bluuebunny/crossref_metadata_2025 huggingface dataset:
Are Referees and Editors in Economics Gender Neutral?*
Authors: Card David , DellaVigna Stefano , Funk Patricia , Iriberri Nagore
Published: November 2019

We study the role of gender in the evaluation of economic research using submissions to four leading journals. We find that referee gender has no effect on the relative assessment of female- versus male-authored papers, suggesting that any differential biases of male referees are negligible. To determine whether referees as a whole impose different standards for female authors, we compare citations for female- and male-authored papers, holding constant referee evaluations and other characteristics. We find that female-authored papers receive about 25% more citations than observably similar male-authored papers. Editors largely follow the referees, resulting in a 1.7 percentage point lower probability of a revise and resubmit verdict for papers with female authors relative to a citation-maximizing benchmark. In their desk rejection decisions, editors treat female authors more favorably, though they still impose a higher bar than would be implied by citation maximization. We find no differences in the informativeness of female versus male referees or in the weight that editors place on the recommendations of female versus male referees. We also find no differences in editorial delays for female- versus male-authored papers.
A coaxially extruded heterogeneous core–shell fiber with Schwann cells and neural stem cells
Authors: Li Xinda , Zhou Dezhi , Jin Zhizhong , Chen Hongqing , Wang Xuanzhi , Zhang Xinzhi , Xu Tao
Published: November 2019

Cellular therapies play a critical role in the treatment of spinal cord injury (SCI). Compared with cell-seeded conduits, fully cellular grafts have more similarities with autografts, and thus might result in better regeneration effects. In this study, we fabricated Schwann cell (SC)-neural stem cell (NSC) core–shell alginate hydrogel fibers in a coaxial extrusion manner. The rat SC line RSC96 and mouse NSC line NE-4C were used in this experiment. Fully cellular components were achieved in the core portion and the relative spatial positions of these two cells partially mimic the construction of nerve fibers in vivo. SCs were demonstrated to express more genes of neurotrophic factors in alginate shell. Enhanced proliferation and differentiation tendency of NSCs was observed when they were co-cultured with SCs. This model has strong potential for application in SCI repair.
Enhanced osteogenesis of hydroxyapatite scaffolds by coating with BMP-2-loaded short polylactide nanofiber: a new drug loading method for porous scaffolds
Authors: Xu Taotao , Sheng Luyao , He Lei , Weng Jie , Duan Ke
Published: November 2019

Porous hydroxyapatite (HA) is widely used in porous forms to assist bone defect healing. However, further improvements in biological functions are desired for meeting complex clinical situations such as impaired bone regeneration in poor bone stock. The extracellular matrix (ECM) of human tissues is characterized by nanofibrous structures and a variety of signal molecules. Emulating these characteristics are expected to create a favorable microenvironment for cells and simultaneously allow release of osteogenic molecules. In this study, short polylactide fibers containing BMP-2 were prepared by electrospinning and coated on porous HA scaffolds. The coating did not affect porosity or pore interconnectivity of the scaffold but improved its compressive strength markedly. This fiber coating produced burst BMP-2 release in 1 day followed by a linear release for 24 days. The coating had a significantly lower rat calvarial osteoblasts (RCOBs) adhesion (vs. uncoated scaffold) but allowed normal proliferation subsequently. Bone marrow stem cells (MSCs) on the coated scaffolds expressed a significantly increased alkaline phosphatase activity relative to the uncoated ones. After implantation in canine dorsal muscles, the coated scaffolds formed significantly more new bone at Weeks 4 and 12, and more blood vessels at Week 12. This method offers a new option for drug delivery systems.
Is the Risk of Sea Level Rise Capitalized in Residential Real Estate?
Authors: Murfin Justin , Spiegel Matthew
Published: November 2019

Using a comprehensive database of coastal home sales merged with data on elevation relative to local tides, we compare prices for houses based on their inundation threshold under projections of sea level rise. The analysis separates the sensitivity of housing to rising seas from other confounding characteristics by exploiting cross-sectional differences in relative sea level rise due to vertical land motion. This provides variation in the expected time to inundation for properties of similar elevation and distance from the coast. In a variety of specifications and test settings, we find precisely estimated null results suggesting limited price effects.
Sectarianism, the Nonconformist Conscience, and ‘British Pluralism’: The Digital Humanities and the Language of Home Rule, c.1910–1914
Authors: Colbrook Stephen
Published: November 2019

In recent years, historians have reassessed the political importance of the third Home Rule Bill. Important works by G. K. Peatling, Daniel Jackson, and David Thackeray have overturned the once-dominant view that the measure was a straightforward distraction from social reform. Yet, this scholarship has focused almost exclusively on the response of Unionists to Home Rule, and few works discuss the measure’s significance for Edwardian Liberals. This article rectifies this historiographical oversight by comparing the Liberal and Unionist response to the third Home Rule Bill in Devonshire and Lancashire. Using techniques from the digital humanities, I have shown that the measure dominated the grassroots political discourse of both parties before the First World War.
Disentangling the Mechanisms of Retirement Adjustment: Determinants and Consequences of Subjective Well-Being
Authors: Hansson Isabelle , Buratti Sandra , Thorvaldsson Valgeir , Johansson Boo , Berg Anne Ingeborg
Published: November 2019

