bluuebunny/crossref_metadata_2025 huggingface dataset:
Cold-Start Modeling and On-Line Optimal Control of the Three-Way Catalyst
Authors: Lock Jonathan , Clasén Kristoffer , Sjöblom Jonas , McKelvey Tomas
Published: October 2021

We present a three-way catalyst (TWC) cold-start model, calibrate the model based on experimental data from multiple operating points, and use the model to generate a Pareto-optimalcold-start controller suitable for implementation in standard engine control unit hardware. The TWC model is an extension of a previously presented physics-based model that predicts carbon monoxide, hydrocarbon, and nitrogen oxides tailpipe emissions. The model axially and radially resolves the temperatures in the monolith using very few state variables, thus allowing for use with control-policy based optimal control methods. In this paper, we extend the model to allow for variable axial discretization lengths, include the heat of reaction from hydrogen gas generated from the combustion engine, and reformulate the model parameters to be expressed in conventional units. We experimentally measured the temperature and emission evolution for cold-starts with ten different engine load points, which was subsequently used to tune the model parameters (e.g. chemical reaction rates, specific heats, and thermal resistances). The simulated cumulative tailpipe emission modeling error was found to be typically − 20% to + 80% of the measured emissions. We have constructed and simulated the performance of a Pareto-optimal controller using this model that balances fuel efficiency and the cumulative emissions of each individual species. A benchmark of the optimal controller with a conventional cold-start strategy shows the potential for reducing the cold-start emissions.
Ultrafine Ductile and Austempered Ductile Irons by Solidification in Ultrasonic Field
Authors: Ahmed M. , Riedel E. , Kovalko M. , Volochko A. , Bähr R. , Nofal A.
Published: October 2021

In this research, ultrasonic melt treatment (UST) was used to produce a new ultrafine grade of spheroidal graphite cast iron (SG iron) and austempered ductile iron (ADI) alloys. Ultrasonic treatment was numerically simulated and evaluated based on acoustic wave streaming. The simulation results revealed that the streaming of the acoustic waves propagated as a stream jet in the molten SG iron along the centerline of the ultrasonic source (sonotrode) with a maximum speed of 0.7 m/s and gradually decreased to zero at the bottom of the mold. The metallographic analysis of the newly developed SG iron alloy showed an extremely ultrafine graphite structure. The graphite nodules’ diameter ranging between 6 and 9 µm with total nodule count ranging between 900 to more than 2000 nodules per mm2, this nodule count has never been mentioned in the literature for castings of the same diameter, i.e., 40 mm. In addition, fully ferritic matrix was observed in all UST SG irons. Further austempering heat treatments were performed to produce different austempered ductile iron (ADI) grades with different ausferrite morphologies. The dilatometry studies for the developed ADI alloys showed that the time required for the completion of the ausferrite formation in UST alloys was four times shorter than that required for statically solidified SG irons. SEM micrographs for the ADI alloys showed an extremely fine and short ausferrite structure together with small austenite blocks in the matrix. A dual-phase intercritically austempered ductile iron (IADI) alloy was also produced by applying partial austenitization heat treatment in the intercritical temperature range, where austenite + ferrite + graphite phases coexist. In dual-phase IADI alloy, it was established that introducing free ferrite in the matrix would provide additional refinement for the ausferrite.
Temporal Relationships Between Pain During Intercourse (PDI), Loneliness, and Depressive Symptoms Among Women
Authors: Stout Madison E. , Hawkins Misty A.W.
Published: October 2021

Background

Painful sex can lead to increased psychological distress, including major depressive disorder, and the experience of loneliness may explain this association.

Aims

We aimed to investigate loneliness as a mediator between painful sex and depressive symptoms and hypothesized that women who experienced greater pain during intercourse (ie, more severe and more frequent pain) would endorse higher rates of loneliness and, in turn, higher rates of depressive symptoms at a 6-month follow-up.

Methods

Participants were 148 adults who were assigned female at birth (78.4% white, 77% partnered, 31.14 ± 10.9 years old) and completed an online, anonymous survey including the Female Sexual Function Index (FSFI), UCLA Loneliness Scale-3 (ULS), and demographic information.

Main Outcome Measure

Depressive symptoms, measured via the Patient Health Questionnaire-8 (PHQ8) at baseline (T1) and 6-month follow-up (T2) were used as the outcomes of the present study.

Results

Painful sex and ULS at T1 were significantly correlated with each other and with PHQ8 at T1 (r = 0.590). However, change in PHQ8 from T1 to T2 was not significantly correlated with ULS (r = 0.024) or any other key study variables, indicating that that ULS was not a significant mediator of the relationship between painful sex at T1 and change in PHQ8 (standardized indirect effect = 0.011; 99% CI = −0.114 to 0.188).

