bluuebunny/crossref_metadata_2025 huggingface dataset:
Intersectional Discrimination and Change in Blood Pressure Control Among Older Adults: The Health and Retirement Study
Authors: Sims Kendra D , Smit Ellen , Batty G David , Hystad Perry W , Odden Michelle C
Published: August 2021

Background

Associations between multiple forms of discrimination and blood pressure control in older populations remain unestablished.

Methods

Participants were 14 582 noninstitutionalized individuals (59% women) in the Health and Retirement Study aged at least 51 years (76% non-Hispanic White, 15% non-Hispanic Black, 9% Hispanic/Latino). Primary exposures included the mean frequency of discrimination in everyday life, intersectional discrimination (defined as marginalization ascribed to more than one reason), and the sum of discrimination over the life span. We assessed whether discrimination was associated with a change in measured hypertension status (N = 14 582) and concurrent medication use among reported hypertensives (N = 9 086) over 4 years (2008–2014).

Results

There was no association between the frequency of everyday discrimination and change in measured hypertension. Lifetime discrimination was associated with higher odds of hypertension 4 years later among men (odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.08–1.36) but not women (OR: 0.98, 95% CI: 0.86–1.13). Only among men, everyday discrimination due to at least 2 reasons was associated with a 1.44-fold (95% CI: 1.03–2.01) odds of hypertension than reporting no everyday discrimination, reporting intersectional discrimination was not associated with developing hypertension among women (OR: 0.91, 95% CI: 0.70–1.20). All 3 discriminatory measures were inversely related to time-averaged antihypertensive medication use, without apparent gender differences (eg, OR for everyday discrimination–antihypertensive use associations: 0.85, 95% CI: 0.77–0.94).

Conclusions

Gender differences in marginalization may more acutely elevate hypertensive risk among older men than similarly aged women. Experiences of discrimination appear to decrease the likelihood of antihypertensive medication use among older adults overall.
Compact magnetization vector inversion
Authors: Ghalehnoee Mohammad Hossein , Ansari Abdolhamid
Published: August 2021

Magnetization vector inversion (MVI) has attracted considerable attention in recent years since by this inversion both distribution of the magnitude and direction of the magnetization are obtained; therefore, it is easy to distinguish between the magnetic causative bodies especially when magnetic data are affected by different remanent magnetization. In this research, the compact magnetization vector inversion is presented: a 3-D magnetic modelling is proposed from surface data measurements to obtain compact magnetization distribution. The equations are solved in data-space least squares and the algorithm includes a combination of two weights as depth weighting and compactness weighting in the Cartesian system. The re-weighted compactness weighting matrix handles sparsity constraints imposed on the magnitude of magnetization for varying Lp-norms ($0 \le p \le 2$). The low value of the norm leads to more focused or compact inversion, and using a large value of p obtains a smooth model. The method is validated with two synthetic examples, the first is a cube that has significant remanent magnetization and the second consists of two causative cube bodies with significant different magnetization directions at different depths. The case study is the magnetic data of Galinge iron ore deposit (China) that the apparent susceptibility and magnetization directions are reconstructed. The compact model reveals that the results agree with drilling and geological information.
Propagation of a precursory detachment front along a seismogenic plate interface in a rate–state friction model of earthquake cycles
Authors: Kato Naoyuki
Published: August 2021

A numerical simulation of earthquake cycles at the subduction zone of a plate interface was conducted, using a rate- and state-dependent friction law, to examine aseismic sliding processes propagating into a locked plate interface. In the model, a reverse fault is assumed in a 2-D uniform elastic half-space, and relative plate motion is imposed with a constant velocity. Simulated earthquakes occur repeatedly at a shallower seismogenic plate interface with a velocity-weakening frictional property, while stable sliding occurs in the deeper part, in which a velocity-strengthening frictional property is assumed. During interseismic periods, deep stable sliding causes shear stress to concentrate at the deeper edge of the locked plate interface, and a partial drop in stress occurs, resulting in plate detachment. The resulting detachment front propagates upwards along the seismogenic plate interface until an earthquake occurs, causing aseismic sliding with a sliding velocity significantly lower than the imposed relative plate velocity. The propagation velocity of the detachment front is almost constant in each case, and it is proportional to the relative plate velocity and inversely proportional to the effective normal stress. Episodic events of increased slip velocity occur in the latter half of an interseismic period when the characteristic slip distance is small. Updip propagation of episodic slip is arrested by a low stress barrier, and episodic slips backpropagate downdip. During the final few years of the simulation cycle, the average sliding velocity is approximately inversely proportional to the time to occurrence for a large interplate earthquake.
Conditional and Relevant Common Information
Authors: Graczyk Robert , Lapidoth Amos , Wigger Michèle
Published: August 2021

