bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of plasma gelsolin with frailty phenotype and mortality among octogenarian community-dwelling men: a cohort study
Authors: Strandberg Timo E. , Levinson Susan L. , DiNubile Mark J. , Jyväkorpi Satu , Kivimäki Mika
Published: February 2022

Background

Biomarkers are needed for frailty, a common phenotype often associated with muscle loss in older people. Plasma gelsolin (pGSN) is a protein largely synthesized and secreted by skeletal muscle.

Aims

To investigate whether pGSN could be a biomarker of the frailty phenotype and predict mortality.

Methods

A homogenous cohort of males (born 1919–1934, baseline n = 3490) has been followed since the 1960s. In 2010/11, frailty phenotypes by modified Fried criteria were assessed. pGSN was measured in a convenience subset (n = 469, mean age 83) and re-measured in survivors (n = 127) in 2017. Mortality through December 31, 2018 was retrieved from national registers. Regression models were used for analyses.

Results

Of 469 males, 152 (32.4%) were robust, 284 (60.6%) prefrail, and 33 (7.0%) frail in 2010/11. There was a graded (p = 0.018) association between pGSN (mean 58.1 ug/mL, SD 9.3) and frailty. After multivariable adjustment, higher pGSN levels were associated with lower odds of having contemporaneous phenotypic prefrailty (OR per 1 SD 0.73, 95% CI 0.58–0.92) and frailty (OR per 1 SD 0.70, 95% CI 0.44–1.11). By 2018, 179 males (38.2%) had died, and higher baseline pGSN predicted a lower 7-year mortality rate (HR per 1 SD 0.85, 95% CI 0.72–1.00). pGSN concentrations in 2010/11 and 2017 were correlated (n = 127, r = 0.34, p < 0.001).

Discussion

Higher baseline pGSN concentrations were associated with a persistently robust phenotype and lower mortality rate over 7 years in a cohort of octogenarian males with high socioeconomic status and may be a promising laboratory biomarker for the development of a frailty phenotype.
Polyurethane grouting materials with different compositions for the treatment of mud pumping in ballastless track subgrade beds: properties and application effect
Authors: Huang Zhichao , Su Qian , Huang Junjie , Dong Minqi , Li Dong , Liu Ting
Published: February 2022

Mud pumping in subgrade beds under ballastless tracks will deteriorate the dynamic performance of infrastructure under railway lines, reduce the smoothness of the railway lines, and seriously affect the comfort and safety of the trains. Due to their good mechanical properties, two-component polyurethane materials can be used for grouting to treat the fouling problems caused by ballastless track mud pumping. To develop a polyurethane formula suitable for the treatment of ballastless track mud pumping, we first performed indoor experiments to investigate the mechanical properties and gelation time of polyurethane elastomers synthesized with different raw material composition ratios, to determine an optimal composition ratio of the raw materials. Then, we conducted a dynamic field test to verify the remediation effect of the polyurethane material fabricated according to the design ratio. The results showed that polyurethane grouting material with the selected design ratios improved the contact characteristics between the surface layer of the subgrade bed and the base plate in the area, coordinating the dynamic response between the track structure and the subgrade bed. Thus, the obtained polyurethane grouting material could be used to renovate mud pumping areas of ballastless tracks with a good treatment effect.
Mental Health Risk and Protective Factors of Nigerian Male Asylum Seekers Hosted in Southern Italy: a Culturally Sensitive Quantitative Investigation
Authors: Tessitore Francesca , Parola Anna , Margherita Giorgia
Published: February 2022

This study provides a culturally sensitive quantitative investigation aimed at assessing the post-traumatic symptomatology, post-migratory difficulties, and resilience of 36 Nigerian male asylum seekers hosted in the province of Caserta, South Italy. A survey composed by the Harvard Trauma Questionnaire-Revised (HTQ-R), the Post-Migratory Checklist (PLMD), and the Connor-Davidson Resilience Scale (CD-RISC) was administered to participants. Descriptive and correlation analyses were made in order to describe the mental health risk and protective factors and understand the relation between these. A linear regression analysis was used to evaluate the influence of post-migratory difficulties and resilience on PTSD. Stratified bivariate analyses were also computed to detect PTSD group and no-PTSD group differences about post-migration difficulties and resilience levels. Regression analysis showed that PMLD numbers significantly increased the risk of having PTSD. No significant effect emerged for the level of resilience. Statistically significant differences between the PTSD group and non-PTSD group in relation to post-migratory difficulties were also found. No differences in the resilience factors emerged. The results offer a glimpse into a specific ethnic group of asylum seekers and its mental health risks and protective factors, taking into consideration the specificities of their past and current life-story experiences. Clinical implications for professionals working in the field of forced migration will be outlined.
The fundamental solutions of the curve shortening problem via the Schwarz function
Authors: McDonald N. R.
Published: February 2022

Curve shortening in the z-plane in which, at a given point on the curve, the normal velocity of the curve is equal to the curvature, is shown to satisfy $$S_tS_z=S_{zz}$$

