bluuebunny/crossref_metadata_2025 huggingface dataset:
The Perception of Residential Water Tariff, Consumption, and Cost: Evidence of its Determinants Using Survey Data
Authors: Barberán Ramón , López-Laborda Julio , Rodrigo Fernando
Published: June 2022

In a survey of 1,500 households in Zaragoza (Spain), we found that respondents did not accurately know what the price of water was, and what the characteristics of the water tariff were, how much water they consumed, or how much it cost them; they thought they consumed less water than they actually did, and thought that their consumption level was normal; they believed they paid more than they really did, and considered the payments to be appropriate or expensive. Based on this sample of households, this paper analyses what determines the level of accuracy in the perception of consumers about their water tariff, their water consumption, and their total water cost, or, in other words, what determines the closeness between their perception and reality. The methodology applied is based on maximum likelihood estimates using various probit/logit models. The results obtained allow to identify the collectives to whom an information policy should be directed in order to approximate their perceptions closer to the real tariff, consumption and cost of water in households, and to point out the kind of information that should be transmitted in order to contribute to the preservation of water resources.
The PICLS high-throughput screening method for agents extending cellular longevity identifies 2,5-anhydro-D-mannitol as novel anti-aging compound
Authors: Alfatah Mohammad , Eisenhaber Frank
Published: June 2022

Although aging is the biggest risk factor for human chronic (cancer, diabetic, cardiovascular, and neurodegenerative) diseases, few interventions are known besides caloric restriction and a small number of drugs (with substantial side effects) that directly address aging. Thus, there is an urgent need for new options that can generally delay aging processes and prevent age-related diseases. Cellular aging is at the basis of aging processes. Chronological lifespan (CLS) of yeast Saccharomyces cerevisiae is the well-established model system for investigating the interventions of human post-mitotic cellular aging. CLS is defined as the number of days cells remain viable in a stationary phase. We developed a new, cheap, and fast quantitative method for measuring CLS in cell cultures incubated together with various chemical agents and controls on 96-well plates. Our PICLS protocol with (1) the use of propidium iodide for fluorescent-based cell survival reading in a microplate reader and (2) total cell count measurement via OD600nm absorption from the same plate provides real high-throughput capacity. Depending on logistics, large numbers of plates can be processed in parallel so that the screening of thousands of compounds becomes feasible in a short time. The method was validated by measuring the effect of rapamycin and calorie restriction on yeast CLS. We utilized this approach for chemical agent screening. We discovered the anti-aging/geroprotective potential of 2,5-anhydro-D-mannitol (2,5-AM) and suggest its usage individually or in combination with other anti-aging interventions.
Ethical Issues in Social Science Research Employing Big Data
Authors: Hosseini Mohammad , Wieczorek Michał , Gordijn Bert
Published: June 2022

This paper analyzes the ethics of social science research (SSR) employing big data. We begin by highlighting the research gap found on the intersection between big data ethics, SSR and research ethics. We then discuss three aspects of big data SSR which make it warrant special attention from a research ethics angle: (1) the interpretative character of both SSR and big data, (2) complexities of anticipating and managing risks in publication and reuse of big data SSR, and (3) the paucity of regulatory oversight and ethical recommendations on protecting individual subjects as well as societies when conducting big data SSR. Against this backdrop, we propose using David Resnik’s research ethics framework to analyze some of the most pressing ethical issues of big data SSR. Focusing on the principles of honesty, carefulness, openness, efficiency, respect for subjects, and social responsibility, we discuss three clusters of ethical issues: those related to methodological biases and personal prejudices, those connected to risks arising from data availability and reuse, and those leading to individual and social harms. Finally, we advance considerations to observe in developing future ethical guidelines about big data SSR.
Examining what Mental Toughness, Ego Resiliency, Self-efficacy, and Grit measure: An exploratory structural equation modelling bifactor approach
Authors: Denovan Andrew , Dagnall Neil , Drinkwater Kenneth
Published: June 2022

Despite conceptual similarities among the established non-cognitive constructs of Mental Toughness, Ego Resiliency, Self-efficacy, and Grit, preceding research typically considered these as adversary rather than complementary and potentially additive. Subsequently, comparatively few studies have examined these together. This paper, via two independent studies, examined commonality within Mental Toughness, Ego Resiliency, Self-efficacy, and Grit. This identified key elements that contribute to a broad, non-cognitive, resource-based construct. Study 1 (N = 2137) assessed shared variance among the non-cognitive constructs relative to a general factor. Study 2 (N = 1148) evaluated the replicability of the results from Study 1 and examined measurement invariance. Respondents completed established self-report measures indexing the study variables. Exploratory structural equation modelling bifactor analyses consistently revealed that Mental Toughness, the Ego-Resiliency Optimal Regulation subscale, and Self-efficacy loaded highly on a general factor, which the authors labelled as Non-Cognitive Adaptive Resourcefulness (NCAR). Invariance analyses supported the stability of this model across study context. This paper advanced conceptual understanding of the core shared features of independent non-cognitive constructs. The authors discuss the potential of NCAR and advocate the need for further research.
Strobilanthes Blume (Acanthaceae) in Myanmar, a new species and an updated checklist
Authors: Wood John R. I. , Aung Mu Mu , Wells Tom , Armstrong Kate E.
Published: June 2022

