bluuebunny/crossref_metadata_2025_split huggingface dataset:
E2F1 methylation by SETD6 regulates SETD6 expression via positive feedback mechanism
Authors: Kublanovsky Margarita , Ulu Gizem T. , Weirich Sara , Levy Nurit , Feldman Michal , Jeltsch Albert , Levy Dan 
Published: June 2023

AbstractThe protein lysine methyltransferase SETD6 has been shown to influence different cellular activities and are critically involved in the regulation of diverse developmental and pathological processes. However, the upstream signal which regulates the mRNA expression of SETD6 is not known. Bioinformatics analysis revealed that SETD6 promoter has a binding site for the transcription factor E2F1. Using various experimental systems, we confirmed that E2F1 binds to the SETD6 promoter and regulates SETD6 mRNA expression. Our further observation that this phenomenon is SETD6 dependent, suggested that SETD6 and E2F1 are linked. We next demonstrate that SETD6 mono-methylates E2F1 specifically at K117in-vitroand in cells. Finally, we show that E2F1 methylation at K117 positively regulates the expression level of SETD6 mRNA. Depletion of SETD6 or overexpression of E2F1 K117R mutant which canot be methylated by SETD6, reverses the effect. Taken together, our data provide evidence for a positive feedback mechanism which regulates the expression of SETD6 by E2F1 in a SETD6 methylation dependent manner and highlight the importance of protein lysine methyltransferases and lysine methylation signaling in the regulation of gene transcription.
Unique vulnerability ofRAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints
Authors: Cannon Alexa C. , Budagyan Konstantin , Uribe-Alvarez Cristina , Kurimchak Alison M. , Araiza-Olivera Daniela , Cai Kathy Q. , Peri Suraj , Zhou Yan , Duncan James S. , Chernoff Jonathan 
Published: June 2023

ABSTRACTRAC1P29Sis the third most prevalent hotspot mutation in sun-exposed melanoma.RAC1alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. AlthoughRAC1P29Smutations in melanoma andRAC1alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identification of alternative therapeutic targets forRAC1P29S-harboring melanomas. To investigate the RAC1P29S-driven effect on downstream molecular signaling pathways, we generated an inducible RAC1P29Sexpression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identified CDK9 as a potential new and specific target in RAC1P29S-mutant melanoma cells.In vitro, CDK9 inhibition impeded the proliferation of in RAC1P29S-mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins.In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1P29Smutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.
Loss ofBacteroides thetaiotaomicronbile acid altering enzymes impact bacterial fitness and the global metabolic transcriptome
Authors: McMillan Arthur S. , Foley Matthew H. , Perkins Caroline E. , Theriot Casey M. 
Published: June 2023

AbstractBacteroides thetaiotaomicron(B. theta) is a Gram-negative gut bacterium that encodes enzymes that alter the bile acid pool in the gut. Primary bile acids are synthesized by the host liver and are modified by gut bacteria.B. thetaencodes two bile salt hydrolases (BSHs), as well as a hydroxysteroid dehydrogenase (HSDH). We hypothesize thatB. thetamodifies the bile acid pool in the gut to provide a fitness advantage for itself. To investigate each gene’s role, different combinations of genes encoding bile acid altering enzymes (bshA, bshB, andhsdhA) were knocked out by allelic exchange, including a triple KO. Bacterial growth and membrane integrity assays were done in the presence and absence of bile acids. To explore ifB. theta’sresponse to nutrient limitation changes due to the presence of bile acid altering enzymes, RNASeq analysis of WT and triple KO strains in the presence and absence of bile acids was done. WTB. thetais more sensitive to deconjugated bile acids (CA, CDCA, and DCA) compared to the triple KO, which also decreased membrane integrity. The presence ofbshBis detrimental to growth in conjugated forms of CDCA and DCA. RNA-Seq analysis also showed bile acid exposure impacts multiple metabolic pathways inB. theta, but DCA significantly increases expression of many genes in carbohydrate metabolism, specifically those in polysaccharide utilization loci or PULs, in nutrient limited conditions. This study suggests that bile acidsB. thetaencounters in the gut may signal the bacteria to increase or decrease its utilization of carbohydrates. Further study looking at the interactions between bacteria, bile acids, and the host may inform rationally designed probiotics and diets to ameliorate inflammation and disease.ImportanceRecent work on BSHs in Gram-negative bacteria, such asBacteroides, has primarily focused on how they can impact host physiology. However, the benefits bile acid metabolism confers to the bacterium that performs it is not well understood. In this study we set out to define if and howB. thetauses its BSHs and HSDH to modify bile acids to provide a fitness advantage for itselfin vitroandin vivo. Genes encoding bile acid altering enzymes were able to impact howB. thetaresponds to nutrient limitation in the presence of bile acids, specifically carbohydrate metabolism, affecting many polysaccharide utilization loci (PULs). This suggests thatB. thetamay be able to shift its metabolism, specifically its ability to target different complex glycans including host mucin, when it comes into contact with specific bile acids in the gut. This work will aid in our understanding of how to rationally manipulate the bile acid pool and the microbiota to exploit carbohydrate metabolism in the context of inflammation and other GI diseases.
Eukaryotic antiviral immune proteins arose via convergence, horizontal transfer, and ancient inheritance
Authors: Culbertson Edward M. , Levin Tera C. 
Published: June 2023