S
t

S
z

=

S

zz

, where S(z, t) is the Schwarz function of the curve. This equation is shown to have a parametric solution from which the known explicit solutions for curve shortening flow; the circle, grim reaper, paperclip and hairclip, can be recovered.
Bioinspired Adaptive, Elastic, and Conductive Graphene Structured Thin-Films Achieving High-Efficiency Underwater Detection and Vibration Perception
Authors: Wang Qiling , Xiao Peng , Zhou Wei , Liang Yun , Yin Guangqiang , Yang Qiu , Kuo Shiao-Wei , Chen Tao
Published: February 2022

Underwater exploration has been an attractive topic for understanding the very nature of the lakes and even deep oceans. In recent years, extensive efforts have been devoted to developing functional materials and their integrated devices for underwater information capturing. However, there still remains a great challenge for water depth detection and vibration monitoring in a high-efficient, controllable, and scalable way. Inspired by the lateral line of fish that can sensitively sense the water depth and environmental stimuli, an ultrathin, elastic, and adaptive underwater sensor based on Ecoflex matrix with embedded assembled graphene sheets is fabricated. The graphene structured thin film is endowed with favourable adaptive and morphable features, which can conformally adhere to the structural surface and transform to a bulged state driven by water pressure. Owing to the introduction of the graphene-based layer, the integrated sensing system can actively detect the water depth with a wide range of 0.3–1.8 m. Furthermore, similar to the fish, the mechanical stimuli from land (e.g. knocking, stomping) and water (e.g. wind blowing, raining, fishing) can also be sensitively captured in real time. This graphene structured thin-film system is expected to demonstrate significant potentials in underwater monitoring, communication, and risk avoidance.
Control of High-Temperature Static and Transient Thermomechanical Behavior of SiMo Ductile Iron by Al Alloying
Authors: Lekakh S. N. , Johnson C. , Godlewski L. , Li Mei
Published: February 2022

Silicon and molybdenum (SiMo) ductile iron is commonly used for exhaust manifolds because these components experience thermal cycling in oxidizing environment, which requires resistance to fatigue during transient thermomechanical loads. Previous studies have demonstrated that alloying elements, such as Al, to SiMo ductile iron reduces the amount of surface degradation during static high-temperature exposure. However, deterioration of sphericity of the graphite nodules and a decrease in ductility could affect the tendency of cracking during thermal cycling. In this article, the effect of Al alloying on static and transient thermomechanical behavior of SiMo ductile iron was investigated to optimize the amount of Al alloying. A thermodynamic approach was used to confirm the effect of the Al alloying on the phase transformations in two SiMo cast irons, alloyed by 1.8% Al and 3% Al. These two alloys were cast in a laboratory along with the baseline SiMo ductile iron. Several experimental methods were used to evaluate the dimensional stability, physical properties, static oxidation, and failure resistance during constrained thermal cycling testing to compare their high-temperature capability. Experimental results verified that Al alloying increases the temperature range and decreases volume change during eutectoid transformation, which together with enhancement of oxidation protection improved the dimensional stability. Thermocycling tests showed that the number of cycles to failure depends on the amount of Al alloying and the applied high-temperature exposure during each cycle. SEM/EDX, high-resolution TEM and µCT analysis were used to verify the mechanism resulting from the Al alloying protection. It was shown that an optimal level of Al alloying for balancing oxidation and thermal cracking resistance depends on thermomechanical conditions of application.
University freshmen recollect their academic integrity literacy experience during their K-12 years: results of an empirical study
Authors: Hossain Zakir
Published: February 2022

Academic Integrity Literacy (AIL) is a critical transdisciplinary skill for academic success but many students do not receive this skill in their K-12 years regardless of their schooling system or characteristics of the community they belong to. Numerous research studies in higher education document that high school graduates lack AIL skills, but hardly any studies attempt to empirically investigate students’ K-12 years AIL education experience. Using a mixed-method approach, this study explores university freshmen’s AIL education experience in their K-12 years, and their opinions on the appropriate grade level to introduce AIL education. Of the university freshmen surveyed (n = 431), roughly 1 in 10 received AIL education in middle school and 1 in 5 during high school. The survey of students’ current university instructors indicates a handful of freshmen have a fair understanding of academic integrity and plagiarism but their combined AIL application capacity, such as adhering to a referencing style and the quality of in-text source attributions in academic writing, is limited. The study results and professional experience allow the author to suggest rigorous AIL instruction and policy development for K-12 institutions to educate, empower and execute AIL education.
Aqueous Solubility of Zn Incorporated into Mg-Al-Layered Double Hydroxides
Authors: Dabizha Anna , Kersten Michael
Published: February 2022