A brief history of the discovery ofStrobilanthesspecies in Myanmar is presented. The revival of fieldwork in recent years has resulted in many new records, so an updated checklist of all known species from the country is needed. Selected specimens are cited and distribution notes provided. One new species,Strobilanthes hiansJ.R.I.Wood & K.Armstr., with unusual pollen, is described and illustrated bringing the total of recognised species in the country to 81 with six additional infraspecific taxa.
Fractional characteristic functions, and a fractional calculus approach for moments of random variables
Authors: Tomovski Živorad , Metzler Ralf , Gerhold Stefan
Published: June 2022

In this paper we introduce a fractional variant of the characteristic function of a random variable. It exists on the whole real line, and is uniformly continuous. We show that fractional moments can be expressed in terms of Riemann–Liouville integrals and derivatives of the fractional characteristic function. The fractional moments are of interest in particular for distributions whose integer moments do not exist. Some illustrative examples for particular distributions are also presented.
Chemistry and bioactivities of natural steroidal alkaloids
Authors: Xiang Mei-Ling , Hu Bin-Yuan , Qi Zi-Heng , Wang Xiao-Na , Xie Tian-Zhen , Wang Zhao-Jie , Ma Dan-Yu , Zeng Qi , Luo Xiao-Dong
Published: June 2022

Steroidal alkaloids possess the basic steroidal skeleton with a nitrogen atom in rings or side chains incorporated as an integral part of the molecule. They have demonstrated a wide range of biological activities, and some of them have even been developed as therapeutic drugs, such as abiraterone acetate (Zytiga®), a blockbuster drug, which has been used for the treatment of prostate cancer. Structurally diverse natural steroidal alkaloids present a wide spectrum of biological activities, which are attractive for natural product chemistry and medicinal chemistry communities. This review comprehensively covers the structural classification, isolation and various biological activities of 697 natural steroidal alkaloids discovered from 1926 to October 2021, with 363 references being cited.
Transcervical Fibroid Ablation (TFA) with the Sonata System: Updated Review of a New Paradigm for Myoma Treatment
Authors: Lindner L. H. , Roy K. , Toub D. B.
Published: June 2022

Purpose of Review

This paper provides an update of the recent evidence related to transcervical fibroid ablation (TFA) with the Sonata® System.

Recent Findings

An additional 27 papers representing over 400 women and more than 800 treated fibroids have been published. These demonstrate consistent, positive results, representing multiple prospective clinical trials, subgroup analyses, health economic analyses, case series, and systematic reviews of TFA. These include a 147-patient prospective clinical trial of TFA (the SONATA Clinical Trial) that demonstrated sustained symptom relief and an 8.2% cumulative reintervention rate through 3 years, a long-term study (VITALITY) confirming durable symptom relief with an 11.8% reintervention rate over > 5 years of mean follow-up, a clinical trial (OPEN) suggesting minimal potential for intrauterine adhesiogenesis post-TFA, preliminary results of a global registry (SAGE), and two subgroup analyses of TFA reporting favorable and safe outcomes in women with large fibroids > 5 cm in diameter. Three comparative health economic studies demonstrate favorable economic outcomes against both myomectomy and hysterectomy. A recent ACOG Practice Bulletin also noted equivalent outcomes for transcervical, laparoscopic, and transvaginal fibroid ablation.

Summary

Accumulated clinical evidence, including systematic reviews and longitudinal prospective clinical trials, continues to confirm the safety and efficacy of TFA in women with symptomatic fibroids, including myomata > 5 cm. As a transcervical treatment modality that can safely address all nonpedunculated uterine fibroid types, the continued evidence base confirms TFA as an innovative and useful treatment option that meets a significant unmet clinical need, including among underserved populations, delivering significant durable reductions in fibroid symptoms.
Risk, benefit, and social value in Covid-19 human challenge studies: pandemic decision making in historical context
Authors: Rosenheck Mabel
Published: June 2022

During the Covid-19 pandemic, ethicists and researchers proposed human challenge studies as a way to speed development of a vaccine that could prevent disease and end the global public health crisis. The risks to healthy volunteers of being deliberately infected with a deadly and novel pathogen were not low, but the benefits could have been immense. This essay is a history of the three major efforts to set up a challenge model and run challenge studies in 2020 and 2021. The pharmaceutical company Johnson and Johnson, the National Institutes of Health in the United States, and a private-public partnership of industry, university, and government partners in Britain all undertook preparations. The United Kingdom’s consortium began their Human Challenge Programme in March of 2021.

