bluuebunny/crossref_metadata_2025 huggingface dataset:
FISHFactor: A Probabilistic Factor Model for Spatial Transcriptomics Data with Subcellular Resolution
Authors: Walter Florin C. , Stegle Oliver , Velten Britta
Published: November 2021

Motivation

Factor analysis is a widely used tool for unsupervised dimensionality reduction of high-throughput data sets in molecular biology, with recently proposed extensions designed specifically for spatial transcriptomics data. However, these methods expect (count) matrices as data input and are therefore not directly applicable to single molecule resolution data, which are in the form of coordinate lists annotated with genes and provide insight into subcellular spatial expression patterns. To address this, we here propose FISHFactor, a probabilistic factor model that combines the benefits of spatial, non-negative factor analysis with a Poisson point process likelihood to explicitly model and account for the nature of single molecule resolution data. In addition, FISHFactor shares information across a potentially large number of cells in a common weight matrix, allowing consistent interpretation of factors across cells and yielding improved latent variable estimates.

Results

We compare FISHFactor to existing methods that rely on aggregating information through spatial binning and cannot combine information from multiple cells, and show that our method leads to more accurate results on simulated data. We demonstrate on a real data set that FISHFactor is able to identify major subcellular expression patterns and spatial gene clusters in a data-driven manner.

Availability and Implementation

The model implementation, data simulation and experiment scripts are available under https://www.github.com/bioFAM/FISHFactor.

Contact

b.velten@dkfz.de
The Effect of A1/A2 Reactive Astrocyte Expression on Hydrocephalus Shunt Failure
Authors: Khodadadei Fatemeh , Arshad Rooshan , Morales Diego M. , Gluski Jacob , Marupudi Neena I. , McAllister James P. , Limbrick David D. , Harris Carolyn A.
Published: November 2021

Understanding the composition characteristics of the glial scar contributing to the high failure rate of neuroprosthetic devices implanted in the brain has been limited, to date, with the evaluation of cells, tissue, and biomarkers obstructing the implant. However, there remains a critical knowledge gap in gene expression profiles of the obstructing cells. This first-time study investigates the phenotypic expression specific to astrocyte scarring from those cells on hydrocephalus shunt surfaces at the time of failure, aimed at the development of therapeutic approaches to target reactive astrocytes for improved functional outcome. Recent evidence has indicated that the tissue obstructing shunts is over 80% inflammatory, with a more exaggerated astrocytic response. To understand how to mitigate the astrocyte immune response to shunts, we performed gene expression profiling of the C3 and EMP1 genes to quantify if astrocytes were classically activated and pro-inflammatory (A1) or alternatively activated and anti-inflammatory (A2), respectively. Shunt catheters were removed from patients at the time of failure and categorized by obstructed vs non-obstructed shunts. RNAscope fluorescent in situ hybridization and quantitative PCR analysis of the C3 and EMP1 expressed genes revealed that a heterogeneous mixed population of both the A1 and A2 reactive phenotype exist on the shunt surface. However, the number of A2 reactive astrocytes are significantly higher on obstructed shunts compared to A1 reactive astrocytes. ELISA data also confirmed higher levels of IL-6 for obstructed shunts involved in A2 reactive astrocyte proliferation and glial scar formation on the shunt surface. Since TNF-α and IL-1β propel resting astrocytes into an A2 reactive state, by simply blocking the secretion or action of these cytokines, astrocyte activation and attachment on obstructing shunts could be inhibited.
Prioritising the eradication of invasive species from island archipelagos with high reinvasion risk
Authors: Kumar Viney , Nunez Andre , Brown Kaitlyn , Agarwal Kanupriya , Hall Samuel , Bode Michael
Published: November 2021

Eradicating invasive species from islands is a proven method for safeguarding threatened and endangered species from extinction. Island eradications can deliver lasting benefits, but require large up-front expenditure of limited conservation resources. The choice of islands must therefore be prioritised. Numerous tools have been developed to prioritise island eradications, but none fully account for the risk of those eradicated species later returning to the island: reinvasion. In this paper, we develop a prioritisation method for island eradications that accounts for the complexity of the reinvasion process. By merging spatially-explicit metapopulation modelling with stochastic dynamic optimisation techniques, we construct a decision-support tool that optimises conservation outcomes in the presence of reinvasion risk. We applied this tool to two different case studies – rat (Rattus rattus) invasions in the Seaforth archipelago in New Zealand, and cane toad (Rhinella marina) invasions in the Dampier archipelago in Australia – to illustrate how state-dependent optimal policies can maximise expected conservation gains. In both case studies, incorporating reinvasion risk dramatically altered the optimal order of island eradications, and improved the potential conservation benefits. The increase in benefits was larger in Dampier than Seaforth (42% improvement versus 6%), as a consequence of both the characteristics of the invasive species, and the arrangement of the islands. Our results illustrate the potential consequences of ignoring reinvasion risk, and demonstrate that including reinvasion in eradication prioritisation can dramatically improve conservation outcomes.
Salidroside protects lipopolysaccharide-induced acute lung injury by regulating miR-145/ cytosolic phospholipase A2
Authors: Gu Lanxin , Shi Zhaoling
Published: November 2021