Conclusion

These findings are consistent with previous studies highlighting that painful sex is related to depressive symptoms through loneliness cross-sectionally, suggesting that future treatments for depressive symptoms among women who experience painful sex might target loneliness.
Risk of Fecal Incontinence Following Receptive Anal Intercourse: Survey of 21,762 Men Who Have Sex with Men
Authors: Garros Aurélien , Bourrely Michel , Sagaon-Teyssier Luis , Sow Abdourahmane , Lydie Nathalie , Duchesne Lucie , Higuero Thierry , Damon Henri , Velter Annie , Abramowitz Laurent
Published: October 2021

Background

The prevalence of receptive anal intercourse (RAI) is increasing. A few studies, with heterogeneous designs, have investigated the associated risk of fecal incontinence (FI).

Aim

The primary objective of this study was to determine FI prevalence in a population of men who have sex with men (MSM) engaging in RAI. The secondary objective was to identify risk factors for severe FI.

Methods Outcomes

An online survey of 24,308 MSM was performed in 2019. Demographic and socioeconomic data were collected, together with information about RAI sexual practices, and FI defined by: “During the last month, have you experienced any involuntary leakage of stools?”

Results Clinical Implications

In total, 1,734 (8%) of the 21,762 participants reported FI. Mean age was 35.3 years. The prevalence of FI was correlated with RAI frequency: 12.7% (if RAI ≥ 1 /wk) versus 5.7% (if no RAI). In multivariate analysis, the factors associated with FI were age (OR: 1.01), low socioeconomic status (OR 1.32 to 1.40), HIV-seropositivity (OR: 1.78), high RAI frequency (OR: 1.64), chemsex (OR: 1.67) and fist-fucking (OR: 1.61).

Strengths and Limitations

Main strengths of our study are population size and assessment of detailed modalities of sexual practices. Main limitations are the use of a convenience non-random sample and the assessment of FI only during the past month.

CONCLUSION

This study of a large MSM population, highlights risk factors for FI among RAI practices: RAI ≥ 1 /wk, chemsex, fist-fucking, low socioeconomic status.
Simulation of the orbital decay of a spacecraft in low Earth orbit due to aerodynamic drag
Authors: Kumar R. , Singh R. , Chinnappan A.K. , Appar A.
Published: October 2021

Orbiting objects in space are exposed to the risk of collision with space debris over their lifetime. Space debris orbiting in space experiences orbital decay due to various orbital perturbations. This work considers only orbital perturbations due to aerodynamic forces, which spacecraft experience due to the presence of a rarefied atmosphere, causing tumbling motion and orbital decay. Analysis of the orbital decay of a spacecraft is carried out by considering the variation of the drag coefficient as a function of its shape, motion and angle-of-attack. An in-house Direct Simulation Monte Carlo (DSMC) solver is modified for aerodynamic analysis of a spacecraft orbiting in the free molecular regime in low Earth orbit. In addition, an orbital dynamics model is developed to simulate the tumbling motion of a spacecraft and its orbital decay. The orbital decay trajectory is predicted for two sample spacecrafts using the aerodynamic coefficients obtained from the in-house DSMC solver as inputs to the orbital decay model. This study analyses and explores in detail the effects of the aerodynamic coefficients and shape of a spacecraft on its orbital decay.
Role of Clients, Lawyers, Judges, and Institutions in Hiking Litigation Costs in Bangladesh: An Empirical Study
Authors: Tahura Ummey
Published: October 2021

This paper investigates how individuals such as judges, lawyers, clients, and court staffers as well as institutions are elevating litigation costs in Bangladesh in multiple ways. It explores how the existing law and procedures as well as key institutions further promote case delay. It also examines the ways in which police departments and the prosecution contribute to elongate criminal trials and invite additional litigation costs. Empirical data collected through in-depth interviews are analyzed, drawing propositions to individuals’ contributions to delay in case-processing time and hike up litigation costs. Data analysis also assesses common people’s perceptions and expectations from the justice sector. Contemporary legal research has been critically analyzed, where needed.
Between Centre and Periphery: The Small Towns of Pomerelia during the Period of Hanse Domination
Authors: Starski Michał
Published: October 2021