Hydrotalcite minerals are layered double hydroxides (LDH) which play an important role in immobilizing hazardous compounds to decontaminate industrial wastewaters. The stability of an LDH is mostly evaluated in terms of its low solubility in water. However, the solubility of divalent trace metals immobilized by Mg-Al-type LDHs is not well known. Hydrotalcites containing Zn in solid solution, (Mg+Zn)3-Al-LDH, were synthesized by alkaline co-precipitation. A series of eleven LDH phases with Zn mole fractions XZn = Zn/(Mg+Zn) of 0–1 were characterized by powder X-ray diffractometry (XRD), Fourier-transform infrared (FTIR) spectroscopy, thermogravimetry (TGA), scanning and transmission electron microscopy (SEM/TEM), Brunauer-Emmett-Teller (BET) surface area analysis, and inductively coupled plasma mass (ICP-MS) spectrometry. The XRD analysis provided sharp characteristic spacings for d003 and d006 which occurred for all samples, confirming a layered LDH structure. Cell parameters (a, c) obeyed Vegard’s law and confirmed the formation of a regular solid-solution series without a mixing gap. An aqueous equilibrium time was determined by kinetic dissolution experiments. Steady-state solubility occurred after 120 days, but the experiments continued up to 240 days. The XRD and SEM/TEM analyses indicated no phase changes during the long-term dissolution experiments; neither were phase impurities detected after 240 days. The solubility products of the Mg- and Zn-bearing endmember compositions were calculated from experimentally determined total cation and anion concentrations using the Visual Minteq code for considering element speciation and ion pairing. The solubility product decreased as the Zn mole fraction increased, suggesting that the Zn-bearing LDH phases were more stable than the pure Mg3-Al-LDHs. Solid-solution aqueous-solution thermodynamic equilibrium modeling using the Lippmann “total solubility product” approach and applying Lippmann diagrams with logarithmic x-axes revealed a log-linear decrease in aqueous Zn solubility. The results are promising for remediation of metal-bearing liquid wastes because the metals that co-precipitated with the LDH were more strongly retained and, therefore, less soluble than the hydroxides or carbonates of the trace metal.
Post-translational modification: a strategic response to high temperature in plants
Authors: Han Danlu , Yu Zhibo , Lai Jianbin , Yang Chengwei
Published: February 2022

With the increasing global warming, high-temperature stress is affecting plant growth and development with greater frequency. Therefore, an increasing number of studies examining the mechanism of temperature response contribute to a more optimal understanding of plant growth under environmental pressure. Post-translational modification (PTM) provides the rapid reconnection of transcriptional programs including transcription factors and signaling proteins. It is vital that plants quickly respond to changes in the environment in order to survive under stressful situations. Herein, we discuss several types of PTMs that occur in response to warm-temperature and high-temperature stress, including ubiquitination, SUMOylation, phosphorylation, histone methylation, and acetylation. This review provides a valuable resolution to this issue to enable increased crop productivity at high temperatures.
Explainable machine learning practices: opening another black box for reliable medical AI
Authors: Ratti Emanuele , Graves Mark
Published: February 2022

In the past few years, machine learning (ML) tools have been implemented with success in the medical context. However, several practitioners have raised concerns about the lack of transparency—at the algorithmic level—of many of these tools; and solutions from the field of explainable AI (XAI) have been seen as a way to open the ‘black box’ and make the tools more trustworthy. Recently, Alex London has argued that in the medical context we do not need machine learning tools to be interpretable at the algorithmic level to make them trustworthy, as long as they meet some strict empirical desiderata. In this paper, we analyse and develop London’s position. In particular, we make two claims. First, we claim that London’s solution to the problem of trust can potentially address another problem, which is how to evaluate the reliability of ML tools in medicine for regulatory purposes. Second, we claim that to deal with this problem, we need to develop London’s views by shifting the focus from the opacity of algorithmic details to the opacity of the way in which ML tools are trained and built. We claim that to regulate AI tools and evaluate their reliability, agencies need an explanation of how ML tools have been built, which requires documenting and justifying the technical choices that practitioners have made in designing such tools. This is because different algorithmic designs may lead to different outcomes, and to the realization of different purposes. However, given that technical choices underlying algorithmic design are shaped by value-laden considerations, opening the black box of the design process means also making transparent and motivating (technical and ethical) values and preferences behind such choices. Using tools from philosophy of technology and philosophy of science, we elaborate a framework showing how an explanation of the training processes of ML tools in medicine should look like.
Metabolic signatures of Arabidopsis thaliana abiotic stress responses elucidate patterns in stress priming, acclimation, and recovery
Authors: Xu Yuan , Freund Dana M. , Hegeman Adrian D. , Cohen Jerry D.
Published: February 2022

