bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteasomal regulation of ASK family kinases dictates cell fate under hyperosmotic stress
Authors: Zhou Xiangyu , Watanabe Kengo , Morishita Kazuhiro , Hamazaki Jun , Murata Shigeo , Naguro Isao , Ichijo Hidenori 
Published: May 2023

SummaryThe proteasome has an essential role in proteostasis maintenance and is critical for cell survival under proteotoxic conditions including hyperosmotic stress. However, it is unknown how proteasome activity is linked to cell survival/death under hyperosmotic stress. We have previously reported that apoptosis signal-regulating kinase 3 (ASK3) contributes to cell survival through its inactivation under hyperosmotic stress. 19S regulatory particle subunits of the proteasome were enriched in the ASK3 inactivator candidates identified through our genome-wide small interfering RNA (siRNA) screen. In this study, we demonstrate that the proteasome regulates ASK3 inactivation through its proteolytic activity. Intriguingly, the proteasome inactivates ASK3 via degradation of not ASK3 per se but another ASK family member ASK1 which activates ASK3 in a kinase activity-dependent manner. Furthermore, the elevated ASK1 level under proteasome inhibition sensitizes cells to hyperosmotic stress. These findings suggest that ASK family maintenance links proteasome capacity to cell fate bifurcation under hyperosmotic stress.
Assessing the validity of a calcifying oral biofilm model as a suitable proxy for dental calculus
Authors: Bartholdy Bjørn Peare , Velsko Irina M. , Gur-Arieh Shira , Fagernäs Zandra , Warinner Christina , Henry Amanda G. 
Published: May 2023

AbstractDental calculus is increasingly used by researchers to study dietary patterns in past populations. The benefits of using dental calculus for this purpose have been clearly demonstrated in previous studies, with dental calculus harbouring a wealth of microremains and biomarkers for health and diet within its mineral matrix. Previous studies have demonstrated some of the limitations and biases of how methods of processing may overlook, or even remove, some of the important information contained within the mineralised matrix. However, there are many factors that are impossible to account forin vivoand in archaeological material, such as exact dietary intake, and individual factors such as pH and enzyme activity, leaving some limitations that may not be addressed through these types of studies and will require a different approach.We present a protocol for creating a calcifying oral biofilm model that can be used to explore the biases and limitations of dental calculus as a medium for paleodietary reconstructions. We report the microbial and mineral composition of our model in an effort to validate the model calculus as an appropriate proxy to natural dental calculus. The microbial profile and species diversity of our model was determined using metagenomic classification with the nf-core/eager pipeline and Kraken2, and compared to various reference samples from oral sites, including saliva, plaque, and dental calculus. We then assessed whether our model calculus mineralises in a manner similar to natural dental calculus using Fourier transform infrared (FTIR) spectroscopy. The metagenomic classification showed a microbial profile predominantly made up of (facultative) anaerobes, with a community structure that was somewhat distinct from other oral reference samples. The core genera of the model consisted of oral species, but clustered separately from oral reference samples, with a higher abundance of anaerobes.Mineral and organic components of our model mimic that of the modern and archaeological reference calculus that was used as a comparison. There was an overall increase in the inorganic component relative to organic over the course of the experiment, with carbonated hydroxyapatite as the principal compound, consistent with natural human-derived calculus.We conclude that oral biofilm models, such as the one presented in this study, have great potential to validate current methods used in the analysis of archaeological dental calculus, and should be used to complement, rather than replace currentin vivostudies.
Cataloging the Phylogenetic Diversity of Human Bladder Bacterial Isolates
Authors: Du Jingjie , Khemmani Mark , Halverson Thomas , Ene Adriana , Limeira Roberto , Tinawi Lana , Hochstedler-Kramer Baylie R. , Noronha Melline Fontes , Putonti Catherine , Wolfe Alan J. 
Published: May 2023

