bluuebunny/crossref_metadata_2025 huggingface dataset:
Atherosclerosis is a smooth muscle cell-driven tumor-like disease
Authors: Pan Huize , Ho Sebastian E. , Xue Chenyi , Cui Jian , Ross Leila S. , Li Fang , Solomon Robert A. , Connolly E. Sander , Reilly Muredach P.
Published: March 2023

Atherosclerosis, the leading cause of cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC “phenotypic switching” plays a central role in atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that atherosclerosis, in terms of SMC behaviors, share extensive commonalities with tumors. SMC-derived cells in the disease show multiple characteristics of tumor cell biology, including genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. SMC-specific expression of oncogenicKrasG12Daccelerates SMC phenotypic switching and exacerbates atherosclerosis. Moreover, we present a proof of concept showing that niraparib, an anti-cancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that atherosclerosis is a tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic cardiovascular disease.
Peroxisomal compartmentalization of amino acid biosynthesis reactions imposes an upper limit on compartment size
Authors: Gu Ying , Alam Sara , Oliferenko Snezhana
Published: March 2023

Cellular metabolism relies on just a few redox cofactors. Selective compartmentalization may prevent competition between metabolic reactions requiring the same cofactor. Is such compartmentalization necessary for optimal cell function? Is there an optimal compartment size? Here we probe these fundamental questions using peroxisomal compartmentalization of the last steps of lysine and histidine biosynthesis in the fission yeastSchizosaccharomyces japonicus. We show that compartmentalization of these NAD+dependent reactions together with a dedicated NADH/NAD+recycling enzyme supports optimal growth when an increased demand for anabolic reactions taxes cellular redox balance. In turn, compartmentalization constrains the size of individual organelles, with larger peroxisomes accumulating all the required enzymes but unable to support both biosynthetic reactions at the same time. We propose that compartmentalized biosynthetic reactions are sensitive to the size of the compartment, likely due to scaling-dependent changes within the system, such as enzyme packing density.
Genomic evidence reveals three sequential W-autosome fusions in Heliconius butterflies
Authors: Rueda-M Nicol , Pardo-Diaz Carolina , Montejo-Kovacevich Gabriela , McMillan W. Owen , Kozak Krzysztof M. , Arias Carlos F. , Ready Jonathan , McCarthy Shane , Durbin Richard , Jiggins Chris D. , Meier Joana , Salazar Camilo
Published: March 2023

Sex chromosomes are evolutionarily labile in many animals and sometimes fuse with autosomes, creating so-called neo-sex chromosomes. Fusions between sex chromosomes and autosomes have been proposed to reduce sexual conflict and to promote adaptation and reproductive isolation among species. Recently, advances in genomics have fuelled the discovery of such fusions across the tree of life. Here, we discovered multiple fusions leading to neo-sex chromosomes in the sara/sapho clade of the classical adaptive radiation of Heliconius butterflies. Heliconius butterflies generally have 21 chromosomes with very high synteny. However, the five species in the sapho subclade show large variation in chromosome number ranging from 21 to 60. We found that the W chromosome is fused with chromosome 4 in all of them. Two sister species pairs showed subsequent fusions between the W and chromosomes 9 or 14, respectively. These sequential fusions between autosomes and sex chromosomes make Heliconius butterflies an ideal system for studying the role of neo-sex chromosomes in adaptive radiations and the degeneration of sex chromosomes over time. Our findings emphasize the capability of WGS technology to detect neo-sex chromosomes even when sex chromosomes are not explicitly assembled.
MK2 deficiency decreases mortality during the inflammatory phase after myocardial infarction in mice
Authors: Trépanier Joëlle , Nawaito Sherin A. , Sahadevan Pramod , Sahmi Fatiha , Duquette Natacha , Gélinas Danielle , Gillis Marc-Antoine , Shi Yanfen , Torok Cynthia , Clavet-Lanthier Marie-Élaine , Matthias Gaestel , Sirois Martin G. , Tardif Jean-Claude , Allen Bruce G.
Published: March 2023

Background:

Altering the onset, intensity, or duration of inflammation can impact the recovering heart’s structure and function following myocardial infarction (MI). Substrates of MAP kinase-activated protein kinase 2 (MK2) include proteins that regulate the stability of AU-rich transcripts, including those of several pro-inflammatory cytokines. This study was to determine if MK2-deficiency impaired the inflammatory phase of post-MI wound repair.