Two variations on Wyner’s common information are proposed: conditional common information and relevant common information. These are shown to have operational meanings analogous to those of Wyner’s common information in appropriately defined distributed problems of compression, simulation and channel synthesis. For relevant common information, an additional operational meaning is identified: on a multiple-access channel with private and common messages, it is the minimal common-message rate that enables communication at the maximum sum-rate under a weak coordination constraint on the inputs and output. En route, the weak-coordination problem over a Gray-Wyner network is solved under the no-excess-rate constraint.
Optimal portfolio execution with a Markov chain approximation approach
Authors: Chen Jingnan , Feng Liming , Peng Jiming , Zhang Yu
Published: August 2021

We study the problem of executing a large multi-asset portfolio in a short time period where the objective is to find an optimal trading strategy that minimizes both the trading cost and the trading risk measured by quadratic variation. We contribute to the existing literature by considering a multi-dimensional geometric Brownian motion model for asset prices and proposing an efficient Markov chain approximation (MCA) approach to obtain the optimal trading trajectory. The MCA approach allows us not only to numerically compute the optimal strategy but also to theoretically analyse the influence of factors such as price impact, risk aversion and initial asset price on the optimal strategy, providing both quantitative and qualitative guidance on the trading behaviour. Numerical results verify the theoretical conclusions in the paper. They further illustrate the effects of cross impact and correlations on the optimal execution strategy in a multi-asset liquidation problem.
Row orientation affects the uniformity of light absorption, but hardly affects crop photosynthesis in hedgerow tomato crops
Authors: van der Meer Maarten , de Visser Pieter H B , Heuvelink Ep , Marcelis Leo F M
Published: August 2021

Light distribution within canopies is important for plant growth. We aimed to quantify the influence of row orientation on inter- and within-row variation of light absorption and photosynthesis in a hedgerow crop. An experiment with two row orientations of a tomato crop was conducted which was then used to calibrate a functional–structural plant model (FSPM). The FSPM was used to analyse light absorption and photosynthesis for each of the row facing directions in the double-row trellis system (e.g. north- and south-facing rows for the east–west row orientation). The measured leaf area decreased by 18 % and specific leaf area by 10 %, while fruit dry weight increased by 7 % for south-facing compared to north-facing rows, but total plant dry weight did not significantly differ. Model simulations showed a 7 % higher light absorption for the south-facing rows than north-facing rows, while net photosynthesis was surprisingly −4 % lower, due to local light saturation. When in the model leaf area was kept equal between the rows, light absorption for the south-facing rows was 19 % and net photosynthesis 8 % higher than for north-facing rows. We conclude that although south-facing rows would be expected to have a higher photosynthesis than north-facing rows, plants can adapt their morphology such that differences in light absorption and photosynthesis between north- and south-facing rows are minimal. Rows oriented north–south were more uniform in light absorption and photosynthesis than east–west rows, but the overall crop light absorption and photosynthesis were minimally affected (both 3 % lower compared to east–west orientation).
Detecting effective starting point of genomic selection by divergent trends from best linear unbiased prediction and single-step genomic best linear unbiased prediction in pigs, beef cattle, and broilers
Authors: Abdollahi-Arpanahi Rostam , Lourenco Daniela , Misztal Ignacy
Published: August 2021

Genomic selection has been adopted nationally and internationally in different livestock and plant species. However, understanding whether genomic selection has been effective or not is an essential question for both industry and academia. Once genomic evaluation started being used, estimation of breeding values with pedigree best linear unbiased prediction (BLUP) became biased because this method does not consider selection using genomic information. Hence, the effective starting point of genomic selection can be detected in two possible ways including the divergence of genetic trends and Realized Mendelian sampling (RMS) trends obtained with BLUP and single-step genomic BLUP (ssGBLUP). This study aimed to find the start date of genomic selection for a set of economically important traits in three livestock species by comparing trends obtained using BLUP and ssGBLUP. Three datasets were used for this purpose: 1) a pig dataset with 117k genotypes and 1.3M animals in pedigree, 2) an Angus cattle dataset consisted of ~842k genotypes and 11.5M animals in pedigree, and 3) a purebred broiler chicken dataset included ~154k genotypes and 1.3M birds in pedigree were used. The genetic trends for pigs diverged for the genotyped animals born in 2014 for average daily gain (ADG) and backfat (BF). In beef cattle, the trends started diverging in 2009 for weaning weight (WW) and in 2016 for postweaning gain (PWG), with little divergence for birth weight (BTW). In broiler chickens, the genetic trends estimated by ssGBLUP and BLUP diverged at breeding cycle 6 for two out of the three production traits. The RMS trends for the genotyped pigs diverged for animals born in 2014, more for ADG than for BF. In beef cattle, the RMS trends started diverging in 2009 for WW and in 2016 for PWG, with a trivial trend for BTW. In broiler chickens, the RMS trends from ssGBLUP and BLUP diverged strongly for two production traits at breeding cycle 6, with a slight divergence for another trait. Divergence of the genetic trends from ssGBLUP and BLUP indicates the onset of the genomic selection. The presence of trends for RMS indicates selective genotyping, with or without the genomic selection. The onset of genomic selection and genotyping strategies agrees with industry practices across the three species. In summary, the effective start of genomic selection can be detected by the divergence between genetic and RMS trends from BLUP and ssGBLUP.
Why are Jews Forbidden to Eat Meat and Milk Together? the Function of Eating Restrictions in Human Societies
Authors: Viezel Eran , Avieli Nir
Published: August 2021

