bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Impact of an Artificial Intelligence–based Mammography Triage Algorithm on Performance and Workload in a Population-based Screening Sample
Authors: Watanabe Alyssa T , Vu Hoanh , Chim Chi Y , Litt Andrew W , Retson Tara , Mayo Ray C
Published: August 2024

Objective

To evaluate potential screening mammography performance and workload impact using a commercial artificial intelligence (AI)–based triage device in a population-based screening sample.

Methods

In this retrospective study, a sample of 2129 women who underwent screening mammograms were evaluated. The performance of a commercial AI-based triage device was compared with radiologists’ reports, actual outcomes, and national benchmarks using commonly used mammography metrics. Up to 5 years of follow-up examination results were evaluated in cases to establish benignity. The algorithm sorted cases into groups of “suspicious” and “low suspicion.” A theoretical workload reduction was calculated by subtracting cases triaged as “low suspicion” from the sample.

Results

At the default 93% sensitivity setting, there was significant improvement (P <.05) in the following triage simulation mean performance measures compared with actual outcome: 45.5% improvement in recall rate (13.4% to 7.3%; 95% CI, 6.2-8.3), 119% improvement in positive predictive value (PPV) 1 (5.3% to 11.6%; 95% CI, 9.96-13.4), 28.5% improvement in PPV2 (24.6% to 31.6%; 95% CI, 24.8-39.1), 20% improvement in sensitivity (83.3% to 100%; 95% CI, 100-100), and 7.2% improvement in specificity (87.2% to 93.5%; 95% CI, 92.4-94.5). A theoretical 62.5% workload reduction was possible. At the ultrahigh 99% sensitivity setting, a theoretical 27% workload reduction was possible. No cancers were missed by the algorithm at either sensitivity.

Conclusion

Artificial intelligence–based triage in this simulation demonstrated potential for significant improvement in mammography performance and predicted substantial theoretical workload reduction without any missed cancers.
Serving with a Smile on Airbnb: Analyzing the Economic Returns and Behavioral Underpinnings of the Host’s Smile
Authors: Zhang Shunyuan , Friedman Elizabeth M S , Srinivasan Kannan , Dhar Ravi , Zhang Xupin
Published: August 2024

Non-informational cues, such as facial expressions, can significantly influence judgments and interpersonal impressions. While past research has explored how smiling affects business outcomes in offline or in-store contexts, relatively less is known about how smiling influences consumer choice in e-commerce settings when there is no face-to-face interaction. In this article, we use a longitudinal Airbnb dataset and a facial attribute classifier to quantify the effect of a smile in the host’s profile photo on property demand and identify factors that influence when a host’s smile is likely to have the biggest effect. A smile in the host’s profile photo increases property demand by 3.5% on average. This effect is moderated by a variety of host and property characteristics that provide evidence for the role of uncertainty underlying why smiling increases demand. Specifically, when there is greater uncertainty regarding either the quality of the accommodations or the interaction with the host, a host’s smile will have a greater effect on demand. Online experiments confirm this pattern, offering further support for uncertainty perceptions driving the effect of smiling on increased Airbnb demand, and show that the effect of smiling on demand generalizes beyond Airbnb.
Evolution of the division of labour between templates and catalysts in spatial replicator models
Authors: Fu Yao , Takeuchi Nobuto
Published: August 2024

The central dogma of molecular biology can be conceptualised as the division of labour between templates and catalysts, where templates transmit genetic information, catalysts accelerate chemical reactions, and the information flows from templates to catalysts but not from catalysts to templates. How can template-catalyst division evolve in primordial replicating systems? A previous study has shown that even if the template-catalyst division does not provide an immediate fitness benefit, it can evolve through symmetry breaking between replicating molecules when the molecules are compartmentalised into protocells. However, cellular compartmentalisation may have been absent in primordial replicating systems. Here, we investigate whether cellular compartmentalisation is necessary for the evolution of the template-catalyst division via symmetry breaking using an individual-based model of replicators in a two-dimensional space. Our results show that replicators evolve the template-catalyst division via symmetry breaking when their diffusion constant is sufficiently high, a condition that results in low genetic relatedness between replicators. The evolution of the template-catalyst division reduces the risk of invasion by “cheaters,” replicators that have no catalytic activities, encode no catalysts, but replicate to the detriment of local population growth. Our results suggest that the evolution of the template-catalyst division via symmetry breaking does not require cellular compartmentalization and is, instead, a general phenomenon in replicators with structured populations.
Agglomeration and the Italian North–South divide
Authors: Buzzacchi Luigi , De Marco Antonio , Pagnini Marcello
Published: August 2024