Methods and Results:

Myocardial infarctions were induced by permanent ligation of the left anterior descending coronary artery in 12-week-old male MK2+/+and MK2-/-littermate mice. Five days post-MI, survival was 100% in MI-MK2-/-(n = 20) and 79% in MI-MK2+/+mice (n = 29; Mandel-Cox test:P< 0.05). Area at risk and infarct size were similar. Echocardiographic imaging revealed that both systolic and diastolic LV diameters were greater in MI-MK2+/+than MI-MK2-/-mice. MK2-deficiency did not affect the increase in wall motion score index. Infiltration of neutrophils or monocytes did not differ significantly. Cytokine and chemokine transcripts were quantified in infarcted and non-infarcted LV tissue using qPCR arrays (QIAGEN). Three days post-MI,Ifna2was increased andIl16was decreased in infarcted tissue from MK2-/-hearts, compared with infarcted MK2+/+tissue, whereas in the non-infarcted MK2-/-myocardiumIl27increased andTnfsf11,Ccl3, andIl1rnwere decreased. Five days post-MI,Ctf16andIl10increased in infarcted MK2-/-tissue whereas in the non-infarcted MK2-/-myocardiumCcl9, Nodal, and Xcl2increased andIl15decreased.

Conclusions:

The findings of this study suggest MK2-deficiency is an advantage during the inflammatory phase of cardiac wound repair post-MI.

Clinical Perspective

What is new?

-The effects of MAP kinase-activated protein kinase 2 (MK2) deficiency on survival, cardiac structure and function, and the inflammatory phase of wound healing following myocardial infarction were assessed using a constitutive, pan MK2-null mouse model.

-MK2-deficiency reduced mortality but did not alter area at risk or infarct size post-myocardial infarction. Inflammatory cell infiltration was also unaffected.

-MK2-deficiency altered the abundance of several cytokines (increased, decreased) in infarcted and non-infarcted myocardium post-MI.

What are the clinical implications?

-The initial phase of wound repair post-MI involves inflammation.

-The risk of damage to the myocardium and mortality may be reduced by inhibition of MK2 activity during the inflammatory phase of wound healing post-MI.
Single-Cell Map of Dynamic Multicellular Ecosystem of Radiation-Induced Intestinal Injury
Authors: Lu Hao , Yan Hua , Xing Yuan , Ye Yumeng , Jiang Siao , Ma Luyu , Zuo Hongyan , Hao Yanhui , Yu Chao , Li Yang , Lu Yiming , Zhou Gangqiao
Published: March 2023

Intestine is a highly radiation-sensitive organ that could be injured during the radiotherapy for abdominal or pelvic cavity tumors. However, the dynamic change of the intestinal microenvironment related to radiation-induced intestine injury (RIII) is still unclear. Using single-cell RNA sequencing, we pictured a dynamic landscape of the intestinal microenvironment during RIII and regeneration. We showed that the multicellular ecosystem of intestine exhibited heterogeneous radiosensitivities. We revealed the distinct dynamic patterns of three subtypes of intestinal stem cells (ISCs), and the cellular trajectory analysis suggested a complex interconversion pattern among them. For the immune cells, we found thatLy6c+monocytes can give rise to both pro-inflammatory macrophages and resident macrophages after RIII. Besides, through cellular communication analysis, we identified a positive feedback loop between the macrophages and endothelial cells, which could amplify the inflammatory response induced by radiation. Overall, our study provides a valuable single-cell map of the dynamic multicellular ecosystem during RIII and regeneration, which may facilitate the understanding of the mechanism of RIII.
Lethal giant larvae gene family (Llgl1andLlgl2) functions as a tumor suppressor in mouse skin epidermis
Authors: Bii Victor M. , Rudoy Dmytro , Klezovitch Olga , Vasioukhin Valeri
Published: March 2023

Loss of cell polarity and tissue disorganization occurs in majority of epithelial cancers. Studies in simple model organisms identified molecular mechanisms responsible for the establishment and maintenance of cellular polarity, which play a pivotal role in establishing proper tissue architecture. The exact role of these cell polarity pathways in mammalian cancer is not completely understood. Here we analyzed the mammalian orthologs of drosophila apical-basal polarity gene lethal giant larvae (lgl), which regulates asymmetric stem cell division and functions as a tumor suppressor in flies. There are two mammalian orthologs oflgl(Llgl1andLlgl2). To determine the role of the entire lgl signaling pathway in mammals we generated mice with ablation of bothLlgl1andLlgl2in skin epidermis using K14-Cre (Llgl1/2-/-cKO mice). Surprisingly, we found that ablation ofLlgl1/2genes does not impact epidermal polarity in adult mice. However, oldLlgl1/2cKO mice present with focal skin lesions which are missing epidermal layer and ripe with inflammation. To determine the role of lgl signaling pathway in cancer we generatedTrp53-/-/Llgl1/2-/-cKO andTrp53-/+/Llgl1/2-/-cKO mice. Loss ofLlgl1/2promoted squamous cell carcinoma (SCC) development inTrp53-/-cKO and caused SCC inTrp53-/+cKO mice, while no cancer was observed inTrp53-/+cKO controls. Mechanistically, we show that ablation ofLlgl1/2causes activation of aPKC and upregulation of NF-kB signaling pathway, which may be necessary for SCC inTrp53-/+/Llgl1/2-/-cKO mice. We conclude that Lgl signaling pathway functions as a tumor suppressor in mammalian skin epidermis.
adequaSSE: Model Adequacy Testing for Trait-Dependent Diversification Models
Authors: Schwery Orlando , Freyman Will , Goldberg Emma E.
Published: March 2023