Retirement from work is a major life event requiring adaptation to new life circumstances. The resource-based dynamic model of retirement adjustment suggests that well-being will change due to changes in individual resources. In the present study, we test this hypothesis by investigating longitudinal and bidirectional associations between life satisfaction and perceived resources (i.e., self-esteem, autonomy, social support, self-rated physical health, self-rated cognitive ability, and financial satisfaction) over a 4-year period in the transition from work to retirement. Our sample included annual assessment data from 497 older adults (aged 60–66) in the population-based HEalth, Ageing, and Retirement Transitions in Sweden (HEARTS) study. Results from bivariate latent change score models showed weak but consistent associations between changes in perceived resources and changes in life satisfaction over the retirement transition. Analyses of cross-lagged effects also revealed bidirectional associations. Self-esteem, self-rated physical health, and total resource capability were positively related to changes in life satisfaction, and life satisfaction was positively related to changes in self-esteem, autonomy, self-rated physical health, and self-rated cognitive ability. The total resource capability accounted for 12% of the changes in life satisfaction in the first years following retirement. Life satisfaction accounted for 16% of the changes in autonomy in the transition from work to retirement. Our findings demonstrate that perceived resources are important for life satisfaction in the retirement transition, at the same time as overall life satisfaction accounts for how we perceive and evaluate our own resources during this process.
Minute and diverse in fossil sticky stuff: Tanytarsini (Diptera: Chironomidae) from early Eocene Indian Cambay amber
Authors: Zakrzewska Marta , Singh Hukam , Wagner-Wysiecka Ewa , Giłka Wojciech
Published: November 2019

We here present a pioneering systematic review of fossil dipterans of the tribe Tanytarsini (family Chironomidae) discovered in Indian amber from Cambay. The specimens examined belong to five species: Gujaratomyia miripes,Stempellina stebneri sp. nov., Stempellinella pollex sp. nov., Tanytarsus forfex sp. nov. andTanytarsus ramus sp. nov., which are described. All species belong to the oldest known Tanytarsini and come from the Cambay shale formation in Tadkeshwar, dated to the early Eocene (~54 Mya). Displaying unusual characters/structures of diagnostic and phylogenetic importance, the specimens studied are discussed against the background of the evolution and systematics of the oldest fossil (Eocene) and extant representatives in the tribe. An updated checklist and key to the identification of genera and species of Tanytarsini from Eocene amber is also provided. The spectral characteristics and physical properties of Cambay amber are similar to those of glessite resins, which are discussed in detail in order to substantiate the identity of the amber and the origin of the inclusions studied.
DUSP22 suppresses prostate cancer proliferation by targeting the EGFR‐AR axis
Authors: Lin Hsiu‐Ping , Ho Hui‐Min , Chang Cheng‐Wei , Yeh Shauh‐Der , Su Yu‐Wen , Tan Tse‐Hua , Lin Wen‐Jye
Published: November 2019

Dual‐specificity phosphatases (DUSPs) regulate the activity of various downstream kinases through serine or threonine or tyrosine dephosphorylation. Loss of function and aberrant expression of DUSPs has been implicated in cancer progression and poor survival, yet the function of DUSP22 in prostate cancer (PCa) cells is not clear. Gene Expression Omnibus and cBioPortal microarray database analyses showed that DUSP22 expression was lower in PCa tissues than normal prostate tissues, and altered DUSP22 expression was associated with shorter progression‐free and disease‐free survival of patients with PCa. Exogenous DUSP22 expression in LNCaP, PC3, and C4‐2B PCa cells inhibited cellular proliferation and colony formation, supporting a growth inhibitory role for DUSP22 in PCa cells. DUSP22 expression significantly attenuated epidermal growth factor (EGF) receptor (EGFR) and its downstream ERK1/2 signaling by dephosphorylation. However, DUSP22 failed to suppress the growth of CWR22Rv1 and DU145 cells with elevated phosphorylated (p‐)ERK1/2 levels. A serine‐to‐alanine mutation at position 58, a potential ERK1/2‐targeted phosphorylation site in DUSP22, was sufficient to suppress growth of CWR22Rv1 cells with elevated p‐ERK1/2 levels, suggesting a mutually antagonistic relationship between DUSP22 and ERK1/2 dependent on phosphorylation status. We showed that DUSP22 can suppress prostate‐specific antigen gene expression through phosphatase‐dependent pathways, suggesting that DUSP22 is an important regulator of the androgen receptor (AR) in PCa cells. Mechanistically, DUSP22 can interact with AR as a regulatory partner and interfere with EGF‐induced AR phosphorylation at Tyr534, suggesting that DUSP22 serves as a crucial suppressor of both EGFR and AR‐dependent signaling in PCa cells via dephosphorylation. Our findings indicate that loss of function of DUSP22 in PCa cells leads to aberrant activation of both EGFR‐ERKs and AR signaling and ultimately progression of PCa, supporting the potential for novel therapeutic design of harnessing DUSP22 in the treatment of PCa.—Lin, H.‐P., Ho, H.‐M., Chang, C.‐W., Yeh, S.‐D., Su, Y.‐W., Tan, T.‐H., Lin, W.‐J. DUSP22 suppresses prostate cancer proliferation by targeting the EGFR‐AR axis. FASEB J. 33, 14653‐14667 (2019). www.fasebj.org
Valuing Carbon Stocks across a Tropical Lagoon after Accounting for Black and Inorganic Carbon: Bulk Density Proxies for monitoring
Authors: Gallagher John Barry , Chew Swee-Theng , Madin John , Thorhaug Anitra
Published: November 2019