Beyond documenting each effort, the essay puts these scientific and ethical debates in dialogue with the social, epidemiological, and institutional conditions of the pandemic as well as the commercial, intellectual, and political systems in which medical research and Covid-19 challenge studies operated. It shows how different institutions understood risk, benefit, and social value depending on their specific contexts. Ultimately the example of Covid-19 challenge studies highlights the constructedness of such assessments and reveals the utility of deconstructing them retrospectively so as to better understand the interplay of medical research and research ethics with larger social systems and historical contexts.
Parents’ Perceptions on the Debated Parenting Practice of Cognitive Enhancement in Healthy Children and Adolescents
Authors: Hiltrop Kati , Sattler Sebastian
Published: June 2022

First evidence shows that some parents engage in the health-endangering practice of (mis-)using prescription drugs to boost their children’s school performance. But little is known about parental perspectives on this phenomenon. This study aims to better understand parents’ perspectives on the non-medical use of prescription drugs to improve healthy children’s cognitive functioning. We conducted twelve semi-structured face-to-face interviews with a diverse sample of parents in Germany, and applied qualitative content analysis to explore their perspectives on instrumentalizing prescription drugs for improving the performance of healthy children, including their underlying knowledge (gaps), moral evaluations, evaluations of accompanied risks and benefits, opinions on potential motivators, and wishes regarding policy-making. The results show that parents typically believed themselves knowledgeable about such prescription drug (mis-)use, although they were not aware of anyone in their social environment taking them for enhancement. Parents generally considered such behavior to be morally reprehensible, cheating, and similar to doping in sports, and they typically claimed that no situation or occasion could motivate them to administer prescription drugs to their healthy children. Health risks (including side effects or addiction) were a typical expectation of drug use. That doctors should give such drugs to healthy young people was seen as unjustifiable. The results suggest that morality and risk–benefit evaluations of parents play a major role in their decision-making concerning this potentially risky instrumentalization of non-medical drugs. These insights are of distinct importance, especially for future research and further discussions on this topic, such as an evidence-based public dialog and ethics debates.
A rock-cut tomb of the Mongol period in the Ilkhanid capital of Maraghe
Authors: Moradi Amin
Published: June 2022

By the time of Kublai’s death, the Mongol Empire had fractured into four separate khanates or empires including the Golden Horde [Kipchak] in the northwest, the Chagatai Khanate in Central Asia, the Ilkhanate, based in modern-day Iran, and the Yuan Dynasty in the east. Although the burial architecture of the Yuan Dynasty and their funeral ritual have been the foci of the archaeologist, there have been no convincing conclusions about the other branches of the Mongol Empire. According to historical literature, all of the Ilkhanid Khans before Ghazan (1271–1304 CE) were buried in unknown places after their death. Archaeologically, not only we have no clue to trace the royal tombs of the pre-Ghazan period, even the identifiable tombs of the royal family members of the Ilkhanid Iran and high-ranking Mongol nobles have not discovered. Taking Maraghe, in Northwest Iran, as the first Ilkhanid capital (1256–1265 CE), the aim of this paper is to study the archaeological remains of the enigmatic rock-cut complex in the village of Varōy [Varjavy] to provide a more detailed description of the current remains. The results show that, while reassessment of the possible functions regarding this site suggest and outright contradict to the traditional views of scholars as a mithraeum, the architectural layout of this building is deeply intertwined with Mongol funeral sites and has much to tell about the relationship between rock-cut complexes and Ilkhanid cemeteries.
The Babel Lexicon of Language
Authors: McIntyre Dan , Jeffries Lesley , Evans Matt , Price Hazel , Gold Erica
Published: June 2022

What's the word that describes the process of making supportive noises when you're listening to someone? What is syntax and how does it differ from grammar? Do you know what a morpheme is? And did you know that it's not only an atom that has a nucleus? The Babel Lexicon of Language is an entertaining and accessible introduction to the key terminology involved in the study of language. It defines over 500 terms and uses contemporary language examples, explaining complex issues in an easy-to-understand way. Written by the expert editorial team behind Babel, the popular language magazine, and assuming no prior knowledge of linguistics, The Babel Lexicon of Language is an invaluable resource for students, teachers and anyone with an interest in language.
Measuring reciprocity in a directed preferential attachment network
Authors: Wang Tiandong , Resnick Sidney I.
Published: June 2022

Empirical studies (e.g. Jiang et al. (2015) and Mislove et al. (2007)) show that online social networks have not only in- and out-degree distributions with Pareto-like tails, but also a high proportion of reciprocal edges. A classical directed preferential attachment (PA) model generates in- and out-degree distributions with power-law tails, but the theoretical properties of the reciprocity feature in this model have not yet been studied. We derive asymptotic results on the number of reciprocal edges between two fixed nodes, as well as the proportion of reciprocal edges in the entire PA network. We see that with certain choices of parameters, the proportion of reciprocal edges in a directed PA network is close to 0, which differs from the empirical observation. This points out one potential problem of fitting a classical PA model to a given network dataset with high reciprocity, and indicates that alternative models need to be considered.
Abolishing Gender on D
Authors: Conrod Kirby
Published: June 2022

