bluuebunny/crossref_metadata_2025 huggingface dataset:
Image Processing Robustness Assessment of Small-Body Shapes
Authors: Buonagura Carmine , Pugliatti Mattia , Topputo Francesco
Published: November 2022

Asteroids and comets are triggering interest due to the richness of precious materials, their scientific value as well as for their potential hazardousness. Owing to their significant diversity, minor bodies do not exhibit uniform shapes: they can range from spherical to irregularly shaped objects with rocky, uneven, and cratered surface. Nowadays, space probes rely more and more on optical navigation techniques, due to the increasing demand for autonomy. When dealing with minor bodies, the diversified range of shapes can significantly affect the performance of these techniques. In order to enable deep space probes to confidently deal with uncertainties, the need for robust image processing methods arises. Commonly, few image processing methods are designed and tested with limited shapes to meet mission requirements. In this work, we depart from this paradigm by developing a new framework, which includes extensive testing of the image processing algorithms with various shapes. The shapes are not randomly analyzed, yet they are arranged in a hierarchical structure called hyper-cube. The cube allows for a better understanding of the methods performance and to infer the way they shift from one shape to the other. The novelty of this approach lies both in the cube representation, which allows a better understanding of the link between the image processing algorithms and shape of the object, but also in the extensive number of shapes that have been tested, which has never been done before. In this analysis, four methods are considered, namely: center of brightness, intensity weighted centroiding, correlation with Lambertian spheres, and least-squares-based ellipse fitting. Results from this test allow us correlating the methods performances to the bodies shape, to suggest the best performing method for each shape family, and to assess their robustness.
Urinary epidermal growth factor/monocyte chemotactic peptide 1 ratio as non-invasive predictor of Mayo clinic imaging classes in autosomal dominant polycystic kidney disease
Authors: Rocchetti Maria Teresa , Pesce Francesco , Matino Silvia , Piscopo Giovanni , di Bari Ighli , Trepiccione Francesco , Capolongo Giovanna , Perniola Maria Antonietta , Song Xuewen , Khowaja Saima , Haghighi Amirreza , Peters Dorien , Paolicelli Simona , Pontrelli Paola , Netti Giuseppe Stefano , Ranieri Elena , Capasso Giovambattista , Moschetta Marco , Pei York , Gesualdo Loreto ,   (Studio PRE. MED. (MEDicina di PREcisione) Prog.n.F/050065/01-02/X32)
Published: November 2022

Background

Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes.

Methods

Urinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery, n = 74 and validation set, n = 177) and healthy controls (n = 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A–1B) and fast progressors (1C–1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression.

Results

Baseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r = − 0.6, p < 0.001), estimated glomerular filtration rate (r = 0.69 p < 0.001), discriminated between Mayo Clinic Imaging Classes (p < 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r = − 0.51, p < 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p = 6.51E−16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p = 0.006, r = 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 ± 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: − 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) and Pkd1 knock-out mouse kidney (Egf: − 14.8-fold, fdr = 2.37E-20, Mcp1: 2.8-fold, fdr = 6.82E−15).

Conclusion

The ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease.
Negative calcium balance despite normal plasma ionized calcium concentrations during citrate anticoagulated continuous venovenous hemofiltration (CVVH) in ICU patients
Authors: de Jonge Evert , van der Vooren Marije , Gillis Judith M. E. P. , del Prado Michael R. , Wigbers Jeanette , Bakhshi-Raiez Ferishta , Elzo Kraemer Carlos V.
Published: November 2022

Background

Supplementation of calcium during continuous venovenous hemofiltration (CVVH) with citrate anticoagulation is usually titrated using a target blood ionized calcium concentration. Plasma calcium concentrations may be normal despite substantial calcium loss, by mobilization of calcium from the skeleton. Aim of our study is to develop an equation to calculate CVVH calcium and to retrospectively calculate CVVH calcium balance in a cohort of ICU-patients.

Methods

This is a single-center retrospective observational cohort study. In a subcohort of patients, all calcium excretion measurements in patients treated with citrate CVVH were randomly divided into a development set (n = 324 in 42 patients) and a validation set (n = 441 in 42 different patients). Using mixed linear models, we developed an equation to calculate calcium excretion from routinely available parameters. We retrospectively calculated calcium balance in 788 patients treated with citrate CVVH between 2014 and 2021.

Results

Calcium excretion (mmol/24 h) was − 1.2877 + 0.646*[Ca]blood,total * ultrafiltrate (l/24 h) + 0.107*blood flow (ml/h). The mean error of the estimation was − 1.0 ± 6.7 mmol/24 h, the mean absolute error was 4.8 ± 4.8 mmol/24 h. Calculated calcium excretion was 105.8 ± 19.3 mmol/24 h. Mean daily CVVH calcium balance was − 12.0 ± 20.0 mmol/24 h. Mean cumulative calcium balance ranged from − 3687 to 448 mmol.

