bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases
Authors: Bustos Bernabe I. , Krainc Dimitri , Lubbe Steven J. ,   for The International Parkinson’s Disease Genomics Consortium (IPDGC)
Published: June 2020

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95×10−26, beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease- and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.
Cross-neutralization antibodies against SARS-CoV-2 and RBD mutations from convalescent patient antibody libraries
Authors: Lou Yan , Zhao Wenxiang , Wei Haitao , Chu Min , Chao Ruihua , Yao Hangping , Su Junwei , Li Yanan , Li Xiulan , Cao Yu , Feng Yanyan , Wang Ping , Xia Yongyang , Shang Yushuan , Li Fengping , Ge Pingju , Zhang Xinglin , Gao Wenjing , Du Bing , Liang Tingbo , Qiu Yunqing , Liu Mingyao
Published: June 2020

The emergence of coronavirus disease 2019 (COVID-19) pandemic led to an urgent need to develop therapeutic interventions. Among them, neutralizing antibodies play crucial roles for preventing viral infections and contribute to resolution of infection. Here, we describe the generation of antibody libraries from 17 different COVID-19 recovered patients and screening of neutralizing antibodies to SARS-CoV-2. After 3 rounds of panning, 456 positive phage clones were obtained with high affinity to RBD (receptor binding domain). Then the positive clones were sequenced and reconstituted into whole human IgG for epitope binning assays. After that, all 19 IgG were classified into 6 different epitope groups or Bins. Although all these antibodies were shown to have ability to bind RBD, the antibodies in Bin2 have more superiority to inhibit the interaction between spike protein and angiotensin converting enzyme 2 receptor (ACE2). Most importantly, the antibodies from Bin2 can also strongly bind with mutant RBDs (W463R, R408I, N354D, V367F and N354D/D364Y) derived from SARS-CoV-2 strain with increased infectivity, suggesting the great potential of these antibodies in preventing infection of SARS-CoV-2 and its mutations. Furthermore, these neutralizing antibodies strongly restrict the binding of RBD to hACE2 overexpressed 293T cells. Consistently, these antibodies effectively neutralized pseudovirus entry into hACE2 overexpressed 293T cells. In Vero-E6 cells, these antibodies can even block the entry of live SARS-CoV-2 into cells at only 12.5 nM. These results suggest that these neutralizing human antibodies from the patient-derived antibody libraries have the potential to become therapeutic agents against SARS-CoV-2 and its mutants in this global pandemic.
Quantitative nascent proteome profiling by dual pulse labeling withO-propargyl-puromycin and stable isotope labeled amino acids
Authors: Uchiyama Junki , Ishihama Yasushi , Imami Koshi
Published: June 2020

Monitoring translational regulation in response to environmental signals is crucial for understanding cellular proteostasis. However, only limited approaches are currently available for quantifying acute changes in protein synthesis induced by stimuli. Recently, a clickable puromycin analog,O-propargyl-puromycin (OPP), was developed and applied to label the C-termini of nascent polypeptide chains (NPCs). Following affinity purification via a click reaction, OPP allows for a proteomic analysis of NPCs. Despite its advantage, the affinity purification of NPCs using magnetic beads or resins inherently suffers from significant non-specific protein binding, which hinders accurate quantification of the nascent proteins. To address this issue, we employed dual pulse labeling of NPCs with both OPP and stable isotope labeled amino acids to distinguishbona fideNPCs from non-specific proteins, thereby enabling the accurate quantitative profiling of NPCs. We applied this method to dissecting the transcription-coupled translation responses and quantified ~3,000 nascent proteins. We found that the translation of a subset of ribosomal proteins (e.g., RPSA, RPLP0) as well as signaling proteins (e.g., BCAR3, EFNA1, DUSP1) was significantly repressed by transcription inhibition. Together, the present method provides an accurate and broadly applicable nascent proteome profiling for many biological applications at the level of translation.
Proinflammatory S100A9 Regulate Differentiation and Aggregation of Neural Stem Cells
Authors: Tian Yin , Cao Rui , Che Bingchen , Tang Yong , Jiang Lin , Qiao Bai , Liu Yonggang , Morozovaroche Ludmilla A , Zhang Ce
Published: June 2020

Inflammation is the primary pathological feature of neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease. Proinflammatory molecules (e.g. S100A9) play important roles during progression of the diseases by regulating behavior and fate of multiple cell types in the nervous system (1). Our earlier studies reveal that S100A9 is toxic to neurons, and its interaction with Aβpeptides leads to the formation of large non-toxic amyloidogenic aggregates, suggesting a protective role of Aβamyloids (2). We herein, demonstrate that S100A9 interacts with neural stem cells (NSCs) and causes NSC differentiation. In the brain of transgenic AD mouse models, we found large quantities of proinflammatory S100A9, which colocalizes with the differentiated NSCs. NSC sphere formation, which is a representative character of NSC stemness, is also substantially inhibited by S100A9. These results suggest that S100A9 is a representative marker for the inflammatory conditions in AD, and it promotes NSC differentiation. Intriguingly, in contrast to the death of both stem and differentiated NSCs caused by high S100A9 doses, S100A9 at a moderate concentration is toxic only to the early differentiated NSCs (i.e. progenitor cells and immature neurons), but not the stem cells. We therefore postulate that at the early stage of AD, expression of S100A9 leads to NSC differentiation, which remedies the neuron damages. The application drugs, which help maintain NSC stemness (e.g. PDGF), may help overcome the acute inflammatory conditions and improve the efficacy of NSC transplantation therapy.
Site-Specific Incorporation of Citrulline into Proteins in Mammalian Cells
Authors: Mondal Santanu , Wang Shu , Zheng Yunan , Sen Sudeshna , Chatterjee Abhishek , Thompson Paul R.
Published: June 2020