The presence of large variation in speciation and extinctin rates across the tree of life has long been hypothesized to be driven by the evolution of traits that affect diversification. To test such hypotheses, phylogenetic biologists have developed a wide class of state-dependent birth-death processes that jointly model trait evolution and the diversification process. However, it has since been shown that these models are sensitive to falsely linking traits to diversification. Here we present a Bayesian approach to test the adequacy of statedependent birth-death models by statistically checking whether they describe the variation observed in the data. Our method generates posterior predictive distributions for a suite of informative test statistics, providing a general framework for testing diversification processes and models of trait evolution. We simulate data sets under different violations of model assumptions and find that our approach successfully detects the inadequacy of the model for them. We further show that the manner in which a model fails to fit the data can reveal insights into the processes of trait evolution and diversification.
Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders
Authors: Cilleros-Portet Ariadna , Lesseur Corina , Marí Sergi , Cosin-Tomas Marta , Lozano Manuel , Irizar Amaia , Burt Amber , García-Santisteban Iraia , Martín Diego Garrido , Escaramís Geòrgia , Hernangomez-Laderas Alba , Soler-Blasco Raquel , Breeze Charles E. , Gonzalez-Garcia Bárbara P. , Santa-Marina Loreto , Chen Jia , Llop Sabrina , Fernández Mariana F. , Vrijhed Martine , Ibarluzea Jesús , Guxens Mònica , Marsit Carmen , Bustamante Mariona , Bilbao Jose Ramon , Fernandez-Jimenez Nora
Published: March 2023

Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placentalcis-mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placentalcis-mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type- imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.
Uracil Repair - A Source of DNA Glycosylase Dependent Genome Instability
Authors: Krawczyk Claudia , Bentele Marc , Latypov Vitaly , Woolcock Katrina , Noreen Faiza , Fritsch Olivier , Schär Primo
Published: March 2023

Uracil DNA glycosylases (UDGs) excise uracil from DNA arising from dUMP misincorporation during replication or from cytosine deamination. Besides functioning in canonical uracil repair, UDGs cooperate with DNA base modifying enzymes to effect mutagenesis or DNA demethylation. Mammalian cells express four UDGs, the functional dissection of which represents a challenge. Here, we usedSchizosaccharomyces pombewith only two UDGs, Ung1 and Thp1, as a simpler model to study functional interactions in uracil repair. We show that despite a predominance of Ung1 activity in cell extracts, both UDGs act redundantly against genomic uracil accumulation and mutations from cytosine deamination in cells. Notably, Thp1 but not Ung1-dependent repair is cytotoxic under genomic uracil stress induced by 5-fluorouracil exposure or AID expression. Also, Thp1-but not Ung1-mediated base excision is recombinogenic, accounting for more than 60% of spontaneous mitotic recombination events in a recombination assay. Hence, the qualitative outcome of uracil repair depends on the initiating UDG; while Ung1 shows expected features of a bona-fide DNA repair enzyme, Thp1-initiated repair appears slow and rather non-productive, suggesting a function beyond canonical DNA repair. Given the epigenetic role of TDGs, the mammalian orthologs of Thp1, we performed transcriptome analyses and identified a possible function of Thp1 in stabilizing gene expression.
Temporal dynamics of Na/K pump mediated memory traces: insights from conductance-based models ofDrosophilaneurons
Authors: Megwa Obinna F. , Pascual Leila May , Günay Cengiz , Pulver Stefan R. , Prinz Astrid A.
Published: March 2023

Sodium potassium ATPases (Na/K pumps) mediate long-lasting, dynamic cellular memories that can last tens of seconds. The mechanisms controlling the dynamics of this type of cellular memory are not well understood and can be counterintuitive. Here, we use computational modeling to examine how Na/K pumps and the ion concentration dynamics they influence shape cellular excitability. In aDrosophilalarval motor neuron model, we incorporate a Na/K pump, a dynamic intracellular Na+concentration, and a dynamic Na+reversal potential. We probe neuronal excitability with a variety of stimuli, including step currents, ramp currents, and zap currents, then monitor the sub- and suprathreshold voltage responses on a range of time scales. We find that the interactions of a Na+-dependent pump current with a dynamic Na+concentration and reversal potential endow the neuron with rich response properties that are absent when the role of the pump is reduced to the maintenance of constant ion concentration gradients. In particular, these dynamic pump-Na+interactions contribute to spike rate adaptation and result in long-lasting excitability changes after spiking and even after sub-threshold voltage fluctuations on multiple time scales. We further show that modulation of pump properties can profoundly alter a neuron’s spontaneous activity and response to stimuli by providing a mechanism for bursting oscillations. Our work has implications for experimental studies and computational modeling of the role of Na/K pumps in neuronal activity, information processing in neural circuits and the neural control of animal behavior.
Logging disrupts the ecology of molecules in headwater streams
Authors: Freeman Erika C , Emilson Erik JS , Webster Kara , Dittmar Thorsten , Tanentzap Andrew J
Published: March 2023