This article offers new evidence on agglomeration economies by examining the link between total factor productivity (TFP) and employment density in Italy. We investigate whether and how the TFP–density nexus contributes to explaining a relevant share of the marked productivity gap between the northern and the southern Italian regions. We estimate TFP for a large sample of manufacturing firms and then aggregate it at the level of local labour market areas. We tackle the endogeneity issues stemming from the presence of omitted covariates and reverse causation with an innovative set of diagnostic tests and an instrumental variable approach that relies on geological and historical data. Our estimate of the TFP elasticity to the spatial concentration of economic activities is about 0.045, a magnitude comparable to those measured for other developed countries. We also show that no significant heterogeneity emerges in the intensity of agglomeration economies across the country and that the positive TFP difference in favour of the firms located in the North is not due to the tougher competition taking place in those areas.
From Photography to Radiology: How Physicians Leveraged Early Hospital X-ray Machines to Supplant Photographers
Authors: Bishop Joseph
Published: August 2024

At the end of the nineteenth century, the advent of x-ray machines fueled American medicine’s reliance on technology, transforming hospitals and the medical profession. X-ray manufacturers pursued the nascent hospital market as competition and patent feuds accelerated x-ray machine modifications. Hospitals incorporated clunky new machines and employed x-ray photographers, but as the unruly apparatus stabilized, physicians joining the new specialty of radiology discounted the toils of machine troubleshooting and promoted their medically qualified x-ray interpretations. This article frames early medical radiography in terms of boundary work, highlighting how discourse among physicians, x-ray photographers, and hospital administrators vied to establish a privileged demarcation between radiological science and photographic craft. Ultimately, radiologists supplanted x-ray photographers by leveraging the automation of x-ray machines and capitalizing on the epistemic shift from photographic objectivity to qualified interpretations. By focusing on this overlooked aspect of x-ray incorporation into hospitals, this work provides a unique perspective on how harnessing mechanization and authoritative medical interpretations can shift professional boundaries.
Modality across different logics
Authors: Freire Alfredo Roque , Martins Manuel A
Published: August 2024

In this paper, we deal with the problem of putting together modal worlds that operate in different logic systems. When evaluating a modal sentence $\Box \varphi $, we argue that it is not sufficient to inspect the truth of $\varphi $ in accessed worlds (possibly in different logics). Instead, ways of transferring more subtle semantic information between logical systems must be established. Thus, we will introduce modal structures that accommodate communication between logic systems by fixing a common lattice $L$ that contains as sublattices the semantics operating in each world. The value of a formula $\Box \varphi $ in a world with lattice $L^{\prime}$ will be defined in terms of the values of $\varphi $ in accessible worlds relativized to $L^{\prime}$ using the common order of $L$. We will investigate natural instances where formulas $\varphi $ can be said to be necessary/possible even though all the accessible world falsify $\varphi $. Further, we will discuss frames that characterize dynamic relations between logic systems: classically increasing, classically decreasing and dialectic frames. Finally, we formalize the semantics of considering worlds operating in classical logic or logic of paradox, exemplifying the kind of issue one should face in this kind of formalization.
The key universal quality of logical abductive inferences: Does optimization of eco-cognitive situatedness supersede other criteria like minimality, consistency, relevance and plausibility?
Authors: Magnani Lorenzo
Published: August 2024

Throughout my investigation into abductive cognition, which is also associated with the endeavor to naturalize logic of its special consequence relation, I stressed the relevance of the following key elements: ‘optimization of eco-cognitive situatedness’, ‘maximization of changeability’ of both input and output of the general form of an inferential abductive problem and high ‘information-sensitiveness’. These elements will be summarized and further deepened in this article. In addition, I will demonstrate how, in contrast to traditional demonstrative logical ideal systems, which are typified by what I refer to as the ‘maximization of memorylessness’, a naturalized logic of abduction demonstrates the necessity of recording the ‘past life’ of abductive inferential praxes. Lastly, I will analyze the significance and nature of the maximization of eco-cognitive openness, which characterizes abduction in science and describes how the many above-mentioned elements are relevant to the aims of new eco-cognitive epistemology.
Trends in negative interpersonal relationships at work and awareness of occupational safety and health services: a 2014-2019 trend analysis
Authors: Backhaus Insa , Dragano Nico , Di Tecco Cristina , Iavicoli Sergio , Hoven Hanno
Published: August 2024

Objective: A good psychosocial climate at work, including positive interpersonal relationships, is a protective factor for health, whereas social conflict imposes a considerable health risk. Occupational safety and health (OSH) services can help create a positive working environment. In the present study, we analyzed trends in the awareness of OSH services and interpersonal relationships and whether these are linked.

Methods: We used time series data from the Italian Survey on Health and Safety at Work (INSuLa) from 2014 and 2019 (n = 16 000 employees). Negative interpersonal relationships included workplace bullying and lack of workplace support. The availability of OSH services was measured through items inquiring about the awareness of OSH representatives and OSH training. We used Poisson regression in reporting prevalence ratios and provided predicted probabilities and average marginal effects to show trends and differences in interpersonal relationships and OSH availability.

Results: Our findings suggest that negative interpersonal relationships at work increased, whereas awareness about OSH services declined between 2014 and 2019. These trends were particularly strong for young workers, for whom workplace bullying increased by 6.3% and awareness of OSH training declined by 11.7%. We also found that unawareness about OSH services is associated with negative interpersonal relationships at work.