This article offers an overview of specific aspects of the material culture of Pomerelian minor towns in the late Middle Ages. Although small urban centres in Pomerelia (also known as Gdańsk Pomerania) were located off the main trade routes and in the hinterland of the Hanseatic world, archaeological excavations have revealed numerous remains related to the Hanseatic way of life. The analysis of buildings, pottery, glassware, and metalware reveal the Baltic towns’ participation in urban culture, providing an insight into the status of the smaller towns in relation to the main trade centres of the Baltic Sea.
The ASKAP Variables and Slow Transients (VAST) Pilot Survey
Authors: Murphy Tara , Kaplan David L. , Stewart Adam J. , O’Brien Andrew , Lenc Emil , Pintaldi Sergio , Pritchard Joshua , Dobie Dougal , Fox Archibald , Leung James K. , An Tao , Bell Martin E. , Broderick Jess W. , Chatterjee Shami , Dai Shi , d’Antonio Daniele , Doyle Gerry , Gaensler B. M. , Heald George , Horesh Assaf , Jones Megan L. , McConnell David , Moss Vanessa A. , Raja Wasim , Ramsay Gavin , Ryder Stuart , Sadler Elaine M. , Sivakoff Gregory R. , Wang Yuanming , Wang Ziteng , Wheatland Michael S. , Whiting Matthew , Allison James R. , Anderson C. S. , Ball Lewis , Bannister K. , Bock D. C.-J. , Bolton R. , Bunton J. D. , Chekkala R. , Chippendale A. P , Cooray F. R. , Gupta N. , Hayman D. B. , Jeganathan K. , Koribalski B. , Lee-Waddell K. , Mahony Elizabeth K. , Marvil J. , McClure-Griffiths N. M. , Mirtschin P. , Ng A. , Pearce S. , Phillips C. , Voronkov M. A.
Published: October 2021

The Variables and Slow Transients Survey (VAST) on the Australian Square Kilometre Array Pathfinder (ASKAP) is designed to detect highly variable and transient radio sources on timescales from 5 s to$\sim\!5$yr. In this paper, we present the survey description, observation strategy and initial results from the VAST Phase I Pilot Survey. This pilot survey consists of$\sim\!162$h of observations conducted at a central frequency of 888 MHz between 2019 August and 2020 August, with a typical rms sensitivity of$0.24\ \mathrm{mJy\ beam}^{-1}$and angular resolution of$12-20$arcseconds. There are 113 fields, each of which was observed for 12 min integration time, with between 5 and 13 repeats, with cadences between 1 day and 8 months. The total area of the pilot survey footprint is 5 131 square degrees, covering six distinct regions of the sky. An initial search of two of these regions, totalling 1 646 square degrees, revealed 28 highly variable and/or transient sources. Seven of these are known pulsars, including the millisecond pulsar J2039–5617. Another seven are stars, four of which have no previously reported radio detection (SCR J0533–4257, LEHPM 2-783, UCAC3 89–412162 and 2MASS J22414436–6119311). Of the remaining 14 sources, two are active galactic nuclei, six are associated with galaxies and the other six have no multi-wavelength counterparts and are yet to be identified.
Low-frequency integrated radio spectra of diffuse, steep-spectrum sources in galaxy clusters: palaeontology with the MWA and ASKAP
Authors: Duchesne S. W. , Johnston-Hollitt M. , Bartalucci I.
Published: October 2021

Galaxy clusters have been found to host a range of diffuse, non-thermal emission components, generally with steep, power law spectra. In this work we report on the detection and follow-up of radio halos, relics, remnant radio galaxies, and other fossil radio plasmas in Southern Sky galaxy clusters using the Murchison Widefield Array and the Australian Square Kilometre Array Pathfinder. We make use of the frequency coverage between the two radio interferometers—from 88 to$\sim\!900$MHz—to characterise the integrated spectra of these sources within this frequency range. Highlights from the sample include the detection of a double relic system in Abell 3186, a mini-halo in RXC J0137.2–0912, a candidate halo and relic in Abell 3399, and a complex multi-episodic head-tail radio galaxy in Abell 3164. We compare this selection of sources and candidates to the literature sample, finding sources consistent with established radio power–cluster mass scaling relations. Finally, we use the low-frequency integrated spectral index,$\alpha$($S_v \propto v^\alpha$), of the detected sample of cluster remnants and fossil sources to compare with samples of known halos, relics, remnants and fossils to investigate a possible link between their electron populations. We find the distributions of$\alpha$to be consistent with relic and halo emission generated by seed electrons that originated in fossil or remnant sources. However, the present sample sizes are insufficient to rule out other scenarios.
Older age as a time to contribute: a scoping review of generativity in later life
Authors: Villar Feliciano , Serrat Rodrigo , Pratt Michael W.
Published: October 2021