Global demand for wood products is increasing forest harvest. One understudied consequence of logging is that it accelerates mobilization of dissolved organic matter (DOM) from soils to aquatic ecosystems. Here, we tested how logging changed DOM in headwaters of hardwood-dominated catchments in northern Ontario, Canada. We apply a before-after control-impact experiment across four catchments for three years. DOM concentration in streams from logged catchments quadrupled, on average, after the first year post-harvest, but resulting changes to the molecular composition of DOM persisted for at least two-years. Ultrahigh-resolution mass spectrometry revealed that DOM within logged catchments was more energy-rich and chemically diverse than in controls, with novel highly unsaturated polyphenols, carboxylic-rich alicyclic, and nitrogen-containing formulae. The molecular composition of stream DOM measured fortnightly post-harvest was most strongly associated with DOM composition within intermediate and deeper layers of contributing soils, likely due to increased hydrological connectivity post-harvest. We estimate logging increased the total annual flux of dissolved organic carbon in streams by 6.4% of extracted wood carbon, and this carbon was more likely to be released into the atmosphere. Carbon accounting of forestry, including as a natural climate solution, must now consider the transport and fate of DOM from land into water.
Spatial positioning of preimplantation mouse embryo blastomeres is regulated by mTORC1 and 7mG-cap dependent translation at the 8- to 16-cell transition
Authors: Gahurova Lenka , Tomankova Jana , Cerna Pavlina , Bora Pablo , Kubickova Michaela , Virnicchi Giorgio , Kovacicova Kristina , Potesil David , Hruska Pavel , Zdrahal Zbynek , Anger Martin , Susor Andrej , Bruce Alexander W.
Published: March 2023

Preimplantation stages of mouse embryo development involve temporal and spatial specification and segregation of three late blastocyst cell lineages; trophectoderm (TE), primitive endoderm (PrE) and epiblast (EPI). Spatial separation of the outer TE lineage from the two inner cell mass (ICM) lineages (PrE and EPI) starts with the 8- to 16-cell transition and concludes following transit through the 16- to 32-cell stages. This results in an early blastocyst ICM derived from descendants of primary founding inner cells and a secondarily contributed population, of which subsequent relative EPI versus PrE potencies are subject to debate. Here, we report generation of primary but not the secondary ICM populations is highly dependent on temporally discreet activation of the mammalian target of Rapamycin (mTOR – specifically mTORC1) during M-phase entry at the 8-cell stage. This role is mediated via regulation of the 7-methylguanosine-(7mG) cap binding initiation complex (EIF4F), linked to translation of a subset of key mRNAs containing 5’ UTR terminal oligopyrimidine (TOP-) or TOP-like sequence motifs; as knockdown of identified TOP-like motif containing transcripts also impairs generation of 16-cell stage primary ICM founders. However, mTOR inhibition induced ICM cell number deficits at the early blastocyst stage can be compensated by the late blastocyst stage, in the absence of inhibition. This compensation is likely initiated at the 32-cell stage when supernumerary outer cells in mTOR-inhibited embryos exhibit molecular characteristics of inner cells. Collectively, the data identify a novel mechanism specifically governing initial spatial segregation of blastomeres in the mouse embryo, that is distinct from those directing subsequent inner cell formation and contributes to germane segregation of late blastocyst lineages.
A host recognition module shared among distantAlteromonasbacteriophage families features tail fibers with transient chaperone “caps”
Authors: Gonzalez-Serrano Rafael , Rosselli Riccardo , Roda-Garcia Juan J. , Martin-Cuadrado Ana-Belen , Rodriguez-Valera Francisco , Dunne Matthew
Published: March 2023

The host recognition modules encoding the injection machinery and receptor binding proteins (RBPs) of bacteriophages are variable genomic units predisposed to mutation and recombination to maintain infectivity toward co-evolving bacterial hosts. In this study, we reveal howAlteromonas mediterraneaschitovirus A5 shares its host recognition module, including tail fiber (TF) and cognate chaperone, with phages from distantly related families includingAlteromonasmyovirus, V22. While the chaperone of V22 is essential for producing active TFs, here we demonstrate production of functional A5 TFs regardless of chaperone co-expression. AlphaFold-generated models of TF and chaperone pairs from phages A5, V22, and otherAlteromonasphages reveal how amino acid insertions within both A5-like proteins results in a knob domain duplication in the TF and a β-hairpin “tentacle” extension of the chaperone. These structural modifications are linked to chaperone dependency differences between the A5 and V22 TFs. Structural similarity between the chaperones and intramolecular chaperone domains of other phage RBPs suggests an additional function of these chaperones as transient TF “caps”. Finally, our identification of homologous host recognition modules used by morphologically distinct phages implies that HGT and recombination events between unrelated phages may be a more common process than previously thought amongCaudoviricetesphages.
Dissecting embryonic and extra-embryonic lineage crosstalk with stem cell co-culture
Authors: Wei Yulei , Zhang E , Yu Leqian , Ci Baiquan , Guo Lei , Sakurai Masahiro , Takii Shino , Liu Jian , Schmitz Daniel A. , Ding Yi , Zhan Linfeng , Zheng Canbin , Sun Hai-Xi , Xu Lin , Okamura Daiji , Ji Weizhi , Tan Tao , Wu Jun
Published: March 2023