AbstractAnimals use a variety of cell-autonomous innate immune proteins to detect viral infections and prevent replication. Recent studies have discovered that a subset of mammalian antiviral proteins have homology to anti-phage defense proteins in bacteria, implying that there are aspects of innate immunity that are shared across the Tree of Life. While the majority of these studies have focused on characterizing the diversity and biochemical functions of the bacterial proteins, the evolutionary relationships between animal and bacterial proteins are less clear. This ambiguity is partly due to the long evolutionary distances separating animal and bacterial proteins, which obscures their relationships. Here, we tackle this problem for three innate immune families (CD-NTases [including cGAS], STINGs, and Viperins) by deeply sampling protein diversity across eukaryotes. We find that Viperins and OAS family CD-NTases are truly ancient immune proteins, likely inherited since the last eukaryotic common ancestor and possibly longer. In contrast, we find other immune proteins that arose via at least four independent events of horizontal gene transfer (HGT) from bacteria. Two of these events allowed algae to acquire new bacterial viperins, while two more HGT events gave rise to distinct superfamilies of eukaryotic CD-NTases: the Mab21 superfamily (containing cGAS) which has diversified via a series of animal-specific duplications, and a previously undefined eSMODS superfamily, which more closely resembles bacterial CD-NTases. Finally, we found that cGAS and STING proteins have substantially different histories, with STINGs arising via convergent domain shuffling in bacteria and eukaryotes. Overall, our findings paint a picture of eukaryotic innate immunity as highly dynamic, where eukaryotes build upon their ancient antiviral repertoires through the reuse of protein domains and by repeatedly sampling a rich reservoir of bacterial anti-phage genes.
Decreased efficacy of a COVID-19 vaccine due to mutations present in early SARS-CoV-2 variants of concern
Authors: Weidenbacher Payton A.-B. , Friedland Natalia , Sanyal Mrinmoy , Morris Mary Kate , Do Jonathan , Hanson Carl , Kim Peter S. 
Published: June 2023