This article presents a Minimalist syntactic analysis of sociopragmatically conditioned gender features on pronouns. To account for inter- and intra-speaker variation, I locate the parameter for social gender in the presence or absence of an unvalued gender feature on the phase head D. Supporting this analysis, I show that variation in English speakers’ acceptability and use of definite, specific singular they, as in (i), is sensitive to reference; this sensitivity is robustly explained by the location of gender features on D.

(i) Taylori is writing theiri own autobiography.

For speakers who report (i) as ungrammatical, a crash results from the uGender feature on D remaining unvalued. For innovative speakers, uGender is not present on D and no crash results from a lack of gender features. This analysis explains why a pragmatic feature like social gender can cause true syntactic ungrammaticality, since the narrow syntax encodes certain pragmatic features as obligatory.
Engaging community in the translational process: Environmental scan of adaptive capacity and preparedness of Clinical and Translational Science Award Program hubs
Authors: Volkov Boris B. , Hoyo Verónica , Hunt Joe
Published: June 2022

This paper is part of the Environmental Scan of Adaptive Capacity and Preparedness of Clinical and Translational Science Award (CTSA) hubs, illuminating challenges, practices, and lessons learned related to CTSA hubs’ efforts of engaging community partners to reduce the spread of the virus, address barriers to COVID-19 testing, identify treatments to improve health outcomes, and advance community participation in research. CTSA researchers, staff, and community partners collaborated to develop evidence-based, inclusive, accessible, and culturally appropriate strategies and resources helping community members stay healthy, informed, and connected during the pandemic. CTSA institutions have used various mechanisms to advance co-learning and co-sharing of knowledge, resources, tools, and experiences between academic professionals, patients, community partners, and other stakeholders. Forward-looking and adaptive decision-making structures are those that prioritize sustained relationships, mutual trust and commitment, ongoing communication, proactive identification of community concerns and needs, shared goals and decision making, as well as ample appreciation of community members and their contributions to translational research. There is a strong need for further community-engaged research and workforce training on how to build our collective and individual adaptive capacity to sustain and improve processes and outcomes of engagement with and by communities—in all aspects of translational science.
Artificial Intelligence Risks and Algorithmic Regulation
Authors: Fortes Pedro Rubim Borges , Baquero Pablo Marcello , Amariles David Restrepo
Published: June 2022

In this editorial article, we aim to map out the central features of algorithmic regulation and its conceptual basis – seeking to bring together different strands of the literature relating to the topic that have often remained apart. We then reflect on the ways through which algorithmic law could evolve to address the challenges of artificial intelligence in the legal domain, particularly by examining the potential of applying a “prudential” test in order to determine whether automated decision-making systems are suitable to adequately support legal decision-making.
Theoretical analysis of close-contact melting on superhydrophobic surfaces
Authors: Kozak Yoram
Published: June 2022

The present study deals with close-contact melting of a vertical cylinder on a horizontal isothermal superhydrophobic surface with an array of circular posts. A new numerical model for this phenomenon is formulated under several simplifying assumptions. For the limiting case of perfect slip and thermal contact, based on the model assumptions, it is demonstrated that superhydrophobic surfaces can enhance the melting time by no more than 30 %. Numerical solution of the new model reveals that the effect of superhydrophobic hydrodynamic slip can decrease the molten layer thickness. However, due to the dominant effect of thermal slip, the heat transfer rate can be decreased significantly, and the melting time can be roughly doubled. An approximate analytical model is developed for understanding the problem dynamics better. The analytical model predictions are compared extensively against the numerical model results. For sufficiently low surface volume fractions, the analytical model provides excellent estimations of the numerical model predictions. Dimensional analysis reveals that according to the analytical model, the ratio between the melting times for superhydrophobic and regular surfaces is governed by a single dimensionless group. Moreover, according to the analytical model, the melting time on a superhydrophobic surface is always longer than on a regular surface, which agrees qualitatively with the numerical model results. Based on this analysis, a dimensionless condition for the analytical model range of validity is formulated. Finally, a conservative criterion for the liquid–gas interface stability under a close-contact melting process is established.
Episodes of liberalization in autocracies: a new approach to quantitatively studying democratization
Authors: Wilson Matthew C. , Medzihorsky Juraj , Maerz Seraphine F. , Lindenfors Patrik , Edgell Amanda B. , Boese Vanessa A. , Lindberg Staffan I.
Published: June 2022