Managing seagrass and mangrove can be enhanced through carbon valued payment incentives schemes. Success will depend on the accuracy and extent of the carbon stock mitigation and accessible methods of monitoring and marking changes. In a relatively closed socioecological Southeast Asian lagoon we estimated the value of total organic carbon stocks (TOC) of both seagrass and mangroves. Mitigation corrections were also made for black carbon (BC) and calcareous inorganic carbon equivalents (PICequiv), and their sediment dry bulk density (DBD) tested as a cost effective means of both estimating those stock concepts and possible impacts outside their parameter confidence intervals. Overall, seagrass and mangroves TOC densities across the lower lagoon ranged from 15.3±4.3 and 124.3±21.1 Mg C ha-1respectively, 175.2±46.9 and 103.2±19.0 Mg C ha-1for seagrass and 355.0±24.8 and 350.3±35.2 Mg C ha-1) for mangroves across the two upper lagoon branches. Only mangrove biomass made significant additional contributions ranging from 178.5±62.3 to 120.7±94.8 Mg C ha-1for lower and upper regions respectively. The difference between the lagoons total seagrass and mangroves TOC stocks (5.98±0.69 and 390±33.22 GgC respectively) was further amplified by the lagoons’ larger mangrove area. When corrected for BC and PICequiv, the carbon stock mitigation was only reduced by a moderate 14.2%. Across the lagoon the sedimentary DBD showed strong (R2= 0.85,P< 0.001) to moderate (R2= 0.67,P< 0.001) linear correlations with seagrass and mangrove [TOC] respectively, moderate correlations with seagrass [PIC] (R2= 0.6,P< 0.001), but an invariant and relatively constant response to mangrove [PIC] (2.7 kg m-3± 0.07). Valuations as CO2ewas worth on average 0.44 million US$ y-1over 20 years; less than the total income of the indigenous users as potential custodians (1.8 and 7.4 million US$ y-1). Implications of this valuation was discussed.
Phylogenetic relationships in the southern African genusDrosanthemum(Ruschioideae, Aizoaceae)
Authors: Liede-Schumann Sigrid , Grimm Guido W. , Nürk Nicolai M. , Potts Alastair J. , Meve Ulrich , Hartmann Heidrun E.K.
Published: November 2019

Background

Drosanthemum,the only genus of the tribe Drosanthemeae, is widespread over the Greater Cape Floristic Region in southern Africa. With 114 recognized species,Drosanthemumtogether with the highly succulent and species-rich tribe Ruschieae constitute the ‘core ruschioids’ in Aizoaceae. WithinDrosanthemum, nine subgenera have been described based on flower and fruit morphology. Their phylogenetic relationships, however, have not yet been investigated, hampering understanding of monophyletic entities and patterns of geographic distribution.

Methods

Using chloroplast and nuclear DNA sequence data, we performed network- and tree-based phylogenetic analyses of 73 species represented by multiple accessions ofDrosanthemum. A well-curated, geo-referenced occurrence data set comprising the phylogenetically studied and 867 further accessions was used to describe the distributional ranges of intrageneric lineages and the genus as a whole.

Results

Phylogenetic inference supports nine clades withinDrosanthemum, seven of them group in two major clades, while the remaining two show ambiguous affinities. The nine clades are generally congruent to previously described subgenera withinDrosanthemum, with exceptions such as (pseudo-) cryptic species. In-depth analyses of sequence patterns in each gene region revealed phylogenetic affinities not obvious in the phylogenetic tree. We observe a complex distribution pattern including widespread, species-rich clades expanding into arid habitats of the interior (subgeneraDrosanthemump.p., Vespertina, Xamera) that are molecular and morphologically diverse. In contrast, less species-rich, molecularly less divergent, and morphologically unique lineages are restricted to the central Cape region and more mesic conditions (Decidua,Necopina, Ossicula, Quastea, Quadrata, Speciosa). Our results suggest initial rapid radiation generating the main lineages, with some clades showing subsequent diversification.
A Multimodal and Integrated Approach to Interrogate Human Kidney Biopsies with Rigor and Reproducibility: The Kidney Precision Medicine Project
Authors: El-Achkar Tarek M. , Eadon Michael T. , Menon Rajasree , Lake Blue B. , Sigdel Tara K. , Alexandrov Theodore , Parikh Samir , Zhang Guanshi , Dobi Dejan , Dunn Kenneth W. , Otto Edgar A. , Anderton Christopher R. , Carson Jonas M. , Luo Jinghui , Park Chris , Hamidi Habib , Zhou Jian , Hoover Paul , Schroeder Andrew , Joanes Marianinha , Azeloglu Evren U. , Sealfon Rachel , Winfree Seth , Steck Becky , He Yongqun , D’Agati Vivette , Iyengar Ravi , Troyanskaya Olga G , Barisoni Laura , Gaut Joseph , Zhang Kun , Laszik Zoltan , Rovin Brad , Dagher Pierre C. , Sharma Kumar , Sarwal Minnie , Hodgin Jeffrey B. , Alpers Charles E. , Kretzler Matthias , Jain Sanjay ,   For the Kidney Precision Medicine Project
Published: November 2019