Citrullination is a post-translational modification (PTM) of arginine that is crucial for several physiological processes, including gene regulation and neutrophil extracellular trap formation. Despite recent advances, studies of protein citrullination remain challenging due to the difficulty of accessing proteins homogeneously citrullinated at a specific site. Herein, we report a novel technology that enables the site-specific incorporation of citrulline (Cit) into proteins in mammalian cells. This approach exploits anE. coli-derived engineered leucyl tRNA synthetase-tRNA pair that incorporates a photocaged-citrulline (SM60) into proteins in response to a nonsense codon. Subsequently,SM60is readily converted to Cit with lightin vitroand in living cells. To demonstrate the utility of the method, we biochemically characterized the effect of incorporating Cit at two known autocitrullination sites in Protein Arginine Deiminase 4 (PAD4, R372 and R374) and showed that the R372Cit and R374Cit mutants are 181- and 9-fold less active than the wild-type enzyme. This powerful technology possesses immense potential to decipher the biology of citrullination.
An In situ Collagen-HA Hydrogel System Promotes Survival and Preserves the Proangiogenic Secretion of hiPSC-derived Vascular Smooth Muscle Cells
Authors: Dash Biraja C. , Duan Kaiti , Xing Hao , Kyriakides Themis R. , Hsia Henry C.
Published: June 2020

Human induced pluripotent stem cell-derived vascular smooth muscle cells (hiPSC-VSMCs) with proangiogenic properties have huge therapeutic potential. While hiPSC-VSMCs have already been utilized for wound healing using a biomimetic collagen scaffold, an in situ forming hydrogel mimicking the native environment of skin offers the promise of hiPSC-VSMC mediated repair and regeneration. Herein, the impact of a collagen type-I-hyaluronic acid (HA) in situ hydrogel cross-linked using a PEG-based cross-linker on hiPSC-VSMCs viability and proangiogenic paracrine secretion was investigated. Our study demonstrated increases in cell viability, maintenance of phenotype and proangiogenic growth factor secretion, and proangiogenic activity in response to the conditioned medium. The optimally cross-linked and functionalized collagen type-I/HA hydrogel system developed in this study shows promise as an in situ hiPSC-VSMC carrier system for wound regeneration.
Single nucleus multi-omics regulatory atlas of the murine pituitary
Authors: Ruf-Zamojski Frederique , Zhang Zidong , Zamojski Michel , Smith Gregory R. , Mendelev Natalia , Liu Hanqing , Nudelman German , Moriwaki Mika , Pincas Hanna , Gomez Castanon Rosa , Nair Venugopalan D. , Seenarine Nitish , Amper Mary Anne S. , Zhou Xiang , Ongaro Luisina , Toufaily Chirine , Schang Gauthier , Nery Joseph R. , Bartlett Anna , Aldridge Andrew , Jain Nimisha , Childs Gwen V. , Troyanskaya Olga G. , Ecker Joseph R. , Turgeon Judith L. , Welt Corrine K. , Bernard Daniel J. , Sealfon Stuart C.
Published: June 2020

The pituitary regulates growth, reproduction and other endocrine systems. To investigate transcriptional network epigenetic mechanisms, we generated paired single nucleus (sn) transcriptome and chromatin accessibility profiles in single mouse pituitaries and genome-wide sn methylation datasets. Our analysis provided insight into cell type epigenetics, regulatory circuit and gene control mechanisms. Latent variable pathway analysis detected corresponding transcriptome and chromatin accessibility programs showing both inter-sexual and inter-individual variation. Multi-omics analysis of gene regulatory networks identified cell type-specific regulons whose composition and function were shaped by the promoter accessibility state of target genes. Co-accessibility analysis comprehensively identified putative cis-regulatory regions, including a domain 17kb upstream ofFshbthat overlapped the fertility-linked rs11031006 human polymorphism.In vitroCRISPR-deletion at this locus increasedFshblevels, supporting this domain’s inferred regulatory role. The sn pituitary multi-omics atlas (snpituitaryatlas.princeton.edu) is a public resource for elucidating cell type-specific gene regulatory mechanisms and principles of transcription circuit control.
Heterozygous, polyploid, giant bacterium,Achromatium, possesses an identical functional inventory worldwide across drastically different ecosystems
Authors: Ionescu Danny , Zoccarato Luca , Zaduryan Artur , Schorn Sina , Bižić Mina , Pinnow Solvig , Cypionka Heribert , Grossart Hans-Peter
Published: June 2020