This paper introduces a new approach to the quantitative study of democratization. Building on the comparative case-study and large-N literature, it outlines an episode approach that identifies the discrete beginning of a period of political liberalization, traces its progression, and classifies episodes as successful versus different types of failing outcomes, thus avoiding potentially fallacious assumptions of unit homogeneity. We provide a description and analysis of all 383 liberalization episodes from 1900 to 2019, offering new insights on democratic “waves”. We also demonstrate the value of this approach by showing that while several established covariates are valuable for predicting the ultimate outcomes, none explain the onset of a period of liberalization.
Global biogeography of estuary-associated fishes
Authors: Harrison Trevor D. , Whitfield Alan K.
Published: June 2022

This study examines global zoogeographic patterns of estuary-associated fishes using meta-assemblages compiled at the marine ecoregion scale. The classification of biogeographic regions based on estuary-associated fish species is assessed in relation to marine and freshwater zoogeographic patterns. Historical (palaeobiogeographic) and contemporary environmental factors that contribute to the establishment and maintenance of these regions are also discussed. Global patterns in estuary-associated fish species richness demonstrated that tropical ecoregions are more diverse and richer in species than temperate ecoregions; the tropical Indo-Pacific and the tropical western Atlantic were two major centres of high global species richness. Multivariate analyses identified several ecoregion groupings that broadly corresponded with both freshwater and marine biogeographic regions. These groupings could also be related to global marine palaeobiogeographic processes such as the closure of the Tethys Sea linkage during the Cenozoic as well as contemporary factors such ocean currents, upwelling areas and climatic factors, particularly rainfall and runoff.
THE TECHNOLOGY OF PUBLIC SHAMING
Authors: Frye Harrison
Published: June 2022

This essay argues that online public shaming can be productively understood as a problem of technology. In particular, the technology of public shaming is ambiguous between two senses. On the one hand, public shaming depends on various technologies, such as social media posts or, more historically, pillories. These are the artifacts of shame. On the other hand, public shaming itself is a social technology. In particular, public shaming is a way for communities to promote cooperation. Ultimately, I claim there is a mismatch between the artifacts of shame and this important social technology of shame. Social media drifts toward disintegrative shame, which tends to corrode cooperation. This suggests that we must either realign the technology of public shame or reject shame as a legitimate option.
URBAN PLANNING AND URBAN VALUES: A JACOBSIAN ANALYSIS
Authors: Ikeda Sanford
Published: June 2022

The great urbanist Jane Jacobs details how urban planning impacts the social interactions and social networks responsible for the economic death or life of a city. How might urban planning impinge on the moral values that underlie that development? I draw on Jacobs’s work on the moral foundations of commercial society to identify two “urban values” (tolerance and innovation). I then examine how these values support the social networks and processes that facilitate urban-based innovation and how urban planning can strengthen or undermine those values. I use the examples of urban planning in the 15th Ward of Syracuse, New York and of city building in the private development of Cayalá in Guatemala City to illustrate these points.
Effectiveness of Usual-Care Cognitive Behavioral Therapy for Adolescents with School Absenteeism
Authors: Walter Daniel , Heindrichs Lena , Rademacher Christiane , Matthias Eva Katharina , Doepfner Manfred
Published: June 2022

Abstract. Objective: Highly-controlled, randomized controlled trials have provided considerable evidence for the efficacy of outpatient cognitive-behavioral therapy (CBT) for patients with school absenteeism and anxiety disorders. However, the effectiveness of outpatient CBT under routine-care conditions for youth with school absenteeism remains unproven. Methods: This observational study used file records to analyze the changes under routine CBT in a sample of n = 49 clinically referred adolescents aged 11 to 18 years with school absenteeism and mental disorders who were being treated in a university outpatient clinic. At the start and end of treatment, we assessed the severity of school absenteeism as well as mental health problems as rated by parents and by the adolescents themselves. Results: The analysis yielded a statistically highly significant decline in school absenteeism (large effect, Cohen’s r = 0.80) and in mental health problems (small-to-large effect, Cohen’s d = 0.33 to d = 0.82). However, a substantial proportion of the sample remained in the clinical range at the end of treatment. Conclusions: These findings suggest that CBT is effective for adolescents with school absenteeism when administered under routine-care conditions, though the results must be interpreted with caution because of the lack of a control condition.
A Numerical Investigation of the Effect of Wave‐Induced Mixing on Tropical Cyclones Using a Coupled Ocean‐Atmosphere‐Wave Model
Authors: Zhang Wenqing , Zhao Dongliang , Zhu Donglin , Li Jingkai , Guan Changlong , Sun Jian
Published: June 2022