Research on later-life generativity has promoted a new view of older persons that, far from the traditional images of disability, dependence and frailty, recognises their capacities, and potential to continue growing, while underlining their participation and contributions to families, communities and society. The goal of this study was to carry out a scoping review on later-life generativity, the first one conducted on this topic as far as we know, to show how studies in this area have evolved, which aspects of generativity in later life have been studied, and the methodological and epistemological approaches that are dominant in this area of inquiry. Our scoping review shows that research into generativity in later life has grown steadily over the past 30 years, and particularly during the last decade. However, our results also show how such growing interest has focused on certain methodological approaches, epistemological frameworks and cultural contexts. We identify four critical gaps and leading-edge research questions that should be at the forefront of future research into generativity in later life, gaps that reflect biases in the existing literature identified in the study. These are classified as methodological, developmental, contextual and ‘dark-side’ gaps.
The updated ICRC Commentary on the Third Geneva Convention: A new tool to protect prisoners of war in the twenty-first century –CORRIGENDUM
Authors: Arman Jemma , Henckaerts Jean-Marie , Hiemstra Heleen , Krotiuk Kvitoslava
Published: October 2021

The Authors apologise for two errors within their published Article. These appear on pages 391 and 416.
Global Responses of Gravity Waves and Zonal Mean Winds to the Madden‐Julian Oscillation and the Latitudinal Dependence of Their Relations Using MERRA‐2
Authors: Li Jintai , Lu Xian
Published: October 2021

Using 17 years of Modern‐Era Retrospective analysis for Research and Applications, Version 2 (MERRA‐2) data, significant responses of gravity wave (GW) variances, zonal winds and parameterized GW drag to the Madden‐Julian Oscillation (MJO) are identified globally during boreal winter, and their relations are examined. The relative anomalies of GW variances range from −4% (phase 7) to 8% (phase 4) in tropics, and −20% (phase 1) to 20% (phase 5) in the northern polar region (NPR). The anomalies of zonal winds are from −3–3 m/s and −4–8 m/s in tropics and NPR, respectively. The vertical and latitudinal structures of MJO signals in GW, wind and GW drag show coherent patterns. Further analysis implies that in the NPR, the eastward wind leads to westward momentum flux carried by the GWs. This flux leads to westward drag, which drives that of zonal winds and imprint the MJO signal in GWs to the wind.
Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma
Authors: Bosnakovski Darko , Ener Elizabeth T. , Cooper Mark S. , Gearhart Micah D. , Knights Kevin A. , Xu Natalie C. , Palumbo Christian A. , Toso Erik A. , Marsh Graham P. , Maple Hannah J. , Kyba Michael
Published: October 2021

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.
Hair glucocorticoids are associated with childhood adversity, depressive symptoms and reduced global and lobar grey matter in Generation Scotland
Authors: Green Claire , Stolicyn Aleks , Harris Mathew A. , Shen Xueyi , Romaniuk Liana , Barbu Miruna C. , Hawkins Emma L. , Wardlaw Joanna M. , Steele J. Douglas , Waiter Gordon D. , Sandu Anca-Larisa , Campbell Archie , Porteous David J. , Seckl Jonathan R. , Lawrie Stephen M. , Reynolds Rebecca M. , Cavanagh Jonathan , McIntosh Andrew M. , Whalley Heather C.
Published: October 2021

Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (βrange = −0.057 to −0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; βrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (β = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: β = −0.059, P = 0.043; nucleus accumbens: β = −0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.
Childhood urbanicity interacts with polygenic risk for depression to affect stress-related medial prefrontal function
Authors: Zhang Xiao , Yan Hao , Yu Hao , Zhao Xin , Shah Shefali , Dong Zheng , Yang Guang , Zhang Xiaoxi , Muse Timothy , Li Jing , Jiang Sisi , Liao Jinmin , Zhang Yuyanan , Chen Qiang , Weinberger Daniel R. , Yue Weihua , Zhang Dai , Tan Hao Yang
Published: October 2021

Urbanization is increasing globally, and is associated with stress and increased mental health risks, including for depression. However, it remains unclear, especially at the level of brain function, how urbanicity, social threat stressors, and psychiatric risk may be linked. Here, we aim to define the structural and functional MRI neural correlates of social stress, childhood urbanicity, and their putative mechanistic relevance to depressive illness risk, in terms of behavioral traits and genetics. We studied a sample of healthy adults with divergent urban and rural childhoods. We examined childhood urbanicity effects on brain structure as suggested by MRI, and its functional relevance to depression risk, through interactions between urbanicity and trait anxiety-depression, as well as between urbanicity and polygenic risk for depression, during stress-related medial prefrontal cortex (mPFC) engagement. Subjects with divergent rural and urban childhoods were similar in adult socioeconomic status and were genetically homogeneous. Urban childhood was associated with relatively reduced mPFC gray matter volumes as suggested by MRI. MPFC engagement under social status threat correlated with the higher trait anxiety-depression in subjects with urban childhoods, but not in their rural counterparts, implicating an exaggerated physiological response to the threat context with urbanicity, in association with behavioral risk for depression. Stress-associated mPFC engagement also interacted with polygenic risk for depression, significantly predicting a differential mPFC response in individuals with urban but not rural childhoods. Developmental urbanicity, therefore, appears to interact with genetic and behavioral risk for depression on the mPFC neural response to a threat context.
FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer
Authors: Yao Jing , Yang Jun , Yang Zhe , Wang Xin-Ping , Yang Tong , Ji Bing , Zhang Zheng-Yun
Published: October 2021