Achromatiumis large, hyperpolyploid and the only known heterozygous bacterium. Single cells contain ca. 300 different chromosomes with allelic diversity typical of entire bacterial communities. Surveying all publicly available sediment sequence archives, we showAchromatiaare common worldwide, spanning temperature, salinity, pH, and depth ranges normally resulting in bacterial speciation. Nevertheless,Achromatiadisplay no ecotypic phylogenetic signal and contain a, globally identical, complete functional inventory.Achromatiacells from differing ecosystems (e.g. freshwater vs. saline) are, unexpectedly, equally functionally equipped but differ in gene expression patterns by transcribing only relevant genes. We suggest environmental adaptation occurs by increasing the copy number of relevant genes across the cell’s hundreds of chromosomes, without losing irrelevant ones, thus maintaining the ability to survive in any ecosystem type. The functional versatility ofAchromatium, and its genomic features, reveal alternative genetic and evolutionary mechanisms, expanding our understanding of the role and evolution of polyploidy in bacteria while challenging the bacterial species concept and drivers of bacterial speciation.
TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells
Authors: De La Cena Kyle Oliver Corcino , Ho Rachel Xi-Yeen , Amraei Razie , Woolf Nick , Tashjian Joseph Y. , Zhao Qing , Richards Sean , Walker Josh , Huang Juanni , Chitalia Vipul , Rahimi Nader
Published: June 2020

Colorectal cancer (CRC) is a leading non-familial cause of cancer mortality among men and women. Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remains incompletely understood. In this study, we demonstrate that cell adhesion molecule transmembrane and immunoglobulin domain containing1 (TMIGD1) is highly expressed in mouse and human normal intestinal epithelial cells. We have developed TMIGD1 knockout mice and show that the loss of TMIGD1 in mice results in the development of adenomas in small intestine and colon. Additionally, the loss of TMIGD1 in mouse impaired intestinal epithelium brush border formation, junctional polarity and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation, cell migration, arrests cell cycle at G2/M phase and induces expression of p21CIP1(cyclin-dependent kinase inhibitor 1), and p27KIP1(cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, we demonstrate that TMIGD1 is progressively downregulated in sporadic human CRC and correlates with poor overall survival. Our findings identify TMIGD1 as a novel tumor suppressor gene and provide insights into the pathogenesis of colorectal cancer and possibilities as a potential therapeutic target.
The histone methyltransferase SETD2 couples transcription and splicing by engaging pre-mRNA processing factors through its SHI domain
Authors: Bhattacharya Saikat , Levy Michaella J. , Zhang Ning , Li Hua , Florens Laurence , Washburn Michael P. , Workman Jerry L.
Published: June 2020

Heterogeneous ribonucleoproteins (hnRNPs) are RNA binding molecules that are involved in key processes such as RNA splicing and transcription. One such hnRNP protein, hnRNP L, regulates alternative splicing (AS) by binding to pre-mRNA transcripts. However, it is unclear what factors contribute to hnRNP L-regulated AS events. Using proteomic approaches, we identified several key factors that co-purify with hnRNP L. We demonstrate that one such factor, the histone methyltransferase SETD2, specifically interacts with hnRNP Lin vitroandin vivo. This interaction occurs through a previously uncharacterized domain in SETD2, the SETD2-hnRNP L Interaction (SHI) domain, the deletion of which, leads to a reduced H3K36me3 deposition. Functionally, SETD2 regulates a subset of hnRNP L-targeted AS events. Our findings demonstrate that SETD2 by interacting with Pol II as well as hnRNP L, can mediate the crosstalk between the transcription and the splicing machinery.
Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to energy sensing and autophagy
Authors: Amraei Razie , Alwani Tooba , Ho Rachel Xi-Yeen , Aryan Zahra , Wang Shawn , Rahimi Nader
Published: June 2020

Immunoglobulin (Ig) and proline-rich receptor-1 (IGPR-1) is a cell adhesion molecule that regulates angiogenesis and endothelial barrier function. IGPR-1 is activated by shear stress and mediates endothelial cell’s response to shear stress. Autophagy plays critical roles in the maintenance of endothelial cells in response to cellular stress caused by blood flow. However, whether IGPR-1 is activated in response to, and mediates autophagy remains unknown. In this study, we demonstrate that IGPR-1 is activated by autophagy inducing stimuli, such as amino acid starvation, nutrient deprivation, rapamycin and lipopolysaccharide (LPS). We have identified IκB kinaseβ (IKKβ) as a key serine/threonine kinase activated by autophagy stimuli and mediates phosphorylation of IGPR-1 at Ser220. Activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase (AMPK), which leads to phosphorylation of key pro-autophagy proteins, ULK1 and Beclin-1 (BECN1), increased LC3-II levels and accumulation of LC3 punctum. This study demonstrates that IGPR-1 is activated by and regulates autophagy, connecting cell adhesion to autophagy, a finding that has important significance for autophagy-driven pathologies such cardiovascular diseases and cancer.
A chromosome-level genome assembly for the Eastern Fence Lizard (Sceloporus undulatus), a reptile model for physiological and evolutionary ecology
Authors: Westfall Aundrea K. , Telemeco Rory S. , Grizante Mariana B. , Waits Damien S. , Clark Amanda D. , Simpson Dasia Y. , Klabacka Randy L. , Sullivan Alexis P. , Perry George H. , Sears Michael W. , Cox Christian L. , Cox Robert M. , Gifford Matthew E. , John-Alder Henry B. , Langkilde Tracy , Angilletta Michael J. , Leaché Adam D. , Tollis Marc , Kusumi Kenro , Schwartz Tonia S.
Published: June 2020