Conclusion: The results suggest that low OSH awareness may be an increasing problem, whereas exposure to an adverse social climate at work became more frequent at the same time. Given the role of OSH services in ensuring a positive working climate, it is important to increase workers’ awareness about OSH services.
Opening up or closing down? Non-state actors in UN cybersecurity governance
Authors: Herbst Lena , Jakobi Anja P
Published: August 2024

How can we explain the varying participation of non-state actors in UN cybersecurity governance? While research often underlines the importance of non-state actors in governing cybersecurity, research on international non-state actors’ activities also shows that shrinking spaces reduce opportunities for these actors. So far, we do not know how these two seemingly opposing developments impact UN cybersecurity governance. In this article, we analyze how state interests, ideas on representation, and institutional context affect non-state actor participation in three UN forums for cybersecurity, namely the IGF, OEWG, and AHC. Based on qualitative data and a quantitative participation analysis, we find that institutional mandates of forums remain open to non-state actors but to varying degrees. Conflicts among states affect non-state actors strongly, but often indirectly, because their participation becomes politicized, and states increasingly contest ideas on their participation. These effects concern all groups of non-state actors. All in all, our results suggest that UN cybersecurity governance is still open to non-state actors, but despite functional arguments, their participation is facing growing resistance over time. At the same time, reasons why non-state actors choose to participate or not require more consideration.
Unintentional poisoning exposures: how does modeling the opening of child-resistant containers influence children’s behaviors?
Authors: Morrongiello Barbara A , Vander Hoeven Erin
Published: August 2024

Objective

Unintentional poisoning in the home is a risk for children. Over-the-counter medicinal products in child-resistant containers (CRC) are common causes of pediatric poisoning. The current study examined children’s abilities to open three types of CRC mechanisms (twist, flip, and push) and corresponding control containers, comparing their ability to do so spontaneously and after explicit modeling. The study also examined if inhibitory control (IC) was associated with children’s overall score for spontaneous openings.

Method

Children 5–8 years old were randomly assigned to one of three mechanism conditions (between-participants factor): twist, flip, and push, with each child experiencing both a risk and a control container (within-participants factor) having that mechanism. Children were first left alone with a container (measures: engagement with container, spontaneous opening) for up to 2 min and subsequently observed an adult explicitly model opening the container before the child was asked to do so (measure: opening after modeling).

Results

Children were more engaged with and likely to spontaneously open control containers than CRCs, though some (4%–10%) also opened CRCs. After modeling, significantly more children opened each of the three types of CRCs, with nearly all children opening the push mechanism CRC. IC positively predicted children being more engaged with and spontaneously opening more containers.

Conclusions

Implications for improving pediatric poison prevention are discussed.
Did Shakespeare influence Seinfeld?
Authors: Date Sachin
Published: August 2024

A casual observation leads Sachin Date to a probing investigation into how leading stand-up comedians influence each other
“Aw, sadistics. The most evil of math”
Authors: Glanz Hunter
Published: August 2024

Ever had to teach introductory statistics to reluctant and terrified students? Hunter Glanz shares your pain – as well as his thoughts on giving your class the skills they need
Interaction of PASTICCINO2 with Golgi anti-apoptotic proteins confers resistance to endoplasmic reticulum stress and is dependent on very-long-chain fatty acids
Authors: Tang Xiao-Han , Zhou Yan , He Yu-Ting , Zhang Wei , Chen Xi , Tan Jing , Guo Kun , Liu Yu-Ting , Zhao Shu-Heng , Ning Yi-Qiu , Sun Yue , Li Xiao-Fang
Published: August 2024

The endoplasmic reticulum (ER) is crucial for maintaining cell homeostasis because it is the primary site for synthesizing secreted and transmembrane proteins and lipids. The unfolded protein response (UPR) is activated to restore the homeostasis of the ER when it is under stress; however, the relationship between lipids and the ER stress response in plants is not well understood. Arabidopsis GOLGI ANTI-APOPTOTIC PROTEINS (GAAPs) are involved in resisting ER stress, and in this study, we found that PASTICCINO2 (PAS2), which is involved in very-long-chain fatty acid (VLCFA) synthesis, interacts with GAAPs and INOSITOL REQUIRING ENZYME 1. The pas2 single-mutant and the gaap1 pas2 and gaap2 pas2 double-mutants exhibited increased seedling damage and an impaired UPR response under chronic ER stress. Site mutation combined with genetic analysis revealed that the role of PAS2 in resisting ER stress depended on its VLCFA synthesis domain. VLCFA contents were increased under ER stress, and this required GAAPs. Exogenous VLCFAs partially restored the defect in the activation of the UPR caused by mutation of PAS2 or GAAP under chronic ER stress. Our findings demonstrate that the association of PAS2 with GAAPs confers plant resistance to ER stress by regulating VLCFA synthesis and the UPR. This provides a basis for further studies on the connection between lipids and cell-fate decisions under stress.
Common RBC antigens in O type Tunisian blood donors and their importance in alloimmunization
Authors: Sellami Mohamed Hichem , Aïssa Wafa , Ferchichi Hamida , Ghazouani Eya , Châabane Manel , Kâabi Houda , Hmida Slama
Published: August 2024

Background

The presence of some red blood cell (RBC) antigens may affect the preference for using type O blood in emergency situations because they may induce complex or multiple alloimmunization in special circumstances.