AbstractAlthough the human bladder is reported to harbor unique microbiota, our understanding of how these microbial communities interact with their human hosts is limited, mostly owing to the lack of isolates to test mechanistic hypotheses. Niche-specific bacterial collections and associated reference genome databases have been instrumental in expanding knowledge of the microbiota of other anatomical sites, e.g., the gut and oral cavity. To facilitate genomic, functional, and experimental analyses of the human bladder microbiota, here we present a bladder-specific bacterial reference collection comprised of 1134 genomes. These genomes were culled from bacterial isolates obtained by a metaculturomic method from bladder urine collected by transurethral catheterization. This bladder-specific bacterial reference collection includes 196 different species, including representatives of major aerobes and facultative anaerobes, as well as some anaerobes. It captures 72.2 % of the genera found when we reexamined previously published 16S rRNA gene sequencing of 392 adult female bladder urine samples. Comparative genomic analysis found that the taxonomies and functions of the bladder microbiota shared more similarities with the vaginal microbiota than the gut microbiota. Whole-genome phylogenetic and functional analyses of 186 bladderE. coliisolates and 387 gutE. coliisolates supports the hypothesis that phylogroup distribution and functions ofE. colistrains differ dramatically between these two very different niches. This bladder-specific bacterial reference collection is a unique resource that will enable hypothesis-driven bladder microbiota research and comparison to isolates from other anatomical sites.
Real TimeIn vivoAnalysis of Pancreatic Beta-cell Autophagic Flux Reveals Impairment Before Onset of Autoimmune Diabetes
Authors: Melnyk Olha , Muralidharan Charanya , Duffett Bryce E. , Novak Alissa N. , Perez-Aviles Glorian , Martinez Michelle M. , Crowder Justin J. , Linnemann Amelia K. 
Published: May 2023

AbstractThe catabolic pathway of autophagy is critical for pancreatic beta-cell function and is defective in established type 1 diabetes (T1D). However, it is unclear when and how this critical cell process becomes defective during diabetes pathogenesis. To study the nature of autophagy dysfunction in the context of autoimmune diabetes, we utilized intravital microscopy to study autophagic fluxin vivoin real time. We generated a custom AAV8- packaged mCherry-eGFP-LC3B biosensor driven by the insulin promoter for beta-cell-selective expression. For real time autophagic flux evaluation, fluorescent signal from eGFP and mCherry fluorophores was correlated in space and time to follow the process of autophagosome-lysosome fusion. We observed autophagic flux defects in the beta-cells of non-obese diabetic (NOD) mouse model of T1D prior to hyperglycemia onset that were less apparent in mice without a functional immune system. We also evaluated autophagic flux in human donor islets that were transplanted under the kidney capsule of immune incompetent mice. Collectively, we provide the first evaluation of autophagic fluxin vivoin 4D and demonstrate that autophagy defects precede hyperglycemia in NOD mice suggesting a potential causative role for these defects in beta-cell demise during T1D pathogenesis.
"Cold" Orthogonal Translation by Psychrophilic Pyrrolysyl-tRNA Synthetase Boosts Genetic Code Expansion
Authors: Koch Nikolaj G. , Goettig Peter , Rappsilber Juri , Budisa Nediljko 
Published: May 2023

AbstractUsing orthogonal translation systems (OTSs) is the most efficient way to produce unnatural proteins by incorporating non-canonical amino acids (ncAAs) into the genetic code. Traditionally, efforts to expand substrate specificity start with a (hyper-)stable enzyme capable of withstanding the structural changes resulting from necessary mutations. However, we adopt a radically different approach by starting with an enzyme that evolved to cope with instability, potentially offering resilience to mutations. By engineering a psychrophilic ("cold") OTS fromMethanococcoides burtonii,we developed an alternative to the commonly used mesophilic and thermophilic systems. This OTS exhibited remarkablein vivoefficiency and promiscuity, even at very low ncAA concentrations. Given the broad range of applicable host organisms, we anticipate that Cold-OTS will significantly advance the transformation of the expanded genetic code from an academic discipline into a high-value chemistry-driven biotechnology.
HIV-1 Vpr-induced DNA damage activates NF-κB through ATM-NEMO independent of cell cycle arrest
Authors: Sandoval Carina , Nisson Karly , Fregoso Oliver I. 
Published: May 2023