Temperature, water, and light are three abiotic stress factors that have major influences on plant growth, development, and reproduction. Plants can be primed by a prior mild stress to enhance their resistance to future stress. We used an untargeted metabolomics approach to examine Arabidopsis thaliana 11-day-old seedling’s abiotic stress responses including heat (with and without priming), cold (with and without priming), water-deficit and high-light before and after a 2-day-recovery period. Analysis of the physiological phenotypes showed that seedlings with stress treatment resulted in a reduction in fresh weight, hypocotyl and root length but remained viable. Several stress responsive metabolites were identified, confirmed with reference standards, quantified, and clustered. We identified shared and specific stress signatures for cold, heat, water-deficit, and high-light treatments. Central metabolism including amino acid metabolism, sugar metabolism, glycolysis, TCA cycle, GABA shunt, glutathione metabolism, purine metabolism, and urea cycle were found to undergo changes that are fundamentally different, although some shared commonalities in response to different treatments. Large increases in cysteine abundance and decreases in reduced glutathione were observed following multiple stress treatments highlighting the importance of oxidative stress as a general phenomenon in abiotic stress. Large fold increases in low-turnover amino acids and maltose demonstrate the critical role of protein and starch autolysis in early abiotic stress responses.
Pricing Rice Quality Attributes and Returns to Quality Upgrading in Sub-Saharan Africa
Authors: Twine Edgar E. , Ndindeng Sali Atanga , Mujawamariya Gaudiose , Futakuchi Koichi
Published: February 2022

The study applies parametric and nonparametric estimation methods to determine hedonic prices of rice quality attributes, and a partial equilibrium model to determine the payoff to investing in quality improvement in five countries in Sub-Saharan Africa. Results indicate that consumers are willing to pay price premiums for head rice, slender grains, peak viscosity, parboiled rice, and rice sold in urban markets. However, they strongly discount amylose content, rice with impurities and imported rice. Investing in quality improvement through amylose content reduction leads to net welfare gains with a benefit-cost ratio of 47.86 and internal rate of return of 90%.
The Ethics of Alternative Currencies
Authors: Larue Louis , Meyer Camille , Hudon Marek , Sandberg Joakim
Published: February 2022

Alternative currencies are means of payment that circulate alongside—as an alternative or complement to—official currencies. While these currencies have existed for a long time, both society and academia have shown a renewed interest in their potential to decentralize the governance of monetary affairs and to bring people and organizations together in more ethical or sustainable ways. This article is a review of the ethical and philosophical implications of these alternative monetary projects. We first discuss various classifications of these currencies before analyzing the ethical challenges linked to the way they tackle social and environmental issues. We also examine the incentive-based and coercive mechanisms used by these currencies from an ethical perspective and debate the promises and perils of monetary decentralization and democracy. We conclude by identifying an agenda for future research.
Character and Repeat-Offender Sentencing
Authors: Brand Jeffrey
Published: February 2022

Repeat offenders receive longer sentences than first offenders in virtually every modern jurisdiction. Such prior-record enhancements are politically popular. Scholars are more divided, especially regarding severe enhancements. Retributivists have long disagreed about which enhancements, if any, are morally justifiable and on what basis. This article advances the debate, offering lessons for retributivists on all sides. I address an intuitive argument that justifies enhancements in terms of character. This argument has been caricatured and dismissed, with defenders of enhancements preferring character-independent arguments. I reconstruct an argument for enhancements that assumes recidivism constitutes evidence of culpability-aggravating character traits. The argument seems at least coherent, inferentially valid, and intuitively plausible. I then raise what I see as the real threats to the argument, which are neither conceptual nor normative, but empirical. I identify some formal features that the character argument requires of culpability-aggravating traits. To support enhancements, such traits must also correlate properly with criminal records. One place to look for characterizations of such traits, and evidence of correlation, is criminology, in theories of criminogenesis and criminality. I conclude that character arguments for prior-record enhancements cannot be dismissed, although their thorough evaluation awaits answers to complex empirical questions.
From Each According to Their Ability? An Analysis of Endowment Taxation and Potential Earnings
Authors: Sam Erick J.
Published: February 2022

This Article examines ability taxation, which is a tax on a person’s earning ability or potential earnings, rather than earned income. Despite this regime’s longstanding favor as a theoretical ideal for fair and efficient taxation among public finance economists, certain political philosophers, and tax law scholars, insufficient effort has been made to provide an analysis of what ‘potential earnings’ means. This Article explores competing understandings of this notion, and situates them within a multipart taxonomy. In so doing, it unearths a tension at the core of the ability tax program involving a fundamental misalignment between the metaphysics (or correct conceptual analysis) of potential earnings and the economics of its taxation. It concludes that once we correctly understand its requirements, we should reject ability taxation as the first-best normative ideal it has been held out to be on the grounds that it is overly burdensome and unfair to certain individuals.
Sensitivity of musculoskeletal models to variation in muscle architecture parameters
Authors: Kramer Patricia Ann , Feuerriegel Elen M. , Lautzenheiser Steven G. , Sylvester Adam D.
Published: February 2022