Ocean surface waves play a significant role in regulating the sea surface temperature and mixed layer depth, which are essential for accurate prediction of tropical cyclone (TC) intensity. The effects of wave breaking and wave orbital motion induced mixing on the TC intensity and size are investigated using a coupled ocean‐atmosphere‐wave model for both idealized and real TC cases. The results show that both wave breaking and wave orbital motion lead to greater sea surface temperature cooling and mixed layer deepening, resulting in decreases in TC intensity and size owing to the reduction of air‐sea heat fluxes. Wave orbital motion has a slightly greater effect than wave breaking on the TC intensity and size when the mixed layer is shallow, whereas it has a much greater effect when the mixed layer is deep. In addition, including wave orbital motion induced mixing in models can effectively reduce the error in simulated TC size.
Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging
Authors: Jung Jeesun , McCartney Daniel L. , Wagner Josephin , Rosoff Daniel B. , Schwandt Melanie , Sun Hui , Wiers Corinde E. , de Carvalho Luana Martins , Volkow Nora D. , Walker Rosie M. , Campbell Archie , Porteous David J. , McIntosh Andrew M. , Marioni Riccardo E. , Horvath Steve , Evans Kathryn L. , Lohoff Falk W.
Published: June 2022

Chronic heavy alcohol consumption is associated with increased mortality and morbidity and often leads to premature aging; however, the mechanisms of alcohol-associated cellular aging are not well understood. In this study, we used DNA methylation derived telomere length (DNAmTL) as a novel approach to investigate the role of alcohol use on the aging process. DNAmTL was estimated by 140 cytosine phosphate guanines (CpG) sites in 372 individuals with alcohol use disorder (AUD) and 243 healthy controls (HC) and assessed using various endophenotypes and clinical biomarkers. Validation in an independent sample of DNAmTL on alcohol consumption was performed (N = 4219). Exploratory genome-wide association studies (GWAS) on DNAmTL were also performed to identify genetic variants contributing to DNAmTL shortening. Top GWAS findings were analyzed usingin-silicoexpression quantitative trait loci analyses and related to structural MRI hippocampus volumes of individuals with AUD. DNAmTL was 0.11-kilobases shorter per year in AUD compared to HC after adjustment for age, sex, race, and blood cell composition (p = 4.0 × 10−12). This association was partially attenuated but remained significant after additionally adjusting for BMI, and smoking status (0.06 kilobases shorter per year,p = 0.002). DNAmTL shortening was strongly associated with chronic heavy alcohol use (ps < 0.001), elevated gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) (ps < 0.004). Comparison of DNAmTL with PCR-based methods of assessing TL revealed positive correlations (R = 0.3,p = 2.2 × 10−5), highlighting the accuracy of DNAmTL as a biomarker. The GWAS meta-analysis identified a single nucleotide polymorphism (SNP), rs4374022 and 18 imputed ones in Thymocyte Expressed, Positive Selection Associated 1(TESPA1), at the genome-wide level (p = 3.75 × 10−8). The allele C of rs4374022 was associated with DNAmTL shortening, lower hippocampus volume (p < 0.01), and decreased mRNA expression in hippocampus tissue (p = 0.04). Our study demonstrates DNAmTL-related aging acceleration in AUD and suggests a functional role forTESPA1in regulating DNAmTL length, possibly via the immune system with subsequent biological effects on brain regions negatively affected by alcohol and implicated in aging.
Signal pathways and precision therapy of small-cell lung cancer
Authors: Yuan Min , Zhao Yu , Arkenau Hendrik-Tobias , Lao Tongnei , Chu Li , Xu Qing
Published: June 2022

Small-cell lung cancer (SCLC) encounters up 15% of all lung cancers, and is characterized by a high rate of proliferation, a tendency for early metastasis and generally poor prognosis. Most of the patients present with distant metastatic disease at the time of clinical diagnosis, and only one-third are eligible for potentially curative treatment. Recently, investigations into the genomic make-up of SCLC show extensive chromosomal rearrangements, high mutational burden and loss-of-function mutations of several tumor suppressor genes. Although the clinical development of new treatments for SCLC has been limited in recent years, a better understanding of oncogenic driver alterations has found potential novel targets that might be suitable for therapeutic approaches. Currently, there are six types of potential treatable signaling pathways in SCLC, including signaling pathways targeting the cell cycle and DNA repair, tumor development, cell metabolism, epigenetic regulation, tumor immunity and angiogenesis. At this point, however, there is still a lack of understanding of their role in SCLC tumor biology and the promotion of cancer growth. Importantly optimizing drug targets, improving drug pharmacology, and identifying potential biomarkers are the main focus and further efforts are required to recognize patients who benefit most from novel therapies in development. This review will focus on the current learning on the signaling pathways, the status of immunotherapy, and targeted therapy in SCLC.
Australian arm of the International Spinal Cord Injury (Aus-InSCI) Community Survey: 2. Understanding the lived experience in people with spinal cord injury
Authors: Middleton James W. , Arora Mohit , Kifley Annette , Clark Jillian , Borg Samantha J. , Tran Yvonne , Atresh Sridhar , Kaur Jasbeer , Shetty Sachin , Nunn Andrew , Marshall Ruth , Geraghty Timothy
Published: June 2022

Study design

Cross-sectional survey.