The prohibition against eating meat and milk together is among the most widely known legal requirements in Judaism. This prohibition is not mentioned explicitly in the Bible (the Biblical commandment not to boil a kid in its mother’s milk does not necessarily imply its post-Biblical interpretation), and it apparently was not known even at the end of the Second Temple period. However, in the first centuries of the common era it was firmly established, and to this day it is a practice that distinguishes religiously observant Jews from the non-observant. Over the course of Jewish history, the prohibition against eating meat and milk together was at the centre of many lively discussions. The sages sought to justify and explain the prohibition in a variety of ways, and the considerations they raised show the complexity that arises from the encounter of daily eating practices with the dictates of faith. In this paper, we will examine the different explanations proposed, and we will propose a new solution to the question of the explanation for this restriction, along with other dietary restrictions recognized in world religions.
‘God has had Mercy on Me’: Theology and Soteriology in Philo of Alexandria’s de Sacrificiis Abelis et Caini
Authors: Mackie Scott D
Published: August 2021

Philo of Alexandria’s treatise De sacrificiis Abelis et Caini offers a rich example of his theology and soteriology. The majestic God of De sacrificiis is transcendent, omnipresent, and absolutely unique. Anthropomorphic and anthropopathic conceptions of God also are memorably discussed and dismissed. Standing in tension with these ontological characteristics are relational attributes of God, which often are expressed in redemptive acts. Thus, the merciful God of De sacrificiis ‘transcends his transcendence’, and compassionately reaches out to humans in need. A full array of soteriological themes populate the pages of the treatise, including the war against the passions, the allegory of the soul, transformative revelatory experiences, salvific worship, contemplative ascent, and the vision of God. Furthermore, the agential acts and roles played by God and humans are complexly intertwined, demonstrating a sophisticated, experientially informed soteriology. Though these important Philonic themes typically are interpreted thematically and systemically, thus ‘ironing out’ any idiosyncrasies, this essay closely attends to the particular thought of this treatise. As a consequence, unique elements and emphases emerge, which in addition to distinctive depictions of divine compassion and soteriological agency, include a Stoic emphasis on reason, the relative absence of mediatorial figures, and a rare portrayal of an unequivocal visio Dei.
Chlamydomonas proteases: classification, phylogeny, and molecular mechanisms
Authors: Zou Yong , Bozhkov Peter V
Published: August 2021

Proteases can regulate myriad biochemical pathways by digesting or processing target proteins. While up to 3% of eukaryotic genes encode proteases, only a tiny fraction of proteases are mechanistically understood. Furthermore, most of the current knowledge about proteases is derived from studies of a few model organisms, including Arabidopsis thaliana in the case of plants. Proteases in other plant model systems are largely unexplored territory, limiting our mechanistic comprehension of post-translational regulation in plants and hampering integrated understanding of how proteolysis evolved. We argue that the unicellular green alga Chlamydomonas reinhardtii has a number of technical and biological advantages for systematic studies of proteases, including reduced complexity of many protease families and ease of cell phenotyping. With this end in view, we share a genome-wide inventory of proteolytic enzymes in Chlamydomonas, compare the protease degradomes of Chlamydomonas and Arabidopsis, and consider the phylogenetic relatedness of Chlamydomonas proteases to major taxonomic groups. Finally, we summarize the current knowledge of the biochemical regulation and physiological roles of proteases in this algal model. We anticipate that our survey will promote and streamline future research on Chlamydomonas proteases, generating new insights into proteolytic mechanisms and the evolution of digestive and limited proteolysis.
Persistent homology of the cosmic web – I. Hierarchical topology in ΛCDM cosmologies
Authors: Wilding Georg , Nevenzeel Keimpe , van de Weygaert Rien , Vegter Gert , Pranav Pratyush , Jones Bernard J T , Efstathiou Konstantinos , Feldbrugge Job
Published: August 2021