Musculoskeletal models, like all theoretical models of physical processes, depend on the assumptions needed to construct the model. For musculoskeletal models, these assumptions include, among other things, the kinematic data, the kinetic data and the muscle parameters. The former (dynamic) data can be acquired relatively easily from living subjects, but the latter are usually based on limited information, frequently determined from cadaver studies performed on elderly individuals. Previously, we determined the sensitivity of forces to dynamic differences among 10 humans walking on a straight path. Here, we assess the sensitivity of the muscle and joint reaction forces developed in human walking to variable muscle parameters obtained from 10 living adults, whose data were recently reported, and compared the results with the values from a standard model that depends on cadaveric data. We found that, while the force patterns across the stance cycle were similar among muscle parameter models, differences of as much as 15% in the force magnitude were produced. Whether or not the variation between the standard model and other muscle parameters is important depends on why the forces are required.
Power/resistance: External actors, local agency, and the Burundian peacebuilding project
Authors: Féron Elise , Krause Keith
Published: February 2022

Peacebuilding policies and practices represent strong attempts by external actors to exercise power in postconflict settings. Yet the extensive theoretical treatments of power in International Relations remain somewhat disconnected from empirical analyses of peacebuilding, and how external actors exercise power is under-conceptualised in the literature. Likewise, the literature on forms of resistance by local actors is seldom examined as an exercise of power in itself, and as part of a multidimensional relationship of power/resistance between external and local actors. This article thus theorises the different dimensions of power/resistance, with a detailed focus on an exemplary case – international efforts at peacebuilding in Burundi – that spans more than twenty years. It deploys a tripartite conception of both to analyse the ways in which different forms of power and resistance can be uncovered in peacebuilding practices, We demonstrate this via an analysis of postconflict peacebuilding in Burundi, and in particular the longer-term efforts of local actors to overtly and covertly bend and fuse peacebuilding practices to their own ends.
Quantitative modelling of fine-scale variations in the Arabidopsis thaliana crossover landscape
Authors: Hsu Yu-Ming , Falque Matthieu , Martin Olivier C.
Published: February 2022

In, essentially, all species where meiotic crossovers (COs) have been studied, they occur preferentially in open chromatin, typically near gene promoters and to a lesser extent, at the end of genes. Here, in the case of Arabidopsis thaliana, we unveil further trends arising when one considers contextual information, namely summarised epigenetic status, gene or intergenic region size, and degree of divergence between homologs. For instance, we find that intergenic recombination rate is reduced if those regions are less than 1.5 kb in size. Furthermore, we propose that the presence of single nucleotide polymorphisms enhances the rate of CO formation compared to when homologous sequences are identical, in agreement with previous works comparing rates in adjacent homozygous and heterozygous blocks. Lastly, by integrating these different effects, we produce a quantitative and predictive model of the recombination landscape that reproduces much of the experimental variation.
Dynamic apico-basal enrichment of the F-actin during cytokinesis in Arabidopsis cells embedded in their tissues
Authors: Lebecq Alexis , Fangain Aurélie , Boussaroque Alice , Caillaud Marie-Cécile
Published: February 2022

Cell division is a tightly regulated mechanism, notably in tissues where malfunctions can lead to tumour formation or developmental defects. This is particularly true in land plants, where cells cannot relocate and therefore cytokinesis determines tissue topology. In plants, cell division is executed in radically different manners than in animals, with the appearance of new structures and the disappearance of ancestral mechanisms. Whilst F-actin and microtubules closely co-exist, recent studies mainly focused on the involvement of microtubules in this key process. Here, we used a root tracking system to image the spatio-temporal dynamics of both F-actin reporters and cell division markers in dividing cells embedded in their tissues. In addition to the F-actin accumulation at the phragmoplast, we observed and quantified a dynamic apico-basal enrichment of F-actin from the prophase/metaphase transition until the end of the cytokinesis.
Nicholas Temperley, Edward Loder, and Retrospect Opera's Raymond and Agnes
Authors: Vickers Justin
Published: February 2022

In memory of Nicholas Temperley
High-Definition Imaging of the Subsurface with Cosmic Ray Muons
Authors: Ol�h L�szl� , Tanaka Hiroyuki , Varga Dezső
Published: February 2022

A new book describes muography, an imaging technique that can be used to visualize the internal density composition of geological structures.
Lipidome profile predictive of disease evolution and activity in rheumatoid arthritis
Authors: Koh Jung Hee , Yoon Sang Jun , Kim Mina , Cho Seonghun , Lim Johan , Park Youngjae , Kim Hyun-Sook , Kwon Sung Won , Kim Wan-Uk
Published: February 2022

