bluuebunny/crossref_metadata_2025 huggingface dataset:
RBBP4 modulates gene activity through acetylation and methylation of histone H3 lysine 27
Authors: Mu Weipeng , Murcia Noel S , Smith Keriayn N. , Menon Debashish U , Yee Della , Magnuson Terry
Published: September 2021

RBBP4 is a core subunit of polycomb repressive complex 2 (PRC2) and HDAC1/2-containing complexes, which are responsible for histone H3 lysine 27 (H3K27) methylation and deacetylation respectively. However, the mechanisms by which RBBP4 modulates the functions of these complexes remain largely unknown. We generated viable mouse embryonic stem cell lines with RBBP4 mutations that disturbed methylation and acetylation of H3K27 on target chromatin and found that RBBP4 is required for PRC2 assembly and H3K27me3 establishment on target chromatin. Moreover, in the absence of EED and SUZ12, RBBP4 maintained chromatin binding on PRC2 loci, suggesting that the pre-existence of RBBP4 on nucleosomes serves to recruit PRC2 to restore H3K27me3 on newly synthesized histones. As such, disruption of RBBP4 function led to dramatic changes in transcriptional profiles. In spite of the PRC2 association, we found that transcriptional changes were more closely tied to the deregulation of H3K27ac rather than H3K27me3 where increased levels of H3K27ac were found on numerous cis-regulatory elements, especially putative enhancers. These data suggest that RBBP4 controls acetylation levels by adjusting the activity of HDAC complexes. As histone methylation and acetylation have been implicated in cancer and neural disease, RBBP4 could serve as a potential target for disease treatment.
A virus-encoded microRNA contributes to evade innate immune response during SARS-CoV-2 infection
Authors: Singh Meetali , Chazal Maxime , Quarato Piergiuseppe , Bourdon Loan , Malabat Christophe , Vallet Thomas , Vignuzzi Marco , van der Werf Sylvie , Behillil Sylvie , Donati Flora , Sauvonnet Nathalie , Nigro Giulia , Bourgine Maryline , Jouvenet Nolwenn , Cecere Germano
Published: September 2021

SARS-CoV-2 infection results in impaired interferon response in severe COVID-19 patients. However, how SARS-CoV-2 interferes with host immune response is incompletely understood. Here, we sequenced small RNAs from SARS-CoV-2-infected human cells and identified a micro-RNA (miRNA) encoded in a recently evolved region of the viral genome. We show that the virus-encoded miRNA produces two miRNA isoforms in infected cells by the enzyme Dicer and they are loaded into Argonaute proteins. Moreover, the predominant miRNA isoform targets the 3’UTR of interferon-stimulated genes and represses their expression in a miRNA-like fashion. Finally, the two viral miRNA isoforms were detected in nasopharyngeal swabs from COVID-19 patients. We propose that SARS-CoV-2 employs a virus-encoded miRNA to hijack the host miRNA machinery and evade the interferon-mediated immune response.
A neural hub that coordinates learned and innate courtship behaviors
Authors: Ben-Tov Mor , Duarte Fabiola , Mooney Richard
Published: September 2021

Holistic behaviors often require the coordination of innate and learned movements. The neural circuits that enable such coordination remain unknown. Here we identify a midbrain cell group (A11) that enables male zebra finches to coordinate their learned songs with various innate behaviors, including female-directed calling, orientation and pursuit. Anatomical mapping reveals that A11 is at the center of a complex network including the song premotor nucleus HVC as well as brainstem regions crucial to innate calling and locomotion. Notably, lesioning A11 terminals in HVC blocked female-directed singing, but did not interfere with female-directed calling, orientation or pursuit. In contrast, lesioning A11 cell bodies abolished all female-directed courtship behaviors. However, males with either type of lesion still produced songs when in social isolation. Lastly, monitoring A11 terminals in HVC showed that during courtship A11 inputs to the song premotor cortex signal the transition from innate to learned vocalizations. These results show how a brain region important to reproduction in both birds and mammals coordinates learned vocalizations with innate, ancestral courtship behaviors.
ATM-deficiency induced microglial activation promotes neurodegeneration in Ataxia-Telangiectasia
Authors: Lai Jenny , Demirbas Didem , Kim Junho , Jeffries Ailsa M. , Tolles Allie , Park Junseok , Chittenden Thomas W. , Buckley Patrick G. , Yu Timothy W. , Lodato Michael A. , Lee Eunjung Alice
Published: September 2021