ABSTRACTWith the SARS-CoV-2 virus still circulating and evolving, there remains an outstanding question if variant-specific vaccines represent the optimal path forward, or if other strategies might be more efficacious towards providing broad protection against emerging variants. Here, we examine the efficacy of strain-specific variants of our previously reported, pan-sarbecovirus vaccine candidate, DCFHP-alum, a ferritin nanoparticle functionalized with an engineered form of the SARS-CoV-2 spike protein. In non-human primates, DCFHP-alum elicits neutralizing antibodies against all known VOCs that have emerged to date and SARS-CoV-1. During development of the DCFHP antigen, we investigated the incorporation of strain-specific mutations from the major VOCs that had emerged to date: D614G, Epsilon, Alpha, Beta, and Gamma. Here, we report the biochemical and immunological characterizations that led us to choose the ancestral Wuhan-1 sequence as the basis for the final DCFHP antigen design. Specifically, we show by size exclusion chromatography and differential scanning fluorimetry that mutations in the VOCs adversely alter the antigen’s structure and stability. More importantly, we determined that DCFHP without strain-specific mutations elicits the most robust, cross-reactive response in both pseudovirus and live virus neutralization assays. Our data suggest potential limitations to the variant-chasing approach in the development of protein nanoparticle vaccines, but also have implications for other approaches including mRNA-based vaccines.
SETDB1 modulates the TGFβ response in Duchenne muscular dystrophy myotubes
Authors: Granados Alice , Zamperoni Maeva , Rapone Roberta , Moulin Maryline , Boyarchuk Ekaterina , Bouyioukos Costas , Maestro Laurence Del , Joliot Véronique , Negroni Elisa , Mohamed Myriame , Piquet Sandra , Bigot Anne , Grand Fabien Le , Albini Sonia , Ait-Si-Ali Slimane 
Published: June 2023

SUMMARYOveractivation of the TGFβ signaling in Duchenne muscular dystrophy (DMD) is a major hallmark of disease progression, leading to fibrosis and muscle dysfunction. Here, we investigated the role of SETDB1, a histone lysine methyltransferase involved in muscle differentiation. Our data show that, following TGFβ induction, SETDB1 accumulates in the nuclei of healthy myotubes, while being already present in the nuclei of DMD myotubes where TGFβ signaling is constitutively activated. Interestingly, transcriptomics revealed that depletion of SETDB1 in DMD myotubes leads to downregulation of TGFβ-target genes coding for secreted factors involved in extracellular matrix remodeling and inflammation. Consequently, SETDB1 silencing in DMD myotubes abrogates the deleterious effect of their secretome on myoblast differentiation by impairing myoblast pro-fibrotic response. Our findings indicate that SETDB1 potentiates the TGFβ-driven fibrotic response in DMD muscles, providing a new axis for therapeutic intervention.Key resultsTGFβ induces nuclear accumulation of SETDB1 in healthy myotubesSETDB1 is enriched in DMD myotube nuclei with intrinsic TGFβ pathway overactivationSETDB1 LOF in DMD myotubes attenuates TGFβ-induced pro-fibrotic responseSecretome of TGFβ-treated DMD myotubes with SETDB1 LOF is less deleterious on myoblast differentiation
Analysis of the economic effect of RCEP under the “Indo-Pacific strategy”: the GTAP model
Authors: Pan Su , Zhang Xuanhao , Bhuiyan Miraj Ahmed 
Published: June 2023

PurposeThis study reveals the economic impact of the Indo-Pacific Strategy on the Regional Comprehensive Economic Partnership (RCEP).Design/methodology/approachThis paper uses the GTAP model to analyze the economic effects of RCEP under the effect of the “Indo-Pacific Strategy” under different scenarios.FindingsThe results show that (1) with the improvement of the implementation effect of the US “Indo-Pacific Strategy,” the welfare level of China has gradually had a significant negative impact, while the welfare level of US Allies and partners has been further improved. (2) The implementation of the Indo-Pacific Strategy will further expand the import scale of Japan, South Korea and other Allies that are both RCEP members and the USA and slightly reduce the import scale of the European Union (EU) and other countries. (3) After the USA implemented the “Indo-Pacific Strategy,” its export scale has significantly improved, and it has been able to completely offset the adverse effects of the signing of RCEP on its exports. China's export scale has also gradually declined, and Japan has benefited the most.Originality/valueThere are three main possible contributions to this article: first, the authors combined geopolitical factors to simulate and evaluate the economic effects of RCEP under different Indo-Pacific Strategy implementation scenarios, which is more relevant than analyzing the economic effects of RCEP in a “vacuum.” Second, the standard static GTAP model can only measure the change of equilibrium state before and after the trade policy. At the same time, the dynamic GTAP model (GTAP-Dyn) introduces mechanisms such as capital flow and capital accumulation and treats time as a continuous variable affected by exogenous variables so that each variable has a time dimension so as better to simulate the medium- and long-term economic effects. This paper refers to the dynamic recursion method of Walmsley (2006) and Yang (2011) to update the base year of the GTAP version 10.0 database to 2020, that is the time when RCEP officially reached 2020. The simulation results of shock variables introduced into the baseline scenario are more reliable. Third, the authors analyze the welfare effect of RCEP and the impact on the import and export of relevant countries from the macrolevel and examine the impact on different products in different countries from the microlevel.
Smart tourism in the Baltic states: current developments and trends
Authors: Litavniece Lienite , Lonska Jelena , Zvaigzne Anda , Wieda Nina , Adamoniene Rūta 
Published: June 2023

