvater Felix , Knott Maximilian M. L. , Hölting Tilman L. B. , Hartmann Wolfgang , Dirksen Uta , Kirchner Thomas , Cidre-Aranaz Florencia , Grünewald Thomas G. P.
Published: March 2021

Purpose

Ewing sarcoma (EwS) is a highly aggressive bone- or soft tissue-associated malignancy mostly affecting children, adolescents, and young adults. Although multimodal therapies have strongly improved patients’ overall survival over the past decades, the development of prognostic biomarkers for risk-based patient stratification and more effective therapies with less adverse effects is stagnating. Thus, new personalized medicine approaches are urgently required.

Experimental design

Gene expression data of EwS and normal tissues were crossed with survival data to identify highly overexpressed, prognostically relevant, and actionable potential targets. RNA-interference and dose-response assays as well as tissue-microarray analyses were carried out to explore the functional role and druggability of a prominent candidate genein vitroandin vivo, and to validate its suitability as a prognostic biomarker.

Results

Employing a multilayered screening approach, we discover ribonucleotide reductase regulatory subunit M2 (RRM2) as a promising therapeutic target and prognostic biomarker in EwS. Through analysis of two independent EwS patient cohorts, we show that RRM2 mRNA and protein overexpression is associated with an aggressive clinical phenotype and poor patients’ overall survival. In agreement,RRM2silencing as well as pharmacological inhibition by the specific inhibitor triapine (3-AP) significantly reduces EwS growthin vitroandin vivo. Furthermore, we present evidence that pharmacological RRM2 inhibition by triapine can overcome chemoresistance against doxorubicin or gemcitabine, and synergize with cell cycle checkpoint inhibitors (CHEK1 or WEE1).

Conclusions

Based on the aggressive phenotype mediated by and the druggability of RRM2 our results provide a translational rationale for exploiting RRM2 as a novel therapeutic target in EwS and prompt further clinical investigations.
Differential levels of IFNα subtypes in autoimmunity and viral infection
Authors: Bondet Vincent , Rodero Mathieu P , Posseme Céline , Bost Pierre , Decalf Jérémie , Haljasmägi Liis , Bekaddour Nassima , Rice Gillian , Upasani Vinit , Herbeuval Jean-Philippe , Reynolds John A , Briggs Tracy A , Bruce Ian N , Mauri Claudia , Isenberg David , Menon Madhvi , Hunt David , Schwikowski Benno , Mariette Xavier , Pol Stanislas , Rozenberg Flore , Cantaert Tineke , Gottenberg J Eric , Kisand Kai , Duffy Darragh
Published: March 2021

Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFNα (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFNα2 subtype. Application of this assay, in parallel with our previously described pan-IFNα assay, allowed us to study different IFNα protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFNα protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFNα2 protein measurements but low pan-IFNα measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFNα2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFNα auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFNα proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies.
Stimulation of adaptive gene amplification by origin firing under replication fork constraint
Authors: Whale Alex J. , King Michelle , Hull Ryan M. , Krueger Felix , Houseley Jonathan
Published: March 2021

Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance geneCUP1occurs in response to environmental copper due toCUP1transcriptional activation. Here we dissect the mechanism by whichCUP1transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at theCUP1locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependentCUP1gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32, factors known to alter the frequency of template switching during break induced replication (BIR).CUP1amplification is also critically dependent on late firing replication origins present in theCUP1repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after firing, leaving an epigenetic scar of H3K56 acetylation that promotes template switching during later break induced replication events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution throughde novogene amplification.
Stable nitrogen isotope analysis of amino acids as a new tool to clarify complex parasite-host interactions within marine food webs
Authors: Riekenberg Philip , Joling Tijs , IJsseldijk Lonneke L. , Waser Andreas M. , van der Meer Marcel , Thieltges David W.
Published: March 2021

Traditional bulk isotopic analysis is a pivotal tool for mapping consumer-resource interactions in food webs but has largely failed to adequately describe parasite-host relationships. Thus, parasite-host interactions remain largely understudied in food web frameworks despite these relationships increasing linkage density, connectance, and ecosystem biomass. Compound-specific stable isotopes from amino acids provides a promising novel approach that may aid in mapping parasitic interactions in food webs. However, to date it has not been applied to parasitic trophic interactions.

Here we use a combination of traditional bulk stable isotope analyses and compound-specific isotopic analysis of the nitrogen in amino acids to examine resource use and trophic interactions of five parasites from three hosts from a marine coastal food web (Wadden Sea, European Atlantic). By comparing isotopic compositions of bulk and amino acid nitrogen, we aimed to characterize isotopic fractionation occurring between parasites and their hosts and to clarify the trophic position of the parasites.