Methods

A subgroup of 77 type O blood Tunisian donors were genotyped for 19 common blood alleles using the single specific primer–polymerase chain reaction method. The statistical analysis was done using HaploView software.

Results

The study showed the dominance of the alleles RH*5, KEL*2, FY*2, and CO*1 and the absence of the homozygous state of the KEL*1 and CO*2 alleles. Furthermore, a complete linkage disequilibrium between the RH*2/RH*4 and RH*3/RH*5 loci and the FY*Null/FY*Exp and FY*A/FY*B loci was detected. Additionally, it seems that sensitization to MNS:3, FY:1, and RH:3 may constitute a potential factor for alloimmunization after transfusion with O blood type units: the probabilities of simple alloimmunizations are 24.5 per 100, 18.5 per 100, and 18 per 100, respectively. Multiple alloimmunization against RH:1;KEL:1 or RH:1;KEL:1;RH:3 phenotypes may occur, with probabilities of 7 per 1000 and 2 per 1000, respectively.

Conclusion

Some O-type RBC units may contain blood with very immunogenic phenotypes, the use of which in an emergency requires great caution because it can be a step towards subsequent alloimmunization.
The MAGPI survey: evidence against the bulge–halo conspiracy
Authors: Derkenne C , McDermid R M , Santucci G , Poci A , Thater S , Bellstedt S , Mendel J T , Foster C , Harborne K E , Lagos C D P , Wisnioski E , Croom S , Remus R- S , Valenzuela L M , van de Sande J , Sweet S M , Ziegler B
Published: August 2024

Studies of the internal mass structure of galaxies have observed a ‘conspiracy’ between the dark matter and stellar components, with total (stars$+$dark) density profiles showing remarkable regularity and low intrinsic scatter across various samples of galaxies at different redshifts. Such homogeneity suggests the dark and stellar components must somehow compensate for each other in order to produce such regular mass structures. We test the conspiracy using a sample of 22 galaxies from the ‘Middle Ages Galaxy Properties with Integral field spectroscopy’ Survey that targets massive galaxies at $z \sim 0.3$. We use resolved, 2D stellar kinematics with the Schwarzschild orbit-based modelling technique to recover intrinsic mass structures, shapes, and dark matter fractions. This work is the first implementation of the Schwarzschild modelling method on a sample of galaxies at a cosmologically significant redshift. We find that the variability of structure for combined mass (baryonic and dark) density profiles is greater than that of the stellar components alone. Furthermore, we find no significant correlation between enclosed dark matter fractions at the half-light radius and the stellar mass density structure. Rather, the total density profile slope, $\gamma _{\mathrm{tot}}$, strongly correlates with the dark matter fraction within the half-light radius, as $\gamma _{\mathrm{tot}} = (1.3 \pm 0.2) f_{\mathrm{DM}} - (2.44 \pm 0.04)$. Our results refute the bulge–halo conspiracy and suggest that stochastic processes dominate in the assembly of structure for massive galaxies.
Imprints of supermassive black hole evolution on the spectral and spatial anisotropy of nano-hertz stochastic gravitational-wave background
Authors: Sah Mohit Raj , Mukherjee Suvodip , Saeedzadeh Vida , Babul Arif , Tremmel Michael , Quinn Thomas R
Published: August 2024

The formation and evolution of supermassive black holes (SMBHs) remains an open question in the field of modern cosmology. The detection of nanohertz (n-Hz) gravitational waves via pulsar timing arrays (PTAs) in the form of individual events and the stochastic gravitational wave background (SGWB) offers a promising avenue for studying SMBH evolution across cosmic time, with SGWB signal being the immediately detectable signal with the currently accessible telescope sensitivities. By connecting the galaxy properties in the large scale (Gpc scale) cosmological simulation such as MICECAT with the small scale ($\sim$Mpc scale) galaxy simulations from ROMULUS, we show that different scenarios of galaxy–SMBH evolution with redshift leads to a frequency-dependent spatial anisotropy in the SGWB signal. The presence of slow evolution of the SMBHs in the Universe leads to a pronounced blue anisotropic spectrum of the SGWB. In contrast, if SMBHs grow faster in the Universe in lighter galaxies, the frequency-dependent spatial anisotropy exhibits a more flattened anisotropic spectrum. This additional aspect of the SGWB signal on top of the monopole SGWB signal, can give insight on how the SMBHs form in the high-redshift Universe and its interplay with the galaxy formation from future measurements.
Clinical features and risk factors for Baker’s cyst in patients with rheumatoid arthritis
Authors: Jiang Wan Lan , Xu Ting , Zhang Bi Qing , Zhang Lu , Wu Min , Xie Wen
Published: August 2024

Objectives

Baker’s cyst (BC) is a complex complication of rheumatoid arthritis (RA), with a poor prognosis. This paper aimed to analyse the clinical features and risk factors for BC in patients with RA to assist clinicians in early warning and appropriate action.