PurposeThe purpose of this paper is to evaluate and compare the current trends in development of the second largest cities in each Baltic state – Tartu (Estonia), Kaunas (Lithuania), and Daugavpils (Latvia) – as smart destinations, based on publicly available tourism information.Design/methodology/approachThe study uses a case study employing a descriptive research method, and the authors reached their conclusions based on this material. Furthermore, the paper primarily focuses on literature and new research which deals with tourism in the 21st century, its innovations, changes, and trends.FindingsThe levels and directions of development of Tartu, Kaunas, and Daugavpils as a smart tourism destination are different. Although all three are the second largest cities in each Baltic State, their initial historical development, availability of resources, locations, and strategic development of the country show differences in development. Tartu conforms to the standards in all four categories. However, the category of digitalization receives the most attention and contributes to the positive smart destination result in the other three categories. Comparatively, Daugavpils records fewer current achievements according to the STDC, although the authors believe that there is potential that can be seen in the strategic policy documents. However, judging by all four categories, Daugavpils, similarly to Kaunas, currently demonstrates the greatest achievements in the culture heritage and creativity category.Originality/valueThis paper presents data and compares smart tourism development trends in the second largest cities in each Baltic country.
Worldviews about change: Their structure and their implications for understanding responses to sustainability, technology, and political change
Authors: Bain Paul G. , Bongiorno Renata , Tinson Kellie , Heanue Alanna , Gómez Ángel , Guan Yanjun , Lebedeva Nadezhda , Kashima Emiko , González Roberto , Chen Sylvia Xiaohua , Blumen Sheyla , Kashima Yoshihisa 
Published: June 2023

AbstractPeople hold different perspectives about how they think the world is changing or should change. We examined five of these “worldviews” about change: Progress, Golden Age, Endless Cycle, Maintenance, and Balance. In Studies 1–4 (total N = 2733) we established reliable measures of each change worldview, and showed how these help explain when people will support or oppose social change in contexts spanning sustainability, technological innovations, and political elections. In mapping out these relationships we identify how the importance of different change worldviews varies across contexts, with Balance most critical for understanding support for sustainability, Progress/Golden Age important for understanding responses to innovations, and Golden Age uniquely important for preferring Trump/Republicans in the 2016 US election. These relationships were independent of prominent individual differences (e.g., values, political orientation for elections) or context‐specific factors (e.g., self‐reported innovativeness for responses to innovations). Study 5 (N = 2140) examined generalizability in 10 countries/regions spanning five continents, establishing that these worldviews exhibited metric invariance, but with country/region differences in how change worldviews were related to support for sustainability. These findings show that change worldviews can act as a general “lens” people use to help determine whether to support or oppose social change.
La migration interprovinciale chez les immigrants musulmans : La francophonie comme vecteur d'intégration?
Authors: Legault‐Leclair Jacob 
Published: June 2023