WhileATMloss-of-function has long been identified as the genetic cause of Ataxia Telangiectasia (A-T), how this genetic mutation leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear.ATMexpression is enriched in microglia, the resident immune cell of the central nervous system, throughout cerebellar development and adulthood. Microglial activation has been strongly implicated in neurodegenerative disease and observed in rodent and cellular models ofATMdeficiency. Here, we find evidence of prominent inflammation of microglia in cerebellum from A-T patients using single-nucleus RNA-sequencing. A-T microglia have transcriptomic signatures of aging and neurodegenerative disease associated microglia. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis related genes in granule and Purkinje neurons, and microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we studied microglia and neurons that we generated from A-T patient vs. control induced pluripotent stem cells (iPSCs). Transcriptomic profiling of A-T iPSC-derived microglia revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, adding A-T microglia to co-cultures with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may play a critical role in the development and progression of neurodegeneration in Ataxia Telangiectasia.
Genetic, epigenetic, and environmental mechanisms govern allele-specific gene expression
Authors: Pierre Celine L St. , Macias-Velasco Juan F , Wayhart Jessica P , Yin Li , Semenkovich Clay F , Lawson Heather A
Published: September 2021

Allele-specific expression (ASE) is a phenomenon where one allele is preferentially expressed over the other. Genetic and epigenetic factors cause ASE by altering the final allelic composition of a gene’s product, leading to expression imbalances that can have functional consequences on phenotypes. Environmental signals also impact allele-specific gene regulation, but how they contribute to this crosstalk remains understudied. Here, we explored how allelic genotype, parent-of-origin, tissue type, sex, and dietary fat simultaneously influence ASE biases in a F1reciprocal cross mouse model. Male and female mice from a F1reciprocal cross of the LG/J and SM/J strains were fed a high fat or low fat diet. We harnessed strain-specific variants to distinguish between two classes of ASE: parent-of-origin dependent (unequal expression based on an allele’s parental origin) and sequence dependent (unequal expression based on an allele’s nucleotide identity). We present a comprehensive map of ASE patterns in 2,853 genes across three metabolically-relevant tissues and nine environmental contexts. We found that both ASE classes are highly dependent on tissue type and environmental context. They vary across metabolic tissues, between males and females, and in response to dietary fat levels. Surprisingly, we found 45 genes with inconsistent ASE biases that switched direction across tissues and/or contexts (e.g. SM/J biased in one cohort, LG/J biased in another). We also integrated ASE and QTL data from populations at various degrees of intercrossing the LG/J and SM/J strains. ASE genes in these tissues are often enriched in QTLs for metabolic and musculoskeletal traits, highlighting how this orthogonal approach can prioritize candidate genes for functional validation. Together, our results provide novel insights into how genetic, epigenetic, and environmental mechanisms govern allele-specific gene regulation, which is an essential step towards deciphering the genotype to phenotype map.
Osteoblast-osteoclast co-cultures: a systematic review and map of available literature
Authors: Remmers S. J. A. , de Wildt B. W. M. , Vis M. A. M. , Spaander E. S. R. , de Vries R.B.M. , Ito K. , Hofmann S.
Published: September 2021

Drug research with animal models is expensive, time-consuming and translation to clinical trials is often poor, resulting in a desire to replace, reduce, and refine the use of animal models. One approach to replace and reduce the use of animal models in research is usingin vitrocell-culture models.

To study bone physiology, bone diseases and drugs, many studies have been published using osteoblast-osteoclast co-cultures. The use of osteoblast-osteoclast co-cultures is usually not clearly mentioned in the title and abstract, making it difficult to identify these studies without a systematic search and thorough review. As a result, researchers are all developing their own methods from the ground up, leading to conceptually similar studies with many methodological differences and, as a direct consequence, incomparable results.

The aim of this study was to systematically review existing osteoblast-osteoclast co-culture studies published up to 6 January 2020, and to give an overview of their methods, predetermined outcome measures (formation and resorption, and ALP and TRAP quantification as surrogate markers for formation and resorption, respectively), and other useful parameters for analysis. Information regarding these outcome measures was extracted and collected in a database, and each study was further evaluated on whether both the osteoblasts and osteoclasts were analyzed using relevant outcome measures. From these studies, additional details on methods, cells and culture conditions were extracted into a second database to allow searching on more characteristics.

The two databases presented in this publication provide an unprecedented amount of information on cells, culture conditions and analytical techniques for using and studying osteoblast-osteoclast cocultures. They allow researchers to identify publications relevant to their specific needs and allow easy validation and comparison with existing literature. Finally, we provide the information and tools necessary for others to use, manipulate and expand the databases for their needs.
The efficacy of a ketogenic diet in preclinical models of IDH wild-type and IDH mutant glioma
Authors: Javier Rodrigo , Wang Wenxia , Drumm Michael , McCortney Kathleen , Sarkaria Jann N. , Horbinski Craig
Published: September 2021

Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1) or, less commonly, IDH2 (together called “IDHmut”). These mutations alter cellular biochemistry, and IDHmut gliomas are generally less aggressive than IDH wild-type (IDHwt) gliomas. Some preclinical studies and clinical trials have suggested that a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, not all studies have shown promising results, and to date, no study has addressed whether IDHmut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of KD in preclinical models of IDHwt versus IDHmut gliomas. In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDHwt or IDHmut glioma cells. Likewise, a cycling KD, wherein mice alternated between KD and a standard diet (SD), had no effect on the in vivo growth of patient-derived IDHwt or IDHmut gliomas, even though the cycling KD did result in persistently elevated circulating ketones. Furthermore, KD conferred no survival benefit in mice engrafted with Sleeping-Beauty transposase-engineered IDHmut glioma. These data suggest that neither IDHwt nor IDHmut gliomas are particularly responsive to KD.
Resurgent Na+ currents promote ultrafast spiking in projection neurons that drive fine motor control
Authors: Zemel Benjamin M. , Nevue Alexander A. , Dagostin Andre , Lovell Peter V. , Mello Claudio V. , von Gersdorff Henrique
Published: September 2021