Conclusion

During citrate CVVH, calcium balance was negative in most patients, despite supplementation of calcium based on plasma ionized calcium levels. This may contribute to demineralization of the skeleton. We propose that calcium supplementation should be based on both plasma ionized calcium and a simple calculation of calcium excretion by CVVH.

Graphical abstract
Defect Passivation on Lead-Free CsSnI3 Perovskite Nanowires Enables High-Performance Photodetectors with Ultra-High Stability
Authors: Gao Zheng , Zhou Hai , Dong Kailian , Wang Chen , Wei Jiayun , Li Zhe , Li Jiashuai , Liu Yongjie , Zhao Jiang , Fang Guojia
Published: November 2022

In recent years, Pb-free CsSnI3 perovskite materials with excellent photoelectric properties as well as low toxicity are attracting much attention in photoelectric devices. However, deep level defects in CsSnI3, such as high density of tin vacancies, structural deformation of SnI6− octahedra and oxidation of Sn2+ states, are the major challenge to achieve high-performance CsSnI3-based photoelectric devices with good stability. In this work, defect passivation method is adopted to solve the above issues, and the ultra-stable and high-performance CsSnI3 nanowires (NWs) photodetectors (PDs) are fabricated via incorporating 1-butyl-2,3-dimethylimidazolium chloride salt (BMIMCl) into perovskites. Through materials analysis and theoretical calculations, BMIM+ ions can effectively passivate the Sn-related defects and reduce the dark current of CsSnI3 NW PDs. To further reduce the dark current of the devices, the polymethyl methacrylate is introduced, and finally, the dual passivated CsSnI3 NWPDs show ultra-high performance with an ultra-low dark current of 2 × 10–11 A, a responsivity of up to 0.237 A W−1, a high detectivity of 1.18 × 1012 Jones and a linear dynamic range of 180 dB. Furthermore, the unpackaged devices exhibit ultra-high stability in device performance after 60 days of storage in air (25 °C, 50% humidity), with the device performance remaining above 90%.
Identification and analysis of long-term changes in river deltas and riparian zones using time-series multispectral data
Authors: Kontopoulos Christos , Kitsiou Dimitra , Chlorokostas Stavros , Charalampopoulou Betty , Grammalidis Nikos , Tzepkenlis Anastasios
Published: November 2022

Today’s remote sensing data and technologies offer the capability to effectively monitor diverse and challenging environments around the world, such as coastal river and riparian zones. Coastal riparian zones and river deltas usually demonstrate extreme coastline changes in terms of the extent of water coverage of inland territories due to flood events, low and high tides, the climate, specific environmental characteristics, etc. In this paper, we exploit freely available multispectral time series data for previous decades, utilizing Landsat missions in order to develop an open-source-based image processing pipeline for the extraction of the actual yearly average coastline status of riparian river delta areas. The latter present significant temporal coastline changes between years, semesters, and months. Average mean maps are generated and then compared to several temporal levels in order to distinguish long-term significant changes and ecosystem threats. Additionally, a custom long short-term memory (LSTM) neural network is deployed to forecast the evolution of the coastline by exploiting the average value for each pixel across all available images as a training sample and producing a forecast output for the next period. The network achieves accuracy scores of 89.77% over 'non-water' depicting pixels and 84.26% over 'water' depicting pixels, for regions that present frequent changes between land and water coverage over time. The predicted map presents high statistical agreement with the respective average map generated in two different validation approaches, with kappa coefficients of 85.9% and 91.4%, respectively.
Öffentliches Sprechen über Suizide zwischen Eindeutigkeit und Uneindeutigkeit
Authors: Stein Stephan
Published: November 2022

Das Thema »Sterben und Tod« gilt als Bereich gesellschaftlicher Tabuisierung par excellence. Mehr noch scheint das für den Umgang mit Suiziden zu gelten. Naheliegend und erwartbar ist beim Sprechen über Suizide eine Ausdruckstypik, die durch Formen des Verbergens und Verhüllens geprägt ist. Der Beitrag geht am Beispiel verschiedener Textsorten der Frage nach, wie aus der jeweiligen Perspektive – Berichterstattung in den Medien, Todes- und Traueranzeigen von Hinterbliebenen, Gedenk‑/Kondolenztexte von Anteilnahme Bekundenden, Abschiedsbriefe von Suizidenten – mit dem Thema »Suizid« umgegangen wird, um das Spannungsverhältnis zwischen Offenlegen und Verbergen zu verdeutlichen.
Beliefs and perceptions of patient safety event reporting in a Canadian Emergency Department: a qualitative study
Authors: Skutezky Trevor , Small Serena S. , Peddie David , Balka Ellen , Hohl Corinne M.
Published: November 2022

Objectives

Patient safety events (PSEs) are unwanted or unexpected events that occur during medical care. High cognitive loads and frequent interruptions make emergency departments (EDs) uniquely error prone environments. Yet, frontline clinicians rarely report PSEs using incident reporting systems. The incidence, severity, and preventability of PSEs thus remain poorly understood, and contributing factors are understudied. We sought to understand ED staff beliefs and perceptions about their PSE reporting system and what features they believe are important in such a system.