Methods

The clinical features of the hospitalized RA patients with knee affected were analysed retrospectively. The R software was used for the statistical analysis, while logistic regression analyses were used to determine independent risk factors.

Results

A total of 367 RA patients with knee affected were studied, and BC was diagnosed in 15.3% of them. The BC group exhibited a higher proportion of knee-only affected than the non-BC group (P < .05), while the attributes linked to disease activity exhibited no disparity. Logistic regression analyses selected two independent risk factors for BC: knee-only affected and anaemia. A total of 26.8% of patients with BC developed rupture, exhibiting a higher proportion of knee-only affected (P < .05), compared to those unruptured.

Conclusions

The occurrence and rupture of BC in RA patients were significantly related to local inflammation, but not to systemic one. Incorporating local treatment may be a more advantageous option compared to solely relying on systemic therapy.
Safety of baricitinib in Japanese patients with rheumatoid arthritis in clinical use: 3-year data of all-case postmarketing surveillance study
Authors: Okamoto Nami , Atsumi Tatsuya , Takagi Michiaki , Takahashi Nobunori , Takeuchi Tsutomu , Tamura Naoto , Nakajima Atsuo , Nakajima Ayako , Fujii Takao , Matsuno Hiroaki , Ishii Taeko , Tsujimoto Naoto , Nishikawa Atsushi , Minatoya Machiko , Tanaka Yoshiya , Kuwana Masataka
Published: August 2024

Objectives

To assess safety of baricitinib in Japanese patients with rheumatoid arthritis (RA) in real-world clinical practice.

Methods

This all-case postmarketing surveillance study included patients initiating baricitinib for RA from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from initiation (up to 4 weeks postdiscontinuation in discontinuing patients).

Results

Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3-year Kaplan–Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients [incidence rate (IR) 10.42/100 patient-years (PY); 95% confidence interval, 9.76–11.09]. There were 39 deaths [IR 0.43 (0.30–0.57)/100 PY]. Adverse events of special interest IRs per 100 PY were herpes zoster 4.68 (4.22–5.14), serious infection 3.05 (2.68–3.41), malignancy 1.09 (0.87–1.30), major adverse cardiovascular events 0.35 (0.23–0.48), and venous thromboembolism 0.25 (0.15–0.36). IRs did not increase with prolonged exposure.

Conclusions

No new safety concerns were identified during this 3-year postmarketing surveillance study of baricitinib in Japanese patients with RA. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.
Cyto- and genotoxicity evaluation of water samples collected from two rivers in the Kosovo
Authors: Asllani Fisnik H , Alija Avdulla J , Eckl Peter M , Bresgen Nikolaus
Published: August 2024

River water in Kosovo is exposed to various discharges from industrial and agricultural activities as well as to urban wastewater. Rivers Sitnica and Drenica are among the most affected ones and water samples drawn from these rivers show the presence of various toxic substances. Genotoxic effects are seen in fish living in these rivers indicating a cytotoxic and mutagenic potential of the river water. Aiming at substantiating these observations, we assessed the cyto- and genotoxic effects of water samples collected at different locations from the Drenica and Sitnica rivers. Samples drawn from Lake Badovc served for comparison. To address seasonal effects, samples were collected at different seasons/time points during the period of summer 2016—spring 2018. The water samples were analyzed employing primary rat hepatocytes as a reliable in vitro cell model for the assessment of cytotoxic effects (mitotic arrest and cell death) and DNA damage/genotoxicity (micronucleus assay and Comet assay). The results do not account for significant effects associated with specific locations but demonstrate seasonal differences of the genotoxic potential of the water samples collected along both rivers, which are accompanied by a limited cytotoxic potential. Our data provide substantial support to earlier observations and strongly warrant the need for continuous chemical as well as biological monitoring of the river water in Kosovo, focusing on improved toxicant profiling of the river water and investigations addressing the observed seasonal variations.
Senataxin RNA/DNA helicase promotes replication restart at co-transcriptional R-loops to prevent MUS81-dependent fork degradation
Authors: Rao Satyajeet , Andrs Martin , Shukla Kaustubh , Isik Esin , König Christiane , Schneider Stefan , Bauer Michael , Rosano Vinicio , Prokes Jiri , Müller Anne , Janscak Pavel
Published: August 2024