Colorectal tumorigenesis is a heterogeneous disease driven by multiple genetic and epigenetic alterations. F-box and WD repeat domain containing 11 (FBXW11) is a member of the F-box protein family that regulates the ubiquitination of key factors associated with tumor growth and aggressiveness. Our study aimed to explore the role of FBXW11 in the development and metastasis of colorectal cancer (CRC). FBXW11 was overexpressed in colorectal tumor tissues and its overexpression was associated with a poor prognosis of CRC patients. The upregulation of FBXW11 not only promoted cell proliferation, invasion, and migration, but also contributed to maintaining stem-cell features in colorectal tumor cells. Further analysis revealed that FBXW11 targeted hypermethylated in cancer 1 (HIC1) and reduced its stability in CRC cells through ubiquitination. Moreover, the expression of sirtuin 1 (SIRT1), a deacetylase in tumor cells was upregulated by FBXW11 via regulating HIC1 expression. The mouse xenograft models of CRC confirmed that FBXW11 knockdown impeded colorectal tumor growth and liver metastasis in vivo. In summary, our study identified FBXW11 as an oncogenic factor that contributed to stem-cell-like properties and liver metastasis in CRC via regulating HIC1-mediated SIRT1 expression. These results provide a rationale for the development of FBXW11-targeting drugs for CRC patients.
Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review
Authors: Zhang Quanlong , Pan Yan , Ji Jingjing , Xu Yuxin , Zhang Qiaoyan , Qin Luping
Published: October 2021

WNT family member 4 (WNT4), which belongs to the conserved WNT protein family, plays an important role in the development and differentiation of many cell types during the embryonic development and adult homeostasis. Increasing evidence has shown that WNT4 is a special ligand that not only activates the β-catenin independent pathway but also acts on β-catenin signaling based on different cellular processes. This article is a summary of the current knowledge about the expression, regulation, and function of WNT4 ligands and their signal pathways in cell differentiation and human disease processes. WNT4 is a promoter in osteogenic differentiation in bone marrow stromal cells (BMSCs) by participating in bone homeostasis regulation in osteoporotic diseases. Non-canonical WNT4 signaling is necessary for metabolic maturation of pancreatic β-cell. WNT4 is also necessary for decidual cell differentiation and decidualization, which plays an important role in preeclampsia. WNT4 promotes neuronal differentiation of neural stem cell and dendritic cell (DC) into conventional type 1 DC (cDC1). Besides, WNT4 mediates myofibroblast differentiation in the skin, kidney, lung, and liver during scarring or fibrosis. On the negative side, WNT4 is highly expressed in cancer tissues, playing a pro-carcinogenic role in many cancer types. This review provides an overview of the progress in elucidating the role of WNT4 signaling pathway components in cell differentiation in adults, which may provide useful clues for the diagnosis, prevention, and therapy of human diseases.
SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury
Authors: Zhang Yingting , Long Xidai , Ruan Xin , Wei Qian , Zhang Lin , Wo Lulu , Huang Dongdong , Lin Longshuai , Wang Difei , Xia Li , Zhao Qinghua , Liu Junling , Zhao Qian , He Ming
Published: October 2021