Using a set of Lambda cold dark matter simulations of cosmic structure formation, we study the evolving connectivity and changing topological structure of the cosmic web using state-of-the-art tools of multiscale topological data analysis (TDA). We follow the development of the cosmic web topology in terms of the evolution of Betti number curves and feature persistence diagrams of the three (topological) classes of structural features: matter concentrations, filaments and tunnels, and voids. The Betti curves specify the prominence of features as a function of density level, and their evolution with cosmic epoch reflects the changing network connections between these structural features. The persistence diagrams quantify the longevity and stability of topological features. In this study, we establish, for the first time, the link between persistence diagrams, the features they show, and the gravitationally driven cosmic structure formation process. By following the diagrams’ development over cosmic time, the link between the multiscale topology of the cosmic web and the hierarchical buildup of cosmic structure is established. The sharp apexes in the diagrams are intimately related to key transitions in the structure formation process. The apex in the matter concentration diagrams coincides with the density level at which, typically, they detach from the Hubble expansion and begin to collapse. At that level many individual islands merge to form the network of the cosmic web and a large number of filaments and tunnels emerge to establish its connecting bridges. The location trends of the apex possess a self-similar character that can be related to the cosmic web’s hierarchical buildup. We find that persistence diagrams provide a significantly higher and more profound level of information on the structure formation process than more global summary statistics like Euler characteristic or Betti numbers.
To “Fill Up, Completely, the Whole Capacity of the Mind”: Listening with Attention in Late Eighteenth-Century Scotland
Authors: Raz Carmel
Published: August 2021

This essay explores a hitherto unsuspected intellectual relationship among three important thinkers of the Scottish Enlightenment. The great philosopher and economist Adam Smith is known to have had a conception of instrumental music exceptional for his time in its foreshadowing of ideas generally associated with Eduard Hanslick. As I show here, Smith’s views were decisively influenced by the psychological theories of his countryman Thomas Reid in all likelihood by way of the extraordinary proto-cognitivist music theory of their contemporary John Holden, in particular the latter’s conceptualization of the faculty of attention. The innovative contributions of these writers constitute a compact and suggestive case study in the circulation of ideas about perception and listening between philosophy and music, and suggest that the Scottish Enlightenment attitude to psychology enabled a new kind of theorizing about the musical experience: one that foregrounded the importance of the faculty of attention in the process of perceiving music and sound.
Structural basis of l-tryptophan-dependent inhibition of release factor 2 by the TnaC arrest peptide
Authors: Su Ting , Kudva Renuka , Becker Thomas , Buschauer Robert , Komar Tobias , Berninghausen Otto , von Heijne Gunnar , Cheng Jingdong , Beckmann Roland
Published: August 2021

In Escherichia coli, elevated levels of free l-tryptophan (l-Trp) promote translational arrest of the TnaC peptide by inhibiting its termination. However, the mechanism by which translation-termination by the UGA-specific decoding release factor 2 (RF2) is inhibited at the UGA stop codon of stalled TnaC-ribosome-nascent chain complexes has so far been ambiguous. This study presents cryo-EM structures for ribosomes stalled by TnaC in the absence and presence of RF2 at average resolutions of 2.9 and 3.5 Å, respectively. Stalled TnaC assumes a distinct conformation composed of two small α-helices that act together with residues in the peptide exit tunnel (PET) to coordinate a single L-Trp molecule. In addition, while the peptidyl-transferase center (PTC) is locked in a conformation that allows RF2 to adopt its canonical position in the ribosome, it prevents the conserved and catalytically essential GGQ motif of RF2 from adopting its active conformation in the PTC. This explains how translation of the TnaC peptide effectively allows the ribosome to function as a L-Trp-specific small-molecule sensor that regulates the tnaCAB operon.
A novel view on an old drug, 5-fluorouracil: an unexpected RNA modifier with intriguing impact on cancer cell fate
Authors: Chalabi-Dchar Mounira , Fenouil Tanguy , Machon Christelle , Vincent Anne , Catez Frédéric , Marcel Virginie , Mertani Hichem C , Saurin Jean-Christophe , Bouvet Philippe , Guitton Jérôme , Venezia Nicole Dalla , Diaz Jean-Jacques
Published: August 2021

5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by altering DNA metabolism. However, 5-FU mode of action is more complex than previously anticipated since 5-FU is an extrinsic source of RNA modifications through its ability to be incorporated into most classes of RNA. In particular, a recent report highlighted that, by its integration into the most abundant RNA, namely ribosomal RNA (rRNA), 5-FU creates fluorinated active ribosomes and induces translational reprogramming. Here, we review the historical knowledge of 5-FU mode of action and discuss progress in the field of 5-FU-induced RNA modifications. The case of rRNA, the essential component of ribosome and translational activity, and the plasticity of which was recently associated with cancer, is highlighted. We propose that translational reprogramming, induced by 5-FU integration in ribosomes, contributes to 5-FU-driven cell plasticity and ultimately to relapse.
Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1
Authors: Nicholas Taylor R , Metcalf Stephanie A , Greulich Benjamin M , Hollenhorst Peter C
Published: August 2021