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate 3-dimensional (3D) molecular atlases of healthy and diseased kidney biopsies using multiple state-of-the-art OMICS and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single cell level or in 3D space is a significant challenge that can be a futile exercise if not well controlled. We describe a “follow the tissue” pipeline for generating a reliable and authentic single cell/region 3D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation and harmonization across different OMICS and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis and sharing. We established benchmarks for quality control, rigor, reproducibility and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multi-OMICS and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.
Morphogenesis guided by 3D patterning of growth factors in biological matrices
Authors: Broguiere Nicolas , Lüchtefeld Ines , Traschel Lucca , Mazunin Dmitry , Bode Jeffrey , Lutolf Matthias P. , Zenobi-Wong Marcy
Published: November 2019

Three-dimensional (3D) control over the placement of bioactive cues is fundamental to understand cell guidance and develop engineered tissues. Two-photon patterning (2PP) provides such placement at micro- to millimeter scale, but non-specific interactions between proteins and functionalized extracellular matrices (ECMs) restrict its use. Here we report a 2PP system based on non-fouling hydrophilic photocages and Sortase A-based enzymatic coupling offering unprecedented orthogonality and signal-to-noise ratio in both inert hydrogels and complex mammalian matrices. Improved photocaged peptide synthesis, and protein functionalization protocols with broad applicability are introduced. Importantly, the method enables 2PP in a single step and in the presence of fragile biomolecules and cells. As a corollary, we demonstrate the guidance of axons through 3D-patterned nerve growth factor (NGF) within brain-mimetic ECMs. Our approach allows for the interrogation of the role of complex signaling molecules in 3D matrices, thus helping to better understand biological guidance in tissue development and regeneration.
MoBPS - Modular Breeding Program Simulator
Authors: Pook T. , Schlather M. , Simianer H.
Published: November 2019

The R-package MoBPS provides a computationally efficient and flexible framework to simulate complex breeding programs and compare their economic and genetic impact. Simulations are performed on the base of individuals and haplotypes are calculated on-the-fly by only saving founder haplotypes, points of recombination and mutations. MoBPS utilizes a highly efficient implementation with bit-wise storage of data and matrix multiplications from the associated R-package miraculix allowing to handle large scale populations. The modular structure of MoBPS allows to combine rather coarse simulations, as needed to generate founder populations, with a very detailed modeling of todays’ complex breeding programs, making use of all available biotechnologies. MoBPS provides pre-implemented functions for common breeding practices such as optimum genetic contributions and single-step GBLUP but also allows the user to replace certain steps with personalized and/or self-written solutions.
Systemic inflammation suppresses lymphoid tissue remodeling and B cell immunity during concomitant local infection
Authors: Alexandre Yannick O , Devi Sapna , Park Simone L , Mackay Laura K. , Heath William R. , Mueller Scott N.
Published: November 2019

Concurrent infection with multiple pathogens occurs frequently in individuals and can result in exacerbated infections and altered immunity. However, the impact of such coinfections on immune responses remains poorly understood. Here we reveal that systemic infection results in an inflammation-induced suppression of local immunity. During localized infection or vaccination in barrier tissues including the skin or respiratory tract, concurrent systemic infection induced a type I interferon-dependent lymphopenia that impairs lymphocyte recruitment to the draining lymph node (dLN). This leads to suppressed lymphoid stromal cell expansion and dLN remodeling and impaired induction of B cell responses and antibody production. Our data suggest that contemporaneous systemic inflammation constrains the induction of regional immunity.
Effects of genetic variability of CYP2D6 on neural substrates of sustained attention during on-task activity
Authors: Viviani Roberto , Messina Irene , Bosch Julia E. , Dommes Lisa , Paul Anna , Schneider Katharina L. , Scholl Catharina , Stingl Julia C.
Published: November 2019

The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data while N=415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.
Regulation of electron transport is essential for photosystem I stability and plant growth
Authors: Storti Mattia , Segalla Anna , Mellon Marco , Alboresi Alessandro , Morosinotto Tomas
Published: November 2019