Salidroside is one of the main active components from the root ofRhodiola rosea. Previous reports showed that salidroside exhibits anti-inflammatory properties, but the underlying mechanisms are not fully understood. Here, we observed the effects of salidroside on lipopolysaccharide (LPS)-induced acute lung injury (ALI) bothin vivoandin vitro. As revealed by survival study, salidroside reduced mortality of rats and prolonged their survival time. Meanwhile, salidroside significantly improved LPS-induced lung histopathologic changes, decreased lung wet-to-dry and lung-to-body weight ratios, inhibited lung myeloperoxidase (MPO) activity. Salidroside also suppressed the expression of cytosolic PLA2(cPLA2), the activity of phospholipase A2(PLA2) in LPS-treated rats and the metabolites of PLA2in bronchoalveolar lavage fluid (BALF), which was confirmed by results of prostaglandin E2(PGE2), leukotriene B4(LTB4) and thromboxane B2(TXB2) detection. And the expression of microRNA-145 in LPS-treated rats was up-regulated by salidroside. Besides, salidroside raised the level of miR-145and reduced PLA2activity in LPS-induced A549 cells in a concentration-dependent manner, which was obviously reversed by miR-145 inhibition. In conclusion, the current study demonstrated that salidroside exhibited a protective effect on LPS-induced ALI by inhibiting of the inflammatory response, which may involve in the up-regulation of miR-145 and the suppression of cPLA2.

Highlights

Salidroside reduces acute lung injury by inhibiting the increment and metabolism of phospholipase A2;

Salidroside inhibits LPS-induced PLA2 increase dependent on miR-145;

The inhibitory effect of Salidroside on Phospholipases A2 provides a link between the identification of new targets and potential new therapeutic agents for the treatment of acute lung injury.
The COVID19 pandemic has changed women’s experiences of pregnancy in the UK
Authors: Sturrock Sarah , Turner Kim , Lee-Wo Chelone , Greening Vanessa , Khalil Asma , Heath Paul T , Doare Kirsty Le
Published: November 2021

Introduction

During the SARS-CoV-2 pandemic, maternity care has been substantially altered to reduce transmission of the SARS-CoV-2 virus. Many antenatal services are now restricted or delivered online, and visiting has been restricted during labour and in the postnatal period.

Methods

We conducted an online survey from 1st August to 31st December 2020 to investigate the experiences of women who were pregnant or breastfeeding in the UK during the SARS-CoV-2 pandemic. The survey included 55 open and closed questions and required 5 minutes to complete. We publicised the survey using social media.

Results

We received 96 responses, including 66 currently pregnant women and 22 women who were pregnant during the pandemic. The response rate was 70.1% of survey views. We found mixed experiences of the impact of the pandemic on antenatal and perinatal care, notably with some women feeling visiting restrictions were insufficient and others feeling they were too strict. Twenty-nine women received no information about COVID-19, and 6 women found it very difficult to find information. Thirty-nine women would have liked to have more information about breastfeeding after a pregnancy affected by COVID-19, and 37 women wanted more information about antibody persistence and transfer.

Discussion

Additional support is required for pregnant and lactating women during the current pandemic. Provision of information and support, including via social media, may improve women’s experiences of pregnancy in the current environment.

Significance

Maternity services in the UK have been significantly restructured to prevent transmission of the SARS-CoV-2 virus, including restrictions to in-person antenatal care, and perinatal visiting. It is not fully known how these changes are perceived by pregnant and breastfeeding women.

Reactions to changes in antenatal care are mixed, including whether restrictions were too lenient or too strict. Most women underwent online antenatal care in addition in-person visits. Some received no information about COVID-19, and a significant proportion of women would have liked more information, particularly regarding antibody transfer and benefits of breastfeeding during the pandemic.

Ethical statement

This study was approved by North East - Newcastle & North Tyneside 1 Research Ethics Committee
A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity
Authors: Richardson Simone I. , Manamela Nelia P. , Motsoeneng Boitumelo M. , Kaldine Haajira , Ayres Frances , Makhado Zanele , Mennen Mathilda , Skelem Sango , Williams Noleen , Sullivan Nancy J. , Misasi John , Gray Glenda G. , Bekker Linda-Gail , Ueckermann Veronica , Rossouw Theresa M. , Boswell Michael T. , Ntusi Ntobeko A. B. , Burgers Wendy A. , Moore Penny L.
Published: November 2021

SARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with decreased disease severity and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.
Targeting SerpinE1 reverses cellular features of Hutchinson-Gilford progeria syndrome
Authors: Catarinella Giorgia , Nicoletti Chiara , Bracaglia Andrea , Procopio Paola , Salvatori Illari , Taggi Marilena , Ferri Alberto , Valle Cristiana , Canipari Rita , Puri Pier Lorenzo , Latella Lucia
Published: November 2021