Lipid mediators are crucial for the pathogenesis of rheumatoid arthritis (RA); however, global analyses have not been undertaken to systematically define the lipidome underlying the dynamics of disease evolution, activation, and resolution. Here, we performed untargeted lipidomics analysis of synovial fluid and serum from RA patients at different disease activities and clinical phases (preclinical phase to active phase to sustained remission). We found that the lipidome profile in RA joint fluid was severely perturbed and that this correlated with the extent of inflammation and severity of synovitis on ultrasonography. The serum lipidome profile of active RA, albeit less prominent than the synovial lipidome, was also distinguishable from that of RA in the sustained remission phase and from that of noninflammatory osteoarthritis. Of note, the serum lipidome profile at the preclinical phase of RA closely mimicked that of active RA. Specifically, alterations in a set of lysophosphatidylcholine, phosphatidylcholine, ether-linked phosphatidylethanolamine, and sphingomyelin subclasses correlated with RA activity, reflecting treatment responses to anti-rheumatic drugs when monitored serially. Collectively, these results suggest that analysis of lipidome profiles is useful for identifying biomarker candidates that predict the evolution of preclinical to definitive RA and could facilitate the assessment of disease activity and treatment outcomes.
A mouse model of gestational diabetes shows dysregulated lipid metabolism post-weaning, after return to euglycaemia
Authors: Furse Samuel , Fernandez-Twinn Denise S. , Beeson Jessica H. , Chiarugi Davide , Ozanne Susan E. , Koulman Albert
Published: February 2022

Background

Gestational diabetes is associated with increased risk of type 2 diabetes mellitus and cardiovascular disease for the mother in the decade after delivery. However, the molecular mechanisms that drive these effects are unknown. Recent studies in humans have shown that lipid metabolism is dysregulated before diagnosis of and during gestational diabetes and we have shown previously that lipid metabolism is also altered in obese female mice before, during and after pregnancy. These observations led us to the hypothesis that this persistent dysregulation reflects an altered control of lipid distribution throughout the organism.

Methods

We tested this in post-weaning (PW) dams using our established mouse model of obese GDM (high fat, high sugar, obesogenic diet) and an updated purpose-built computational tool for plotting the distribution of lipid variables throughout the maternal system (Lipid Traffic Analysis v2.3).

Results

This network analysis showed that unlike hyperglycaemia, lipid distribution and traffic do not return to normal after pregnancy in obese mouse dams. A greater range of phosphatidylcholines was found throughout the lean compared to obese post-weaning dams. A range of triglycerides that were found in the hearts of lean post-weaning dams were only found in the livers of obese post-weaning dams and the abundance of odd-chain FA-containing lipids differed locally in the two groups. We have therefore shown that the control of lipid distribution changed for several metabolic pathways, with evidence for changes to the regulation of phospholipid biosynthesis and FA distribution, in a number of tissues.

Conclusions

We conclude that the control of lipid metabolism is altered following an obese pregnancy. These results support the hypothesis that obese dams that developed GDM maintain dysregulated lipid metabolism after pregnancy even when glycaemia returned to normal, and that these alterations could contribute to the increased risk of later type 2 diabetes and cardiovascular disease.
On the horizon: Hedgehog signaling to heal broken bones
Authors: Kuwahara Stephanie T. , Liu Shuwan , Chareunsouk Andrew , Serowoky Maxwell , Mariani Francesca V.
Published: February 2022

Uncovering the molecular pathways that drive skeletal repair has been an ongoing challenge. Initial efforts have relied on in vitro assays to identify the key signaling pathways that drive cartilage and bone differentiation. While these assays can provide some clues, assessing specific pathways in animal models is critical. Furthermore, definitive proof that a pathway is required for skeletal repair is best provided using genetic tests. Stimulating the Hh (Hedgehog) pathway can promote cartilage and bone differentiation in cell culture assays. In addition, the application of HH protein or various pathway agonists in vivo has a positive influence on bone healing. Until recently, however, genetic proof that the Hh pathway is involved in bone repair has been lacking. Here, we consider both in vitro and in vivo studies that examine the role of Hh in repair and discuss some of the challenges inherent in their interpretation. We also identify needed areas of study considering a new appreciation for the role of cartilage during repair, the variety of cell types that may have differing roles in repair, and the recent availability of powerful lineage tracing techniques. We are optimistic that emerging genetic tools will make it possible to precisely define when and in which cells promoting Hh signaling can best promote skeletal repair, and thus, the clinical potential for targeting the Hh pathway can be realized.
Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer
Authors: Chu Liping , Qu Yuxiu , An Yang , Hou Linjun , Li Juewan , Li Weijia , Fan Gaofeng , Song Bao-Liang , Li En , Zhang Liye , Qi Wei
Published: February 2022

The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a valid drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. Focusing on MAK683-sensitive tumors with SMARCB1 or ARID1A loss, we identified a group of PRC2 target genes with high H3K27me3 signal through epigenomic and transcriptomic analysis. Multiple senescence-associated secretory phenotype (SASP) genes, such as GATA4, MMP2/10, ITGA2 and GBP1, are in this group besides previously identified CDKN2A/p16. Upon PRC2 inhibition, the de-repression of SASP genes is detected in multiple sensitive models and contributes to decreased Ki67+, extracellular matrix (ECM) reorganization, senescence associated inflammation and tumor regression even in CDKN2A/p16 knockout tumor. And the combination of PRC2 inhibitor and CDK4/6 inhibitor leads to better effect. The genes potential regulated by PRC2 in neuroblastoma samples exhibited significant enrichment of ECM and senescence associated inflammation, supporting the clinical relevance of our results. Altogether, our results unravel the pharmacological mechanism of PRC2 inhibitors and propose a combination strategy for MAK683 and other PRC2 drugs.
E-cigarette and food flavoring diacetyl alters airway cell morphology, inflammatory and antiviral response, and susceptibility to SARS-CoV-2
Authors: Langel Stephanie N. , Kelly Francine L. , Brass David M. , Nagler Andrew E. , Carmack Dylan , Tu Joshua J. , Travieso Tatianna , Goswami Ria , Permar Sallie R. , Blasi Maria , Palmer Scott M.
Published: February 2022