ABSTRACTLentiviral accessory genes enhance replication through diverse mechanisms. HIV-1 accessory protein Vpr modulates the host DNA damage response (DDR) at multiple steps through DNA damage, cell cycle arrest, the degradation of host proteins, and both the activation and repression of DDR signaling. Vpr also alters host and viral transcription; however, the connection between Vpr-mediated DDR modulation and transcriptional activation remains unclear. Here, we determined the cellular consequences of Vpr-induced DNA damage using Vpr mutants that allow us to separate the ability of Vpr to induce DNA damage from cell cycle arrest and other DDR phenotypes including host protein degradation and repression of DDR. RNA-sequencing of cells expressing Vpr or Vpr mutants identified that Vpr alters cellular transcription through mechanisms both dependent and independent of cell cycle arrest. In tissue-cultured U2OS cells and primary human monocyte-derived macrophages (MDMs), Vpr-induced DNA damage activates the ATM-NEMO pathway and alters cellular transcription via NF-κB/RelA signaling. HIV-1 infection of primary MDMs validated Vpr-dependent NF-κB transcriptional activation during infection. Both virion delivered andde novoexpressed Vpr induced DNA damage and activated ATM-NEMO dependent NF-κB transcription, suggesting that engagement of the DDR and transcriptional reprogramming can occur during early and late stages of viral replication. Together, our data identifies a mechanism by which Vpr activates NF-κB through DNA damage and the ATM-NEMO pathway, which occur independent of cell cycle arrest. We propose this is essential to overcoming restrictive environments, such as in macrophages, to enhance viral transcription and replication.IMPORTANCEThe HIV accessory protein Vpr is multi-functional and required for viral replicationin vivo, yet how Vpr enhances viral replication is unknown. Emerging literature suggests that a conserved function of Vpr is engagement of the host DNA damage response (DDR). For example, Vpr activates DDR signaling, causes DDR-dependent cell cycle arrest, promotes degradation of various DDR proteins, and alters cellular consequences of DDR activation. However, a central understanding of how these phenotypes connect and how they affect HIV-infected cells remains unknown. Here, we found that Vpr-induced DNA damage alters the host transcriptome by activating an essential transcription pathway, NF-κB. This occurs early during infection of primary human immune cells, suggesting NF-κB activation and transcriptome remodeling are important for establishing productive HIV-1 infection. Together, our study provides novel insights into how Vpr alters the host environment through the DDR, and what roles Vpr and the DDR play to enhance HIV replication.
House price bubble detection in Ukraine
Authors: Shmygel Alona , Hoesli Martin 
Published: May 2023

PurposeThe purpose of this paper is to present a framework for the assessment of the fundamental value of house prices in the largest Ukrainian cities, as well as to identify the thresholds, the breach of which would signal a bubble.Design/methodology/approachHouse price bubbles are detected using two approaches: ratios and regression analysis. Two variants of each method are considered. The authors calculate the price-to-rent and price-to-income ratios that can identify a possible overvaluation or undervaluation of house prices. Then, the authors perform regression analyses by considering individual multi-factor models for each city and by using a within regression model with one-way (individual) effects on panel data.FindingsThe only pronounced and prolonged period of a house price bubble is the one that coincides with the Global Financial Crisis. The bubble signals produced by these methods are, on average, simultaneous and in accordance with economic sense.Research limitations/implicationsThe framework described in this paper can serve as a model for the implementation of a tool for detecting house price bubbles in other countries with emerging, small and open economies, due to adjustments for high inflation and significant dependence on reserve currencies that it incorporates.Practical implicationsA tool for measuring fundamental house prices and a bubble indicator for housing markets will be used to monitor the systemic risks stemming from the real estate market. Thus, it will help the National Bank of Ukraine maintain financial stability.Social implicationsThe framework presented in this research will contribute to the enhancement of the systemic risk analysis toolkit of the National Bank of Ukraine. Therefore, it will help to prevent or mitigate risks that might originate in the real estate market.Originality/valueThe authors show how to implement an instrument for detecting house price bubbles in Ukraine. This will become important in the context of the after-war reconstruction of Ukraine, with mortgages potentially becoming the main tool for the financing of the rebuilding/renovation of the residential real estate stock.
Host, environment, and anthropogenic factors drive landscape dynamics of an environmentally transmitted pathogen: Sarcoptic mange in the bare‐nosed wombat
Authors: Ringwaldt E. M. , Brook B. W. , Buettel J. C. , Cunningham C. X. , Fuller C. , Gardiner R. , Hamer R. , Jones M. , Martin A. M. , Carver S. 
Published: May 2023

Abstract

Understanding the spatial dynamics and drivers of wildlife pathogens is constrained by sampling logistics, with implications for advancing the field of landscape epidemiology and targeted allocation of management resources. However, visually apparent wildlife diseases, when combined with remote‐surveillance and distribution modelling technologies, present an opportunity to overcome this landscape‐scale problem.