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal disease caused by Lamin A mutation, leading to altered nuclear architecture, loss of perinuclear heterochromatin and deregulated gene expression. HGPS patients eventually die by coronary artery disease and cardiovascular alterations. However, how deregulated transcriptional networks at the cellular level impact on the systemic disease phenotype is currently unclear. We have performed a longitudinal genome-wide analysis of gene expression in primary HGPS fibroblasts from patients at two sequential stages of disease that revealed a progressive activation of Rho signaling and SerpinE1, also known as Plasminogen Activator Inhibitor (PAI-1). siRNA-mediated downregulation or pharmacological inhibition of SerpinE1 by TM5441 could revert key pathological features of HGPS in patient-derived fibroblasts, including re-activation of cell cycle progression, reduced DNA damage signaling, decreased expression of pro-fibrotic genes and recovery of mitochondrial defects. These effects were accompanied by reduced levels of Progerin and correction of nuclear abnormalities. These data point to SerpinE1 as a novel potential effector of HGPS pathogenesis and target for therapeutic interventions.
Parental genomes segregate into different blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts
Authors: De Coster Tine , Masset Heleen , Tšuiko Olga , Catteeuw Maaike , Dierckxsens Nicolas , Debrock Sophie , Peeraer Karen , Smits Katrien , Van Soom Ann , Vermeesch Joris Robert
Published: November 2021

The zygotic division enables two haploid genomes to segregate into two biparental diploid blastomeres. This fundamental tenet was challenged by the observation that blastomeres with different genome ploidy or parental genotypes can coexist within individual embryos. We hypothesized that whole parental genomes can segregate into distinct blastomere lineages during the first division through “heterogoneic division”. Here, we map the genomic landscape of 82 blastomeres from 25 embryos that underwent multipolar zygotic division. The coexistence of androgenetic and diploid or polyploid blastomeres with or without anuclear blastomeres, and androgenetic and gynogenetic blastomeres within the same embryo proofs the existence of heterogoneic division. We deduced distinct segregation mechanisms and demonstrate these genome-wide segregation errors to persist to the blastocyst stage in both human and cattle. Genome-wide zygotic segregation errors contribute to the high incidence of embryonic arrest and provide an overarching paradigm for the development of mixoploid and chimeric individuals and moles.
Internal state dependent control of feeding behaviour via hippocampal ghrelin signalling
Authors: Wee Ryan W. S. , Mishchanchuk Karyna , AlSubaie Rawan , MacAskill Andrew F.
Published: November 2021

Hunger is an internal state that not only invigorates feeding, but also acts as a contextual cue for the higher-order control of anticipatory feeding-related behaviour. The ventral hippocampus is a brain region crucial for differentiating optimal behaviour across different contexts, but how internal context such as hunger influence hippocampal circuits to define behaviour is not known. Pyramidal neurons in the ventral hippocampus, including the ventral CA1/subiculum border (vS) express the receptor for the peripheral hunger hormone ghrelin, and ghrelin is known to cross the blood brain barrier and directly influence hippocampal circuitry. But how ghrelin influences vS has not been directly investigated. In this study, we used a combination of electrophysiology, optogenetics andin vivocalcium imaging in mice to investigate the role of vS during feeding behaviour across different states of hunger. We found that activity of a unique subpopulation of vS neurons that project to the nucleus accumbens (vS-NAc) increased when animals approached and investigated food, and this activity inhibited the transition to begin eating. Increases in peripheral ghrelin reduced vS-NAc activity during this anticipatory phase of feeding behaviour by increasing the postsynaptic influence of inhibition, and promoted the initiation of eating. Furthermore, this peripheral ghrelin-induced inhibition required postsynaptic expression of the ghrelin receptor GHSR1a in vS-NAc neurons, and removal of GHSR1a from vS-NAc neurons impaired ghrelin-induced changes in feeding-related behaviour. Together, these experiments define a ghrelin-sensitive hippocampal circuit that informs the decision to eat based on internal state.
Injectable Nanoporous Microgels Generate Vascularized Constructs and Support Bone Regeneration in Critical-sized Defects
Authors: Patrick Matthew D. , Keys Jeremy F. , Sureshkumar Harshini , Annamalai Ramkumar T.
Published: November 2021

Large and aberrant bone fractures require ossification and concomitant vascularization for proper healing. Evidence indicates that osteogenesis and vessel growth are coupled in bone fractures. Although the synergistic role of endothelial cells has been recognized, vascularizing large bone grafts remains a challenge and has apprehended the clinical translation of engineered bone constructs. Here, we describe a facile method to fabricate vascularized constructs using chitosan and gelatin-based microgels that promote osteogenesis of human mesenchymal stromal cells (MSC) while supporting endothelial sprouting and network formation. The microgels are enzymatically degradable and had a high hydration rate with a volume swelling ratio of ~560% and a polymer density of ~430 mg/cm3, which is comparable to that of native skeletal tissues. AFM indentation of the surface showed an average Young’s modulus of 189 kPa, falling in a range that is conducive to both osteogenesis and vasculogenesis. The osteogenic microgel containing chitosan, gelatin, and hydroxyapatite, mimicking the bone matrix, supported robust attachment, proliferation, and differentiation of MSC. On the other hand, the vasculogenic microgels containing only gelatin, enriched endothelial phenotype and enabled vascular networks formation when embedded in 3D matrices. Combining the two types of microgels created a hybrid construct that sustained the functions of both osteogenic and vasculogenic microgels and enhanced one another. Using a murine model, we also show that the osteogenic microgels regenerate bone in a critical-sized defect with >95% defect closure by week 12. These multifunctional microgels can be administered minimally invasively and can conformally fill large bone defects. This work lays the foundation to establish principles of designing multiphasic scaffolds with tissue-specific biophysical and biochemical properties for regenerating vascularized and interfacial tissues.
Assessment of AI-based Protein Structure Prediction for the NLRP3 Target
Authors: Yin Jian , Lei Junkun , Yu Jialin , Cui Weiren , Zhou Yifan , Feng Hua , Deng Jason , Su Wenji , Kuai Letian
Published: November 2021