Faithful embryogenesis requires precise coordination between embryonic and extraembryonic tissues. Although stem cells from embryonic and extraembryonic origins have been generated for several mammalian species(Bogliotti et al., 2018; Choi et al., 2019; Cui et al., 2019; Evans and Kaufman, 1981; Kunath et al., 2005; Li et al., 2008; Martin, 1981; Okae et al., 2018; Tanaka et al., 1998; Thomson et al., 1998; Vandevoort et al., 2007; Vilarino et al., 2020; Yu et al., 2021b; Zhong et al., 2018), they are grown in different culture conditions with diverse media composition, which makes it difficult to study cross-lineage communication. Here, by using the same culture condition that activates FGF, TGF-β and WNT signaling pathways, we derived stable embryonic stem cells (ESCs), extraembryonic endoderm stem cells (XENs) and trophoblast stem cells (TSCs) from all three founding tissues of mouse and cynomolgus monkey blastocysts. This allowed us to establish embryonic and extraembryonic stem cell co-cultures to dissect lineage crosstalk during early mammalian development. Co-cultures of ESCs and XENs uncovered a conserved and previously unrecognized growth inhibition of pluripotent cells by extraembryonic endoderm cells, which is in part mediated through extracellular matrix signaling. Our study unveils a more universal state of stem cell self-renewal stabilized by activation, as opposed to inhibition, of developmental signaling pathways. The embryonic and extraembryonic stem cell co-culture strategy developed here will open new avenues for creating more faithful embryo models and developing more developmentally relevant differentiation protocols.
Development of Fully Human, Bispecific Antibodies that Effectively Block Omicron Variant Pseudovirus Infections
Authors: Allen Jason , Gonzalez Michelle , Kaur Jasbir , Smith Melinda , You Junping , Yang Guojun , Zha Dongxing , Tian Ze , Al-Shami Amin , Shi Chunhua , Molldrem Jeffrey , Heffernan Tim
Published: March 2023

The emergence of highly immune invasive and transmissible variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has decreased the effectiveness of existing vaccines. It is, therefore, critical to develop effective and safe therapeutics for SARS-CoV-2 infections, especially for the most vulnerable and immunocompromised patients. Neutralizing antibodies have been shown to be successful at preventing severe disease from early SARS-CoV-2 strains, although their efficacy has diminished with the emergence of new variants. Here, we aim to develop fully human and broadly neutralizing monoclonal (mAb) and bispecific (BsAb) antibodies against SARS-CoV-2 and its variants. Specifically, we first identified two antibodies from human transgenic mice that bind to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and are capable of neutralizing SARS-CoV-2 and variants of concern with high to moderate affinity. Two non-competing clones with the highest affinity and functional blocking of ACE2 binding were then selected to be engineered into two BsAbs, which were then demonstrated to have relatively improved affinity, ACE2 blocking ability, and pseudovirus inhibition against several variants, including Omicron (B.1.1.529). Our findings provide one mAb candidate and two bsAb candidates for consideration of further clinical development and suggest that the bispecific format may be more effective than mAbs for SARS-CoV-2 treatment.
An innate granuloma eradicates an environmental pathogen usingGsdmdandNos2
Authors: Harvest Carissa K. , Abele Taylor J. , Yu Chen , Beatty Cole J. , Amason Megan E. , Billman Zachary P. , DePrizio Morgan A. , Lacey Carolyn A. , Maltez Vivien I. , Larson Heather N. , McGlaughon Benjamin D. , Saban Daniel R. , Montgomery Stephanie A. , Miao Edward A.
Published: March 2023