Methods

We conducted a qualitative study among healthcare providers working in the ED and departmental leadership. We recruited participants via email and held a series of interviews, focus groups, and participatory workshops. We iteratively analyzed the data using the constant comparative method and used thematic analysis to establish themes.

Results

50 participants attended at least one focus group, interview, or workshop. Participants perceived that PSE reporting through formal channels in the ED was challenging. Clinicians had an inherent desire to report PSEs and do so through numerous informal channels, yet underreported in formal reporting systems. The current PSE reporting system did not meet frontline staff needs and was viewed as ineffective in improving care quality and safety. We identified three key features for an improved PSE reporting system: (1) clear definitions; (2) transparency; and (3) simplicity.

Conclusions

In this study, we have identified ideal features for PSE reporting processes to meet the needs of both frontline staff and departmental leadership based on perceptions of current PSE reporting practices. Improved PSE reporting processes have the potential to increase PSE reporting in the ED overall, increasing the availability of information about PSEs to support quality improvement and improve patient safety.
A new control problem? Humanoid robots, artificial intelligence, and the value of control
Authors: Nyholm Sven
Published: November 2022

The control problem related to robots and AI usually discussed is that we might lose control over advanced technologies. When authors like Nick Bostrom and Stuart Russell discuss this control problem, they write in a way that suggests that having as much control as possible is good while losing control is bad. In life in general, however, not all forms of control are unambiguously positive and unproblematic. Some forms—e.g. control over other persons—are ethically problematic. Other forms of control are positive, and perhaps even intrinsically good. For example, one form of control that many philosophers have argued is intrinsically good and a virtue is self-control. In this paper, I relate these questions about control and its value to different forms of robots and AI more generally. I argue that the more robots are made to resemble human beings, the more problematic it becomes—at least symbolically speaking—to want to exercise full control over these robots. After all, it is unethical for one human being to want to fully control another human being. Accordingly, it might be seen as problematic—viz. as representing something intrinsically bad—to want to create humanoid robots that we exercise complete control over. In contrast, if there are forms of AI such that control over them can be seen as a form of self-control, then this might be seen as a virtuous form of control. The “new control problem”, as I call it, is the question of under what circumstances retaining and exercising complete control over robots and AI is unambiguously ethically good.
Experiences of clinical teaching-learning among medical and nursing graduates during internship and their supervisors in Tanzania
Authors: Mselle Lilian Teddy , Tarimo Edith A. M. , Mloka Doreen , Mkoka Dickson Ally , Dika Haruna , Laisser Rose Mjawa , Sirili Nathanael , Martin-Holland Judy
Published: November 2022

Background

Health professions training in Tanzania has gradually adopted the competency-based curricula (CBC) approach that focuses on learners’ acquisition of competencies in knowledge skills and aptitude. Feedback from the graduates is crucial for improving CBC implementation and review to ensure that graduates acquire clinical competencies and thus improve patient care.

Objectives

To explore the teaching–learning experiences of medical and nursing graduates during their internship and their supervisors in three teaching hospitals.

Methods

Exploratory qualitative data from in-depth interviews and focus group discussions were analysed using a content analysis framework. Medical and nursing graduates who were in an internship program in three teaching hospitals in Tanzania were conveniently recruited based on their availability during the data collection period.

Results

The use of clinical logbooks, guidelines and protocols, bedside teaching, mentorship, and supervision were important for the acquisition of clinical competencies. Graduates demonstrated inadequate clinical competency including confidence, commitment, and professionalism because of a lack of clear clinical guidelines and protocols, inadequate bedside teaching including supervision by faculty and ineffective communication and feedback.

Conclusions

Clinical teaching–learning tools and approaches facilitate students’ acquisition of clinical competencies. However, inadequate use of guidelines and protocols, bedside teaching, clinical supervision and effective communication was observed. Use of these clinical teaching approaches should be emphasized for students’ clinical competency acquisition.
Privacy, the Housing Research Unit at the University of Edinburgh and the Courtyard House, 1959–70
Authors: Fair Alistair
Published: November 2022

With a focus on post-war Britain (and Scotland in particular), this article contributes to the literature on the history of ’community’ by examining its apparent inverse, namely privacy. In particular, it explores the interest that emerged in 1960s Britain in a type of housing that was considered to provide enhanced privacy for residents — the courtyard house. The article begins by looking at the ways in which privacy was considered in official documentation on homes and housing in the post-war period in both England and Wales, and Scotland. It then turns to the work of the University of Edinburgh’s Housing Research Unit in the 1960s, which included not just the design and construction of housing schemes, but also social investigation of the built results. The article examines the ’urban’ housing designed in Cumbernauld and the ’rural’ counterpart in Prestonpans, both of which were intended to provide enhanced privacy for residents. It then looks at the unit’s evaluation of the completed courtyard housing built at Prestonpans as well as another survey undertaken in Dundee, both of which explored the residents’ experience of privacy. Overall, the article argues that the idea of privacy, as understood by designers and experienced by residents, played an important role in post-war housing, as part of the ambition not just to improve standards, but also to provide new choices.
The First Draft of Serlio’s Sixth Book and its Arrival in Britain, c. 1700
Authors: Campbell Ian
Published: November 2022