Objectives

To identify common problems across key domains of functioning, health and wellbeing, as well as evaluate self-reported quality of life (QoL) by people with SCI, examining differences by age, gender, injury characteristics and level of mobility.

Setting

Data from four state-wide SCI clinical services, one government insurance agency and three not-for-profit consumer organisations.

Methods

Participants were 18 years or over with SCI and at least 12 months post-injury, recruited between Mar’18 and Jan’19. The Aus-InSCI questionnaire comprised 193 questions, including socio-demographics, SCI characteristics, body functions and structures, activities and participation, environmental and personal factors, and appraisal of health and well-being. General linear model was used to examine differences in functioning and QoL.

Results

Participants (mean age 57 years, range 19–94 years) with tetraplegia and/or complete injuries had more health problems, activity/participation problems and environmental barriers. However, self-rated overall QoL did not differ for injury level or completeness. Participants with more recent injuries exhibited lower independence levels, more mental health problems and poorer satisfaction with self and their living conditions. Major activity/participation problems related to intimate relationships and accessing public transportation. Less than half of the working age population were engaged in paid work. The top two environmental barriers frequently related to accessing public places or homes and unfavourable climatic conditions.

Conclusions

This large, comprehensive community survey draws a detailed picture of the lived experience of people with SCI in Australia, identifying priority needs, gaps in services and barriers to achieving a full and satisfying life.
Ethical, legal and social/societal implications (ELSI) of recall-by-genotype (RbG) and genotype-driven-research (GDR) approaches: a scoping review
Authors: Tschigg Katharina , Consoli Luca , Biasiotto Roberta , Mascalzoni Deborah
Published: June 2022

Recall by Genotype (RbG), Genotype-driven-recall (GDR), and Genotype-based-recall (GBR) strategies are increasingly used to conduct genomic or biobanking sub-studies that single out participants as eligible because of their specific individual genotypic information. However, existing regulatory and governance frameworks do not apply to all aspects of genotype-driven research approaches. The recall strategies disclose or withhold personal genotypic information with uncertain clinical utility. Accordingly, this scoping review aims to identify peculiar, explicit and implicit ethical, legal, and societal/social implications (ELSI) of RbG study designs. We conducted a systematic literature search of three electronic databases from November 2020 to February 2021. We investigated qualitative and quantitative research methods used to report ELSI aspects in RbG research. Congruent with other research findings, we identified a lack of qualitative research investigating the particular ELSI challenges with RbG. We included and analysed the content of twenty-five publications. We found a consensus on RbG posing significant ethical issues, dilemmas, barriers, concerns and societal challenges. However, we found that the approaches to disclosure and study-specific recall and communication strategies employed consent models and Return of Research Results (RoRR) policies varied considerably. Furthermore, we identified a high heterogeneity in perspectives of participants and experts about ELSI of study-specific RbG policies. Therefore, further fine-mapping through qualitative and empirical research is needed to draw conclusions and re-fine ELSI frameworks.
Signatures of copy number alterations in human cancer
Authors: Steele Christopher D. , Abbasi Ammal , Islam S. M. Ashiqul , Bowes Amy L. , Khandekar Azhar , Haase Kerstin , Hames-Fathi Shadi , Ajayi Dolapo , Verfaillie Annelien , Dhami Pawan , McLatchie Alex , Lechner Matt , Light Nicholas , Shlien Adam , Malkin David , Feber Andrew , Proszek Paula , Lesluyes Tom , Mertens Fredrik , Flanagan Adrienne M. , Tarabichi Maxime , Van Loo Peter , Alexandrov Ludmil B. , Pillay Nischalan
Published: June 2022

Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage–fusion–bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3–5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.
Measurement of the bound-electron g-factor difference in coupled ions
Authors: Sailer Tim , Debierre Vincent , Harman Zoltán , Heiße Fabian , König Charlotte , Morgner Jonathan , Tu Bingsheng , Volotka Andrey V. , Keitel Christoph H. , Blaum Klaus , Sturm Sven
Published: June 2022

Quantum electrodynamics (QED) is one of the most fundamental theories of physics and has been shown to be in excellent agreement with experimental results1–5. In particular, measurements of the electron’s magnetic moment (or g factor) of highly charged ions in Penning traps provide a stringent probe for QED, which allows testing of the standard model in the strongest electromagnetic fields6. When studying the differences between isotopes, many common QED contributions cancel owing to the identical electron configuration, making it possible to resolve the intricate effects stemming from the nuclear differences. Experimentally, however, this quickly becomes limited, particularly by the precision of the ion masses or the magnetic field stability7. Here we report on a measurement technique that overcomes these limitations by co-trapping two highly charged ions and measuring the difference in their g factors directly. We apply a dual Ramsey-type measurement scheme with the ions locked on a common magnetron orbit8, separated by only a few hundred micrometres, to coherently extract the spin precession frequency difference. We have measured the isotopic shift of the bound-electron g factor of the isotopes 20Ne9+ and 22Ne9+ to 0.56-parts-per-trillion (5.6 × 10−13) precision relative to their g factors, an improvement of about two orders of magnitude compared with state-of-the-art techniques7. This resolves the QED contribution to the nuclear recoil, accurately validates the corresponding theory and offers an alternative approach to set constraints on new physics.
Mechanism of replication origin melting nucleated by CMG helicase assembly
Authors: Lewis Jacob S. , Gross Marta H. , Sousa Joana , Henrikus Sarah S. , Greiwe Julia F. , Nans Andrea , Diffley John F. X. , Costa Alessandro
Published: June 2022