RésuméAu Canada, les immigrants sont plus susceptibles de migrer à l'intérieur du pays—lors de migrations interprovinciales par exemple—que les individus nés au Canada. C'est notamment le cas des immigrants musulmans. Dans cet article, nous cherchons à identifier les caractéristiques déterminantes pour les secondes migrations entreprises par ces immigrants. Pour ce faire, nous avons posé notre regard sur (1) les caractéristiques sociodémographiques propres à cette communauté (la langue en particulier) et (2) au contexte sociopolitique des différentes provinces accueillant ces immigrants. Les résultats nous poussent à relativiser l'hypothèse d'une tension entre le fait d'habiter un milieu francophone au contexte sociopolitique tendu pour la communauté musulmane et un milieu anglophone où les enjeux sociopolitiques propres à cette communauté sont moins présents. Au‐delà des considérations strictement économiques, les immigrants musulmans doivent également négocier leur intégration en tenant compte de la langue et du milieu où certains enjeux sociopolitiques les concernant sont plus ou moins débattus et/ou un milieu où leur langue officielle de choix n'est pas parlée.
Sensitivity of tropical montane birds to anthropogenic disturbance and management strategies for their conservation in agricultural landscapes
Authors: Ausprey Ian J. , Newell Felicity L. , Robinson Scott K. 
Published: June 2023

AbstractTropical montane bird communities are hypothesized to be highly sensitive to anthropogenic disturbance because species are adapted to a narrow range of environmental conditions and display high rates of endemism. We assessed avian sensitivity at regional and continental scales for a global epicenter of montane bird biodiversity, the tropical Andes. Using data from an intensive field study of cloud forest bird communities across 7 landscapes undergoing agricultural conversion in northern Peru (1800–3100 m, 2016–2017) and a pan‐Andean synthesis of forest bird sensitivity, we developed management strategies for maintaining avian biodiversity in tropical countrysides and examined how environmental specialization predicts species‐specific sensitivity to disturbance. In Peru, bird communities occupying countryside habitats contained 29–93% fewer species compared with those in forests and were compositionally distinct due to high levels of species turnover. Fragments of mature forest acted as reservoirs for forest bird diversity, especially when large or surrounded by mixed successional vegetation. In high‐intensity agricultural plots, an addition of 10 silvopasture trees or 10% more fencerows per hectare increased species richness by 18–20%. Insectivores and frugivores were most sensitive to disturbance: abundance of 40–70% of species declined in early successional vegetation and silvopasture. These results were supported by our synthesis of 816 montane bird species studied across the Andes. At least 25% of the species declined due to all forms of disturbance, and the percentage rose to 60% in agricultural landscapes. The most sensitive species were those with narrow elevational ranges and small global range sizes, insectivores and carnivores, and species with specialized trophic niches. We recommend protecting forest fragments, especially large ones, and increasing connectivity through the maintenance of early successional vegetation and silvopastoral trees that increase avian diversity in pastures. We provide lists of species‐specific sensitivities to anthropogenic disturbance to inform conservation status assessments of Andean birds.
International survey of cytopathology training during the pandemic: Water under the bridge?
Authors: Piletska Nataliya 
Published: June 2023

AbstractThe purpose of this study was to assess the impact of the COVID‐19 pandemic on cytopathology training at an international level. An anonymous online questionnaire was distributed by members of the international cytopathological community to medical practitioners in cytopathology. The survey explored perceived changes in cytology workload and workflow during the pandemic, and its effect on both non‐cervical and cervical cytology reporting and teaching. A total of 82 responses were received from seven countries. Approximately half of the respondents reported a decrease in the number and range of cytology cases during the pandemic. Nearly half (47%) saw a reduction in the opportunity to co‐report with consultants/attendings, and 72% of the respondents reported that their consultants/attendings were working remotely during the pandemic. Another 34% of the respondents were redeployed for 3 weeks to 1 year, with 96% stating that this period was only partially compensated for during their training, if at all. The pandemic negatively affected the opportunity to report cervical cytology, perform fine needle aspirations, and participate in multidisciplinary team meetings. Most respondents (69%) saw a decrease in the amount and quality (52%) of face‐to‐face departmental cytology teaching, whereas remote departmental teaching improved in amount (54%) and quality (49%). Almost half (49%) reported that cytology teaching in the regional, national, and international settings increased in both amount and quality. The pandemic catalysed many changes in cytopathology training, affecting the trainees' exposure to cases, the use of remote reporting, consultant/attending working practices, redeployment, and local as well as external teaching.