Diacetyl (DA) is an α-diketone that is used to flavor microwave popcorn, coffee, and e-cigarettes. Occupational exposure to high levels of DA causes impaired lung function and obstructive airway disease. Additionally, lower levels of DA exposure dampen host defenses in vitro. Understanding DA’s impact on lung epithelium is important for delineating exposure risk on lung health. In this study, we assessed the impact of DA on normal human bronchial epithelial cell (NHBEC) morphology, transcriptional profiles, and susceptibility to SARS-CoV-2 infection. Transcriptomic analysis demonstrated cilia dysregulation, an increase in hypoxia and sterile inflammation associated pathways, and decreased expression of interferon-stimulated genes after DA exposure. Additionally, DA exposure resulted in cilia loss and increased hyaluronan production. After SARS-CoV-2 infection, both genomic and subgenomic SARS-CoV-2 RNA were increased in DA vapor- compared to vehicle-exposed NHBECs. This work suggests that transcriptomic and physiologic changes induced by DA vapor exposure damage cilia and increase host susceptibility to SARS-CoV-2.
Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2
Authors: Liang Yu , Zhang Jing , Yuan Run Yu , Wang Mei Yu , He Peng , Su Ji Guo , Han Zi Bo , Jin Yu Qin , Hou Jun Wei , Zhang Hao , Zhang Xue Feng , Shao Shuai , Hou Ya Nan , Liu Zhao Ming , Du Li Fang , Shen Fu Jie , Zhou Wei Min , Xu Ke , Gao Ru Qin , Tang Fang , Lei Ze Hua , Liu Shuo , Zhen Wei , Wu Jin Juan , Zheng Xiang , Liu Ning , Chen Shi , Ma Zhi Jing , Zheng Fan , Ren Si Yu , Hu Zhong Yu , Huang Wei Jin , Wu Gui Zhen , Ke Chang Wen , Li Qi Ming
Published: February 2022

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.
Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice
Authors: Litke Christian , Hagenston Anna M. , Kenkel Ann-Kristin , Paldy Eszter , Lu Jianning , Kuner Rohini , Mauceri Daniela
Published: February 2022

Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Here, we found that, among several histone deacetylases (HDACs), synaptic activity specifically affects HDAC4 in murine spinal cord dorsal horn neurons. Noxious stimuli that induce long-lasting inflammatory hypersensitivity cause nuclear export and inactivation of HDAC4. The development of inflammation-associated mechanical hypersensitivity, but neither acute nor basal sensitivity, is impaired by the expression of a constitutively nuclear localized HDAC4 mutant. Next generation RNA-sequencing revealed an HDAC4-regulated gene program comprising mediators of sensitization including the organic anion transporter OAT1, known for its renal transport function. Using pharmacological and molecular tools to modulate OAT1 activity or expression, we causally link OAT1 to persistent inflammatory hypersensitivity in mice. Thus, HDAC4 is a key epigenetic regulator that translates nociceptive activity into sensitization by regulating OAT1, which is a potential target for pain-relieving therapies.
Cell specific peripheral immune responses predict survival in critical COVID-19 patients
Authors: Amrute Junedh M. , Perry Alexandra M. , Anand Gautam , Cruchaga Carlos , Hock Karl G. , Farnsworth Christopher W. , Randolph Gwendalyn J. , Lavine Kory J. , Steed Ashley L.
Published: February 2022

SARS-CoV-2 triggers a complex systemic immune response in circulating blood mononuclear cells. The relationship between immune cell activation of the peripheral compartment and survival in critical COVID-19 remains to be established. Here we use single-cell RNA sequencing and Cellular Indexing of Transcriptomes and Epitomes by sequence mapping to elucidate cell type specific transcriptional signatures that associate with and predict survival in critical COVID-19. Patients who survive infection display activation of antibody processing, early activation response, and cell cycle regulation pathways most prominent within B-, T-, and NK-cell subsets. We further leverage cell specific differential gene expression and machine learning to predict mortality using single cell transcriptomes. We identify interferon signaling and antigen presentation pathways within cDC2 cells, CD14 monocytes, and CD16 monocytes as predictors of mortality with 90% accuracy. Finally, we validate our findings in an independent transcriptomics dataset and provide a framework to elucidate mechanisms that promote survival in critically ill COVID-19 patients. Identifying prognostic indicators among critical COVID-19 patients holds tremendous value in risk stratification and clinical management.
TLR4 is a regulator of trained immunity in a murine model of Duchenne muscular dystrophy
Authors: Bhattarai Salyan , Li Qian , Ding Jun , Liang Feng , Gusev Ekaterina , Lapohos Orsolya , Fonseca Gregory J. , Kaufmann Eva , Divangahi Maziar , Petrof Basil J.
Published: February 2022