Our results showed that parasitic trophic interactions were more accurately identified when using compound-specific stable isotope analysis due to removal of underlying source isotopic variation for both parasites and hosts, and avoidance of the averaging of amino acid variability in bulk analyses through use of multiple trophic amino acids. The compound-specific method provided clear trophic discrimination factors in comparison to bulk isotope methods, however, those differences varied significantly among parasite species.

Amino acid compound specific isotope analysis has widely been applied to examine trophic position within food webs, but our analyses suggest that the method is particularly useful for clarifying the feeding strategies for parasitic species. Baseline isotopic information provided by source amino acids allows clear identification of the fractionation occurring due to parasite metabolism by integrating underlying isotopic variations from the host tissues. However, like for bulk isotope analysis, the application of a universal trophic discrimination factor to parasite-host relationships remains inappropriate for compound-specific stable isotope analysis. Despite this limitation, compound-specific stable isotope analysis is and will continue to be a valuable tool to increase our understanding of parasitic interactions in marine food webs.
An Essential Role of UBXN3B in B Lymphopoiesis
Authors: Geng Tingting , Yang Duomeng , Lin Tao , Harrison Andrew G. , Wang Binsheng , Torrance Blake , Wang Kepeng , Wang Yanlin , Yang Long , Haynes Laura , Cheng Gong , Vella Anthony T. , Fikrig Erol , Wang Penghua
Published: March 2021

Hematopoiesis is finely regulated to enable timely production of the right numbers and types of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential role of UBXN3B in maintenance of hematopoietic homeostasis and restriction of immunopathogenesis during respiratory viral infection.Ubxn3bdeficient (Ubxn3b−/−) mice are highly vulnerable to SARS-CoV-2 and influenza A infection, characterized by more severe lung immunopathology, lower virus-specific IgG, significantly fewer B cells, but more myeloid cells thanUbxn3b+/+littermates. This aberrant immune compartmentalization is recapitulated in uninfectedUbxn3b−/−mice. Mechanistically, UBXN3B controls precursor B-I (pre-BI) transition to pre-BII and subsequent proliferation in a cell-intrinsic manner, by maintaining BLNK protein stability and pre-BCR signaling. These results reveal an essential role of UBXN3B for the early stage of B cell development.
Decreased KATPchannel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets
Authors: Yang Juxiang , Hammoud Batoul , Li Changhong , Ridler Abigail , Yau Daphne , Kim Junil , Won Kyoung-Jae , Stanley Charles A. , Hoshi Toshinori , Stanescu Diana E.
Published: March 2021

Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We found a lower threshold for glucose-stimulated insulin secretion from freshly isolated embryonic day (E)22 rat islets, which persisted into the first postnatal days. The threshold reached the adult level by postnatal day (P)14. Culturing P14 islets also decreased the glucose threshold. Freshly isolated P1 rat islets had a lower threshold for insulin secretion in response to BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid), a non-metabolizable leucine analog, and diminished insulin release in response to tolbutamide, an inhibitor of β-cell KATPchannels. These findings suggested that decreased KATPchannel function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal a lower expression of KATPsubunit genes in E22 compared to P14 β-cells. The investigation of electrophysiological characteristics of dispersed β-cells showed that early neonatal and cultured cells had fewer functional KATPchannels per unit membrane area. Our findings suggest that decreased surface density of KATPchannels may contribute to the observed differences in glucose threshold for insulin release.
DMWAS: Deep Machine learning omics Wide Association Study & Feature set optimization by clustering & univariate association for Biomarkers discovery as tested on GTEx pilot dataset for death due to heart-attack
Authors: Singh Abhishek Narain
Published: March 2021

Univariate and multivariate methods for association of the genomic variations with the end-or-endo phenotype have been widely used for genome wide association studies. In addition to encoding the SNPs, we advocate usage of clustering as a novel method to encode the structural variations, SVs, in genomes, such as the deletions and insertions polymorphism (DIPs), Copy Number Variations (CNVs), translocation, inversion, etc., that can be used as an independent feature variable value for downstream computation by artificial intelligence methods to predict the endo-or-end phenotype. We introduce a clustering based encoding scheme for structural variations and omics based analysis. We conducted a complete all genomic variants association with the phenotype using deep learning and other machine learning techniques, though other methods such as genetic algorithm can also be applied. Applying this encoding of SVs and one-hot encoding of SNPs on GTEx V7 pilot DNA variation dataset, we were able to get high accuracy using various methods of DMWAS, and particularly found logistic regression to work the best for death due to heart-attack (MHHRTATT) phenotype. The genomic variants acting as feature sets were then arranged in descending order of power of impact on the disease or trait phenotype, which we call optimization and that also uses top univariate association into account. Variant Id P1_M_061510_3_402_P at chromosome 3 & position 192063195 was found to be most highly associated to MHHRTATT. We present here the top ten optimized genomic variant feature set for the MHHRTATT phenotypic cause of death.