Life depends on the ability of photosynthetic organisms to exploit sunlight to fix carbon dioxide into biomass. Photosynthesis is modulated by pathways such as cyclic and pseudocyclic electron flow (CEF and PCEF). CEF transfers electrons from photosystem I to the plastoquinone pool according to two mechanisms, one dependent on proton gradient regulators (PGR5/PGRL1) and the other on the type I NADH dehydrogenase (NDH) complex. PCEF uses electrons from photosystem I to reduce oxygen; in several groups of photosynthetic organisms but not in angiosperms, it is sustained by flavodiiron proteins (FLVs). PGR5/PGRL1, NDH and FLVs are all active in the moss Physcomitrella patens, and mutants depleted in these proteins show phenotypes under specific light regimes. Here, we demonstrated that CEF and PCEF exhibit strong functional overlap and that when one protein component is depleted, the others can compensate for most of the missing activity. When multiple mechanisms are simultaneously inactivated, however, plants show damage to photosystem I and strong growth reduction, demonstrating that mechanisms for the modulation of photosynthetic electron transport are indispensable.
Dopaminergic and opioidergic regulation of implicit hedonic facial reactions during anticipation and consumption of social and nonsocial rewards
Authors: Korb Sebastian , Götzendorfer Sebastian J. , Massaccesi Claudia , Sezen Patrick , Graf Irene , Willeit Matthäus , Eisenegger Christoph , Silani Giorgia
Published: November 2019

The observation of animal hedonic orofacial and behavioral reactions has played a fundamental role for the identification of a dopaminergic motivational, and an opioidergic hedonic component of reward. Translation to humans remains difficult, however, as human research has struggled to adopt a similar operationalization of reward. Here, we investigated the neurochemical basis of hedonic facial and behavioral reactions to different types of rewards in healthy adult volunteers, by pharmacologically reducing dopaminergic and opiodergic receptor-specific action. Subjective ratings, physical effort, and facial reactions to matched primary social (affective touch) and nonsocial (food) rewards were assessed. Both drugs resulted in reduced physical effort and increased negative facial reactions during reward anticipation, but only opioidergic manipulation caused reduced positive facial reactions during reward consumption. This suggest that facial reactions during anticipated and experienced pleasure rely on partly different neurochemical systems, providing novel evidence in support of existing theoretical models of reward.
A macro-ecological approach to predators’ functional response
Authors: Barbier Matthieu , Wojcik Laurie , Loreau Michel
Published: November 2019

Abstract

Predation often deviates from the law of mass action: many micro- and meso-scale experiments have shown that consumption saturates with resource abundance, and decreases due to interference between consumers. But does this observation hold at macro-ecological scales, spanning many species and orders of magnitude in biomass? If so, what are its consequences for large-scale ecological patterns and dynamics?

We perform a meta-analysis of predator-prey pairs of mammals, birds and reptiles, and show that predation losses appear to increase, not as the product of predator and prey densities following the Lotka-Volterra (mass action) model, but rather as the square root of that product. This suggests a phenomenological power-law expression of the effective cross-ecosystem functional response. We discuss whether the same power-law may hold dynamically within an ecosystem, and assuming that it does, we explore its consequences in a simple food chain model. The empirical exponents fall close to the boundary between regimes of donor and consumer limitation. Exponents on this boundary are singular in multiple ways. First, they maximize predator abundance and some stability metrics. Second, they create proportionality relations between biomass and productivity, both within and between trophic levels. These intuitive relations do not hold in general in mass action models, yet they are widely observed empirically. These results provide evidence of mechanisms limiting predation across multiple ecological scales. Some of this evidence was previously associated with donor control, but we show that it supports a wider range of possibilities, including forms of consumer control. As limiting consumption counter-intuitively allows larger populations, it is worthwhile to reconsider whether the observed functional response arises from microscopic mechanisms, or could hint at selective pressure at the population level.

This article has been peer-reviewed and recommended by Peer Community In Ecology (DOI: 10.24072/pci.ecology.100051)
Selective over-synthesis and rapid turnover of mitochondrial protein components of respiratory complexes
Authors: Bogenhagen Daniel F.
Published: November 2019

Mammalian mitochondria assemble four complexes of the respiratory chain (RCI, III, IV and V) by combining 13 polypeptides synthesized within mitochondria on mitochondrial ribosomes (mitoribosomes) with over 70 polypeptides encoded in nuclear DNA, translated on cytoplasmic ribosomes and imported into mitochondria. We report that pulse-chase SILAC can also serve as a valuable approach to study RC assembly as it reveals considerable differences in the rates and efficiency of assembly of different complexes. While assembly of RCV, ATPase, was rapid with little excess synthesis of subunits, RCI, NADH dehydrogenase, assembly was far less efficient with dramatic over-synthesis of numerous proteins, particularly in the matrix exposed N- and Q- Domains. Subunits that do not engage in assembly are generally degraded within three hours. Differential assembly kinetics were also observed for individual complexes immunoprecipitated with complex-specific antibodies. Immunoprecipitation with an antibody that recognizes the ND1 subunit of RCI co-precipitated a number of proteins implicated in FeS cluster assembly as well as newly-synthesized UQCRFS1, the Rieske FeS protein in RCIII, reflecting a degree of coordination of RCI and RCIII assembly.
Systematic assessment of tissue dissociation and storage biases in single-cell and single-nucleus RNA-seq workflows
Authors: Denisenko Elena , Guo Belinda B. , Jones Matthew , Hou Rui , de Kock Leanne , Lassmann Timo , Poppe Daniel , Clement Olivier , Simmons Rebecca K. , Lister Ryan , Forrest Alistair R. R.
Published: November 2019