Dysregulation of the balance between pro-inflammatory and anti-inflammatory macrophages has a key function in the pathogenesis of Duchenne muscular dystrophy (DMD), a fatal genetic disease. We postulate that an evolutionarily ancient protective mechanism against infection, known as trained immunity, drives pathological inflammation in DMD. Here we show that bone marrow-derived macrophages from a murine model of DMD (mdx) exhibit cardinal features of trained immunity, consisting of transcriptional hyperresponsiveness associated with metabolic and epigenetic remodeling. The hyperresponsive phenotype is transmissible by bone marrow transplantation to previously healthy mice and persists for up to 11 weeks post-transplant. Mechanistically, training is induced by muscle extract in vitro. The functional and epigenetic changes in bone marrow-derived macrophages from dystrophic mice are TLR4-dependent. Adoptive transfer experiments further support the TLR4-dependence of trained macrophages homing to damaged muscles from the bone marrow. Collectively, this suggests that a TLR4-regulated, memory-like capacity of innate immunity induced at the level of the bone marrow promotes dysregulated inflammation in DMD.
Manipulating the carrier concentration and phase transition via Nb content in SrTiO3
Authors: Zhang Zhe , Qian Peihua , Yang Xingming , Wu Baixi , Cai H. L. , Zhang F. M. , Wu X. S.
Published: February 2022

SrTiO3is a model of the perovskite-like compounds for structural transition which inducing the intriguing physical properties around the critical phase transition temperature TAFD(antiferrodistortive, abbrev. as AFD). Here we report that the electrical transport behavior is a new way to quantify Nb concentration for Nb-doped SrTiO3. The lattice parameter (c), phase transition temperature (TAFD), and the carrier concentration (n) of SrTiO3may be manipulated by niobium doping. TAFDincreases with increasing the niobium content in a rate of about 30 K per (wt%, i.e. niobium element’s weight verses total weight) niobium and n in a rate of about 2.5$$\times$$×1020/cm3per (wt%) niobium.
Semi-classical Monte Carlo algorithm for the simulation of X-ray grating interferometry
Authors: Tessarini Stefan , Fix Michael Karl , Manser Peter , Volken Werner , Frei Daniel , Mercolli Lorenzo , Stampanoni Marco
Published: February 2022

Traditional simulation techniques such as wave optics methods and Monte Carlo (MC) particle transport cannot model both interference and inelastic scattering phenomena within one framework. Based on the rules of quantum mechanics to calculate probabilities, we propose a new semi-classical MC algorithm for efficient and simultaneous modeling of scattering and interference processes. The similarities to MC particle transport allow the implementation as a flexible c++ object oriented extension of EGSnrc—a well-established MC toolkit. In addition to previously proposed Huygens principle based transport through optics components, new variance reduction techniques for the transport through gratings are presented as transport options to achieve the required improvement in speed and memory costs necessary for an efficient exploration (system design—dose estimations) of the medical implementation of X-ray grating interferometry (GI), an emerging imaging technique currently subject of tremendous efforts towards clinical translation. The feasibility of simulation of interference effects is confirmed in four academic cases and an experimental table-top GI setup. Comparison with conventional MC transport show that deposited energy features of EGSnrc are conserved.
Human ignitions on private lands drive USFS cross-boundary wildfire transmission and community impacts in the western US
Authors: Downing William M. , Dunn Christopher J. , Thompson Matthew P. , Caggiano Michael D. , Short Karen C.
Published: February 2022

Wildfires in the western United States (US) are increasingly expensive, destructive, and deadly. Reducing wildfire losses is particularly challenging when fires frequently start on one land tenure and damage natural or developed assets on other ownerships. Managing wildfire risk in multijurisdictional landscapes has recently become a centerpiece of wildfire strategic planning, legislation, and risk research. However, important empirical knowledge gaps remain regarding cross-boundary fire activity in the western US. Here, we use lands administered by the US Forest Service as a study system to assess the causes, ignition locations, structure loss, and social and biophysical factors associated with cross-boundary fire activity over the past three decades. Results show that cross-boundary fires were primarily caused by humans on private lands. Cross-boundary ignitions, area burned, and structure losses were concentrated in California. Public lands managed by the US Forest Service were not the primary source of fires that destroyed the most structures. Cross-boundary fire activity peaked in moderately populated landscapes with dense road and jurisdictional boundary networks. Fire transmission is increasing, and evidence suggests it will continue to do so in the future. Effective cross-boundary fire risk management will require cross-scale risk co-governance. Focusing on minimizing damages to high-value assets may be more effective than excluding fire from multijurisdictional landscapes.