Replication forks stalled at co-transcriptional R-loops can be restarted by a mechanism involving fork cleavage-religation cycles mediated by MUS81 endonuclease and DNA ligase IV (LIG4), which presumably relieve the topological barrier generated by the transcription-replication conflict (TRC) and facilitate ELL-dependent reactivation of transcription. Here, we report that the restart of R-loop-stalled replication forks via the MUS81-LIG4-ELL pathway requires senataxin (SETX), a helicase that can unwind RNA:DNA hybrids. We found that SETX promotes replication fork progression by preventing R-loop accumulation during S-phase. Interestingly, loss of SETX helicase activity leads to nascent DNA degradation upon induction of R-loop-mediated fork stalling by hydroxyurea. This fork degradation phenotype is independent of replication fork reversal and results from DNA2-mediated resection of MUS81-cleaved replication forks that accumulate due to defective replication restart. Finally, we demonstrate that SETX acts in a common pathway with the DEAD-box helicase DDX17 to suppress R-loop-mediated replication stress in human cells. A possible cooperation between these RNA/DNA helicases in R-loop unwinding at TRC sites is discussed.
Transposition with Tn3-family elements occurs through interaction with the host β-sliding clamp processivity factor
Authors: Tang Yu , Zhang Jianfeng , Guan Jiahao , Liang Wei , Petassi Michael T , Zhang Yumeng , Jiang Xiaofei , Wang Minggui , Wu Wenjuan , Ou Hong-Yu , Peters Joseph E
Published: August 2024

Tn3 family transposons are a widespread group of replicative transposons, notorious for contributing to the dissemination of antibiotic resistance, particularly the global prevalence of carbapenem resistance. The transposase (TnpA) of these elements catalyzes DNA breakage and rejoining reactions required for transposition. However, the molecular mechanism for target site selection with these elements remains unclear. Here, we identify a QLxxLR motif in N-terminal of Tn3 TnpAs and demonstrate that this motif allows interaction between TnpA of Tn3 family transposon Tn1721 and the host β-sliding clamp (DnaN), the major processivity factor of the DNA replication machinery. The TnpA-DnaN interaction is essential for Tn1721 transposition. Our work unveils a mechanism whereby Tn3 family transposons can bias transposition into certain replisomes through an interaction with the host replication machinery. This study further expands the diversity of mobile elements that use interaction with the host replication machinery to bias integration.
qPrimerDB 2.0: an updated comprehensive gene-specific qPCR primer database for 1172 organisms
Authors: Li Xiaodong , Meng Boyu , Zhang Zhi , Wei Lijuan , Chang Wei , Wang Yuhong , Zhang Kai , Li Tian , Lu Kun
Published: August 2024

High-quality primer design is essential for the success of all polymerase chain reaction (PCR)–based experiments. We previously developed a thermodynamics-based gene-specific quantitative PCR (qPCR) primer database for 147 organisms, which has been used extensively in gene expression studies. However, the number of organisms and the imperfection of function in the database limits its potential applications. Here, we improved the functionality of qPrimerDB to create a more comprehensive primer resource. Specifically, we (i) developed an improved primer design tool, qPrimer, building upon the previous qPrimerDB pipeline, to enhance the efficiency and simplicity of genome-scale qPCR primer design; (ii) pre-computed qPCR primer resources from 1 308 genomes of 1172 organisms and (iii) introduced a complete system for identifying, designing, checking, marking, and submitting qPCR primers. qPrimerDB 2.0 is freely available at https://qprimerdb.biodb.org. The qPrimer source code is available at https://github.com/swu1019lab/qPrimer.
Efficacy, biodistribution and safety comparison of chemically modified antisense oligonucleotides in the retina
Authors: Vázquez-Domínguez Irene , Anido Alejandro Allo , Duijkers Lonneke , Hoppenbrouwers Tamara , Hoogendoorn Anita D M , Koster Céline , Collin Rob W J , Garanto Alejandro
Published: August 2024

Antisense oligonucleotides (AONs) are a versatile tool for treating inherited retinal diseases. However, little is known about how different chemical modifications of AONs can affect their biodistribution, toxicity, and uptake in the retina. Here, we addressed this question by comparing splice-switching AONs with three different chemical modifications commonly used in a clinical setting (2′O-methyl-phosphorothioate (2-OMe/PS), 2′O-methoxyethyl-phosphoriate (2-MOE/PS), and phosphorodiamidite morpholino oligomers (PMO)). These AONs targeted genes exclusively expressed in certain types of retinal cells. Overall, studies in vitro and in vivo in C57BL/6J wild-type mouse retinas showed that 2-OMe/PS and 2-MOE/PS AONs have comparable efficacy and safety profiles. In contrast, octa-guanidine-dendrimer-conjugated in vivo PMO-oligonucleotides (ivPMO) caused toxicity. This was evidenced by externally visible ocular phenotypes in 88.5% of all ivPMO-treated animals, accompanied by severe alterations at the morphological level. However, delivery of unmodified PMO-AONs did not cause any toxicity, although it clearly reduced the efficacy. We conducted the first systematic comparison of different chemical modifications of AONs in the retina. Our results showed that the same AON sequence with different chemical modifications displayed different splicing modulation efficacies, suggesting the 2′MOE/PS modification as the most efficacious in these conditions. Thereby, our work provides important insights for future clinical applications.
Invention of circRNA promoting RNA to specifically promote circRNA production
Authors: He Zhilin , Ji Haofei , Xia Bei , Cao Xiuen , Huang Ying , Zhu Qubo
Published: August 2024