This article explores the provenance of the first draft of Sebastiano Serlio’s sixth book, on dwellings, written in the 1540s. It was acquired by the Avery Library at Columbia University, New York, a century ago and published for the first time in 1978. The article proposes that the manuscript and drawings remained in the vicinity of Paris until the late seventeenth century, when they were mounted and bound into an album that may have been sold by a descendant of Jacques Androuet du Cerceau I, either in Paris or the Netherlands. It goes on to demonstrate that, in the early eighteenth century, the manuscript was owned by Francis Bird, a leading British sculptor of his day, who collaborated with leading architects including Christopher Wren, James Gibbs and, possibly, Nicholas Hawksmoor.
French Sinology
Authors: Will Pierre-Étienne
Published: November 2022

The history of French Sinology—that is, of scholarly research on things Chinese by French-speaking authors working from Chinese sources—goes back to the seventeenth century and can be divided into several periods determined in large part by sociopolitical factors, and marked by different approaches and emphases: I propose to describe them as the missionary age (seventeenth–eighteenth centuries); the first academic efflorescence (nineteenth century); the advent of field research and the impact of colonialism and the social sciences (first half of twentieth century); and the postwar era of specialization and internationalization (second half of twentieth century), which marked the end of a certain French domination of Chinese studies in the West.1
The Perpetuity of the Past: Transmission of Political Inequality across Multiple Generations
Authors: LINDGREN KARL-OSKAR , OSKARSSON SVEN
Published: November 2022

It is a well-established fact, from decades of research on political socialization, that the children of politically active parents are more likely to become politically active themselves. This poses a challenge for democracy, as it means that inequalities in political influence are reproduced across generations. The present study argues that this problem may be more severe than has hitherto been acknowledged. The reason for this is that previous research on the topic has focused almost exclusively on political transmission between parents and their children, whereas the role played by more distant forebears, such as grandparents, has been largely neglected. In this study, we use Swedish register data to analyze multigenerational associations in electoral participation. The empirical results clearly indicate that the traditional two-generation approach to the study of political transmission tends to underestimate intergenerational persistence in voting behavior and that this excess persistence has both genetic and social roots.
DISCERNING THE FORM AT THE SECOND STAGE OF VICARIOUS LIABILITY
Authors: Beuermann Christine
Published: November 2022

This article uses Atiyah and Summer's categorisation of the attributes of formal legal reasoning in Form and Substance in Anglo-American Law to examine the type of legal reasoning process used by the courts in England and Wales when determining the second stage of vicarious liability. The analysis shows that, although remaining formal in nature, the shift away from the Salmond test has resulted in a shift in the type of form used by the courts. It is suggested that future guidance issued by the Supreme Court to lower courts when determining the second stage of vicarious liability needs to take account of this change for the guidance to be effective.
Developing teacher curriculum design expertise: using the CDC Model in the music classroom
Authors: McPhail Graham , Tibbles Sally , Cornish Mary
Published: November 2022

The purpose of this paper is to discuss the impact of the Curriculum Design Coherence Model (CDC Model – Rata, 2019) on the design practice of two music teachers in a middle school music class in New Zealand. The CDC Model proposes that deep learning first requires deep design coherence. This coherence is generated by three interrelated design dimensions: (i) the ‘surfacing’ of epistemic structure, (ii) the use of subject concepts and (iii) the interrelationship between ‘knowledge-that’ (knowledge of something) and ‘know-how-to’ (knowing how to do something with that knowledge of something). We discuss how the model has been put to use in the design of a song writing unit of work for students aged 10–12 years in a general music class and note the impact of the model on the developing design expertise of the two music teachers involved in a wider research project.
AN AVERAGING ESTIMATOR FOR TWO-STEP M-ESTIMATION IN SEMIPARAMETRIC MODELS
Authors: Shi Ruoyao
Published: November 2022

In a two-step extremum estimation (M-estimation) framework with a finite-dimensional parameter of interest and a potentially infinite-dimensional first-step nuisance parameter, this paper proposes an averaging estimator that combines a semiparametric estimator based on a nonparametric first step and a parametric estimator which imposes parametric restrictions on the first step. The averaging weight is an easy-to-compute sample analog of an infeasible optimal weight that minimizes the asymptotic quadratic risk. Under Stein-type conditions, the asymptotic lower bound of the truncated quadratic risk difference between the averaging estimator and the semiparametric estimator is strictly less than zero for a class of data generating processes that includes both correct specification and varied degrees of misspecification of the parametric restrictions, and the asymptotic upper bound is weakly less than zero. The averaging estimator, along with an easy-to-implement inference method, is demonstrated in an example.
Observational Evidence of Increasing Compound Tropical Cyclone‐Moist Heat Extremes in India
Authors: Rajeev Akshay , Mishra Vimal
Published: November 2022