Single-cell and single-nucleus RNA sequencing have been widely adopted in studies of heterogeneous tissues to estimate their cellular composition and obtain transcriptional profiles of individual cells. However, the current fragmentary understanding of artefacts introduced by sample preparation protocols impedes the selection of optimal workflows and compromises data interpretation. To bridge this gap, we compared performance of several workflows applied to adult mouse kidneys. Our study encompasses two tissue dissociation protocols, two cell preservation methods, bulk tissue RNA sequencing, single-cell and three single-nucleus RNA sequencing workflows for the 10x Genomics Chromium platform. These experiments enable a systematic comparison of recovered cell types and their transcriptional profiles across the workflows and highlight protocol-specific biases important for the experimental design and data interpretation.
Initiation and regulation of vascular tissue identity in theArabidopsisembryo
Authors: Smit Margot E. , Llavata-Peris Cristina I. , Roosjen Mark , van Beijnum Henriette , Novikova Daria , Levitsky Victor , Slane Daniel , Jürgens Gerd , Mironova Victoria , Brady Siobhan M. , Weijers Dolf
Published: November 2019

Development of plant vascular tissues involves tissue specification, growth, pattern formation and cell type differentiation. While later steps are understood in some detail, it is still largely unknown how the tissue is initially specified. We have used the early Arabidopsis embryo as a simple model to study this process. Using a large collection of marker genes, we find that vascular identity is established in the 16-cell embryo. After a transient precursor state however, there is no persistent uniform tissue identity. Auxin is intimately connected to vascular tissue development. We find that while AUXIN RESPONSE FACTOR5/MONOPTEROS/ (ARF5/MP)-dependent auxin response is required, it is not sufficient for tissue establishment. We therefore used a large-scale enhanced Yeast One Hybrid assay to identify potential regulators of vascular identity. Network and functional analysis of suggest that vascular identity is under robust, complex control. We found that one candidate regulator, the G-class bZIP transcription factor GBF2, modulates vascular gene expression, along with its homolog GBF1. Furthermore, GBFs bind to MP and modulate its activity. Our work uncovers components of a gene regulatory network that controls the initiation of vascular tissue identity, one of which involves the interaction of MP and GBF2 proteins.
CB2 distinguishes cells from background barcodes in 10x Genomics data
Authors: Ni Zijian , Chen Shuyang , Brown Jared , Kendziorski Christina
Published: November 2019

An important challenge in pre-processing data from the 10x Genomics Chromium platform is distinguishing barcodes associated with real cells from those binding background reads. Existing methods test barcodes individually, and consequently do not leverage the strong cell-to-cell correlation present in most datasets. To improve the power to identify real cells and rare subpopulations, we introduce CB2, a cluster-based approach for distinguishing real cells from background barcodes.
Downregulation of GPR183 on Infection Restricts the Early Infection and Intracellular Survival of Mycobacterium tuberculosis in Macrophage
Authors: Tang Jun , Shi Ya’nan , Zhan Lingjun , Qin Chuan
Published: November 2019

GPR183/EBI2 is a key chemotactic receptor for the positioning of B cells in lymphoid organs, and also for the migration of T cells and other immune cells. Here, we demonstrate that the downregulation of GPR183 in macrophage induced during Mtb infection restrains the bacterial early infection and intracellular survival. Overexpression of GPR183 or stimulation with its natural ligand favors Mtb survival in macrophage, while treatment with its antagonist represses both Mtb early infection and intracellular survival. With mutational analysis, we find that substitution of Asp-73, Arg-83, Tyr-112, Tyr-256 abolished the promotive effect of GPR183 on Mtb early infection and survival in macrophage. In conclusion, we demonstrated that beside the known role of chemotaxis receptor, GPR183 also functions directly in the interaction between macrophage and Mtb in a cell-autonomous way.
GeneSwitches : Ordering gene-expression and functional events in single-cell experiments
Authors: Cao Elaine Y. , Ouyang John F. , Rackham Owen J.L.
Published: November 2019

Emerging single-cell RNA-seq technologies has made it possible to capture and assess the gene expression of individual cells. Based on the similarity of gene expression profiles, many tools have been developed to generate an in silico ordering of cells in the form of pseudo-time trajectories. However, these tools do not provide a means to find the ordering of critical gene expression changes over pseudo-time. We present GeneSwitches, a tool that takes any single-cell pseudo-time trajectory and determines the precise order of gene-expression and functional-event changes over time. GeneSwitches uses a statistical framework based on logistic regression to identify the order in which genes are either switched on or off along pseudo-time. With this information, users can identify the order in which surface markers appear, investigate how functional ontologies are gained or lost over time, and compare the ordering of switching genes from two related pseudo-temporal processes.