The underlying mechanisms that promote precise spiking in upper motor neurons controlling fine motor skills are not well understood. Here we report that projection neurons in the adult zebra finch song nucleus RA display: 1) robust high-frequency firing, 2) ultra-short half-width spike waveforms, 3) superfast Na+ current inactivation kinetics and 4) large resurgent Na+ currents (INaR). These spiking properties closely resemble those of specialized pyramidal neurons in mammalian motor cortex and are well suited for precise temporal coding. They emerge during the critical period for vocal learning in males but not females, coinciding with a complete switch of modulatory Na+ channel subunit expression from Navβ3 to Navβ4. Dynamic clamping and dialysis of Navβ4’s C-terminal peptide into juvenile RA neurons provide evidence that this subunit, and its associated INaR, promote neuronal excitability. We propose that Navβ4 underpins INaR that facilitates precise, prolonged, and reliable high-frequency firing in upper motor neurons.
Proton Coupling and the Multiscale Kinetic Mechanism of a Peptide Transporter
Authors: Li Chenghan , Yue Zhi , Newstead Simon , Voth Gregory A.
Published: September 2021

Proton coupled peptide transporters (POTs) are crucial for the uptake of di- and tri-peptides as well as drug and pro-drug molecules in prokaryotes and eukaryotic cells. We illustrate from multiscale modeling how transmembrane proton flux couples within a POT protein to drive essential steps of the full functional cycle: 1) protonation of a glutamate on transmembrane helix (TM) 7 opens the extracellular gate, allowing ligand entry; 2) inward proton flow induces the cytosolic release of ligand by varying the protonation state of a second conserved glutamate on TM10; 3) proton movement between TM7 and TM10 is thermodynamically driven and kinetically permissible via water proton shuttling without the participation of ligand. Our results, for the first time, give direct computational confirmation for the alternating access model of POTs, and point to a quantitative multiscale kinetic picture of the functioning protein mechanism.

SIGNIFICANCE

Proton-coupled peptide transporters (POTs) utilize transmembrane proton gradient to deliver small peptides and peptide-like drug molecules into cells. Despite extensive biochemical and structural studies, major question regarding protonation-induced shift from inward-facing state to outward-facing state remains obscure. Here, we report direct evidence through multiscale simulations that the extracellular salt bridge controls the outward-open conformational transition of POTs, and how proton influx through POTs couples ligand transport. The computational modeling also suggests a multiscale kinetic mechanism of POTs.
Oxidized MIF is an Alzheimer’s Disease drug target relaying external risk factors to tau pathology
Authors: Müller-Schiffmann Andreas , Torres Felix , Kitaygorodskyy Anatolly , Ramani Anand , Alatza Argyro , Tschirner Sarah K. , Prikulis Ingrid , Yu Shaofeng , Dey Debendranath , Mallesh Suguna , Prasad Dharma , Solas Dennis , Bader Verian , Rozemuller Annemieke , Wray Selina , Gopalakrishnan Jay , Riek Roland , Lingappa Vishwanath R. , Korth Carsten
Published: September 2021

The viral life cycle usurps host cellular factors, redirecting them from physiological functions to viral needs thereby revealing their “moonlighting” functions, disturbing cellular proteostasis, and increasing risk of specific, virus-associated protein misfolding diseases (PMD). Identifying such virus-repurposed host proteins therefore allow study of fundamental cellular events leading to associated “sporadic” PMD. Here, we identified a small molecule with unprecedented activity against neurotropic herpes simplex virus 1 (HSV-1) modulating an allosteric site of Macrophage Migration Inhibitory Factor (MIF). The compound efficiently reduced HSV-1-mediated tau phosphorylation or aggregationin vitroandin vivo, even without HSV-1 infection. The lead compound specifically interacted with an oxidized conformer of MIF (oxMIF) from either recombinant MIF orpost-mortembrain homogenates of patients with Alzheimer’s disease (AD). OxMIF thus participates in a host-viral interface connecting HSV-1 infection, and possibly other external stressors, with tau cellular pathology characteristic for PMD, including Alzheime’s disease.
Ankfn1 vestibular defects in zebrafish require mutations in both ancestral and derived paralogs
Authors: Ross Kevin D. , Ren Jie , Zhang Ruilin , Chi Neil C. , Hamilton Bruce A.
Published: September 2021