Protein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation–deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.
Thousands of Qatari genomes inform human migration history and improve imputation of Arab haplotypes
Authors: Razali Rozaimi Mohamad , Rodriguez-Flores Juan , Ghorbani Mohammadmersad , Naeem Haroon , Aamer Waleed , Aliyev Elbay , Jubran Ali ,   Qatar Genome Program Research Consortium,   Qatar Genome Project Management, Ismail Said I. , Al-Muftah Wadha , Badji Radja , Mbarek Hamdi , Darwish Dima , Fadl Tasnim , Yasin Heba , Ennaifar Maryem , Abdellatif Rania , Alkuwari Fatima , Alvi Muhammad , Al-Sarraj Yasser , Saad Chadi , Althani Asmaa ,   Biobank and Sample Preparation, Fethnou Eleni , Qafoud Fatima , Alkhayat Eiman , Afifi Nahla ,   Sequencing and Genotyping group, Tomei Sara , Liu Wei , Lorenz Stephan ,   Applied Bioinformatics Core, Syed Najeeb , Almabrazi Hakeem , Vempalli Fazulur Rehaman , Temanni Ramzi ,   Data Management and Computing Infrastructure group, Saqri Tariq Abu , Khatib Mohammedhusen , Hamza Mehshad , Zaid Tariq Abu , El Khouly Ahmed , Pathare Tushar , Poolat Shafeeq , Al-Ali Rashid ,   Consortium Lead Principal Investigators (in alphabetical order), Albagha Omar , Al-Khodor Souhaila , Alshafai Mashael , Badii Ramin , Chouchane Lotfi , Estivill Xavier , Fakhro Khalid A. , Mokrab Younes , Puthen Jithesh V. , Suhre Karsten , Tatari Zohreh , Clark Andrew G. , Fakhro Khalid A. , Mokrab Younes
Published: October 2021

Arab populations are largely understudied, notably their genetic structure and history. Here we present an in-depth analysis of 6,218 whole genomes from Qatar, revealing extensive diversity as well as genetic ancestries representing the main founding Arab genealogical lineages of Qahtanite (Peninsular Arabs) and Adnanite (General Arabs and West Eurasian Arabs). We find that Peninsular Arabs are the closest relatives of ancient hunter-gatherers and Neolithic farmers from the Levant, and that founder Arab populations experienced multiple splitting events 12–20 kya, consistent with the aridification of Arabia and farming in the Levant, giving rise to settler and nomadic communities. In terms of recent genetic flow, we show that these ancestries contributed significantly to European, South Asian as well as South American populations, likely as a result of Islamic expansion over the past 1400 years. Notably, we characterize a large cohort of men with the ChrY J1a2b haplogroup (n = 1,491), identifying 29 unique sub-haplogroups. Finally, we leverage genotype novelty to build a reference panel of 12,432 haplotypes, demonstrating improved genotype imputation for both rare and common alleles in Arabs and the wider Middle East.
Emergence and melting of active vortex crystals
Authors: James Martin , Suchla Dominik Anton , Dunkel Jörn , Wilczek Michael
Published: October 2021

Melting of two-dimensional (2D) equilibrium crystals is a complex phenomenon characterized by the sequential loss of positional and orientational order. In contrast to passive systems, active crystals can self-assemble and melt into an active fluid by virtue of their intrinsic motility and inherent non-equilibrium stresses. Currently, the non-equilibrium physics of active crystallization and melting processes is not well understood. Here, we establish the emergence and investigate the melting of self-organized vortex crystals in 2D active fluids using a generalized Toner-Tu theory. Performing extensive hydrodynamic simulations, we find rich transition scenarios. On small domains, we identify a hysteretic transition as well as a transition featuring temporal coexistence of active vortex lattices and active turbulence, both of which can be controlled by self-propulsion and active stresses. On large domains, an active vortex crystal with solid order forms within the parameter range corresponding to active vortex lattices. The melting of this crystal proceeds through an intermediate hexatic phase. Generally, these results highlight the differences and similarities between crystalline phases in active fluids and their equilibrium counterparts.
Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
Authors: Schmidt Amand F. , Hunt Nicholas B. , Gordillo-Marañón Maria , Charoen Pimphen , Drenos Fotios , Kivimaki Mika , Lawlor Deborah A. , Giambartolomei Claudia , Papacosta Olia , Chaturvedi Nishi , Bis Joshua C. , O’Donnell Christopher J. , Wannamethee Goya , Wong Andrew , Price Jackie F. , Hughes Alun D. , Gaunt Tom R. , Franceschini Nora , Mook-Kanamori Dennis O. , Zwierzyna Magdalena , Sofat Reecha , Hingorani Aroon D. , Finan Chris
Published: October 2021

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.
Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology
Authors: Osuna de la Peña David , Trabulo Sara Maria David , Collin Estelle , Liu Ying , Sharma Shreya , Tatari Marianthi , Behrens Diana , Erkan Mert , Lawlor Rita T. , Scarpa Aldo , Heeschen Christopher , Mata Alvaro , Loessner Daniela
Published: October 2021

Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.
Brain adiponectin signaling controls peripheral insulin response in Drosophila
Authors: Arquier Nathalie , Bjordal Marianne , Hammann Philippe , Kuhn Lauriane , Léopold Pierre
Published: October 2021