Availability

GeneSwitches is available at https://geneswitches.ddnetbio.com

Contact

owen.rackham@duke-nus.edu.sg

Supplementary Information

is available at http://www.ddnetbio.com/files/GeneSwitches_SI.pdf
MACS: Rapid aqueous clearing system for three-dimensional mapping of intact organs
Authors: Zhu Jingtan , Yu Tingting , Li Yusha , Xu Jianyi , Qi Yisong , Yao Yingtao , Ma Yilin , Wan Peng , Chen Zhilong , Li Xiangning , Gong Hui , Luo Qingming , Zhu Dan
Published: November 2019

Tissue optical clearing techniques have provided important tools for large-volume imaging. Aqueous-based clearing methods are known for good fluorescence preservation and scalable size maintenance, but are limited by either long incubation time, or insufficient clearing performance, or requirements for specialized devices. Additionally, due to the use of high concentration organic solvents or detergents, few clearing methods are compatible with lipophilic dyes while maintaining high clearing performance. To address these issues, we developed a rapid, highly efficient aqueous clearing method with robust compatibility, termed m-xylylenediamine (MXDA)-based Aqueous Clearing System (MACS). MACS can render intact organs highly transparent in a fairly short time and possesses ideal compatibility with multiple probes, especially for lipophilic dyes. Using MACS, we cleared the adult mouse brains within only 2.5 days for three-dimensional (3D) imaging of the neural structures labelled by various techniques. Combining MACS with DiI labelling, we visualized the vascular structures of various organs. MACS provides a useful tool for 3D mapping of intact tissues and is expected to facilitate morphological, physiological and pathological studies of various organs.
A RUNX3 enhancer polymorphism associated with ankylosing spondylitis influences recruitment of Interferon Regulatory Factor 5 and factors of the Nucleosome Remodelling Deacetylase Complex in CD8+ T-cells
Authors: Vecellio Matteo , Cortes Adrian , Bonham Sarah , Selmi Carlo , Knight Julian C , Fischer Roman , Brown Matthew A , Wordsworth B Paul , Cohen Carla J
Published: November 2019

Objectives

To investigate the functional consequences of the single nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter strongly associated with ankylosing spondylitis (AS).

Methods

The effects of rs4648889 on transcription factor (TF) binding were tested by DNA pull-down and quantitative mass spectrometry. The results were validated by electrophoretic mobility gel shift assays (EMSA), Western blot (WB) analysis of the pulled-down eluates, and chromatin immuno-precipitation (ChIP)-qPCR.

Results

Several TFs showed differential allelic binding to a 50bp DNA probe spanning rs4648889. Binding was increased to the AS-risk A allele for IKZF3 (aiolos) in nuclear extracts from CD8+ T-cells (3.7-fold, p<0.03) and several components of the NUcleosome Remodeling Deacetylase (NuRD) complex, including Chromodomain-Helicase-DNA-binding protein 4 (3.6-fold, p<0.05) and Retinoblastoma-Binding Protein 4 (4.1-fold, p<0.02). In contrast, binding of interferon regulatory factor (IRF) 5 was increased to the AS-protective G allele. These results were confirmed by EMSA, WB and ChIP-qPCR.

Conclusions

The association of AS with rs4648889 most likely results from its influence on the binding of this enhancer-like region to TFs, including IRF5, IKZF3 and members of the NuRD complex. Further investigation of these factors and RUNX3-related pathways may reveal important new therapeutic possibilities in AS.
Clonally distinct differentiation trajectories shape CD8+ memory T cell heterogeneity after acute viral infections in humans
Authors: Mold Jeff E. , Modolo Laurent , Hård Joanna , Zamboni Margherita , Larsson Anton J.M. , Eriksson Carl-Johan , Ståhl Patrik L. , Borgström Erik , Picelli Simone , Reinius Björn , Sandberg Rickard , Réu Pedro , Talavera-Lopez Carlos , Andersson Björn , Blom Kim , Sandberg Johan K. , Picard Franck , Michaëlsson Jakob , Frisén Jonas
Published: November 2019

CD8+ T cells play essential roles in immunity to viral and bacterial infections, and to guard against malignant cells. The CD8+ T cell response to an antigen is composed of many T cell clones with unique T cell receptors, together forming a heterogenous repertoire of phenotypically and functionally distinct effector and memory cells1, 2. How individual T cell clones contribute to this heterogeneity during an immune response is key to understand immunity but remains largely unknown. Here, we longitudinally tracked CD8+ T cell clones expanding in response to yellow fever virus vaccination at the single cell level in humans. We show that only a fraction of the clones detected in the acute response persists as circulating memory T cells, indicative of clonal selection. Clones persisting in the memory phase displayed biased differentiation trajectories along a gradient of stem cell memory (SCM) towards terminally differentiated effector memory (EMRA) fates. Reactivation of single memory CD8+ T cells revealed that they were poised to recapitulate skewed differentiation trajectories in secondary responses, and this was generalizable across individuals for both yellow fever and influenza virus. Together, we show that the sum of distinct clonal differentiation repertoires results in the multifaceted T cell response to acute viral infections in humans.
“GPress: a framework for querying General Feature Format (GFF) files and feature expression files in a compressed form”
Authors: Meng Qingxi , Ochoa Idoia , Hernaez Mikel
Published: November 2019