Moist heat stress can lead to the inability of the human body to cool itself due to the impact of high temperature and humidity. The co‐occurrence of tropical cyclones (TCs) and moist heat stress has considerable implications for India's dense population and infrastructure. However, the crucial linkage between TCs and moist heat extremes remains unrecognized. We used the cyclone eAtlas and ERA5 reanalysis to examine the temporally compounding TC and moist heat extremes over India from 1980 to 2021. We find that TC‐Heat stress events in India have increased recently, which can be attributed to the high‐intensity TCs originating from the Arabian Sea. The risk of TC‐Heat stress events is higher (than in other parts of the world) in India due to an overlap of peak moist heat and TCs occurrence during the pre‐monsoon (April–June) season. Landfalling TCs alter the thermodynamic environment causing the moist heat to peak over the region with increased frequency and intensity. The direct and compounded influence of TCs on moist heat can have substantial implications.
Particulate Trace Metal Sources, Cycling, and Distributions on the Southwest African Shelf
Authors: Al‐Hashem Ali A. , Beck Aaron J. , Krisch Stephan , Menzel Barraqueta Jan‐Lukas , Steffens Tim , Achterberg Eric P.
Published: November 2022

We present labile (L‐pTM) and refractory (R‐pTM) particulate trace metal distributions of Fe, Mn, Al, Ti, Co, Zn, Cd, Ni, Pb, Cu, and P for a transect along the southwest African shelf and an off‐shore section at 3°S of the GEOTRACES GA08 section cruise. Particle sources and biogeochemical cycling processes are inferred using particle‐type proxies and elemental ratios. Enhanced concentrations of bio‐essential L‐pTMs (Zn, Cu, Ni, Cd, Co, and P) were observed in the Benguela upwelling region, attributed to enhanced primary production. Bio‐essential pTM stoichiometric ratios (normalized to pP) were consistent with phytoplankton biomass across the transect, except for Fe and Mn, which included adsorbed and labile oxide phases. Low pP lability (∼41%) suggests a potential refractory biogenic source on the Benguela shelf. Variable labilities observed between stations along the transect indicated potentially different biogenic pP labilities among different plankton groups. Benthic resuspension was prevalent in (near‐)bottom waters along the transect and formed an important source of Fe and Mn oxides. Lithogenic particles along the entire shelf were Mn deficient and particles on the Benguela shelf were enriched in Fe, consistent with regional sediment compositions. Enhanced available‐Fe (dissolved + labile particulate Fe) concentrations (up to 39.6 nM) were observed in oxygen‐deficient (near‐)bottom waters of the Benguela shelf coinciding with low L‐pMn. This was attributed to the faster oxidation kinetics of Fe, allowing Fe‐oxide precipitation and retention on the shelf, while Mn oxidation was slower. Enhanced L‐pFe in the Congo River plume, which comprised as much as 93% of the available‐Fe pool, was attributed to increased scavenging and formation of Fe oxides. Increased scavenging of other particle‐reactive trace metals (TMs) (Mn, Al, and Pb) was also apparent in Congo‐influenced waters. However, particles did not play a significant role in transporting TMs off‐shelf within Congo plume waters.
Identification of a novel GR-ARID1a-P53BP1 protein complex involved in DNA damage repair and cell cycle regulation
Authors: Stubbs Felicity E. , Flynn Benjamin P. , Rivers Caroline A. , Birnie Matthew T. , Herman Andrew , Swinstead Erin E. , Baek Songjoon , Fang Hai , Temple Jillian , Carroll Jason S. , Hager Gordon L. , Lightman Stafford L. , Conway-Campbell Becky L.
Published: November 2022

ARID1a (BAF250), a component of human SWI/SNF chromatin remodeling complexes, is frequently mutated across numerous cancers, and its loss of function has been putatively linked to glucocorticoid resistance. Here, we interrogate the impact of siRNA knockdown of ARID1a compared to a functional interference approach in the HeLa human cervical cancer cell line. We report that ARID1a knockdown resulted in a significant global decrease in chromatin accessibility in ATAC-Seq analysis, as well as affecting a subset of genome-wide GR binding sites determined by analyzing GR ChIP-Seq data. Interestingly, the specific effects on gene expression were limited to a relatively small subset of glucocorticoid-regulated genes, notably those involved in cell cycle regulation and DNA repair. The vast majority of glucocorticoid-regulated genes were largely unaffected by ARID1a knockdown or functional interference, consistent with a more specific role for ARID1a in glucocorticoid function than previously speculated. Using liquid chromatography-mass spectrometry, we have identified a chromatin-associated protein complex comprising GR, ARID1a, and several DNA damage repair proteins including P53 binding protein 1 (P53BP1), Poly(ADP-Ribose) Polymerase 1 (PARP1), DNA damage-binding protein 1 (DDB1), DNA mismatch repair protein MSH6 and splicing factor proline and glutamine-rich protein (SFPQ), as well as the histone acetyltransferase KAT7, an epigenetic regulator of steroid-dependent transcription, DNA damage repair and cell cycle regulation. Not only was this protein complex ablated with both ARID1a knockdown and functional interference, but spontaneously arising DNA damage was also found to accumulate in a manner consistent with impaired DNA damage repair mechanisms. Recovery from dexamethasone-dependent cell cycle arrest was also significantly impaired. Taken together, our data demonstrate that although glucocorticoids can still promote cell cycle arrest in the absence of ARID1a, the purpose of this arrest to allow time for DNA damage repair is hindered.
Higher blood pressure in adolescent boys after very preterm birth and fetal growth restriction
Authors: Liefke Jonas , Steding-Ehrenborg Katarina , Sjöberg Pia , Ryd Daniel , Morsing Eva , Arheden Håkan , Ley David , Hedström Erik
Published: November 2022