CircRNA, an essential RNA molecule involved in various biological functions and diseases, often exhibits decreased expression in tumor tissues, playing a role as a tumor suppressor, and suggesting therapeutic potential for cancer. However, current methods for promoting circRNA production are limited. This study introduces a novel approach for enhancing circRNA biogenesis, termed circRNA promoting RNA (cpRNA). CpRNA is designed to complement the flanking sequences of reverse complementary matches (RCMs) within pre-mRNA, thereby facilitating circRNA formation through improved exon circularization. Using a split-GFP reporter system, we demonstrated that cpRNA significantly enhance circGFP production. Optimization identified the best conditions for cpRNA to promote circRNA biogenesis, and these cpRNAs were then used to augment the production of endogenous circRNAs. These results indicate that cpRNAs can specifically increase the production of endogenous circRNAs with RCMs, such as circZKSCAN1 and circSMARCA5 in cancer cells, thereby inhibiting cell proliferation and migration by modulating circRNA-related pathways, showcasing the therapeutic potential of cpRNAs. Mechanistic studies have also shown that cpRNA promotes circRNA biogenesis, in part, by antagonizing the unwinding function of DHX9. Overall, these findings suggest that cpRNA represents a promising strategy for circRNA overexpression, offering a potential treatment for diseases marked by low circRNA levels.
Mitoclone2: an R package for elucidating clonal structure in single-cell RNA-sequencing data using mitochondrial variants
Authors: Story Benjamin , Velten Lars , Mönke Gregor , Annan Ahrmad , Steinmetz Lars
Published: August 2024

Clonal cell population dynamics play a critical role in both disease and development. Due to high mitochondrial mutation rates under both healthy and diseased conditions, mitochondrial genomic variability is a particularly useful resource in facilitating the identification of clonal population structure. Here we present mitoClone2, an all-inclusive R package allowing for the identification of clonal populations through integration of mitochondrial heteroplasmic variants discovered from single-cell sequencing experiments. Our package streamlines the investigation of this phenomenon by providing: built-in compatibility with commonly used tools for the delineation of clonal structure, the ability to directly use multiplexed BAM files as input, annotations for both human and mouse mitochondrial genomes, and helper functions for calling, filtering, clustering, and visualizing variants.
Latent Dirichlet allocation mixture models for nucleotide sequence analysis
Authors: Wang Bixuan , Mount Stephen M
Published: August 2024

Strings of nucleotides carrying biological information are typically described as sequence motifs represented by weight matrices or consensus sequences. However, many signals in DNA or RNA are recognized by multiple factors in temporal sequence, consist of distinct alternative motifs, or are best described by base composition. Here we apply the latent Dirichlet allocation (LDA) mixture model to nucleotide sequences. Using positions in an alignment of human or Drosophila splice sites as samples, we show that LDA readily identifies motifs, including such elusive cases as the intron branch site. Using whole sequences with positional k-mers as features, LDA can identify sequence subtypes enriched in long vs. short introns. LDA with bulk k-mers can reliably distinguish reading frame and species of origin in coding sequences from humans and Drosophila. We find that LDA is a useful model for describing heterogeneous signals, for assigning individual sequences to subtypes, and for identifying and characterizing sequences that do not fit recognized subtypes. Because LDA topic models are interpretable, they also aid the discovery of new motifs, even those present in a small fraction of samples. In summary, LDA can identify and characterize signals in nucleotide sequences, including candidate regulatory factors involved in biological processes.
Characterizing behavioural differentiation in gene regulatory networks with representation graphs
Authors: Viksna Juris , Cerans Karlis , Lace Lelde , Melkus Gatis
Published: August 2024

We introduce the formal notion of representation graphs, encapsulating the state space structure of gene regulatory network models in a compact and concise form that highlights the most significant features of stable states and differentiation processes leading to distinct stability regions. The concept has been developed in the context of a hybrid system-based gene network modelling framework; however, we anticipate that it can also be adapted to other approaches of modelling gene networks in discrete terms. We describe a practical algorithm for representation graph computation as well as two case studies demonstrating their real-world application and utility. The first case study presents models for three phage viruses. It shows that the process of differentiation into lytic and lysogenic behavioural states for all these models is described by the same representation graph despite the distinctive underlying mechanisms for differentiation. The second case study shows the advantages of our approach for modelling the process of myeloid cell differentiation from a common progenitor into different cell types. Both case studies also demonstrate the potential of the representation graph approach for deriving and validating hypotheses about regulatory interactions that must be satisfied for biologically viable behaviours.
Financial toxicity of oral chemotherapy in patients with primary brain tumors
Authors: Patel Mallika P , Affronti Mary Lou , Buckley Evan D , Herndon II James E , Mackowsky Emma M , Johnson Margaret O , Peters Katherine B
Published: August 2024

Background

Cancer treatment costs continue to rise with the development of new agents. Financial toxicity is defined as the quantifiable costs associated with cancer and cancer treatment in addition to the patient’s associated distress. This study’s rationale is to better understand the financial burden of oral chemotherapies from the perspective of patients with primary brain tumors.