High-quality genomic resources facilitate population-level and species-level comparisons to answer questions about behavioral ecology, morphological and physiological adaptations, as well as the evolution of genomic architecture. Squamate reptiles (lizards and snakes) are particularly diverse in characteristics that have intrigued evolutionary biologists, but high-quality genomic resources for squamates are relatively sparse. Lizards in the genusSceloporushave a long history as important ecological, evolutionary, and physiological models, making them a valuable target for the development of genomic resources. We present a high-quality chromosome-level reference genome assembly, SceUnd1.0, (utilizing 10X Genomics Chromium, HiC, and PacBio data) and tissue/developmental stage transcriptomes for the Eastern Fence Lizard,Sceloporus undulatus. We performed synteny analysis with other available squamate chromosome-level assemblies to identify broad patterns of chromosome evolution including the fusion of micro- and macrochromosomes inS. undulatus. Using this newS. undulatusgenome assembly we conducted reference-based assemblies for 34 otherSceloporusspecies to improve draft nuclear genomes assemblies from 1% coverage to 43% coverage on average. Across these species, typically >90% of reads mapped for species within 20 million years divergence fromS. undulatus, this dropped to 75% reads mapped for species at 35 million years divergence. Finally we use RNAseq and whole genome resequencing data to compare the three assemblies as references, each representing an increased level of sequencing, cost and assembly efforts: Supernova Assembly with data from10X Genomics Chromium library; HiRise Assembly that added data from HiC library; and PBJelly Assembly that added data from PacBio sequencing. We found that the Supernova Assembly contained the full genome and was a suitable reference for RNAseq, but the chromosome-level scaffolds provided by the addition of the HiC data allowed the reference to be used for other whole genome analysis, including synteny and whole genome association mapping analyses. The addition of PacBio data provided negligible gains. Overall, these new genomic resources provide valuable tools for advanced molecular analysis of an organism that has become a model in physiology and evolutionary ecology.
Analysis of Hepatitis B virus genotype D in Greenland suggests presence of a novel subgenotype
Authors: de Bernardi Schneider Adriano , Hostager Reilly , Krarup Henrik , Børresen Malene , Tanaka Yasuhito , Morriseau Taylor , Osiowy Carla , Wertheim Joel O.
Published: June 2020

A disproportionate amount of Greenland’s Inuit population is chronically infected with Hepatitis B virus (HBV; 5-10%). HBV genotypes B and D are most prevalent in the circumpolar Arctic. Here, we report 39 novel HBV/D sequences from individuals residing in southwestern Greenland. We performed phylodynamic analyses with ancient HBV DNA calibrators to investigate the origin and relationship of these taxa to other HBV sequences. We inferred a substitution rate of 1.4×10−5 [95% HPD 8.8×10−6, 2.0×10−5] and a time to the most recent common ancestor of 629 CE [95% HPD 37-1138 CE]. The Greenland taxa form a sister clade to HBV/D2 sequences, specifically New Caledonian and Indigenous Taiwanese samples. The Greenland sequences share amino acid signatures with subgenotypes D1 and D2, and approximately 98% sequence identity. Our results suggest the classification of these novel sequences does not fit within the current nomenclature. Thus, we propose these taxa be a novel subgenotype.
Risk and protective factors of SARS-CoV-2 infection – Meta-regression of data from worldwide nations
Authors: Takagi Hisato , Kuno Toshiki , Yokoyama Yujiro , Ueyama Hiroki , Matsushiro Takuya , Hari Yosuke , Ando Tomo
Published: June 2020

Although it has been reported that coexistent chronic diseases are strongly associated with COVID-19 severity, investigations of predictors for SARS-CoV-2 infection itself have been seldom performed. To screen potential risk and protective factors for SARS-CoV-2 infection, meta-regression of data from worldwide nations were herein conducted. We extracted total confirmed COVID-19 cases in worldwide 180 nations (May 31, 2020), nation total population, population ages 0-14/≥65, GDP/GNI per capita, PPP, life expectancy at birth, medical-doctor and nursing/midwifery-personnel density, hypertension/obesity/diabetes prevalence, annual PM2.5 concentrations, daily ultraviolet radiation, population using safely-managed drinking-water/sanitation services and hand-washing facility with soap/water, inbound tourism, and bachelor’s or equivalent (ISCED 6). Restricted maximum-likelihood meta-regression in the random-effects model was performed using Comprehensive Meta-Analysis version 3. To adjust for other covariates, we conducted the hierarchical multivariate models. A slope (coefficient) of the meta-regression line for the COVID-19 prevalence was significantly negative for population ages 0-14 (–0.0636; P = .0021) and positive for obesity prevalence (0.0411; P = .0099) and annual PM2.5 concentrations in urban areas (0.0158; P = .0454), which would indicate that the COVID-19 prevalence decreases significantly as children increase and that the COVID-19 prevalence increases significantly as the obese and PM2.5 increase. In conclusion, children (negatively) and obesity/PM2.5 (positively) may be independently associated with SARS-CoV-2 infection.
Agriculture intensification reduces plant taxonomic and functional diversity across European arable systems
Authors: Carmona Carlos P. , Guerrero Irene , Peco Begoña , Morales Manuel B. , Oñate Juan J. , Pärt Tomas , Tscharntke Teja , Liira Jaan , Aavik Tsipe , Emmerson Mark , Berendse Frank , Ceryngier Piotr , Bretagnolle Vincent , Weisser Wolfgang W. , Bengtsson Jan
Published: June 2020

Agricultural intensification is one of the main drivers of species loss worldwide, but there is still a lack of information about its effect on functional diversity of arable weed communities.