The recent success of AlphaFold and RoseTTAFold has demonstrated the values of AI methods in predicting highly accurate protein structures. Despite the advances, their roles in the context of small-molecule drug discovery need to be thoroughly explored. In this study, we evaluated whether the AI-based models can lead to reliable three-dimensional structures of protein-ligand complexes. The structure we predicted was NLRP3, a challenging protein target in terms of obtaining the three-dimensional model both experimentally and computationally. The conformation of the binding pockets generated by the AI models were carefully characterized and compared with experimental structures. Further molecular docking results indicated that AI-predicted protein structures combined with molecular dynamics simulations can be useful in small-molecule drug discovery.
Organizing Principles of Astrocytic Nanoarchitecture in the Mouse Cerebral Cortex
Authors: Salmon Christopher K. , Syed Tabish A. , Kacerovsky J. Benjamin , Alivodej Nensi , Schober Alexandra L. , Pratte Michael T. , Rosen Michael P. , Green Miranda , DasGupta Adario , Vali Hojatollah , Mandato Craig A. , Siddiqi Kaleem , Murai Keith K.
Published: November 2021

Astrocytes have complex roles in central nervous system (CNS) health and disease. Underlying these roles is an elaborate architecture based on frequent, extremely fine, but seemingly haphazard branches, as well as prominent features including tripartite synaptic complexes and perivascular endfeet. While broad categories of structures in astrocytes are known, the fundamental building blocks that compose them and their organizing principles have yet to be adequately defined. This is largely due to the absence of high-resolution datasets that can reveal nanoscopic features of astrocytes (i.e. 10-20nm diameter in x, y, and z) and a lack of computational approaches that can effectively interrogate astrocyte shape, organization, and nanoarchitecture. Here, we produced and analyzed multiple, high-resolution datasets of layer 2/3 mouse somatosensory cortex using focused ion beam scanning electron microscopy (8nm intervals) and computer vision approaches to provide a principled, quantitative analysis of astrocytic nanoarchitecture. A decomposition of astrocytes into fundamental ‘parts’ led to the discovery of unique structural components, recurring structural motifs, and assembly of parts into an organized hierarchy. New relationships were also discerned between astrocytic processes and other CNS microanatomy including mitochondria, tripartite synapses, and cerebrovasculature. By deploying computational resources to quantitatively understand the organizing principles and nanoarchitecture of astrocytes, this study reveals the specialized anatomical adaptations of these complex cells within the CNS.

One Sentence Summary

Using high-resolution serial electron microscopy datasets and computer vision, this study provides a systematic analysis of astrocytic nanoarchitecture from multiple samples of layer 2/3 of adult mouse neocortex, and presents quantitative evidence that astrocytes organize their morphology into purposeful, classifiable assemblies with unique structural and subcellular organelle adaptations related to their physiological functions.
The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless
Authors: Chen Rui , Deng Xiaobing , Zhu Sijun
Published: November 2021

Intermediate neural progenitors (INPs) boost the number and diversity of neurons generated from neural stem cells (NSCs) by undergoing transient proliferation. In the developing Drosophila brains, INPs are generated from type II neuroblasts (NBs). In order to maintain type II NB identity and their capability to produce INPs, the proneural protein Asense (Ase) needs to be silenced by the Ets transcription factor pointed P1 (PntP1), a master regulator of type II NB development. However, the molecular mechanisms underlying the PntP1-mediated suppression of Ase is still unclear. In this study, we utilized genetic and molecular approaches to determine the transcriptional property of PntP1 and identify the direct downstream effector of PntP1 and the cis-DNA elements that mediate the suppression of ase. Our results demonstrate that PntP1 directly activates the expression of the transcriptional repressor, Tailless (Tll), by binding to seven Ets-binding sites, and Tll in turn suppresses the expression of Ase in type II NBs by binding to two hexameric core half-site motifs. We further show that Tll provides positive feedback to maintain the expression of PntP1 and the identity of type II NBs. Thus, our study identifies a novel direct target of PntP1 and reveals mechanistic details of the specification and maintenance of the type II NB identity by PntP1.