Ewing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5′ EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5′ EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5′ EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to either early transcription termination, or breakpoint formation.
Capitalism needs a new social contract
Authors: Shafik Minouche
Published: August 2021

Capitalism needs a new social contract to better manage the consequences of technology and an increasingly diverse and flexible workforce. That social contract should retain the benefits of flexibility but do a better job of providing security in the form of mandatory benefits, putting a floor on incomes, and investing far more in helping workers adapt to economic shocks and rising automation. It also means a new deal with business that would achieve a more level playing field in how capital and labour are taxed.
Phenotyping stomatal closure by thermal imaging for GWAS and TWAS of water use efficiency-related genes
Authors: Pignon Charles P , Fernandes Samuel B , Valluru Ravi , Bandillo Nonoy , Lozano Roberto , Buckler Edward , Gore Michael A , Long Stephen P , Brown Patrick J , Leakey Andrew D B
Published: August 2021

Stomata allow CO2 uptake by leaves for photosynthetic assimilation at the cost of water vapor loss to the atmosphere. The opening and closing of stomata in response to fluctuations in light intensity regulate CO2 and water fluxes and are essential for maintaining water-use efficiency (WUE). However, a little is known about the genetic basis for natural variation in stomatal movement, especially in C4 crops. This is partly because the stomatal response to a change in light intensity is difficult to measure at the scale required for association studies. Here, we used high-throughput thermal imaging to bypass the phenotyping bottleneck and assess 10 traits describing stomatal conductance (gs) before, during and after a stepwise decrease in light intensity for a diversity panel of 659 sorghum (Sorghum bicolor) accessions. Results from thermal imaging significantly correlated with photosynthetic gas exchange measurements. gs traits varied substantially across the population and were moderately heritable (h2 up to 0.72). An integrated genome-wide and transcriptome-wide association study identified candidate genes putatively driving variation in stomatal conductance traits. Of the 239 unique candidate genes identified with the greatest confidence, 77 were putative orthologs of Arabidopsis (Arabidopsis thaliana) genes related to functions implicated in WUE, including stomatal opening/closing (24 genes), stomatal/epidermal cell development (35 genes), leaf/vasculature development (12 genes), or chlorophyll metabolism/photosynthesis (8 genes). These findings demonstrate an approach to finding genotype-to-phenotype relationships for a challenging trait as well as candidate genes for further investigation of the genetic basis of WUE in a model C4 grass for bioenergy, food, and forage production.
Letter to editor: Emerging public health challenge in UK: perception and belief on increased COVID19 death among BAME healthcare workers
Authors: Omotade I , Flisher P , Sivalingam T , Gupta S , Kuah J
Published: August 2021

A cross-sectional survey of Black Asian and minority ethnic (BAME) health care workers evaluating their perception and belief on increased Coronavirus disease-19 (COVID-19) death among BAME health care workers was conducted in Leicester. They found that 72% of respondents had some form of impact on their mental health but the majority were satisfied with the overall support they received from local health care providers. In conclusion, adequate culturally competent mental health support is necessary as the BAME workforce is routinely involved in frontline work.
A Theory of Liquidity Spillover between Bond and CDS Markets
Authors: Sambalaibat Batchimeg
Published: August 2021

I build a search model of bond and credit default swap (CDS) markets with endogenous investor participation and show that shorting bonds through CDS increases the liquidity and price of bonds. By allowing investors to trade the credit risk of bonds without trading the bonds, CDS introduction expands the set of feasible trades and attracts investors into the credit market. Because search is nondirected within the credit market, new investors also trade bonds and consequently increase their price and liquidity. My results suggest that naked CDS bans increased sovereigns’ borrowing costs and thereby exacerbated the 2010–2012 European debt crisis.
XV American Literature to 1900
Authors: McGettigan Katie , White Rebecca
Published: August 2021

This chapter has two sections: 1. Journals; 2. Monographs and Edited Collections. Section 1 is by Katie McGettigan; section 2 is by Katie McGettigan and Rebecca White.
The molecular and cellular basis of copper dysregulation and its relationship with human pathologies
Authors: Maung May T. , Carlson Alyssa , Olea‐Flores Monserrat , Elkhadragy Lobna , Schachtschneider Kyle M. , Navarro‐Tito Napoleon , Padilla‐Benavides Teresita
Published: August 2021