How and to what degree gene duplication events create regulatory innovation, redundancy, or neofunctionalization remain important questions in animal evolution and comparative genetics. Ankfn1 genes are single copy in most invertebrates, partially duplicated in jawed vertebrates, and only the derived copy retained in most mammals. Null mutations in the single mouse homolog have vestibular and neurological abnormalities. Null mutation of the single Drosophila homolog is typically lethal with severe sensorimotor deficits in rare survivors. The functions and potential redundancy of paralogs in species with two copies is not known. Here we define a vestibular role for Ankfn1 homologs in zebrafish based on simultaneous disruption of each locus. Zebrafish with both paralogs disrupted showed vestibular defects and early lethality from swim bladder inflation failure. One intact copy at either locus was sufficient to prevent major phenotypes. Our results show that vertebrate Ankfn1 genes are required for vestibular-related functions, with at least partial redundancy between ancestral and derived paralogs.
Single-cell metabolite detection and genomics reveals uncultivated talented producer
Authors: Kogawa Masato , Miyaoka Rimi , Hemmerling Franziska , Ando Masahiro , Yura Kei , Ide Keigo , Nishikawa Yohei , Hosokawa Masahito , Ise Yuji , Cahn Jackson K. B. , Takada Kentaro , Matsunaga Shigeki , Mori Tetsushi , Piel Jörn , Takeyama Haruko
Published: September 2021

The production of bioactive metabolites is increasingly recognized as an important function of host-associated bacteria. An example is defensive symbiosis that might account for much of the chemical richness of marine invertebrates including sponges (Porifera), one of the oldest metazoans. However, as most complex microbiomes remain largely uncultivated and lack reference genomes, unequivocally linking metabolic functions to a cellular source is a challenge. Here we report an analysis pipeline of microfluidic encapsulation, Raman microscopy, and integrated digital genomics (MERMAID) for an efficient identification of uncultivated producers. We applied this method to the chemically rich bacteriosponge Theonella swinhoei, previously shown to contain ‘Entotheonella’ symbionts providing most of its bioactive substances except for the antifungal aurantosides that lacked biosynthetic gene candidates in the metagenome. Raman-guided single-bacterial analysis and sequencing revealed a cryptic, distinct multiproducer, ‘Candidatus Poriflexus aureus’ from a new Chloroflexi lineage. Its exceptionally large genome contains numerous biosynthetic loci and suggested an even higher chemical richness of this sponge than previously appreciated. This study highlights the importance of complementary technologies to uncover microbiome functions, reveals remarkable parallels between distantly related symbionts of the same host, and adds functional support for diverse chemically prolific lineages being present in microbial dark matter.

Significance Statement

The production of bioactive metabolites is increasingly recognized as an important function of host-associated bacteria. However, the acquisition of integrated genomic and metabolic data from uncultivated environmental bacteria is still challenging. In this work, we explored the combination of Raman microscopy and single-cell sequencing to localize chemical features to a specific bacterium in an uncultivated microbiome, and we specified the bacteria in the uncultured lineage as a producer of aurantoside, an antifungal natural product, from a chemically and microbially complex sponge. This study offers a new methodology as well as insights into chemical functions of uncultivated life.
Positive Feedback Regulation offzd7Expression Robustly Shapes Wnt Signaling Range in Early Heart Development
Authors: Yamamoto Takayoshi , Kambayashi Yuta , Afouda Boni , Otsuka Yuta , Giuraniuc Claudiu , Michiue Tatsuo , Hoppler Stefan
Published: September 2021

Secreted molecules called morphogens govern tissue patterning in a concentration-dependent manner. However, it is still unclear how reproducible patterning can be achieved with diffusing molecules, especially when patterning differentiation of a thin region. Wnt is a morphogen that organizes cardiac development; especially Wnt6 patterns the cardiogenic mesoderm to induce differentiation of a thin pericardium inXenopus. It is, however, unclear how Wnt6 can pattern such a thin tissue. In this study, we reveal that a Wnt receptor,frizzled7, is expressed in a Wnt-dependent manner in the prospective heart region, and that this receptor-feedback is essential for shaping a steep gradient of Wnt. In addition, the feedback imparts robustness against fluctuations of Wnt ligand production and allows the system to reach a steady state quickly. We also found a Wnt antagonist sFRP1, which is expressed at the opposite side of Wnt source, accumulates on a novel type of heparan sulfate (HS), N-acetyl-rich HS, which is highly presented in the outer of cardiogenic mesoderm, achieving local inhibition of Wnt signaling by restricting sFRP1 spreading. These two intricate regulatory systems restrict Wnt signaling and ensure reproducible patterning of a thin pericardium tissue.
A high-quality de novo genome assembly based on nanopore sequencing of a wild-caught coconut rhinoceros beetle (Oryctes rhinoceros)
Authors: Filipović Igor , Rašić Gordana , Hereward James , Gharuka Maria , Devine Gregor J. , Furlong Michael J. , Etebari Kayvan
Published: September 2021