Author summary

Type II neuroblasts (NBs) are the neural stem cells (NSCs) in Drosophila central brains that produce neurons by generating intermediate neural progenitors (INPs) to boost brain complexity, as mammalian NSCs do during the development of neocortex. The key to the generation of INPs from type II NBs is the suppression of proneural protein Asense (Ase) in type II NBs by the Ets family transcription factor Pointed P1 (PntP1), but how PntP1 suppresses Ase expression remains unclear. In this study, we provided evidence to demonstrate that PntP1 directly activates the orphan nuclear receptor Tailless (Tll), which in turn suppresses Ase expression to maintain the capability of type II NBs to produce INPs. Meanwhile, Tll provides positive feedback to maintain the expression of PntP1 and type II NB identity. We further identified seven PntP1 binding sites in the tll enhancer regions and two Tll binding sites in the ase regulatory regions that mediate the activation of tll and the suppression of ase, respectively. Our work reveals detailed mechanisms of the specification and maintenance of the type II NB identity by PntP1.
Stress- and metabolic responses of Candida albicans require Tor1 kinase N-terminal HEAT repeats
Authors: Qi Wanjun , Acosta-Zaldivar Maikel , Flanagan Peter R. , Liu Ning-Ning , Jani Niketa , Fierro José F. , Andrés María T. , Moran Gary P. , Köhler Julia R.
Published: November 2021

Whether to commit limited cellular resources toward growth and proliferation, or toward survival and stress responses, is an essential determination made by Target of Rapamycin Complex 1 (TORC1) for a eukaryotic cell in response to favorable or adverse conditions. Loss of TORC1 function is lethal. The TORC1 inhibitor rapamycin that targets the highly conserved Tor kinase domain kills fungal pathogens like Candida albicans, but is also severely toxic to human cells. The least conserved region of fungal and human Tor kinases are the N-terminal HEAT domains. We examined the role of the 8 most N-terminal HEAT repeats of C. albicans Tor1. We compared nutritional- and stress responses of cells expressing a message for N-terminally truncated Tor1 from repressible tetO, with cells expressing a wild type TOR1 allele from tetO or from the native promoter. Some but not all stress responses were significantly impaired by loss of Tor1 N-terminal HEAT repeats, including those to oxidative-, cell wall-, and heat stress; in contrast, plasma membrane stress and antifungal agents that disrupt plasma membrane function were tolerated by cells lacking this Tor1 region. Translation was inappropriately upregulated during oxidative stress in cells lacking N-terminal Tor1 HEAT repeats despite simultaneously elevated Gcn2 activity, while activation of the oxidative stress response MAP kinase Hog1 was weak. Conversely, these cells were unable to take advantage of favorable nutritional conditions by accelerating their growth. While consuming oxygen more slowly than cells containing wild type TOR1 alleles during growth in glucose, cells lacking N-terminal Tor1 HEAT repeats were capable of utilizing non-fermentable as well as fermentable carbon sources and of growth during severe acid stress, but were uniquely unable to grow on lactate. Genome-wide expression analysis showed paradoxical simultaneous activation of anabolic- and starvation responses in cells lacking Tor1 N-terminal HEAT repeats, with misregulation of carbon metabolism and of translational machinery biosynthesis. Targeting fungal-specific Tor1 N-terminal HEAT repeats with small molecules might abrogate fungal viability, especially when during infection multiple stresses are imposed by the host immune system.
Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells
Authors: Harris Rebecca , Yang Ming , Schmidt Christina , Singh Sarbjit , Natarajan Amarnath , Frezza Christian , Laman Heike
Published: November 2021

Deregulated Fbxo7 expression is associated with many pathologies, including anaemia, male sterility, cancer, and Parkinson’s disease, demonstrating its critical role in a variety of cell types. Although Fbxo7 is an F-box protein that recruits substrates for SCF-type E3 ubiquitin ligases, it also promotes the formation of cyclin D/Cdk6/p27 complexes in an E3-ligase independent fashion. We discovered PFKP, the major gatekeeper of glycolysis, in a screen for Fbxo7 substrates. PFKP has been previously shown to be a critical substrate of Cdk6 for the viability of T-ALL cells. We investigated the molecular relationships between Fbxo7, Cdk6 and PFKP, and the functional effect Fbxo7 has on T cell metabolism, viability, and activation. Fbxo7 promotes Cdk6-independent ubiquitination and Cdk6-dependent phosphorylation of PFKP. Importantly Fbxo7-deficient cells have reduced Cdk6 activity, and haematopoietic and lymphocytic cell lines show a significant dependency on Fbxo7. Compared to WT cells, CD4+ T cells with reduced Fbxo7 expression show increased glycolysis, despite lower cell viability and activation levels. Metabolomic studies of activated CD4+ T cells confirm increased glycolytic flux in Fbxo7-deficient cells, as well as altered nucleotide biosynthesis and arginine metabolism. We show Fbxo7 expression is glucose-responsive at the mRNA and protein level, and we propose Fbxo7 inhibits PFKP and glycolysis via its activation of Cdk6.
Scalable Species Tree Inference with External Constraints
Authors: Liu Baqiao , Warnow Tandy
Published: November 2021