Background

Although preterm birth predisposes for cardiovascular disease, recent studies in children indicate normal blood pressure and arterial stiffness. This prospective cohort study therefore assessed blood pressure and arterial stiffness in adolescents born very preterm due to verified fetal growth restriction (FGR).

Methods

Adolescents (14 (13–17) years; 52% girls) born very preterm with FGR (preterm FGR; n = 24) and two control groups born with appropriate birth weight (AGA), one in similar gestation (preterm AGA; n = 27) and one at term (term AGA; n = 28) were included. 24-hour ambulatory blood pressure and aortic pulse wave velocity (PWV) and distensibility by magnetic resonance imaging were acquired.

Results

There were no group differences in prevalence of hypertension or in arterial stiffness (all p ≥ 0.1). In boys, diastolic and mean arterial blood pressures increased from term AGA to preterm AGA to preterm FGR with higher daytime and 24-hour mean arterial blood pressures in the preterm FGR as compared to the term AGA group. In girls, no group differences were observed (all p ≥ 0.1).

Conclusions

Very preterm birth due to FGR is associated with higher, yet normal blood pressure in adolescent boys, suggesting an existing but limited impact of very preterm birth on cardiovascular risk in adolescence, enhanced by male sex and FGR.

Impact

Very preterm birth due to fetal growth restriction was associated with higher, yet normal blood pressure in adolescent boys.

In adolescence, very preterm birth due to fetal growth restriction was not associated with increased thoracic aortic stiffness.

In adolescence, very preterm birth in itself showed an existing but limited effect on blood pressure and thoracic aortic stiffness.

Male sex and fetal growth restriction enhanced the effect of preterm birth on blood pressure in adolescence.

Male sex and fetal growth restriction should be considered as additional risk factors to that of preterm birth in cardiovascular risk stratification.
Progress and priorities in reducing the time to cancer diagnosis
Authors: Nicholson B. D. , Lyratzopoulos G.
Published: November 2022

Key developments in early diagnosis research and policy since the publication of the highly cited BJC review “Is increased time to diagnosis and treatment associated with poorer outcomes?” by Neal et al. in 2015 are summarised. Progress achieved since 2015 is described and priorities for further research identified.
Genetic prediction of male pattern baldness based on large independent datasets
Authors: Chen Yan , Hysi Pirro , Maj Carlo , Heilmann-Heimbach Stefanie , Spector Timothy D. , Liu Fan , Kayser Manfred
Published: November 2022

Genetic prediction of male pattern baldness (MPB) is important in science and society. Previous genetic MPB prediction models were limited by sparse marker coverage, small sample size, and/or data dependency in the different analytical steps. Here, we present novel models for genetic prediction of MPB based on a large set of markers and large independent subsample sets drawn among 187,435 European subjects. We selected 117 SNP predictors within 85 distinct loci from a list of 270 previously MPB-associated SNPs in 55,573 males of the UK Biobank Study (UKBB). Based on these 117 SNPs with and without age as additional predictor, we trained, by use of different methods, prediction models in a non-overlapping subset of 104,694 UKBB males and tested them in a non-overlapping subset of 26,177 UKBB males. Estimates of prediction accuracy were similar between methods with AUC ranges of 0.725–0.728 for severe, 0.631–0.635 for moderate, 0.598–0.602 for slight, and 0.708–0.711 for no hair loss with age, and slightly lower without, while prediction of any versus no hair loss gave 0.690–0.711 with age and slightly lower without. External validation in an early-onset enriched MPB dataset from the Bonn Study (N = 991) showed improved prediction accuracy without considering age such as AUC of 0.830 for no vs. any hair loss. Because of the large number of markers and the large independent datasets used for the different analytical steps, the newly presented genetic prediction models are the most reliable ones currently available for MPB or any other human appearance trait.
Viral load dynamics of SARS-CoV-2 Delta and Omicron variants following multiple vaccine doses and previous infection
Authors: Woodbridge Yonatan , Amit Sharon , Huppert Amit , Kopelman Naama M.
Published: November 2022