Background

An optimal starting point for relating genome function to organismal biology is a high-quality nuclear genome assembly, and long-read sequencing is revolutionizing the production of this genomic resource in insects. Despite this, nuclear genome assemblies have been under-represented for agricultural insect pests, particularly from the order Coleoptera. Here we present a de novo genome assembly and structural annotation for the coconut rhinoceros beetle, Oryctes rhinoceros (Coleoptera: Scarabaeidae), based on Oxford Nanopore Technologies (ONT) long-read data generated from a wild-caught female, as well as the assembly process that also led to the recovery of the complete circular genome assemblies of the beetle’s mitochondrial genome and that of the biocontrol agent, Oryctes rhinoceros nudivirus (OrNV). As an invasive pest of palm trees, O. rhinoceros is undergoing an expansion in its range across the Pacific Islands, requiring new approaches to management that may include strategies facilitated by genome assembly and annotation.

Results

High-quality DNA isolated from an adult female was used to create four ONT libraries that were sequenced using four MinION flow cells, producing a total of 27.2 Gb of high-quality long-read sequences. We employed an iterative assembly process and polishing with one lane of high-accuracy Illumina reads, obtaining a final size of the assembly of 377.36 Mb that had high contiguity (fragment N50 length = 12 Mb) and accuracy, as evidenced by the exceptionally high completeness of the benchmarked set of conserved single-copy orthologous genes (BUSCO completeness = 99.11%). These quality metrics place our assembly as the most complete of the published Coleopteran genomes. The structural annotation of the nuclear genome assembly contained a highly-accurate set of 16,371 protein-coding genes showing BUSCO completeness of 92.09%, as well as the expected number of non-coding RNAs and the number and structure of paralogous genes in a gene family like Sigma GST.

Conclusions

The genomic resources produced in this study form a foundation for further functional genetic research and management programs that may inform the control and surveillance of O. rhinoceros populations, and we demonstrate the efficacy of de novo genome assembly using long-read ONT data from a single field-caught insect.
The DNMT1 inhibitor GSK-3484862 mediates global demethylation in murine embryonic stem cells
Authors: Portilho Nathalia Azevedo , Saini Deepak , Hossain Ishtiaque , Sirois Jacinthe , Moraes Christopher , Pastor William A.
Published: September 2021

Background

DNA methylation plays an important role in regulating gene expression in mammals. The covalent DNMT1 inhibitors 5-azacytidine and decitabine are widely used in research to reduce DNA methylation levels, but they impart severe cytotoxicity which limits their demethylation capability and confounds interpretation of experiments. Recently, a non-covalent inhibitor of DNMT1 called GSK-3484862 was developed by GlaxoSmithKline. We sought to determine whether GSK-3484862 can induce demethylation more effectively than 5-azanucleosides. Murine embryonic stem cells (mESC) are an ideal cell type in which to conduct such experiments, as they have a high degree of DNA methylation but tolerate dramatic methylation loss.

Results

We determined the cytotoxicity and optimal concentration of GSK-3484862 by treating wild-type (WT) or Dnmt1/3a/3b triple knockout (TKO) mESC with different concentrations of the compound, which was obtained from two commercial sources. Concentrations of 10 µM or below were readily tolerated for 14 days of culture. Known DNA methylation targets such as germline genes and GLN-family transposons were upregulated within two days of the start of GSK-3484862 treatment. By contrast, 5-azacytidine and decitabine induced weaker upregulation of methylated genes and extensive cell death. Whole genome bisulfite sequencing (WGBS) showed that treatment with GSK-3484862 induced dramatic DNA methylation loss, with global CpG methylation levels falling from near 70% in WT mESC to less than 18% after 6 days of treatment with GSK-3484862, similar to the methylation level observed in Dnmt1 deficient mESCs.

Conclusions

GSK-3484862 mediates striking demethylation in mESCs with minimal non-specific toxicity.
Kre28-Spc105 interaction is essential for Spc105 loading at the kinetochore
Authors: Roy Babhrubahan , Sim Janice , Han Simon J. Y. , Joglekar Ajit P.
Published: September 2021

Kinetochores are macromolecular protein assemblies that attach sister chromatids to spindle microtubules and mediate accurate chromosome segregation during mitosis. The outer kinetochore consists of the KMN network, a protein super-complex comprising Knl1 (yeast Spc105), Mis12 (yeast Mtw1), and Ndc80 (yeast Ndc80), which harbors sites for microtubule binding. Within the KMN network, Spc105 acts as an interaction hub of components involved in spindle assembly checkpoint (SAC) signaling. It is known that Spc105 forms a complex with kinetochore component Kre28. However, where Kre28 physically localizes in the budding yeast kinetochore is not clear. The exact function of Kre28 at the kinetochore is also unknown. Here, we investigate how Spc105 and Kre28 interact and how they are organized within bioriented yeast kinetochores using genetics and cell biological experiments. Our microscopy data show that Spc105 and Kre28 localize at the kinetochore with a 1:1 stoichiometry. We also show that the Kre28-Spc105 interaction is important for Spc105 protein turn-over and essential for their mutual recruitment at the kinetochores. We created several truncation mutants of kre28 that affect Spc105 loading at the kinetochores. When over-expressed, these mutants sustain the cell viability, but SAC signaling and kinetochore biorientation are impaired. Therefore, we conclude that Kre28 contributes to chromosome biorientation and high-fidelity segregation at least indirectly by regulating Spc105 localization at the kinetochores.
Impacts of pleiotropy and migration on repeated genetic adaptation
Authors: Battlay Paul , Yeaman Sam , Hodgins Kathryn A.
Published: September 2021