The activation of eukaryotic origins of replication occurs in temporally separated steps to ensure that chromosomes are copied only once per cell cycle. First, the MCM helicase is loaded onto duplex DNA as an inactive double hexamer. Activation occurs after the recruitment of a set of firing factors that assemble two Cdc45–MCM–GINS (CMG) holo-helicases. CMG formation leads to the underwinding of DNA on the path to the establishment of the replication fork, but whether DNA becomes melted at this stage is unknown1. Here we use cryo-electron microscopy to image ATP-dependent CMG assembly on a chromatinized origin, reconstituted in vitro with purified yeast proteins. We find that CMG formation disrupts the double hexamer interface and thereby exposes duplex DNA in between the two CMGs. The two helicases remain tethered, which gives rise to a splayed dimer, with implications for origin activation and replisome integrity. Inside each MCM ring, the double helix becomes untwisted and base pairing is broken. This comes as the result of ATP-triggered conformational changes in MCM that involve DNA stretching and protein-mediated stabilization of three orphan bases. Mcm2 pore-loop residues that engage DNA in our structure are dispensable for double hexamer loading and CMG formation, but are essential to untwist the DNA and promote replication. Our results explain how ATP binding nucleates origin DNA melting by the CMG and maintains replisome stability at initiation.
Peptidoglycan maturation controls outer membrane protein assembly
Authors: Mamou Gideon , Corona Federico , Cohen-Khait Ruth , Housden Nicholas G. , Yeung Vivian , Sun Dawei , Sridhar Pooja , Pazos Manuel , Knowles Timothy J. , Kleanthous Colin , Vollmer Waldemar
Published: June 2022

Linkages between the outer membrane of Gram-negative bacteria and the peptidoglycan layer are crucial for the maintenance of cellular integrity and enable survival in challenging environments1–5. The function of the outer membrane is dependent on outer membrane proteins (OMPs), which are inserted into the membrane by the β-barrel assembly machine6,7 (BAM). Growing Escherichia coli cells segregate old OMPs towards the poles by a process known as binary partitioning, the basis of which is unknown8. Here we demonstrate that peptidoglycan underpins the spatiotemporal organization of OMPs. Mature, tetrapeptide-rich peptidoglycan binds to BAM components and suppresses OMP foldase activity. Nascent peptidoglycan, which is enriched in pentapeptides and concentrated at septa9, associates with BAM poorly and has little effect on its activity, leading to preferential insertion of OMPs at division sites. The synchronization of OMP biogenesis with cell wall growth results in the binary partitioning of OMPs as cells divide. Our study reveals that Gram-negative bacteria coordinate the assembly of two major cell envelope layers by rendering OMP biogenesis responsive to peptidoglycan maturation, a potential vulnerability that could be exploited in future antibiotic design.
Label-free prediction of cell painting from brightfield images
Authors: Cross-Zamirski Jan Oscar , Mouchet Elizabeth , Williams Guy , Schönlieb Carola-Bibiane , Turkki Riku , Wang Yinhai
Published: June 2022

Cell Painting is a high-content image-based assay applied in drug discovery to predict bioactivity, assess toxicity and understand mechanisms of action of chemical and genetic perturbations. We investigate label-free Cell Painting by predicting the five fluorescent Cell Painting channels from brightfield input. We train and validate two deep learning models with a dataset representing 17 batches, and we evaluate on batches treated with compounds from a phenotypic set. The mean Pearson correlation coefficient of the predicted images across all channels is 0.84. Without incorporating features into the model training, we achieved a mean correlation of 0.45 with ground truth features extracted using a segmentation-based feature extraction pipeline. Additionally, we identified 30 features which correlated greater than 0.8 to the ground truth. Toxicity analysis on the label-free Cell Painting resulted a sensitivity of 62.5% and specificity of 99.3% on images from unseen batches. We provide a breakdown of the feature profiles by channel and feature type to understand the potential and limitations of label-free morphological profiling. We demonstrate that label-free Cell Painting has the potential to be used for downstream analyses and could allow for repurposing imaging channels for other non-generic fluorescent stains of more targeted biological interest.