Copper (Cu) is an essential micronutrient required for the activity of redox‐active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+‐transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.
The impact of seasonal factors on the COVID-19 pandemic waves
Authors: Nesteruk Igor , Rodionov Oleksii , Nikitin Anatolii
Published: August 2021

The daily number of new COVID-19 cases per capita is an important characteristic of the pandemic dynamics indicating the appearance of new waves (e.g., caused by new coronavirus strains) and indicate the effectiveness of quarantine, testing and vaccination. Since this characteristic is very random and demonstrates some weekly period, we will use the 7-days smoothing. The second year of the pandemic allows us to compare its dynamics in the spring and the summer of 2020 with the same period in 2021 and investigate the influence of seasonal factors. We have chosen some northern countries and regions: Ukraine, EU, the UK, USA and some countries located in tropical zone and south semi-sphere: India, Brazil, South Africa and Argentina. The dynamics in these regions was compared with COVID-19 pandemic dynamics in the whole world. Some seasonal similarities are visible only for EU and South Africa. In 2020, the southern countries demonstrated the exponential growth, but northern regions showed some stabilization trends.
Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility
Authors: Talwar James , Laub David , Pagadala Meghana , Castro Andrea , Lewis McKenna , Luebeck Georg E. , Gorman Bryan , Pan Cuiping , Dong Frederick N. , Markianos Kyriacos , Hauger Richard , Pyarajan Saiju , Tsao Philip S. , Morris Gerald P. , Salem Rany M. , Thompson Wesley K. , Curtius Kit , Zanetti Maurizio , Carter Hannah
Published: August 2021

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T-cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo and psoriasis predisposing MHC-I alleles conferred a melanoma protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (N = 451) and an independent validation cohort (N = 586), MHC-I autoimmune allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veterans Program cohort (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRS) did not predict autoimmune allele carrier status, suggesting these alleles provide new risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles (population frequency > 1%). However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte conserved antigens suggesting a potential relationship between antigen processing, binding, and cell-surface presentation. Overall, this study presents evidence that MHC-I autoimmune risk alleles modulate melanoma risk unaccounted for by current PRS.
Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant
Authors: Liu Yang , Liu Jianying , Johnson Bryan A. , Xia Hongjie , Ku Zhiqiang , Schindewolf Craig , Widen Steven G. , An Zhiqiang , Weaver Scott C. , Menachery Vineet D. , Xie Xuping , Shi Pei-Yong
Published: August 2021

SARS-CoV-2 Delta variant has rapidly replaced the Alpha variant around the world. The mechanism that drives this global replacement has not been defined. Here we report that Delta spike mutation P681R plays a key role in the Alpha-to-Delta variant replacement. In a replication competition assay, Delta SARS-CoV-2 efficiently outcompeted the Alpha variant in human lung epithelial cells and primary human airway tissues. Delta SARS-CoV-2 bearing the Alpha-spike glycoprotein replicated less efficiently than the wild-type Delta variant, suggesting the importance of Delta spike in enhancing viral replication. The Delta spike has accumulated mutation P681R located at a furin cleavage site that separates the spike 1 (S1) and S2 subunits. Reverting the P681R mutation to wild-type P681 significantly reduced the replication of Delta variant, to a level lower than the Alpha variant. Mechanistically, the Delta P681R mutation enhanced the cleavage of the full-length spike to S1 and S2, leading to increased infection via cell surface entry. In contrast, the Alpha spike also has a mutation at the same amino acid (P681H), but the spike cleavage from purified Alpha virions was reduced compared to the Delta spike. Collectively, our results indicate P681R as a key mutation in enhancing Delta variant replication via increased S1/S2 cleavage. Spike mutations that potentially affect furin cleavage efficiency must be closely monitored for future variant surveillance.
Differential regulation and production of secondary metabolites among isolates of the fungal wheat pathogenZymoseptoria tritici
Authors: Amine Hassani M. , Oppong-Danquah Ernest , Feurtey Alice , Tasdemir Deniz , Stukenbrock Eva H.
Published: August 2021

The genome of the wheat pathogenic fungus,Zymoseptoria tritici,represents extensive presence-absence variation in gene content. Here, we addressed variation in biosynthetic gene clusters (BGCs) content and biochemical profiles among three isolates. We analysed secondary metabolite properties based on genome, transcriptome and metabolome data. The isolates represent highly distinct genome architecture, but harbor similar repertoire of BGCs. Expression profiles for most BGCs show comparable patterns of regulation among the isolates, suggesting a conserved “biochemical infection program”. For all three isolates, we observed a strong up-regulation of an abscisic acid (ABA) gene cluster during biotrophic host colonization, indicating thatZ. triticipotentially interfere with host defenses by the biosynthesis of this phytohormone. Further, duringin vitrogrowth the isolates show similar metabolomes congruent with the predicted BGC content. We assessed if secondary metabolite production is regulated by histone methylation using a mutant impaired in formation of facultative heterochromatin (H3K27me3). In contrast to other ascomycete fungi, chromatin modifications play a less prominent role in regulation of secondary metabolites. In summary, we show thatZ. triticihas a conserved program of secondary metabolite production contrasting the immense variation in effector expression, some of these metabolites might play a key role during host colonization.