Using a large‐scale pan European study including 786 fields within 261 farms from eight countries, we analysed differences in the taxonomic and functional diversity of arable weeds assemblages across different levels of agricultural intensification. We estimated weed species frequency in each field, and collected species' traits (vegetative height, SLA and seed mass) from the TRY plant trait database. With this information, we estimated taxonomic (species richness), functional composition (community weighted means) and functional diversity (functional richness, evenness, divergence and redundancy). We used indicators of agricultural management intensity at the individual field scale (e.g. yield, inputs of nitrogen fertilizer and herbicides, frequency of mechanical weed control practices) and at the landscape scale surrounding the field (i.e. number of crop types, mean field size and proportion of arable land cover within a radius of 500 m from the sampling points).

The effects of agricultural intensification on species and functional richness at the field scale were stronger than those of intensification at the landscape scale, and we did not observe evidence of interacting effects between the two scales. Overall, assemblages in more intensified areas had fewer species, a higher prevalence of species with ruderal strategies (low stature, high leaf area, light seeds), and lower functional redundancy.

Maintaining the diversity of Europe's arable weed communities requires some simple management interventions, for example, reducing the high intensity of field‐level agricultural management across Europe, which could be complemented by interventions that increase landscape complexity.

A free Plain Language Summary can be found within the Supporting Information of this article.
Divergent adaptations in resource‐use traits explain how pikas thrive on the roof of the world
Authors: Feijó Anderson , Ge Deyan , Wen Zhixin , Xia Lin , Yang Qisen
Published: June 2020

Life in extreme environments is possible through multilevel adaptations to physical and biotic stresses. At high elevations, species face numerous challenges, besides low oxygen levels, but previous studies have focused on genetic and physiological adaptations to chronic hypoxia while overlooking other key strategies for thriving in alpine landscapes.

Here, we investigate resource‐use trait adaptations to extreme elevations using pikas as a model, lagomorphs distributed up to 6,200 m and reaching maximum diversity on the Qinghai‐Tibet plateau, the highest plateau on Earth. Specifically, we assess cranial evolution in pikas using geometric morphometric and phylogenetic comparative techniques to determine whether adaptations among high‐elevation biota shown at the molecular and physiological levels also occur in resource‐use traits. We further explore the roles of two contrasting lifestyles (burrowing and rocky‐dwelling) in cranial evolution.

We found that alpine species exhibit striking phenotypic specialization to distinct microhabitats. Contrary to physiological and genetic adaptive convergence, we show that the cranium has undergone adaptive divergence likely reflecting past resource competition in highlands and long‐term association with alpine landscapes. Our analyses also reveal that the evolution of burrowing lifestyle allows high‐elevation pikas to explore novel niches and boosts their phenotypic diversification. In addition to cold and hypoxia tolerance, high cranial specialization, the appearance of burrowing habits and strong niche separation explain how pikas overcome alpine stresses and flourish on the highest plateau on Earth. By contrast, when moving to spatially complex and heterogeneous vegetation zonation, pikas exhibit generalist skull forms able to exploit diverse habitats. These findings mirror previously reported intraspecific patterns in mammals, suggesting a general morphological response in resource‐exploiting traits to cope with distinct selection pressures across elevation zones. Phenotypic diversity is further constrained by rocky habitats, resulting in convergent skulls.

Our study highlights that adaptations to extreme environments occur at multiple levels of organization, but can lead to distinct evolutionary paths depending on which selective forces they respond to. The evolution of burrowing behaviour represents a landmark in the evolutionary history of pikas. We further show that rocky habitats impose strong ecological pressures, leading to convergent responses in resource‐use traits, which is rarely documented in mammals.
Resource availability drives microevolutionary patterns of plant defences
Authors: López‐Goldar Xosé , Zas Rafael , Sampedro Luis
Published: June 2020

The resource availability hypothesis (RAH) was formulated to disentangle patterns of variation among species in plant antiherbivore defences. A novel theoretical framework was recently proposed to expand the RAH among populations within species (RAHintra), but unresolved conceptual issues and considerable gaps surrounding the new hypothesis still need to be addressed.

Here we tested the RAHintra predictions in a pine tree species using population‐level correlations among plant traits and climate as a proxy of resource availability. We analysed genetic variation among 10 maritime pine populations in growth, constitutive and induced chemical defences and resistance to herbivory in a glasshouse experiment. We used a clonally replicated collection with family structure and accounted for the neutral genetic differentiation with Single Nucleotide Polymorphism (SNPs) data.