1

1.1

Motivation

Sequencing data are often summarized at different annotation levels for further analysis. The general feature format (GFF) and its descendants, the gene transfer format (GTF) and GFF3, are the most commonly used data formats for genomic annotations. These files are extensively updated, queried and shared, and hence as the number of generated GFF files increases, efficient data storage and retrieval are becoming increasingly important. Existing GFF utilities for accessing these files, like gffutils and gffread, do not focus on reducing the storage space, significantly increasing it in some cases. Hence, we propose GPress, a framework for querying GFF files in a compressed form. In addition, GPress can also incorporate and compress feature expression files, supporting simultaneous queries on both files.

1.2

Results

We tested GPress on several GFF files of different organisms, and showed that it achieves on average a 98% reduction in size, while being able to retrieve all annotations for a given identifier or a range of coordinates in a few seconds. For example, on a Human GFF file, GPress can find all items with a unique identifier in 2.47 seconds and all items with coordinates within the range of 1,000 to 100,000 in 4.61 seconds. In contrast, gffutils provides faster retrieval but doubles the size of the GFF files. When additionally linking an expression file, we show that GPress can reduce the size of the expression file by more than 92%, while still retrieving the information within seconds. GPress is freely available at https://github.com/qm2/gpress.
JMJD6 participates in the maintenance of ribosomal DNA integrity in response to DNA damage
Authors: Fages Jérémie , Chailleux Catherine , Humbert Jonathan , Jang Suk-Min , Loehr Jérémy , Lambert Jean-Philippe , Côté Jacques , Trouche Didier , Canitrot Yvan
Published: November 2019

Ribosomal DNA (rDNA) is the most transcribed genomic region and contains hundreds of tandem repeats. Maintaining these rDNA repeats as well as the level of rDNA transcription is essential for cellular homeostasis. DNA damages generated in rDNA need to be efficiently and accurately repaired as rDNA repeats instability has been reported in cancer, aging and neurological diseases. Here, we describe that the histone demethylase JMJD6 is rapidly recruited at nucleolar DNA damage and is crucial for the relocalisation of rDNA in nucleolar caps. Yet, JMJD6 is dispensable for rDNA transcription inhibition. Mass spectrometry study revealed that JMJD6 interacts with the nucleolar protein Treacle and modulates its interaction with NBS1. Moreover, cells deficient for JMJD6 show increased sensitivity to nucleolar DNA damage as well as loss and rearrangements of rDNA repeats upon irradiation. Altogether our data reveals that rDNA transcription inhibition is uncoupled from rDNA relocalisation into nucleolar caps and that JMJD6 is required for rDNA stability upon the rDNA damage response through its role in nucleolar caps formation.

Author summary

Ribosomal DNA is the most transcribed genomic region composed of repeated sequences. Transcribed rDNA is essential for cellular homeostasis and cell proliferation. Numerous pathologies such as cancer and neurological disorders are described to present defective rDNA repeats maintenance. The mechanisms involved in the control of rDNA integrity involve major DNA repair pathways such as NonHomologous End-Joining and Homologous Recombination. However, how they are controlled and orchestrated is poorly understood. Here, we identified JMJD6 as a new member of the maintenance of rDNA integrity. We observed that JMJD6 controls the recruitment of NBS1 in the nucleolus in order to lead to the proper response to DNA damage at rDNA repeats.

Author contributions

YC and DT wrote the manuscript with input from their coauthors. JF, CC, JH, S-KM, JL, J-PL and YC performed the experiments. JC supervised JF and JH during purification and mass spectrometry analysis. YC and DT conceived the project, designed research and coordinated the studies.
Brief report: Mutations in SIV Nef that disrupt and restore tetherin downregulation
Authors: Maness Nicholas J , Schouest Blake
Published: November 2019

The H196residue in SIVmac239 Nef is conserved across nearly all HIV and SIV isolates, lies immediately adjacent to the AP-2 (adaptor protein 2) interacting domain (ExxxLM195), and is critical for several described AP-2 dependent Nef functions, including the downregulation of tetherin (BST-2/CD317). Surprisingly, many stocks of the closely related SIVmac251 swarm virus harbor anefallele encoding a Q196, which is associated with loss of multiple AP-2 dependent functions in SIVmac239. Publicly available sequences for SIVmac251 stocks were mined for variants linked to Q196that might compensate for functional defects associated with this mutation. Variants were engineered into the SIVmac239 parental plasmid and mutant viruses were used to test tetherin downregulatory capacity in primary CD4 T cells using flow cytometry. SIVmac251 stocks that encode a Q196residue in Nef uniformly also encode an upstream R191residue. We show that R191restores the ability of Nef to downregulate tetherin in the presence of Q196. However, a published report showed Q196commonly evolves to H196in vivo, suggesting a fitness cost. R191may represent compensatory evolution to restore the ability to downregulate tetherin lost in viruses harboring Q196.