Originality-Significance Statement

Zymoseptoria triticiis one of the most devastating pathogens of wheat. So far the molecular determinants of virulence and their regulation are poorly understood. Previous studies have focused on proteinasous virulence factors and their extensive diversity. In this study, we focus on secondary metabolites produced byZ. tritici. Using a comparative framework, we here characterize core and non-core metabolites produced byZ. triticiby combining genome, transcriptome and metabolome datasets. Our findings indicate highly conserved biochemical profiles contrasting genetic and phenotypic diversity of the field isolates investigated here. This discovery has relevance for future crop protection strategies.
microRNA Expression Levels Change in Neonatal Patients During and After Exposure to Cardiopulmonary Bypass
Authors: Hsieh Lance , Tu Lan , Paquette Alison , Kibiryeva Nataliya , Marshall Jennifer , Bittel Douglas , O’Brien James , Vickers Kasey , Pastuszko Peter , Nigam Vishal
Published: August 2021

Objectives

The systemic inflammation that occurs after exposure to cardiopulmonary bypass (CPB), which is especially severe in neonatal patients, is associated with poorer outcomes and is not well understood. In order to gain deeper insight into how exposure to bypass activates inflammatory responses in circulating leukocytes, we studied changes in microRNA (miRNA) expression during and after exposure to bypass. miRNAs are small non-coding RNAs that have important roles in modulating protein levels and function of cells.

Methods

We performed miRNA-Sequencing on leukocytes isolated from neonatal cardiopulmonary bypass patients (N=5) at 7 timepoints during the process of CPB, including prior to the initiation of bypass, during bypass, and at three time points during the first 24 hours after weaning from bypass. We identified significant differentially expressed miRNAs using generalized linear regression models, and miRNAs were defined as statistically significant using an FDR adjusted p <0.05. We identified gene targets of these miRNAs using the Targetscan database, and identified significantly enriched biological pathways for these gene targets.

Results

We identified 54 miRNAs with differential expression during and after CPB. These miRNAs clustered into 3 groups, including miRNAs that were increased during and after CPB (3 miRNAs), miRNAs that decreased during and after CPB (10 miRNAs), and miRNAs that decreased during CPB but then increased 8-24 hours after CPB. 38.9% of the target genes of these miRNAs were significantly differentially expressed in our previous study. miRNAs with altered expression levels are predicted to significantly modulate pathways related to inflammation and signal transduction.

Conclusions

The unbiased profiling of the miRNA changes that occur in the circulating leukocytes of bypass patients provides deeper insight into the mechanisms that underpin the systemic inflammatory response that occurs in patients after exposure to cardiopulmonary bypass. These data will help the development of novel treatments and biomarkers for bypass associated inflammation.
Cross-species incompatibility between a DNA satellite and the Drosophila Spartan homolog poisons germline genome integrity
Authors: Brand Cara L. , Levine Mia T.
Published: August 2021

Satellite DNA spans megabases of eukaryotic sequence and evolves rapidly. Paradoxically, satellite-rich genomic regions mediate strictly conserved, essential processes like chromosome segregation and nuclear structure. A leading resolution to this paradox posits that satellite DNA and satellite-associated chromosomal proteins coevolve to preserve these essential functions. We experimentally test this model of intra-genomic coevolution by conducting the first evolution-guided manipulation of both chromosomal protein and DNA satellite. The 359bp satellite spans an 11Mb array in D. melanogaster that is absent from its sister species, D. simulans. This species-specific DNA satellite colocalizes with the adaptively evolving, ovary-enriched protein, Maternal Haploid (MH)–the Drosophila homolog of Spartan. To determine if MH and 359 coevolve, we swapped the D. simulans version of MH (“MH[sim]”) into D. melanogaster. MH[sim] triggers ovarian cell death, reduced ovary size, and loss of mature eggs. Surprisingly, the D. melanogaster mh null mutant has no such ovary phenotypes, suggesting that MH[sim] is toxic in a D. melanogaster background. Using both cell biology and genetics, we discovered that MH[sim] poisons oogenesis through a DNA damage pathway. Remarkably, deleting the D. melanogaster-specific 359 satellite array completely restores mh[sim] germline genome integrity and fertility, consistent with a history of coevolution between these two fast-evolving loci. Germline genome integrity and fertility are also restored by overexpressing Topoisomerase II (Top2), suggesting that MH[sim] interferes with Top2-mediated processing of 359. The observed 359-MH[sim] cross-species incompatibility supports a model under which ostensibly inert repetitive DNA and essential chromosomal proteins must coevolve to preserve germline genome integrity.
Gametogenesis in the green seaweed Ulva mutabilis coincides with massive transcriptional restructuring
Authors: Liu Xiaojie , Blomme Jonas , Bogaert Kenny , D’hondt Sofie , Wichard Thomas , De Clerck Olivier
Published: August 2021