An important aspect of vaccine effectiveness is its impact on pathogen transmissibility, harboring major implications for public health policies. As viral load is a prominent factor affecting infectivity, its laboratory surrogate, qRT-PCR cycle threshold (Ct), can be used to investigate the infectivity-related component of vaccine effectiveness. While vaccine waning has previously been observed for viral load during the Delta wave, less is known regarding how Omicron viral load is affected by vaccination status, and whether vaccine-derived and natural infection protection are sustained. By analyzing results of more than 460,000 individuals, we show that while recent vaccination reduces Omicron viral load, its effect wanes rapidly. In contrast, a significantly slower waning rate is demonstrated for recovered COVID-19 individuals. Thus, while the vaccine is effective in decreasing morbidity and mortality, its relatively small effect on transmissibility of Omicron (as measured here by Ct) and its rapid waning call for reassessment of future booster campaigns.
Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA
Authors: Sen Ayesha , Kallabis Sebastian , Gaedke Felix , Jüngst Christian , Boix Julia , Nüchel Julian , Maliphol Kanjanamas , Hofmann Julia , Schauss Astrid C. , Krüger Marcus , Wiesner Rudolf J. , Pla-Martín David
Published: November 2022

Understanding the mechanisms governing selective turnover of mutation-bearing mtDNA is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments. Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs. In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.
An integrated platinum-nanocarbon electrocatalyst for efficient oxygen reduction
Authors: Huang Lei , Wei Min , Qi Ruijuan , Dong Chung-Li , Dang Dai , Yang Cheng-Chieh , Xia Chenfeng , Chen Chao , Zaman Shahid , Li Fu-Min , You Bo , Xia Bao Yu
Published: November 2022

Efficient and robust platinum-carbon electrocatalysts are of great significance for the long-term service of high-performance fuel cells. Here, we report a Pt alloy integrated in a cobalt-nitrogen-nanocarbon matrix by a multiscale design principle for efficient oxygen reduction reaction. This Pt integrated catalyst demonstrates an increased mass activity, 11.7 times higher than that of commercial Pt catalyst, and retains a stability of 98.7% after 30,000 potential cycles. Additionally, this integrated catalyst delivers a current density of 1.50 A cm−2 at 0.6 V in the hydrogen-air fuel cell and achieves a power density of 980 mW cm−2. Comprehensive investigations demonstrate that the synergistic contribution of components and structure in the platinum-carbon integrated catalyst is responsible for the high-efficiency ORR in fuel cells.
Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51
Authors: Heijink Anne Margriet , Stok Colin , Porubsky David , Manolika Eleni Maria , de Kanter Jurrian K. , Kok Yannick P. , Everts Marieke , de Boer H. Rudolf , Audrey Anastasia , Bakker Femke J. , Wierenga Elles , Tijsterman Marcel , Guryev Victor , Spierings Diana C. J. , Knipscheer Puck , van Boxtel Ruben , Ray Chaudhuri Arnab , Lansdorp Peter M. , van Vugt Marcel A. T. M.
Published: November 2022

Sister chromatid exchanges (SCEs) are products of joint DNA molecule resolution, and are considered to form through homologous recombination (HR). Indeed, SCE induction upon irradiation requires the canonical HR factors BRCA1, BRCA2 and RAD51. In contrast, replication-blocking agents, including PARP inhibitors, induce SCEs independently of BRCA1, BRCA2 and RAD51. PARP inhibitor-induced SCEs are enriched at difficult-to-replicate genomic regions, including common fragile sites (CFSs). PARP inhibitor-induced replication lesions are transmitted into mitosis, suggesting that SCEs can originate from mitotic processing of under-replicated DNA. Proteomics analysis reveals mitotic recruitment of DNA polymerase theta (POLQ) to synthetic DNA ends. POLQ inactivation results in reduced SCE numbers and severe chromosome fragmentation upon PARP inhibition in HR-deficient cells. Accordingly, analysis of CFSs in cancer genomes reveals frequent allelic deletions, flanked by signatures of POLQ-mediated repair. Combined, we show PARP inhibition generates under-replicated DNA, which is processed into SCEs during mitosis, independently of canonical HR factors.
Sharp-wave ripple doublets induce complex dendritic spikes in parvalbumin interneurons in vivo
Authors: Judák Linda , Chiovini Balázs , Juhász Gábor , Pálfi Dénes , Mezriczky Zsolt , Szadai Zoltán , Katona Gergely , Szmola Benedek , Ócsai Katalin , Martinecz Bernadett , Mihály Anna , Dénes Ádám , Kerekes Bálint , Szepesi Áron , Szalay Gergely , Ulbert István , Mucsi Zoltán , Roska Botond , Rózsa Balázs
Published: November 2022