Observations of genetically repeated evolution (repeatability) in complex organisms are incongruent with the Fisher-Orr model, which implies that repeated use of the same gene should be rare when mutations are pleiotropic (i.e., affect multiple traits). When spatially divergent selection occurs in the presence of migration, mutations of large effect are more strongly favoured, and hence repeatability is more likely, but it is unclear whether this observation is limited by pleiotropy. Here, we explore this question using individual-based simulations of a two-patch model incorporating multiple quantitative traits governed by mutations with pleiotropic effects. We explore the relationship between fitness trade-offs and repeatability by varying the alignment between mutation effect and spatial variation in trait optima. While repeatability decreases with increasing trait dimensionality, trade-offs in mutation effects on traits do not strongly limit the contribution of a locus of large effect to repeated adaptation, particularly under increased migration. These results suggest that repeatability will be more pronounced for local rather than global adaptation. Whereas pleiotropy limits repeatability in a single-population model, when there is local adaptation with gene flow, repeatability can occur if some loci are able to produce alleles of large effect, even when there are pleiotropic trade-offs.

Article summary

Classical evolutionary theory predicts that genetically repeated evolution should be vanishingly rare in organisms where mutations affect multiple traits. In this article, we use simulations to study such pleiotropic mutations, and explore their effects on local adaptation in two patches under divergent selection. We find that migration between patches increases the likelihood of repeated evolution, even when there are fitness trade-offs imposed by pleiotropy.
Fluctuation of cellular differentiation in limb regeneration is regulated by Pde4b in urodele amphibians
Authors: Satoh Akira , Kashimoto Rena , Ohashi Ayaka , Saya Furukawa , Yamamoto Sakiya , Inoue Takeshi , Hayashi Toshinori , Agata Kiyokazu
Published: September 2021

Urodele amphibians,Pleurodeles waltlandAmbystoma mexicanum, have organ-level regeneration capability, such as limb regeneration. Multipotent cells are induced by an endogenous mechanism in amphibian limb regeneration. It is well known that dermal fibroblasts receive regenerative signals and turn into multipotent cells, called blastema cells. However, the induction mechanism of the blastema cells from matured dermal cells was unknown. We previously found that BMP2, FGF2, and FGF8 (B2FF) could play sufficient roles in blastema induction in urodele amphibians. Here, we show that B2FF treatment can induce dermis-derived cells that can participate in multiple cell lineage in limb regeneration. We first established a newt dermis-derived cell line and confirmed that B2FF treatment on the newt cells provided plasticity in cellular differentiation in limb regeneration. Interspecies comparative analysis clarified thatPde4bupregulation by B2FF specifically took place in the newt cells. Blocking PDE4B signaling by Rolipram suppressed dermis-to-cartilage transformation and the mosaic knockout animals showed consistent results. Our results are a valuable insight into how dermal fibroblasts acquire multipotency during the early phase of limb regenerationviaan endogenous program in amphibian limb regeneration.
Data reduction for serial crystallography using a robust peak finder
Authors: Hadian-Jazi Marjan , Sadri Alireza , Barty Anton , Yefanov Oleksandr , Galchenkova Marina , Oberthuer Dominik , Komadina Dana , Brehm Wolfgang , Kirkwood Henry , Mills Grant , de Wijn Raphael , Letrun Romain , Kloos Marco , Vakili Mohammad , Gelisio Luca , Darmanin Connie , Mancuso Adrian P. , Chapman Henry N. , Abbey Brian
Published: September 2021

A peak-finding algorithm for serial crystallography (SX) data analysis based on the principle of `robust statistics' has been developed. Methods which are statistically robust are generally more insensitive to any departures from model assumptions and are particularly effective when analysing mixtures of probability distributions. For example, these methods enable the discretization of data into a group comprising inliers (i.e. the background noise) and another group comprising outliers (i.e. Bragg peaks). Our robust statistics algorithm has two key advantages, which are demonstrated through testing using multiple SX data sets. First, it is relatively insensitive to the exact value of the input parameters and hence requires minimal optimization. This is critical for the algorithm to be able to run unsupervised, allowing for automated selection or `vetoing' of SX diffraction data. Secondly, the processing of individual diffraction patterns can be easily parallelized. This means that it can analyse data from multiple detector modules simultaneously, making it ideally suited to real-time data processing. These characteristics mean that the robust peak finder (RPF) algorithm will be particularly beneficial for the new class of MHz X-ray free-electron laser sources, which generate large amounts of data in a short period of time.
Chemical state mapping of simulant Chernobyl lava-like fuel containing material using micro-focused synchrotron X-ray spectroscopy
Authors: Ding Hao , Dixon Wilkins Malin C. , Mottram Lucy M. , Blackburn Lewis R. , Grolimund Daniel , Tappero Ryan , Nicholas Sarah L. , Sun Shikuan , Corkhill Claire L. , Hyatt Neil C.
Published: September 2021