The molecular mechanism underlying sexual reproduction in land plants is well understood in model plants and is a target for crop improvement. However, unlike land plants, the genetic basis involved in triggering reproduction and gamete formation remains elusive in most seaweeds, which are increasingly viewed as an alternative source of functional food and feedstock for energy applications. Here, gametogenesis of Ulva mutabilis, a model organism for green seaweeds, is studied. We analyze transcriptome dynamics at different time points during gametogenesis following induction of reproduction by fragmentation and removal of sporulation inhibitors. Analyses demonstrate that 45% of the genes in the genome are differentially expressed during gametogenesis. We identified several transcription factors that potentially play a key role in the early gametogenesis of Ulva given the function of their homologs in higher plants and microalgae. In particular, the detailed expression pattern of an evolutionary conserved transcription factor containing an RWP-RK domain suggests a key role during Ulva gametogenesis. The identification of putative master regulators of gametogenesis provides a starting point for further functional characterization.

Highlight

Transcriptomic analyses of gametogenesis in the green seaweed Ulva highlight the importance of a conserved RWP-RK transcription factor in induction of sexual reproduction.
Caught in Motion: Human NTHL1 Undergoes Interdomain Rearrangement Necessary for Catalysis
Authors: Carroll Brittany L. , Zahn Karl E. , Hanley John P. , Wallace Susan S. , Dragon Julie A. , Doublié Sylvie
Published: August 2021

Base excision repair (BER) is the main pathway protecting cells from the continuous damage to DNA inflicted by reactive oxygen species. BER is initiated by DNA glycosylases, each of which repairs a particular class of base damage. NTHL1, a bifunctional DNA glycosylase, possesses both glycolytic and ß-lytic activities with a preference for oxidized pyrimidine substrates. Defects in human NTLH1 drive a class of polyposis colorectal cancer. We report the first X-ray crystal structure of hNTHL1, revealing an open conformation not previously observed in the bacterial orthologs. In this conformation, the six-helical barrel domain comprising the helix-hairpin-helix (HhH) DNA binding motif is tipped away from the iron sulphur cluster-containing domain, requiring a conformational change to assemble a catalytic site upon DNA binding. We found that the flexibility of hNTHL1 and its ability to adopt an open configuration can be attributed to an interdomain linker. Swapping the human linker sequence for that of Escherichia coli yielded a protein chimera that crystallized in a closed conformation and had a lower binding affinity for lesion-containing DNA. This large scale interdomain rearrangement during catalysis is unprecedented for a HhH superfamily DNA glycosylase and provides important insight into the molecular mechanism of hNTHL1.
Nearest-neighbor effects modulate loxP spacer DNA chemical shifts and guide oligonucleotide design for NMR studies
Authors: Wagner Nicole , Foster Mark P.
Published: August 2021

Cre recombinase catalyzes site-specific DNA recombination at pseudo-palindromic loxP sites through two rounds of strand cleavage, exchange, and religation. Cre is a potential gene editing tool of interest due its lack of requirements for external energy sources or host factors, as well as the fact that it does not generate potentially cytotoxic double-stranded DNA breaks. However, broader applications of Cre in editing noncanonical target sequences requires a deeper understanding of the DNA features that enable target site selection and efficient recombination. Although Cre recombines loxP DNA in a specific and ordered fashion, it makes few direct contacts to the loxP spacer, the region where recombination occurs. Furthermore, little is known about the structural and dynamic features of the loxP spacer that make it a suitable target for Cre. To enable NMR spectroscopic studies of the spacer, we have aimed to identify a fragment of the 34-bp loxP site that retains the structural features of the spacer while minimizing the spectral crowding and line-broadening seen in longer oligonucleotides. We report sequential backbone resonance assignments for loxP oligonucleotides of varying lengths and evaluate chemical shift differences, Δδ, between the oligos. Analysis of flanking sequence effects and mutations on spacer chemical shifts indicates that nearest-neighbor and next-nearest-neighbor effects dominate the chemical environment experienced by the spacer. We have identified a 16-bp oligonucleotide that adequately preserves the structural environment of the spacer, setting the stage for NMR-based structure determination and dynamics investigations.