Species tree inference under the multi-species coalescent (MSC) model is a basic step in biological discovery. Despite the developments in recent years of methods that are proven statistically consistent and that have high accuracy, large datasets create computational challenges. Although there is generally some information available about the species trees that could be used to speed up the estimation, only one method–ASTRAL-J, a recent development in the ASTRAL family of methods–is able to use this information. Here we describe two new methods, NJst-J and FASTRAL-J, that can estimate the species tree given partial knowledge of the species tree in the form of a non-binary unrooted constraint tree.. We show that both NJst-J and FASTRAL-J are much faster than ASTRAL-J and we prove that all three methods are statistically consistent under the multi-species coalescent model subject to this constraint. Our extensive simulation study shows that both FASTRAL-J and NJst-J provide advantages over ASTRAL-J: both are faster (and NJst-J is particularly fast), and FASTRAL-J is generally at least as accurate as ASTRAL-J. An analysis of the Avian Phylogenomics project dataset with 48 species and 14,446 genes presents additional evidence of the value of FASTRAL-J over ASTRAL-J (and both over ASTRAL), with dramatic reductions in running time (20 hours for default ASTRAL, and minutes or seconds for ASTRAL-J and FASTRAL-J, respectively).

Availability

FASTRAL-J and NJst-J are available in open source form at https://github.com/RuneBlaze/FASTRAL-constrained and https://github.com/RuneBlaze/NJst-constrained. Locations of the datasets used in this study and detailed commands needed to reproduce the study are provided in the supplementary materials at http://tandy.cs.illinois.edu/baqiao-suppl.pdf.
Two new threatened species of Rinorea (Violaceae), forest trees from East and South Regions, Cameroon
Authors: Achoundong Gaston , Cheek Martin
Published: November 2021

Two tree species are described as new to science: Rinorea spongiocarpa Achound. sp. nov (placed in Rinorea [unranked] Brachypetalae) and Rinorea dimakoensis Achound. sp. nov.( placed in Rinorea [unranked] Ilicifolieae). Both species are endemic to Cameroon, occurring south of the Sanaga river, the first from South and East Regions, occurring in evergreen forest from Ebolowa to Dja, while the second occurs in the northern part of East Region in semi-deciduous forest towards the interface with woodland habitats in the Dimako-Bertoua area. The two species are illustrated, and their affinities and conservation status according to the 2012 IUCN categories and criteria are discussed. Both species are threatened with extinction due to habitat destruction, the first is assessed as Vulnerable, the second Endangered.
Rational Designed Hybrid Peptides Show up to a 6-fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides measured by BioSAXS
Authors: Hilpert Kai , Gani Jurnorain , Rumancev Christoph , Simpson Nathan , Lopez-Perez Paula Matilde , Garamus Vasil M. , von Gundlach Andreas Robert , Markov Petar , Scocchi Marco , Mikut Ralf , Rosenhahn Axel
Published: November 2021

Antimicrobial peptides (AMPs) are a promising class of compounds being developed against multi-drug resistant bacteria. Hybridization has been reported to increase antimicrobial activity. Here, two proline-rich peptides (consP1: VRKPPYLPRPRPRPL-CONH2 and Bac5-v291: RWRRPIRRRPIRPPFWR-CONH2) were combined with two arginine-isoleucine-rich peptides (optP1: KIILRIRWR-CONH2 and optP7: KRRVRWIIW-CONH2). Proline-rich antimicrobial peptides (PrAMPs) are known to inhibit the bacterial ribosome, shown also for Bac5-v291, whereas it is hypothesized a “dirty drug” model for the arginine-isoleucine-rich peptides. That hypothesis was underpinned by transmission electron microscopy and biological small-angle X-ray scattering (BioSAXS). The hybrid peptides showed a stronger antimicrobial activity compared to the proline-rich peptides, except when compared to Bac5-v291 against E. coli. The increase in activity compared to the arginine-isoleucine-rich peptides was up to 6-fold, however, it was not a general increase but was dependent on the combination of peptides and bacteria. BioSAXS experiments revealed that proline-rich peptides and arginine-isoleucine-rich peptides induce very different ultrastructural changes in E. coli, whereas a hybrid peptide (hyP7B5GK) shows changes, different to both parental peptides and the untreated control. These different ultrastructural changes indicated that the mode of action of the parental peptides is different from each other as well as from the hybrid peptide hyP7B5GK. All peptides showed very low haemolytic activity, some of them showed a 100-fold or larger therapeutic window, demonstrating the potential for further drug development.
Sequence conservation, domain architectures, and phylogenetic distribution of the HD-GYP type c-di-GMP phosphodiesterases
Authors: Galperin Michael Y. , Chou Shan-Ho
Published: November 2021