Neuronal plasticity has been shown to be causally linked to coincidence detection through dendritic spikes (dSpikes). We demonstrate the existence of SPW-R-associated, branch-specific, local dSpikes and their computational role in basal dendrites of hippocampal PV+ interneurons in awake animals. To measure the entire dendritic arbor of long thin dendrites during SPW-Rs, we used fast 3D acousto-optical imaging through an eccentric deep-brain adapter and ipsilateral local field potential recording. The regenerative calcium spike started at variable, NMDA-AMPA-dependent, hot spots and propagated in both direction with a high amplitude beyond a critical distance threshold (~150 µm) involving voltage-gated calcium channels. A supralinear dendritic summation emerged during SPW-R doublets when two successive SPW-R events coincide within a short temporal window (~150 ms), e.g., during more complex association tasks, and generated large dSpikes with an about 2.5-3-fold amplitude increase which propagated down to the soma. Our results suggest that these doublet-associated dSpikes can work as a dendritic-level temporal and spatial coincidence detector during SPW-R-related network computation in awake mice.
Functionalized graphene grids with various charges for single-particle cryo-EM
Authors: Lu Ye , Liu Nan , Liu Yongbo , Zheng Liming , Yang Junhao , Wang Jia , Jia Xia , Zi Qinru , Peng Hailin , Rao Yu , Wang Hong-Wei
Published: November 2022

A major hurdle for single particle cryo-EM in structural determination lies in the specimen preparation impaired by the air-water interface (AWI) and preferential particle-orientation problems. In this work, we develop functionalized graphene grids with various charges via a dediazoniation reaction for cryo-EM specimen preparation. The graphene grids are paraffin-assistant fabricated, which appear with less contaminations compared with those produced by polymer transfer method. By applying onto three different types of macromolecules, we demonstrate that the high-yield charged graphene grids bring macromolecules away from the AWI and enable adjustable particle-orientation distribution for more robust single particle cryo-EM structural determination.
Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions
Authors: Sakai Katsuya , Sugano-Nakamura Nozomi , Mihara Emiko , Rojas-Chaverra Nichole Marcela , Watanabe Sayako , Sato Hiroki , Imamura Ryu , Voon Dominic Chih-Cheng , Sakai Itsuki , Yamasaki Chihiro , Tateno Chise , Shibata Mikihiro , Suga Hiroaki , Takagi Junichi , Matsumoto Kunio
Published: November 2022

Short half-lives in circulation and poor transport across the blood–brain barrier limit the utility of cytokines and growth factors acting as receptor agonists. Here we show that surrogate receptor agonists with longer half-lives in circulation and enhanced transport rates across the blood–brain barrier can be generated by genetically inserting macrocyclic peptide pharmacophores into the structural loops of the fragment crystallizable (Fc) region of a human immunoglobulin. We used such ‘lasso-grafting’ approach, which preserves the expression levels of the Fc region and its affinity for the neonatal Fc receptor, to generate Fc-based protein scaffolds with macrocyclic peptides binding to the receptor tyrosine protein kinase Met. The Met agonists dimerized Met, inducing biological responses that were similar to those induced by its natural ligand. Moreover, lasso-grafting of the Fc region of the mouse anti-transferrin-receptor antibody with Met-binding macrocyclic peptides enhanced the accumulation of the resulting Met agonists in brain parenchyma in mice. Lasso-grafting may allow for designer protein therapeutics with enhanced stability and pharmacokinetics.
A structural biology community assessment of AlphaFold2 applications
Authors: Akdel Mehmet , Pires Douglas E. V. , Pardo Eduard Porta , Jänes Jürgen , Zalevsky Arthur O. , Mészáros Bálint , Bryant Patrick , Good Lydia L. , Laskowski Roman A. , Pozzati Gabriele , Shenoy Aditi , Zhu Wensi , Kundrotas Petras , Serra Victoria Ruiz , Rodrigues Carlos H. M. , Dunham Alistair S. , Burke David , Borkakoti Neera , Velankar Sameer , Frost Adam , Basquin Jérôme , Lindorff-Larsen Kresten , Bateman Alex , Kajava Andrey V. , Valencia Alfonso , Ovchinnikov Sergey , Durairaj Janani , Ascher David B. , Thornton Janet M. , Davey Norman E. , Stein Amelie , Elofsson Arne , Croll Tristan I. , Beltrao Pedro
Published: November 2022

Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recent developments in computational methods for protein structure predictions have reached the accuracy of experimentally determined models. Although this has been independently verified, the implementation of these methods across structural-biology applications remains to be tested. Here, we evaluate the use of AlphaFold2 (AF2) predictions in the study of characteristic structural elements; the impact of missense variants; function and ligand binding site predictions; modeling of interactions; and modeling of experimental structural data. For 11 proteomes, an average of 25% additional residues can be confidently modeled when compared with homology modeling, identifying structural features rarely seen in the Protein Data Bank. AF2-based predictions of protein disorder and complexes surpass dedicated tools, and AF2 models can be used across diverse applications equally well compared with experimentally determined structures, when the confidence metrics are critically considered. In summary, we find that these advances are likely to have a transformative impact in structural biology and broader life-science research.