Uranium speciation and redox behaviour is of critical importance in the nuclear fuel cycle. X-ray absorption near-edge spectroscopy (XANES) is commonly used to probe the oxidation state and speciation of uranium, and other elements, at the macroscopic and microscopic scale, within nuclear materials. Two-dimensional (2D) speciation maps, derived from microfocus X-ray fluorescence and XANES data, provide essential information on the spatial variation and gradients of the oxidation state of redox active elements such as uranium. In the present work, we elaborate and evaluate approaches to the construction of 2D speciation maps, in an effort to maximize sensitivity to the U oxidation state at the U L
3-edge, applied to a suite of synthetic Chernobyl lava specimens. Our analysis shows that calibration of speciation maps can be improved by determination of the normalized X-ray absorption at excitation energies selected to maximize oxidation state contrast. The maps are calibrated to the normalized absorption of U L
3 XANES spectra of relevant reference compounds, modelled using a combination of arctangent and pseudo-Voigt functions (to represent the photoelectric absorption and multiple-scattering contributions). We validate this approach by microfocus X-ray diffraction and XANES analysis of points of interest, which afford average U oxidation states in excellent agreement with those estimated from the chemical state maps. This simple and easy-to-implement approach is general and transferrable, and will assist in the future analysis of real lava-like fuel-containing materials to understand their environmental degradation, which is a source of radioactive dust production within the Chernobyl shelter.
Deep-learning-based image registration for nano-resolution tomographic reconstruction
Authors: Fu Tianyu , Zhang Kai , Wang Yan , Li Jizhou , Zhang Jin , Yao Chunxia , He Qili , Wang Shanfeng , Huang Wanxia , Yuan Qingxi , Pianetta Piero , Liu Yijin
Published: September 2021

Nano-resolution full-field transmission X-ray microscopy has been successfully applied to a wide range of research fields thanks to its capability of non-destructively reconstructing the 3D structure with high resolution. Due to constraints in the practical implementations, the nano-tomography data is often associated with a random image jitter, resulting from imperfections in the hardware setup. Without a proper image registration process prior to the reconstruction, the quality of the result will be compromised. Here a deep-learning-based image jitter correction method is presented, which registers the projective images with high efficiency and accuracy, facilitating a high-quality tomographic reconstruction. This development is demonstrated and validated using synthetic and experimental datasets. The method is effective and readily applicable to a broad range of applications. Together with this paper, the source code is published and adoptions and improvements from our colleagues in this field are welcomed.
Job creation and investment in imperfect financial and labor markets
Authors: Rendon Silvio
Published: September 2021

Purpose

This paper aims to weigh the restrictions to job creation imposed by labor market imperfections with respect to financial market imperfections. The authors want to see which restriction is more severe, and thus assess which is more powerful in creating permanent employment if it were removed.

Design/methodology/approach

A structural estimation is performed. The policy rules of the dynamic programming model are integrated into a simulated maximum likelihood procedure by which the model parameters are recovered. Data come from the CBBE (Balance Sheet data from the Bank of Spain). Identification of key parameters comes mainly from the observation of debt variation and sluggish adjustment to permanent labor.

Findings

Long-run permanent employment increases up to 69% when financial constraints are removed, whereas permanent employment only increases up to 54% when employment protection or firing costs are eliminated. The main finding of this paper is that the long-run expansion of permanent employment is larger when financial imperfections are removed than when firing costs are removed, even when there are important wage increases that moderate these employment expansions.

Social implications

The removal of firing costs has been suggested by several economists as a result of the analysis of labor market imperfections. These policies, however, face the strong opposition of labor unions. This paper shows that the goals of permanent job creation can be accomplished without removing employment protection but by means of enhancing financial access to firms.

Originality/value

The connection between financial constraints and employment has been studied in recent years, motivated by the Great Recession. However, there is no assessment of how financial and labor market imperfections compare with each other to restrict permanent job creation. This comparison is crucial for policy analysis. This study is an attempt to fill out this gap in the economic literature. No previous research has attempted to perform this very important comparison.
A framework of firms' business sustainability endeavours with internal and external stakeholders through time across oriental and occidental business contexts
Authors: Lee Tzong-Ru , Lin Ku-Ho , Chen Chang-Hsiung , Otero-Neira Carmen , Svensson Göran
Published: September 2021

Purpose

The purpose of the paper is to test and compare a framework of firms' business sustainability endeavours with internal and external stakeholders in an oriental business context and to verify the validity and reliability of a stakeholder framework through time and across oriental and occidental business contexts.