Most of our results agree with the predictions of the RAHintra. As postulated, growth showed a positive relation with resource availability at population origin. Constitutive investment in phenolics (but not in terpenes) and antiherbivore resistance was also positively related to resource availability at population origin, as theory predicts. Conversely, we did not detect relationships between resource availability and the inducibility of any of the traits. A trade‐off between constitutive investment and inducibility of chemical defences was observed for phenolics, as expected, but not for terpenes. A positive relationship between growth and constitutive resistance was also found likely due to reduced physiological constraints under suitable conditions in the glasshouse experiment.

Our study provides evidence and support for the RAHintra, highlighting the strong influence of resource availability in shaping genetically based patterns of local adaptive variation among populations. We detected clinal patterns in phenolic investment along a resource availability gradient, suggesting that population local adaptation to resource availability has more implications for investment in phenolics than for terpenes. Most patterns emerged only after accounting for the neutral processes in the species, not initially conceived in the RAHintra. Neutral differentiation, as a result of non‐adaptive demographic processes and population isolation, may obscure the influence of resource availability as a driver responsible of local adaptation of populations.

A free Plain Language Summary can be found within the Supporting Information of this article.
Effects of elk and bison carcasses on soil microbial communities and ecosystem functions in Yellowstone, USA
Authors: Risch Anita C. , Frossard Aline , Schütz Martin , Frey Beat , Morris Aaron W. , Bump Joseph K.
Published: June 2020

Carrion is long recognized as important to scavengers. How carrion may affect soil microbial biodiversity and ecosystem processes in natural systems is comparatively unknown, but is important for the intersection of vertebrate food webs, below‐ground processes and ecological heterogeneity.

We assessed in situ soil and plant responses to wolf‐killed mammal carrion in Yellowstone National Park, USA.

Bison and elk carcasses increased soil respiration and vegetation nutrient concentration and the carcasses contain altered bacterial and fungal communities compared to control plots. The ‘fingerprints’ of soil microbial taxa associated with bison compared to elk carcasses differed considerably and taxa are found dependent upon abiotic gradients and soil properties.

We found evidence that soil microbial community changes associated with carcasses may not be as generalizable as previously thought, which is important for a mechanistic understanding of the links between carrion and soil heterogeneity and potentially for applications in forensic science.

This work demonstrates the importance of carrion studies in natural systems. Our findings show that carrion creates distinct ecological patterns that contribute to both above‐ and below‐ground biological heterogeneity, linking carrion distribution dynamics with soil microbial biodiversity and ecosystem functions.
Floral resource diversity drives bee community diversity in prairie restorations along an agricultural landscape gradient
Authors: Lane Ian G. , Herron‐Sweet Christina R. , Portman Zachary M. , Cariveau Daniel P.
Published: June 2020

Grassland ecosystems are imperiled by agricultural activity world‐wide. Restoring grassland habitat is important to conserving grassland fauna and preserving ecosystem services, but more knowledge is needed on the impact that local and landscape factors have on patterns of diversity. We focused on whether prairie grassland restorations along a gradient of increasing agricultural cover in the surrounding landscape would be inhabited by less diverse and/or more homogenous native bee communities. Native bees are a specific target for many grassland restoration efforts, and supporting their local and β‐diversity in reconstructed habitats is of mounting interest. We also investigated if higher floral resource richness within restorations could help ameliorate negative effects of agricultural landscapes.

We sampled 16 prairie restorations in Minnesota (USA) that varied along a gradient of increasing agricultural land cover around the site. We characterized floral resource richness at all sites beginning in mid‐May and ending in mid‐September. We used GLMMs and multivariate analyses to disentangle how floral resource richness and percentage of surrounding land cover in agricultural production are associated with the local and β‐diversity of bee communities.

Local bee diversity increased with increasing local floral resource richness, independent of the surrounding landscape. Bee β‐diversity was not impacted by local floral resource richness or percentage of agricultural cover in the surrounding landscape, indicating local and landscape factors are not substantially impacting the homogeneity of bee communities across restorations.

Synthesis and applications. We found that, regardless of agricultural cover in the surrounding landscape, more florally rich plantings attract more diverse bee communities. We recommend that habitat plantings prioritize local scale diversity, and that potential sites where the landscape is dominated by agricultural production should not be overlooked for restoration.
Managing interacting disturbances: Lessons from a case study in Australian forests
Authors: Lindenmayer David B. , Foster Claire N. , Westgate Martin J. , Scheele Ben C. , Blanchard Wade
Published: June 2020

Ecosystems are shaped by a range of drivers including human and natural disturbances. They also may be subject to interactions between disturbances which can affect ecological processes, biodiversity and ecosystem condition; yet few ecosystems have been subject to multiple studies of the effects of interacting disturbances. This limits the understanding of ways to mitigate the impacts of interacting disturbances.

Over the past 37 years, we have completed a range of studies of interacting effects in the Mountain Ash Eucalyptus regnans forests of south‐eastern Australia. Here we summarize evidence for interacting disturbances in this ecosystem. This includes evidence of linked or coupled disturbances (termed interaction chains; sensu Foster et al., Global Change Biology, 22, 2016, 1325) between logging and subsequent fire severity. We also describe effects of other interacting disturbances such as those resulting from post‐fire (salvage) logging as well as landscape‐level, spatio‐temporal changes in forest cover associated with logging and wildfires.