Granulomas often form around pathogens that cause chronic infections. Here, we discover a novel granuloma model in mice.Chromobacterium violaceumis an environmental bacterium that stimulates granuloma formation that not only successfully walls off but also clears the infection. The infected lesion can arise from a single bacterium that replicates in the presence of a neutrophil swarm. Bacterial replication ceases when macrophages organize around the infection and form a granuloma. This granuloma response is accomplished independently of adaptive immunity that is typically required to organize granulomas. TheC. violaceum-induced granuloma requires at least two separate defense pathways, gasdermin D and iNOS, to maintain the integrity of the granuloma architecture. These innate granulomas successfully eradicateC. violaceuminfection. Therefore, this newC. violaceum-induced granuloma model demonstrates that innate immune cells successfully organize a granuloma and thereby eradicate infection by an environmental pathogen.
O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology
Authors: Balana Aaron T. , Mahul-Mellier Anne-Laure , Nguyen Binh A , Horvath Mian , Javed Afraah , Hard Eldon R. , Jasiqi Yllza , Singh Preeti , Afrin Shumaila , Pedretti Rose , Singh Virender , Lee Virginia M.-Y. , Luk Kelvin C. , Saelices Lorena , Lashuel Hilal A. , Pratt Matthew R.
Published: March 2023

The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the pathogenesis of Alzheimer’s and Parkinson’s disease, can form different types of fibril structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, and pathology spreading patterns in the brain. Therefore, understanding the molecular and structural determinants contributing to the formation of different amyloid strains or their distinct features could open new avenues for developing disease-specific diagnostics and therapies. In this work, we report that O-GlcNAc modification of α-Synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by Cryo-EM, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson’s disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc modified fibrils remain unclear, ourin vitromechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-Synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that post-translational modifications, such as O-GlcNAc modification, of α-Synuclein are key determinants of α-Synuclein amyloid strains and pathogenicity. These findings have significant implications for how we investigate and target amyloids in the brain and could possibly explain the lack of correlation between amyloid burden and neurodegeneration or cognitive decline in some subtypes of NDDs.
Insulin secretion chip (InS-chip) reveals two peaks within first-phase that temporally coincide with a transition in glucose metabolism
Authors: Wang Yufeng , Regeenes Romario , Memon Mahnoor , Rocheleau Jonathan V.
Published: March 2023

First-phase glucose-stimulated insulin secretion is mechanistically linked to type 2 diabetes yet the underlying metabolism driving this early stage of secretion is difficult to discern due to significant islet-to-islet variability. Here, we miniaturize a fluorescence anisotropy immunoassay onto a microfluidic device to measure C-peptide secretion from individual islets as a surrogate for insulin (InS-chip). This method measures secretion from up to four islets at a time with ∼7 s resolution while providing an optical window for real-time live cell imaging. Using the InS-chip, we reveal for the first time two glucose-dependent peaks of insulin secretion (i.e., a double peak) within the first phase (<10 min). By combining real-time secretion and live cell imaging, we show that islets transition from glycolytic to OxPhos-driven metabolism at the nadir of the peaks. Overall, these data validate the InS-chip to measure glucose-stimulated insulin secretion while revealing the first-phase secretion contains two peaks defined by a shift in glucose metabolism.

Significance Statement

Loss of the first phase of glucose-stimulated insulin secretion is one of the earliest signs of type 2 diabetes (T2D). Yet current strategies to measure the early dynamics are inadequate due to the need to pool secretion from multiple islets. In this study, we designed an islet-on-a-chip microfluidic device (InS-chip) to measure insulin secretion from individual islets with <7 s temporal resolution. Our design leaves an optical window for coupled live cell imaging to tease apart the metabolism underlying secretion. Our data reveal that first-phase insulin secretion is composed of two peaks that coincide with a shift in glucose metabolism.
Modulating Factors Affecting Sports-Related Concussion Exposures: A Systematic Review and Analysis
Authors: Edelstein Rachel , Van Horn John Darrell
Published: March 2023

In the United States, the Centers for Disease Control and Prevention estimates that 1.6-to-3.8 million concussions occur annually in sports. This quantitative meta-analysis of one hundred and twenty-one sports-related concussion studies, across fourteen youth sports, investigated the contributions of statistical constructs, and diagnostic methods, considering the impact of nationwide laws and education, as well as distinguished injury surveillance techniques, in this widely diverse literature. Concussion study research designs were found to have differing diagnostic, statistical, and methodological techniques. Among less frequently studied, non-high-contact, sports, a meta-analysis investigated relative rates of concussion and sex differences. Findings indicated considerable variation in reported concussion incidence rates due to the sport played, but also due to the number of study authors listed and the proportion of female athletes represented. Such factors likely influence the reported incidence of sports-related concussions, especially in sports not typically associated with a high risk of head injuries. To better capture the incidence of sports-related head injuries and concussion, a universal data repository for youth concussions might be established to provide an ongoing, comprehensive, and accurate picture of concussions in youth and collegiate athletics.
Reliability and validity of clinical tests of cardiorespiratory fitness: A systematic review and meta-analysis
Authors: Harkin Samuel , Cousins Stephen , Locke Simon , Gordon Brett
Published: March 2023

Introduction

Insufficient physical activity is a significant contributor to non-communicable disease amongst the global population. Insufficient physical activity is directly linked with reduced cardiorespiratory fitness (CRF). CRF is as strong a predictor of mortality as well-established risk-factors such as smoking, hypertension, dyslipidaemia, and type 2 diabetes mellitus, however, it remains the only major risk factor not routinely assessed in primary health care settings. The aim of this review was to assess the validity and reliability of existing submaximal tests of CRF which can be employed in a standard medical consultation for the estimation of CRF and physical function in adults.