The HD-GYP domain, named after two of its conserved sequence motifs, was first described in 1999 as a specialized version of the widespread HD phosphohydrolase domain that had additional highly conserved amino acid residues. Domain associations of HD-GYP indicated its involvement in bacterial signal transduction and distribution patterns of this domain suggested that it could serve as a hydrolase of the bacterial second messenger c-di-GMP, in addition to or instead of the EAL domain. Subsequent studies confirmed the ability of various HD-GYP domains to hydrolyze c-di-GMP to linear pGpG and/or GMP. Certain HD-GYP-containing proteins hydrolyze another second messenger, cGAMP, and some HD-GYP domains participate in regulatory protein-protein interactions. The recently solved structures of HD-GYP domains from four distinct organisms clarified the mechanisms of c-di-GMP binding and metal-assisted hydrolysis. However, the HD-GYP domain is poorly represented in public domain databases, which causes certain confusion about its phylogenic distribution, functions, and domain architectures. Here, we present a refined sequence model for the HD-GYP domain and describe the roles of its most conserved residues in metal and/or substrate binding. We also calculate the numbers of HD-GYPs encoded in various genomes and list the most common domain combinations involving HD-GYP, such as the RpfG (REC–HD-GYP), Bd1817 (DUF3391– HD-GYP), and PmGH (GAF–HD-GYP) protein families. We also provide the descriptions of six HD-GYP–associated domains, including four novel integral membrane sensor domains. This work is expected to stimulate studies of diverse HD-GYP-containing proteins, their N-terminal sensor domains and the signals to which they respond.

IMPORTANCE

The HD-GYP domain forms class II of c-di-GMP phosphodiesterases that control the cellular levels of the universal bacterial second messenger c-di-GMP and therefore affect flagellar and/or twitching motility, cell development, biofilm formation, and, often, virulence. Despite more than 20 years of research, HD-GYP domains are insufficiently characterized; they are often confused with ‘classical’ HD domains that are involved in various housekeeping activities and may participate in signaling, hydrolyzing (p)ppGpp and c-di-AMP. This work provides an updated description of the HD-GYP domain, including its sequence conservation, phylogenetic distribution, domain architectures, and the most widespread HD-GYP-containing protein families. This work shows that HD-GYP domains are widespread in many environmental bacteria and are predominant c-di-GMP hydrolases in many lineages, including clostridia and deltaproteobacteria.
An Entropy-based Directed Random Walk for Pathway Activity Inference Using Topological Importance and Gene Interactions
Authors: Hui Tay Xin , Sutikno Tole , Kasim Shahreen , Md Fudzee Mohd Farhan , Halim Shahliza Abd , Hassan Rohayanti , Sen Seah Choon
Published: November 2021

The integration of microarray technologies and machine learning methods has become popular in predicting pathological condition of diseases and discovering risk genes. The traditional microarray analysis considers pathways as simple gene sets, treating all genes in the pathway identically while ignoring the pathway network’s structure information. This study, however, proposed an entropy-based directed random walk (e-DRW) method to infer pathway activity. This study aims (1) To enhance the gene-weighting method in Directed Random Walk (DRW) by incorporating t-test statistic scores and correlation coefficient values, (2) To implement entropy as a parameter variable for random walking in a biological network, and (3) To apply Entropy Weight Method (EWM) in DRW pathway activity inference. To test the objectives, the gene expression dataset was used as input datasets while the pathway dataset was used as reference datasets to build a directed graph. An equation was proposed to assess the connectivity of nodes in the directed graph via probability values calculated from the Shannon entropy formula. A direct proof of calculation based on the proposed mathematical formula was presented using e-DRW with gene expression data. Based on the results, there was an improvement in terms of sensitivity of prediction and accuracy of cancer classification between e-DRW and conventional DRW. The within-dataset experiments indicated that our novel method demonstrated robust and superior performance in terms of accuracy and number of predicted risk-active pathways compared to the other DRW methods. In conclusion, the results revealed that e-DRW not only improved prediction performance, but also effectively extracted topologically important pathways and genes that are specifically related to the corresponding cancer types.
How to maximize the effectiveness of stealing thunder in crisis communication: the significance of follow-up actions and transparent communication
Authors: Kim Soo-Yeon , Lee Jeong-Hyeon
Published: November 2021

Purpose

This study aims to explore consumers' perceptions of stealing thunder and to investigate significant factors for maximizing its effect.

Design/methodology/approach

This study used a mixed-methods approach. First, qualitative responses from 286 Korean participants were collected and analyzed (Study 1). Second, the experiment employed a randomized 2 (crisis communication timing: stealing thunder vs thunder) × 2 (transparent vs nontransparent communication) × 2 (follow-up actions: good vs poor) between-subjects experimental design with 426 Korean participants to investigate and confirm the results of Study 1.

Findings

Qualitative data showed that the participants' evaluation of corporations' stealing thunder strategy is complicated. Some do not perceive corporate use of stealing thunder at face value, but rather view it as yet another hopeless, selfish and irresponsible crisis communication strategy, distrusting it based on strong cynicism toward all corporations. An experiment confirmed that stealing thunder was significantly more effective in eliciting consumers' ethical judgment (EJ) and word-of-mouth (WOM) on corporations than the thunder strategy. Significant two-way interaction effects between crisis timing and follow-up actions showed that the stealing thunder strategy should be accompanied by follow-up actions to increase consumers' credibility and WOM intentions.