Design/methodology/approach

Quantitative approach based on a questionnaire survey in corporate Taiwan with a response rate of 68.5%. Multivariate analysis is undertaken to uncover the measurement properties of a stakeholder framework.

Findings

A framework of firms' business sustainability endeavours with internal and external stakeholders appears valid and reliable through time and across occidental and oriental business contexts.

Research limitations/implications

This study verifies and fortifies a stakeholder framework through time and across business contexts consisting of five stakeholder groups: upstream, the focal firm, downstream, market and societal.

Practical implications

The framework of firms' business sustainability endeavours provides guidance to firms in their endeavours of business sustainability with internal and external stakeholders.

Originality/value

This study contributes to existing theory and previous studies by validating a stakeholder framework of business sustainability with internal and external stakeholders beyond occidental business context to be also valid and reliable in oriental ones.
Fuzzy bundling of corporate governance practices and performance of Indian firms
Authors: Gupta Pankaj Kumar , Mittal Prabhat
Published: September 2021

Purpose

This paper aims to develop a framework that aids in achieving the desired state of financial performance for corporate enterprises based on distinct configurations of corporate governance (CG) practices.

Design/methodology/approach

This study uses a fuzzy-based system to arrive at a definitive configuration of CG practices that lead to a specific level of firm’s performance.

Findings

This analysis of the panel data of 92 National Stock Exchange–listed companies conducted for RONW on selected CG variables shows that eight fuzzy configurations lead to a particular state of RONW. The authors compare the results with the conventional regression-based scoring models.

Originality/value

Corporate enterprises can use the derived bundles of CG practices leading to a specific set of financial performance (RONW) to aid the decision-making process in defining and implementing their governance structures. The regulators can modify or customize the law-mandated CG practices to reduce redundancies and promote the national agenda of economic efficiency.
Is childcare cost a barrier to women managers' retention and progress at large firms?
Authors: Choudhary Amod
Published: September 2021

Purpose

The impact of childcare cost and childcare responsibilities has generally negatively impacted women in workforce. There has been lack of research on the impact of childcare on women managers in larger US public firms. The purpose of this paper is to determine how childcare costs impact the number of women managers in S&P 500 firms.

Design/methodology/approach

The paper employs Driscoll–Kraay panel regression model using childcare data for ten years and the percent of women managers at S&P 500 firms.

Findings

The results show that increase in childcare cost leads to decrease in percent of women in management positions when the child is an infant. Interestingly, but plausibly the results also show that for preschool-age children as the cost of childcare increases, there is an increase in percent of women in management. Furthermore, childcare costs are still an impediment to careers of women managers, specifically when the child is an infant. The effect is much less when the child grows from an infant to preschool age.

Research limitations/implications

One limitation of this research paper is that the childcare cost data is not directly from the S&P 500 firms. The percent of women management data used is limited to the largest S&P 500 firms. Also, there is no agreement as to definition of a manager at these firms. Moreover, not only childcare cost, but the quality and availability of childcare are factors that also play a role in decision to work and/or use of childcare.

Originality/value

This paper adds to the existing literature by providing evidence that childcare cost impedes women managers' career growth. This finding is more worrisome given that Covid-19 has had a very disproportionate impact on women with child(dren) in the workforce.
Design and analysis of grid-connected sustainable urban residential energy systems
Authors: Kumar Deepak , Tewary Tavishi
Published: September 2021

Purpose

Earlier most of the research groups have designed and developed hybrid renewable energy system models with technological, scientific and industrial advancement for the energy systems, but slight attention has been paid towards the grid-connected sustainable urban residential energy systems (SUReS) for metropolitan cities. The current research wishes to design, model and analyze grid-connected energy system for residential applications for sustainable urban residential energy system. The works aims to explore the potential of the augmented energy system for grid-connected energy system.

Design/methodology/approach

The proposed grid-connected SUReS are validated for a sample location at New Delhi (India) with a hybrid optimization model for electric renewable (HOMER) software to define and understand the various load profile. It presents the sensitivity analysis approach to validate the design of the proposed energy system.

Findings

The obtained results reports the key barriers, proposed model and scenarios for sustainable urban energy system development.

Research limitations/implications

Similar approaches can be replicated to design and develop an independent, self-sustainable cleaner and environmental-friendly energy system in the future scenario for the extension of complex grid infrastructures.

Practical implications

It will assist the stakeholder in solving the complex urban sustainability issues raised due to the shortage of energy.

Social implications

It will offer a clean and environment friendly sustainable energy resources with reduced carbon emissions. It will benefit sustainable energy resources with a mix of challenges and opportunities, to suggest an approach for implementation of efficient energy policies to optimize the existing and forthcoming energy systems.

Originality/value

The current research offers a design and model to analyze grid-connected energy system sustainable urban residential applications. It explores the potential of the augmented energy system. The proposed model are validated for a sample location with HOMER simulation software to define and understand various scenarios of the multiple load profile. The work presents the sensitivity analysis approach to validate the proposed energy system.