Methods

A systematic review of the scientific literature was undertaken to find all studies reporting the reliability and/or validity of submaximal tests of CRF and physical function. Studies published up to 12 January 2023 were included in the search of the Medline, Embase, Cinahl, SPORTdiscus, Cochrane library, Informit Health and Web of Science databases. Risk of bias was assessed using the JBI critical appraisal checklist for analytical cross-sectional studies. Data including reliability of the submaximal protocols as measured by test-retest Pearson’sr(r) or Intraclass co-efficient (ICC); and validity as measured by the correlation between the submaximal protocol results and the graded exercise test results (r) was extracted. Meta-analyses were performed to determine the overall mean r of the correlation coefficients.

Results

In total 1754 studies were identified. Following screening, 143 studies including 15,760 participants were included. All clinical tests included in meta-analysis demonstrated strong reliability. The Siconolfi step test (r=0.81), Incremental shuttle walk test (r=0.768) and 1- minute sit-to-stand test (r=0.65) demonstrated strongest validity following meta-analysis.

Conclusion

Based on the validity of the tests outlined, these can be used as an acceptable method of estimating VO2peak in a broad population, without the cost and access issues of formal GXT.
Comparison of cold sprayed and arc sprayed Zn15Al alloy coating on AZ91D magnesium substrate
Authors: Huang Guosheng , Fu Wei , Zhou Juan , Ma Li , Wang Hongren , Li Xiangbo
Published: March 2023

Purpose

The purpose of this paper is to examine the performance of cold-sprayed Zn15Al alloy coating whether it is capable of protecting magnesium alloy from corrosion, and to compare it with arc-sprayed Zn15Al alloy coating.

Design/methodology/approach

In this paper, Zn15Al alloy coating was prepared with CS-6000 cold spraying system and HDX-800 arc-sprayed system. Corrosion behaviors of the two kinds of coatings were examined with potentiodynamic polarization curves methods combined with SEM, EDS, XRD, etc.

Findings

Corrosion behavior of cold-sprayed Zn15Al alloy coating is superior to arc-sprayed Zn15Al alloy coating. The bonding strength and density of cold-sprayed Zn15Al alloy coating is much higher than that of arc-sprayed Zn15Al alloy coating. The cold-sprayed coating has a dense structure which separate magnesium from corrosion medium completely. The samples behave as Zn15Al instead of AZ91D alloy. The coating has a low probability of pitting corrosion comparing with cold sprayed Al coating through potentiodynamic polarization curve.

Practical implications

Cold-sprayed Zn15Al coating can be used to improve the anticorrosion performance of magnesium significantly and low down the risk of pitting corrosion of coating.

Social implications

Cold-sprayed Zn15Al coating is an environmentally friendly anticorrosion method for light alloy, which is also the most effective way among thermal spray, chemical vapor deposition, sol–gel, plating and anodizing or microarc oxidation.

Originality/value

The present paper used cold spray method to deposit Zn15Al coating, which has an overwhelming performance both in physical and anticorrosion to traditional thermal spray method.
Towards fighting COVID-19: can servant leadership behaviour enhance commitment of medical knowledge-workers
Authors: Ngoma Muhammed , Namono Rehema , Nangoli Sudi , Bashir Hassan , Nakyeyune Swafiyya
Published: March 2023

Purpose

This article examines the potential of increasing commitment of medical knowledge-workers (medical-KWs) in hospitals, particularly in handling deadly pandemics like COVID-19, through servant leadership behaviour. The authors hold that medical-KWs like doctors and nurses form the core team of knowledge-workers (KWs) at the forefront of fighting COVID-19 through seeking possible vaccines, treating patients and promoting behaviours that curtail its spread. Thus research directed towards enhancing their continued commitment is both timely and valuable.

Design/methodology/approach

The study uses an explanatory cross-sectional survey design.

Findings

Results reveal that servant leadership behaviour significantly explains changes in commitment of medical-KWs. Results further establish that perceived fairness – a key psychological factor – significantly explains how servant leadership enhances the commitment of medical-KWs.

Research limitations/implications

Data used were sourced from medical-KWs in selected public hospitals only. Thus results may differ among medical-KWs in private hospitals, yet they have also championed the fight against COVID-19. Never the less these results provide a direction of thought to guide practice and other related studies on a wider-scale.

Practical implications

In their quest to eradicate COVID-19 and its negative effects on social-economic development, nations have to actively promote servant leadership behaviour in the hospitals (by establishing quality relationships, credibility and efficient processes for delivering the shared goal) as mechanisms for sustaining the continued commitment of medical-KWs towards fighting the pandemic.