Policy implications. Insights from research in Mountain Ash forests provide broader lessons for managing interacting disturbances in forest ecosystems. These include the importance of cataloguing and mapping multiple disturbances in both space and time and developing conceptual models of ecosystem dynamics and ecological processes. Where there is a high risk of interactions between disturbances, appropriate management actions could include: (a) eliminating some drivers or re‐assessing levels of human extraction of resources, (b) reducing the spatial and/or temporal overlap of drivers and (c) identifying leverage points where management actions are most likely to be effective.
The Strength of Far‐Right AfD in Eastern Germany: The East‐West Divide and the Multiple Causes behind ‘Populism’
Authors: Weisskircher Manès
Published: June 2020

This article sheds light on one of the key developments in recent German politics and relates it to the broader debate on the electoral success of the far right. The rise of the Alternative für Deutschland (AfD, Alternative for Germany) is also a story about Germany’s internal political divide three decades after reunification, as the party has roughly twice as much support in the east than in the west. The article analyses the country’s east‐west divide, strongly visible in widespread sentiments of societal marginalisation among eastern Germans. The key socio‐structural differences between the east and the west relate to matters of economics, migration, and representation—and provide a setting suitable to AfD strength in the east. In explaining the party’s electoral success in eastern Germany, the article echoes recent scholarship which rejects narrow explanations for the strength of ‘populism’, and instead highlights its multiple causes.
Reflex cytology for triage of high‐risk human papillomavirus positive self‐sampled material in cervical cancer screening: a prospective cohort study
Authors: Loopik DL , Melchers WJG , Vedder JEM , van den Brule AJC , Massuger LFAG , Bekkers RLM , Siebers AG
Published: June 2020

Objective

High‐risk human papillomavirus (HrHPV)‐positive women detected by self‐sampling require an extra visit at the general practitioner for additional cytology testing, but the loss to follow up within this triage is substantial. The aim of this study was to evaluate the clinical utility of reflex cytology on hrHPV‐positive self‐samples for immediate stratification of women who need referral for colposcopy.

Design

A prospective cohort study.

Setting

Two Dutch cervical cancer‐screening laboratories.

Population

1014 screenees who tested hrHPV‐positive on self‐samples between 1 December 2018 and 1 August 2019.

Methods

Self‐samples were directly used for cytological analysis. Cytological and histological outcomes during follow up were obtained from the Dutch Pathology Registry (PALGA).

Main outcome measures

Test performance of reflex cytology on self‐samples was determined for different thresholds and compared with physician‐taken cytology and histological outcomes.

Results

Reflex cytology on self‐samples for detecting abnormal cytology showed a sensitivity of 26.4% (95% CI 21.8–31.3) and specificity of 90.5% (95% CI 87.7–92.8). Of all ≥CIN2 cases, 29.4% (95% CI 22.5–37.1) were detected with reflex cytology on self‐samples. The positive predictive value for detection of ≥CIN2 was higher with cytology on self‐collected samples than on physician‐collected samples. Of women who were lost to follow up, 12.9% were found to have abnormal cytology on their self‐sampled material.

Conclusion

Cytology testing is achievable on hrHPV‐positive self‐samples, could decrease the loss to follow up in screening and is easily implementable in the current clinical practice. Of all hrHPV‐positive women with abnormal cytology on additional physician‐collected samples, 26.4% could have been directly referred for colposcopy if triage with reflex cytology on self‐sampled material had been performed.

Tweetable abstract

Reflex cytology for triage of hrHPV+ self‐samples is of added value for direct referral of women for colposcopy.
Occurrence, sources, and pathways of chemical contaminants in infant formulas
Authors: de Mendonça Pereira Bianca Figueiredo , de Almeida Cristine Couto , Leandro Katia Christina , da Costa Marion Pereira , Conte‐Junior Carlos Adam , Spisso Bernardete Ferraz
Published: June 2020

Infant formulas are manufactured products to meet specific nutritional requirements for infants. However, infant formulas can contain harmful substances, such as chemical contaminants and residues, normally due to possible contamination of the raw material or from the production chain. Some studies have demonstrated that veterinary drugs, pesticides, mycotoxins, heavy metals, packaging materials, within other chemicals are found in infant formulas from different sources of contamination. It is known that some of these substances can be hepatotoxic, carcinogenic, teratogenic, mutagenic, immunotoxic, contributing to antibiotic resistance, among other detrimental consequences for consumers’ health. The purpose of this review is to assess the scientific evidence concerning the occurrence, sources, and pathways of contamination, as well as the detrimental impacts on infant health due to the possible presence of chemical contaminants and residues in infant formulas. Moreover, strategies to reduce the risk of contamination of infant formulas are presented to ensure the highest standards of quality of infant formulas. The entire infant formula manufacturing process should be monitored and controlled to minimize the risk of contamination during processing, storage, and distribution, besides ensuring the use of raw materials with as low as acceptable levels of harmful substances in order to assure that the final product shall comply with the maximum levels and maximum residue limits, when established, for residues and contaminants in the final product.
COVID‐19 of dialysis patients in Japan: Current status and guidance on preventive measures
Authors:   COVID‐19 Task Force Committee of the Japanese Association of Dialysis Physicians,   The Japanese Society for Dialysis Therapy,   The Japanese Society of Nephrology, Kikuchi Kan , Nangaku Masaomi , Ryuzaki Munekazu , Yamakawa Tomoyuki , Hanafusa Norio , Sakai Ken , Kanno Yoshihiko , Ando Ryoichi , Shinoda Toshio , Nakamoto Hidetomo , Akizawa Tadao
Published: June 2020