The brain plays a key role in energy homeostasis, detecting nutrients, metabolites and circulating hormones from peripheral organs and integrating this information to control food intake and energy expenditure. Here, we show that a group of neurons in the Drosophila larval brain expresses the adiponectin receptor (AdipoR) and controls systemic growth and metabolism through insulin signaling. We identify glucose-regulated protein 78 (Grp78) as a circulating antagonist of AdipoR function produced by fat cells in response to dietary sugar. We further show that central AdipoR signaling inhibits peripheral Juvenile Hormone (JH) response, promoting insulin signaling. In conclusion, we identify a neuroendocrine axis whereby AdipoR-positive neurons control systemic insulin response.
Global syndromes induced by changes in solutes of the world’s large rivers
Authors: Wu Jiang , Xu Nan , Wang Yichu , Zhang Wei , Borthwick Alistair G. L. , Ni Jinren
Published: October 2021

Solute-induced river syndromes have grown in intensity in recent years. Here we investigate seven such river syndromes (salinization, mineralization, desalinization, acidification, alkalization, hardening, and softening) associated with global trends in major solutes (Ca2+, Mg2+, Na+, K+, SO42−, Cl−, HCO3−) and dissolved silica in the world’s large rivers (basin areas ≥ 1000 km2). A comprehensive dataset from 600 gauge stations in 149 large rivers reveals nine binary patterns of co-varying trends in runoff and solute concentration. Solute-induced river syndromes are associated with remarkable increases in total dissolved solids (68%), chloride (81%), sodium (86%) and sulfate (142%) fluxes from rivers to oceans worldwide. The syndromes are most prevalent in temperate regions (30~50°N and 30~40°S based on the available data) where severe rock weathering and active human interferences such as urbanization and agricultural irrigation are concentrated. This study highlights the urgency to protect river health from extreme changes in solute contents.
The pupil responds spontaneously to perceived numerosity
Authors: Castaldi Elisa , Pomè Antonella , Cicchini Guido Marco , Burr David , Binda Paola
Published: October 2021

Although luminance is the main determinant of pupil size, the amplitude of the pupillary light response is also modulated by stimulus appearance and attention. Here we ask whether perceived numerosity modulates the pupillary light response. Participants passively observed arrays of black or white dots of matched physical luminance but different physical or illusory numerosity. In half the patterns, pairs of dots were connected by lines to create dumbbell-like shapes, inducing an illusory underestimation of perceived numerosity; in the other half, connectors were either displaced or removed. Constriction to white arrays and dilation to black were stronger for patterns with higher perceived numerosity, either physical or illusory, with the strength of the pupillary light response scaling with the perceived numerosity of the arrays. Our results show that even without an explicit task, numerosity modulates a simple automatic reflex, suggesting that numerosity is a spontaneously encoded visual feature.
Breast Cancer Consensus Subtypes: A system for subtyping breast cancer tumors based on gene expression
Authors: Horr Christina , Buechler Steven A.
Published: October 2021

Breast cancer is heterogeneous in prognoses and drug responses. To organize breast cancers by gene expression independent of statistical methodology, we identified the Breast Cancer Consensus Subtypes (BCCS) as the consensus groupings of six different subtyping methods. Our classification software identified seven BCCS subtypes in a study cohort of publicly available data (n = 5950) including METABRIC, TCGA-BRCA, and data assayed by Affymetrix arrays. All samples were fresh-frozen from primary tumors. The estrogen receptor-positive (ER+) BCCS subtypes were: PCS1 (18%) good prognosis, stromal infiltration; PCS2 (15%) poor prognosis, highly proliferative; PCS3 (13%) poor prognosis, highly proliferative, activated IFN-gamma signaling, cytotoxic lymphocyte infiltration, high tumor mutation burden; PCS4 (18%) good prognosis, hormone response genes highly expressed. The ER− BCCS subtypes were: NCS1 (11%) basal; NCS2 (10%) elevated androgen response; NCS3 (5%) cytotoxic lymphocyte infiltration; unclassified tumors (9%). HER2+ tumors were heterogeneous with respect to BCCS.
Visualizing temperature-dependent phase stability in high entropy alloys
Authors: Evans Daniel , Chen Jiadong , Bokas George , Chen Wei , Hautier Geoffroy , Sun Wenhao
Published: October 2021