Originality/value

Results portray events from an economy that has registered successes in combating pandemics like Ebola and currently COVID-19 and thus offer a plausible benchmark for practice.
Eulerian–Lagrangian CFD model for prediction of heat transfer between aircraft deicing liquid sprays and a surface
Authors: Ernez Sami , Morency François
Published: March 2023

Purpose

The aim of this paper is to present a Eulerian–Lagrangian model of aircraft ground deicing that avoids the scale’s dispersion problem caused by the great distance between the spray nozzle and the surface to be deiced. Verification is done using the case of a hot particle liquid spray impinging on a horizontal flat plate. The impinged particles flow outwards radially from the impingement zone and form a hot film wall. The computed wall heat distribution is verified. In the end, an inclination spray’s angle study is presented.

Design/methodology/approach

The problem is divided into two regions. First, a 3D region is created for the evolution of the Lagrangian particles spray. A second 2D region is provided for the formation of a liquid film. The two regions exchange mass, momentum and energy through an interface. Heat losses are modelled through particles and liquid-film cooling and evaporation, particles splash and heat transfer to a fixed temperature plate.

Findings

For a chamber pressure of 1 bar, the predicted spray penetration is within 10 per cent of the experimental results. For this study case, the heat transfer is maximized with an inclination angle of approximately 30° of the spray.

Originality/value

The model presented makes it possible to simulate the impingement and heat transfer of a large-scale liquid spray with a reasonable computational cost. To the best of the authors’ knowledge, this model is a first attempt of the computational fluid dynamics simulation of ground deicing.
An exploration of determinants of affordable housing choice
Authors: Olanrewaju AbdulLateef , Woon Tan Chai
Published: March 2023

Purpose

Housing sufficiency is an indication of national development, and in recognition of this, a longstanding development objective of the Malaysian Government is the provision of affordable housing. The government has introduced various policies, schemes and regulations to increase housing supply. However, despite these measures, homeownership rates are dropping, and housing prices are outstripping inflation. For this reason, this paper aims to explain the determinants of housing choices. The issues in affordable housing supply in Malaysia are that of shortage and distributions. The problem of distribution is largely addressable through choice reconciliations.

Design/methodology/approach

The research is based on a cross-sectional survey questionnaire, comprising 20 determinants and 468 householders/users. The questionnaire was developed via a review of the literature and the authors’ experience. The survey forms are administered by hand.

Findings

Six determinants were found to be extremely important to households’ choice of housing. The Kaiser’s measure of sampling adequacy (MSA) indicated that the strength of the relationships among the determinants was strong (MSA = 0.762). Bartlett’s test of sphericity, was significant χ2 (1035) = 5013.814, p < 0.001), indicating the data were drawn from the same population and that the determinants were related. Using principal component analysis, all the 20 determinants were reduced to seven factors that accounted for some 60 per cent of the total proportion communalities. The factors were general factor, financial factor, building factor, income factor, accessibility factor, market factor and location factor.

Originality/value

Previous research only addressed factors affecting housing price, not a choice. This is the first study that explains determinants of housing choice determinants in Malaysia. This is the first study that involves large respondents. Previous research addressed housing in general and not affordable housing. The results will be useful to developers, homebuyers and policy makers towards affordable housing delivery.
What drives mobile MOOC's continuous intention? A theory of perceived value perspective
Authors: Dastane Omkar , Haba Herman Fassou
Published: March 2023

Purpose

The purpose of the study is to identify drivers of mobile massive open online course (MOOC) continuous intention (CI) through the lenses of customer perceived value (CPV) theory. Consumer choice is successfully explained by CPV, but lesser attention is given to linking the theory to the mobile MOOC context whereby the majority of theories have adopted approaches like technology acceptance model (TAM), unified theory of acceptance and use of technology (UTAUT), etc.

Design/methodology/approach

A mix-method approach was employed. Study A (qualitative), explores context-specific perceived value (PV) dimensions using nethnographic analysis of 627 learner reviews on Corsera app. Study B (quantitative), collects primary data by administering a questionnaire based on dimensions, and 231 responses were then analysed using structural equation modelling.

Findings

The results revealed that three context-specific PVs (i.e. pedagogy, interface and content) have a positive and significant impact on CI. Pedagogy value is a chief driving force of mobile MOOC CI followed by content value. Ubiquity value demonstrated insignificant impact.

Practical implications

The findings provide insights for MOOC apps and their developers for formulating better value propositions for ensuring sustainable business which may result in gaining a higher share in the growing mobile learning market.

Originality/value

This study bridges an important gap in mobile MOOC literature by providing a novel approach to investigating what drives mobile MOOC CI through the lenses of CPV theory. It is the first study investigating mobile MOOC CI through the specific CPV dimensions identified by employing a mixed-method approach. The study formulates a conceptual framework that may serve as a foundation for future research on mobile MOOCs for which literature is relatively scant.