Here, we investigated dynamics and drivers of landscape‐scale wildlife disease, using clinical signs of sarcoptic mange (caused by Sarcoptes scabiei) in its bare‐nosed wombat (BNW; Vombatus ursinus) host. We used 53,089 camera‐trap observations from over 3261 locations across the 68,401 km2 area of Tasmania, Australia, combined with landscape data and ensemble species distribution modelling (SDM). We investigated: (1) landscape variables predicted to drive habitat suitability of the host; (2) host and landscape variables associated with clinical signs of disease in the host; and (3) predicted locations and environmental conditions at greatest risk of disease occurrence, including some Bass Strait islands where BNW translocations are proposed.

We showed that the Tasmanian landscape, and ecosystems therein, are nearly ubiquitously suited to BNWs. Only high mean annual precipitation reduced habitat suitability for the host. In contrast, clinical signs of sarcoptic mange disease in BNWs were widespread, but heterogeneously distributed across the landscape.

Mange (which is environmentally transmitted in BNWs) was most likely to be observed in areas of increased host habitat suitability, lower annual precipitation, near sources of freshwater and where topographic roughness was minimal (e.g. human modified landscapes, such as farmland and intensive land‐use areas, shrub and grass lands). Thus, a confluence of host, environmental and anthropogenic variables appear to influence the risk of environmental transmission of S. scabiei. We identified that the Bass Strait Islands are highly suitable for BNWs and predicted a mix of high and low suitability for the pathogen.

This study is the largest spatial assessment of sarcoptic mange in any host species, and advances understanding of the landscape epidemiology of environmentally transmitted S. scabiei. This research illustrates how host‐pathogen co‐suitability can be useful for allocating management resources in the landscape.
Different governments, similar agendas? Analyzing more than seven decades of Norwegian policy agendas presented in executive speeches
Authors: Jungblut Jens , Kavli Tuva Marie , Valgermo Jon Bøe 
Published: May 2023

AbstractNorwegian politics have undergone significant changes since 1945. This paper analyzes over seven decades of policy agendas outlined in Norwegian executive speeches focusing on the composition and development of the agenda using categories from the Comparative Agendas Project. The analysis focuses on (a) the dynamics of agenda changes over time, (b) the diversity and distribution of attention, and (c) in how far external shocks or partisan factors drive major agenda shifts. Our results show that the Norwegian executive agenda has become more encompassing over time, that it is comparatively diverse, and that diversity increases as Norwegian politics becomes more complex. While there is generally a high degree of stability in the agenda, sudden punctuations also occur. Partisan factors only play a limited role in explaining these attention shifts, while external shocks seem to be more relevant.
Circular non‐coding RNA circ_0072088 serves as a ceRNA, targeting the miR‐1225‐5p/WT1 axis to regulate non‐small cell lung cancer cell malignant behavior
Authors: Zhu Xiaofang , Wan Jing , You Xu , Yang Wanli , Zhao Lei 
Published: May 2023

AbstractBackgroundCircular RNA (circRNA) circ_0072088 has been reported to be associated with NSCLC cell growth, migration, and invasion. However, the role and mechanism of circ_0072088 on NSCLC development have not yet been determined.MethodsCirc_0072088, microRNA‐1225 (miR‐1225‐5p), and Wilms' tumor (WT1) suppressor gene level was detected by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR). Migration, invasion, and apoptosis were detected using transwell and flow cytometry assays. Matrix metallopeptidase 9 (MMP9), hexokinase 2 (HK2), and WT1 were examined using western blot assay. The biological role of circ_0072088 on NSCLC tumor growth was examined by the xenograft tumor model in vivo. Circular RNA Interactome and TargetScan were used to predict the binding between miR‐1225‐5p and circ_0072088 or WT1, followed by confirmation using a dual‐luciferase reporter.ResultsCirc_0072088 and WT1 were highly expressed in NSCLC tissues and cells, and miR‐1225‐5p was decreased. Knockdown of circ_0072088 might repress migration, invasion, and glycolysis, and facilitate apoptosis of NSCLC cells in vitro. Circ_0072088 silencing also blocked NSCLC tumor growth in vivo. Mechanistically, circ_0072088 acted as a sponge of miR‐1225‐5p to regulate WT1 expression.ConclusionCirc_0072088 knockdown could inhibit cell growth, migration, invasion, and glycolysis partially by regulating the miR‐1225‐5p/WT1 axis, thus providing a promising therapeutic target for NSCLC treatment.
Prepubertal castration eliminates sex differences in lifespan and growth trajectories in genetically heterogeneous mice
Authors: Jiang Nisi , Cheng Catherine J. , Gelfond Jonathan , Strong Randy , Diaz Vivian , Nelson James F. 
Published: May 2023