High entropy alloys (HEAs) contain near equimolar amounts of five or more elements and are a compelling space for materials design. In the design of HEAs, great emphasis is placed on identifying thermodynamic conditions for single-phase and multi-phase stability regions, but this process is hindered by the difficulty of navigating stability relationships in high-component spaces. Traditional phase diagrams use barycentric coordinates to represent composition axes, which require (N – 1) spatial dimensions to represent an N-component system, meaning that HEA systems with N > 4 components cannot be readily visualized. Here, we propose forgoing barycentric composition axes in favor of two energy axes: a formation-energy axis and a ‘reaction energy’ axis. These Inverse Hull Webs offer an information-dense 2D representation that successfully captures complex phase stability relationships in N ≥ 5 component systems. We use our proposed diagrams to visualize the transition of HEA solid-solutions from high-temperature stability to metastability upon quenching, and identify important thermodynamic features that are correlated with the persistence or decomposition of metastable HEAs.
Mitochondrial augmentation of CD34+ cells from healthy donors and patients with mitochondrial DNA disorders confers functional benefit
Authors: Jacoby Elad , Ben Yakir-Blumkin Moriya , Blumenfeld-Kan Shiri , Brody Yehuda , Meir Amilia , Melamed-Book Naomi , Napso Tina , Pozner Gat , Saadi Esraa , Shabtay-Orbach Ayelet , Yivgi-Ohana Natalie , Sher Noa , Toren Amos
Published: October 2021

Mitochondria are cellular organelles critical for numerous cellular processes and harboring their own circular mitochondrial DNA (mtDNA). Most mtDNA associated disorders (either deletions, mutations, or depletion) lead to multisystemic disease, often severe at a young age, with no disease-modifying therapies. Mitochondria have a capacity to enter eukaryotic cells and to be transported between cells. We describe a method of ex vivo augmentation of hematopoietic stem and progenitor cells (HSPCs) with normal exogenous mitochondria, termed mitochondrial augmentation therapy (MAT). Here, we show that MAT is feasible and dose dependent, and improves mitochondrial content and oxygen consumption of healthy and diseased HSPCs. Ex vivo mitochondrial augmentation of HSPCs from a patient with a mtDNA disorder leads to superior human engraftment in a non-conditioned NSGS mouse model. Using a syngeneic mouse model of accumulating mitochondrial dysfunction (Polg), we show durable engraftment in non-conditioned animals, with in vivo transfer of mitochondria to recipient hematopoietic cells. Taken together, this study supports MAT as a potential disease-modifying therapy for mtDNA disorders.
Don’t get it or don’t spread it: comparing self-interested versus prosocial motivations for COVID-19 prevention behaviors
Authors: Jordan Jillian J. , Yoeli Erez , Rand David G.
Published: October 2021

COVID-19 prevention behaviors may be seen as self-interested or prosocial. Using American samples from MTurk and Prolific (total n = 6850), we investigated which framing is more effective—and motivation is stronger—for fostering prevention behavior intentions. We evaluated messaging that emphasized personal, public, or personal and public benefits of prevention. In initial studies (conducted March 14–16, 2020), the Public treatment was more effective than the Personal treatment, and no less effective than the Personal + Public treatment. In additional studies (conducted April 17–30, 2020), all three treatments were similarly effective. Across all these studies, the perceived public threat of coronavirus was also more strongly associated with prevention intentions than the perceived personal threat. Furthermore, people who behaved prosocially in incentivized economic games years before the pandemic had greater prevention intentions. Finally, in a field experiment (conducted December 21–23, 2020), we used our three messaging strategies to motivate contact-tracing app signups (n = 152,556 newsletter subscribers). The design of this experiment prevents strong causal inference; however, the results provide suggestive evidence that the Personal + Public treatment may have been more effective than the Personal or Public treatment. Together, our results highlight the importance of prosocial motives for COVID-19 prevention.
A high temporal/spatial resolution neuro-architecture study of rodent brain by wideband echo planar imaging
Authors: Cheng Po-Wei , Chiueh Tzi-Dar , Chen Jyh-Horng
Published: October 2021

Latest simultaneous multi-slice (SMS) methods greatly benefit MR efficiency for recent studies using parallel imaging technique. However, these methods are limited by the requirement of array coils. The proposed Coherent Wideband method, which employs an extended field of view to separate multiple excited slices, can be applied to any existing MRI instrument, even those without array coils. In this study, the Coherent Wideband echo-planar imaging method was implemented on 7 T animal MRI to exhibit comprehensive enhancements in neuro-architecture, including diffusion tensor imaging (DTI) and functional MR studies (fMRI). Under the same scan time, the time-saving effect can be manipulated to increase the number of averages for DTI SNR improvement, reducing fractional anisotropy difference by 56.9% (from 0.072 to 0.041) and the deviation angle by 64% (from 25.3° to 16.2°). In summary, Coherent Wideband Echo Planar Imaging (EPI) will provide faster, higher resolution, thinner slice, or higher SNR imaging for precision neuro-architecture studies.