In Japan, the first case of COVID‐19 in dialysis patients was reported on March 1, 2020. A total of 31 cases were reported by April 10, and it increased to 95 by May 15. Thereafter, with the rapid increase in the number of COVID‐19 cases in the general population since late March, there was a not surprising increase in the number of COVID‐19 cases in dialysis patients. The mortality rate is 16.2% (16/99 cases) in dialysis patients, which is higher than 5.3% (874/16 532 cases) in the general population. This higher mortality rate in dialysis patients with COVID‐19 might be related to their age; the majority of COVID‐19 cases are aged between 70 and 90 years old in dialysis patients, compared with between 20 and 60 years old in the general population. As COVID‐19 presents with severe symptoms and is associated with a high mortality rate in dialysis patients, dialysis patients who have contracted severe acute respiratory syndrome coronavirus 2 infection confirmed by polymerase chain reaction testing are required to be hospitalized under Japanese government policy. In cases of COVID‐19 hospitalizations, it is essential to prevent nosocomial infection. Therefore, patients must be sufficiently instructed in infection prevention and robust measures to prevent contraction and spread of the infection must be taken at dialysis facilities.
Whole nuña bean (Phaseolus vulgaris L.) flour showed higher direct expansion during extrusion processing at relatively lower temperatures
Authors: Pietrysiak Ewa , Zhu Yujing , Gu Bon‐Jae , Ganjyal Girish M.
Published: June 2020

Nuña bean, also known as “popping” bean, belongs to the group of common beans (Phaseolus vulgaris, L.). Originated in Andean mountains, nuña beans is an important food crop in several South American countries, including Bolivia, Ecuador, and Peru, where it is consumed primarily as a snack. Nuña beans are highly nutritious and have a distinctive nutty flavor, which makes them potentially desirable ingredients in food applications, such as extruded snacks. Thus, the goal of this study was to evaluate the performance of whole seed nuña bean flour during extrusion cooking. Expansion characteristics of whole nuña bean flour were investigated using a twin‐screw extruder. Three levels of moisture contents of 15%, 18%, and 21% (wet basis), three barrel temperatures of 120, 140, and 160 °C, and three screw speeds of 150, 200, and 250 rpm were evaluated, with a die diameter of 3.15 mm. The expansion ratio (ER) ranged from 1.41 to 3.03, within the extrusion conditions studied. The moisture content and screw speed were found to have the most significant impact on the ER. Lower temperature and higher screw speed resulted in higher ER. The maximum ER of 3.03 was observed at a moisture content of 15%, a barrel temperature of 120 °C, and a screw speed of 250 rpm. Nuña bean flour exhibited good expansion properties at relatively low temperatures, which highlights its potential for use in extruded food applications such as nutritious snacks.

Practical Application

There is increasing consumer demand for more nutritional snacks and cereals. Nuña bean flour exhibited potential for use in such nutritious products. This provides the industry with an alternative source of protein and fiber for inclusion in expanded food products.
Interstitial eosinophilic infiltration in diabetic nephropathy is indicative of poor prognosis, with no therapy benefit from steroid
Authors: Wu Wen‐yan , Zhou Xu‐jie , Sun Ping‐ping , Yu Xiao‐juan , Wang Su‐xia , Qu Lei , Zhang Fan , Ma Yi‐yi , Lv Ji‐cheng , Liu Gang , Yang Li
Published: June 2020

Background

Studies suggested that eosinophils in diabetes might be associated with severity of diabetic nephropathy (DN). In a retrospective study of 102 Chinese patients with biopsy‐proven DN, we aimed to evaluate relationships of both blood and renal eosinophils (Eos) to the severity of DN and check whether Eos can serve as an indicator of prognosis as well as the therapeutic effect of steroids.

Methods

One hundred and two patients diagnosed with DN were enrolled. Demographical and clinical data and histopathological scores were associated. Interstitial eosinophilic aggregates (IEA) were defined as the presence of ≥10 Eos in at least one high‐power field. End‐stage renal disease was defined as the end point.

Results

We observed that log2 (blood eosinophil counts) correlated with neutrophil counts, proteinuria, and tubulointerstitial inflammatory cell infiltration. IEA was observed in 33.3% of the DN patients and was associated with decreased estimated glomerular filtration rate, higher proteinuria, hematuria, higher HbA1c, increased blood eosinophil counts, tubular injury, tubulointerstitial chronicity, and interstitial inflammation. IEA was associated with worse renal prognosis (hazard ratio [HR] 2.424, P = 0.008). Consistently, urine eosinophil cationic protein (ECP) (ng/mgCr) was associated with renal injury and poor renal prognosis (HR 1.173, P = 0.020). Patients with IEA were more likely to be treated with steroid/immunosuppressants (47.1% vs 14.7%, P = 0.001) but did not show renal benefit.

Conclusions

It suggested that both blood and renal infiltrated eosinophils were prevalent in DN and associated with severity of DN. IEA in renal pathology showed better fit in correlation with renal prognosis. Treatment with steroid/immunosuppressants showed no significant improvement regarding renal prognosis.