AbstractSex differences in aging and longevity have been widely observed, with females consistently outliving males across human populations. However, the mechanisms driving these disparities remain poorly understood. In this study, we explored the influence of post‐pubertal testicular effects on sex differences in aging by prepubertally castrating genetically heterogeneous (UM‐HET3) mice, a unique mouse model that emulates human sex differences in age‐related mortality. Prepubertal castration eliminated the longevity disparity between sexes by reducing the elevated early‐ to mid‐life mortality rate observed in males and extending their median lifespan to match that of females. Additionally, castration extended the duration of body weight growth and attenuated the inverse correlation between early‐age body weight and lifespan in males, aligning their growth trajectories with those of females. Our findings suggest that post‐pubertal testicular actions in genetically diverse mice are primarily responsible for sex differences in longevity as well as growth trajectories. These findings offer a foundation for further investigation into the fundamental mechanisms driving sex‐specific aging patterns and the development of potential pro‐longevity interventions.
Methylation of eNOS in the rat penile corpus cavernosum under different pathological states and its relationship with erectile function
Authors: Wang Na , Jiang Qilan , Xie Libo , Cheng Bo , Liu Qin‐Wen , Jiang Rui 
Published: May 2023

AbstractBackgroundIt has been shown that methylation in the promoter region of eNOS can downregulate eNOS expression resulting in the endothelial dysfunction. However, it is unclear whether low androgen levels and type 1 diabetes cause ED by methylating the promoter region of eNOS in the penile corpus cavernosum.ObjectiveTo clarify the effects of type 1 diabetes and hypo‐androgen status on the methylation level of the promoter region of the eNOS gene in penile cavernous tissue and their relationship with the erectile function.MethodsFifty‐eight eight‐week‐old male Sprague–Dawley rats were randomly divided into six groups (n = 6): sham operation group, castration group, castration+testosterone (cast+T) group, normoglycemia group, diabetic group, and diabetic+methyltransferase inhibitor (5‐aza‐dc, 1.5 mg/kg) group. The ICPmax/MAP, serum T, the concentration of nitric oxide (NO), the expression of DNMT1, DNMT3a, DNMT3b, and eNOS, and the methylation level of the eNOS promoter region in penile corpus cavernosum of rat were examined 4 weeks after surgery in the sham‐operated group, the castration group, and the castration + testosterone replacement group. Those tests were examined after 6 weeks using of methylation inhibitors in the normoglycemic group, the diabetic group, and the diabetic + methylation inhibitor group.ResultsICPmax/MAP, DNMT1, DNMT3a, DNMT3b, eNOS, and NO levels were significantly lower in castrated rats than in sham and cast+T rats (P < 0.05). ICPmax/MAP, eNOS, and NO levels were lower, and DNMT1, DNMT3a, and DNMT3b expression levels were significantly increased in the diabetic group compared with the normoglycemic and diabetic+methyltransferase inhibitor groups (P < 0.05). There was no significant difference in the methylation level of the promoter region of eNOS in penile cavernous tissue of castrated rats compared with the sham group or the testosterone replacement group. The methylation level of the promoter region of eNOS in penile cavernous tissue was significantly higher in the diabetic group than in the normoglycemic group and diabetic+methyltransferase inhibitor group (P < 0.05).ConclusionAlthough low androgen status inhibited the level of methyltransferase in rat penile cavernous tissue, did not affect the level of methylation in the promoter region of eNOS. Hyperglycemia inhibits the NO level in the penile cavernous tissue and the erectile function of rats by upregulating the methyltransferase level in the penile cavernous tissue and the methylation level in the promoter region of eNOS. Methylation inhibitors can partly improve the erectile function in type 1 diabetic rats.