Originality/value

This study investigated how consumers evaluate stealing thunder by adopting both a qualitative and quantitative approach to explore how they make meaning out of this phenomenon.
Project portfolio risk analysis with the consideration of project interdependencies
Authors: Bai Libiao , Shi Huijing , Kang Shuyun , Zhang Bingbing
Published: November 2021

Purpose

Comprehensive project portfolio risk (PPR) analysis is essential for the success and sustainable development of project portfolios (PPs). However, project interdependency creates complexity for PPR analysis. In this study, considering the interdependency effect among projects, the authors develop a quantitative evaluation model to analyze PPR based on a fuzzy Bayesian network.

Design/methodology/approach

In this paper, the primary purpose is to comprehensively evaluate project portfolio risk considering the interdependency effect using a systematical model. Accordingly, a fuzzy Bayesian network (FBN) is developed based on the existing studies. Specifically, first, the risks in project portfolios are identified from the project interdependencies perspective. Second, a fuzzy Bayesian network is adopted to model and quantify the interaction relationships among risks. Finally, the model is implemented to analyze the occurrence situation and characteristics of risks.

Findings

The interdependency effect can lead to high-stake risks, including weak financial liquidity, a lack of cross-project members and project priority imbalance. Furthermore, project schedule risks and inconsistency between product supply and market demand are relatively sensitive and should also be prioritized. Also, the validity of this risk evaluation model has been proved.

Originality/value

The findings identify the most sensitive risks for guaranteeing portfolio implementation and reveal interdependency effect can trigger some specific risks more often. This study proposes for the first time to measure and analyze project portfolio risk by a systematical model. It can help systematically assess and manage the complicated and interdependent risks associated with project portfolios.
Supply chain risk factors in green construction of residential mega projects – interactions and categorization
Authors: Marandi Alamdari Ardalan , Jabarzadeh Younis , Samson Daniel , Sanoubar Naser
Published: November 2021

Purpose

Green construction has begun implementing sustainable and environmentally friendly practices, but there has not yet been an assessment for green construction supply chain risks in the literature. Identification and assessment of potential risks will result in more appropriate risk mitigation strategies to overcome disruptions affecting higher performance. Thus, this study aims to identify green construction supply chain risks of residential mega-projects.

Design/methodology/approach

Interpretive structural modeling (ISM) provided a hierarchical model composed of seven layers that elucidated the driving influences between the elements. Matrice d’impacts croises-multiplication appliqúe an classement (MICMAC) analysis classified the elements into the driver, linkage and dependent variables based on their dependence and driving powers, providing a clearer understanding of risk factors and their influential characteristics. Using experts' knowledge and experience is compatible with the subjective nature of ‘supply chain risks’ and is more suitable while collecting pertinent quantitative data which is far more challenging.

Findings

Tenable output, using an international expert group, addressed key risk factors. Technical expertise and skilled labor, key customers, and corporate culture are found as elements with most driving power, and the final product and logistics coordination and supply chain configuration found as the most dependent risk factors. Managerial implications addressed the most fundamental risk sources and suggested practical proactive risk management approaches to maximize green supply chain performance.

Originality/value

Identified supply chain oriented key risk factors of the residential green mega projects add novelty to the context of green construction projects' supply chain management. And eliciting the influential relations of the key risk factors provide a bigger picture of key risks in green residential mega projects that can be extended by sub-risks related to process activities. Assessing supply chain risks' interactions in the context of green residential mega projects is a novel contribution to mega construction-project management's body of knowledge. Also, the key risk factors were categorized based on the characteristics known as driving power and dependence.
Identifying high quality ideas in the online context: evidence from a meta-analysis
Authors: Hu Suya , Xu Di
Published: November 2021

Purpose

With the rapid development of web-based ideation platforms, firms are increasingly reaching outside their boundaries to obtain ideas, which makes idea evaluation tricky and ineffective. Numerous studies have investigated the antecedents of idea quality, but few have focused on the fragmented and contradictory conclusions these studies have drawn. Thus, the purpose of this paper is to disentangle conflicting findings regarding factors affecting idea quality.

Design/methodology/approach

A total of 41 independent samples from 40 articles published between 2009 and 2020 were retrieved and encoded to conduct a meta-analysis. By using Comprehensive Meta-analysis 3.0 (CMA 3.0) software, the relationship between identified influencing factors and idea quality, and the moderating effects of potential variables were investigated.

Findings

Factors affecting idea quality were summarized and divided into three categories: idea-related factors, ideator-related factors and platform-related factors. The results indicated that all proposed factors (idea length, supporting evidence, past success, past submissions, past comments, votes received and comments received) had significant positive effects on idea quality. Moreover, the measurement of idea quality and idea type was the causative factor for the inconsistent findings, whereas the moderating effect of platform type was not significant.

Originality/value

This study systematically synthesized the existing research on the factors influencing idea quality and helped to reconcile the mixed results. The findings serve to enrich current knowledge of idea evaluation in the online context, which could have important implications for both scholars and practitioners.