Methods

After one cycle of oral chemotherapy, we requested patients to complete the financial toxicity-functional assessment of chronic illness therapy (COST-FACIT) survey and additional questions relevant to insurance and cost. We summarized responses with descriptive statistics within strata defined by on-label or off-label oral therapy.

Results

Sixty surveys were completed, with most patients (n = 53, 88%) receiving on-label therapy; only 7 patients (12%) received off-label oral agents. The mean overall financial toxicity score was 23.1 (SD = 11.3). When asked if their provider discussed treatment cost before initiation, 21 patients (35%) stated that they did, and 39 patients (65%) said they did not discuss cost or did not recall. However, in the off-label cohort, all 7 patients stated that their provider discussed the cost before prescribing. Most patients (70%) had copays. Nine (17%) in the on-label group and 3 (43%) in the off-label group had chemotherapy-associated costs that negatively affected their quality of life. A higher percentage of financial distress occurred in the off-label group.

Conclusions

Discussing medication costs with patients is an essential part of chemotherapy initiation and may mitigate undue psychosocial and financial distress.
Revisiting the effect of democracy on population health
Authors: Vu Trung V
Published: August 2024

I use a novel dichotomous measure of democracy to simulate a quasi-natural experiment and implement a difference-in-differences analysis to identify the heterogeneous treatment effect of democracy on population health across countries from 1960 to 2010. To counteract potential sources of bias resulting from unparallel and stochastic trends between treated and control units, I adopt a principal components difference-in-differences estimator that exploits factor proxies constructed from control units to account for unobserved trends. The main results indicate that countries that transitioned from non-democracy to democracy are more likely to experience health improvements, compared to countries retaining non-democratic institutions. However, the health-enhancing impact of democratization turns out to be much smaller in size than previously established. I posit that conventional estimates exaggerate the economic significance of the health returns to democratization due to inadequate attention to cross-border spillovers, global common shocks, and worldwide heterogeneity in the democracy-health nexus.
Addressing the urgent need for direct climate cooling: Rationale and options
Authors: Baiman Ron , Clarke Sev , Elsworth Clive , Field Leslie , MacCracken Michael , Macdonald John , Mitchell David , Oeste Franz Dietrich , Reed Suzanne , Salter Stephen , Simmens Herb , Tao Ye , Tulip Robert
Published: August 2024

Emissions reduction and removal are not proceeding at a pace that will limit global average warming to less than the Paris Agreement targets of 1.5°C or 2.0°C. Accelerating global warming is indicated by record high 2023–2024 monthly temperatures and annual 2023 global mean surface temperatures around 1.5°C above pre-industrial levels. Only direct climate cooling has the potential to avert continued temperature rise in the near term and moderate at least some projected climate change disruption including extreme weather, sea level rise, loss of sea ice, glacier and permafrost melting, and coral reef die-off. Strategically deployed at scale, starting in the near term, several cooling measures have the potential to reduce or reverse global warming. Others can exert local or regional cooling influences. The world needs an approach to climate change that extends beyond sole reliance on emission reductions and removal. We propose (i) researching, field testing and deploying one or more large-scale cooling influence(s) perhaps initially in polar regions and applying local and regional cooling measures that also support adaptation, (ii) accelerating emissions reductions with an early prioritization of short-lived climate drivers, and (iii) deploying large scale carbon removal to draw down legacy greenhouse gas. The authors make no attempt to determine what measures or mix of measures is optimal. That will depend on modeling and experimentation. Only by including properly researched emergency cooling “tourniquets,” in the near-term to our “bleeding” Earth can we slow and then reverse ongoing and increasingly severe climate change in the 21st Century.
AIDS and the End of the Soviet Union
Authors: Hearne Siobhán
Published: August 2024

In the mid-1980s, HIV and AIDS were initially dismissed in the Soviet press as infections that could only be contracted by individuals engaged in ‘deviant’ or ‘promiscuous’ sexual behaviour. However, in late 1988 a different narrative took hold when the mass nosocomial infection of children occurred in hospitals in Elista, Volgograd and Rostov-on-Don. These tragedies — and the Soviet government’s lack of action in their aftermath — crystallized the public perception that the spread of HIV and AIDS was primarily due to government negligence and the deficiencies of the Soviet system. In this context, civil society organizations sprang up across the USSR to critique the government’s AIDS response, address the country’s inadequate healthcare infrastructure, and formulate their own solutions. This article explores how this played out in Moscow and Riga in 1989–90, where grassroots AIDS action was inflected by the local political context and indicative of the broader disillusionment with the Soviet government. Because of the specific conditions of Soviet society, AIDS action was more centred on the collapse of the social contract between citizens and the government in a socialist welfare state, and less about the de-stigmatization and liberation of marginalized groups.
Indication of long-range correlations governing city size
Authors: Li Yunfei , Ural Deniz , Kantelhardt Jan W , Rybski Diego
Published: August 2024

City systems are characterized by the functional organization of cities on a regional or country scale. While there is a relatively good empirical and theoretical understanding of city size distributions, insights about their spatial organization remain on a conceptual level. Here, we analyze empirically the correlations between the sizes of cities (in terms of area) across long distances. Therefore, we (i) define city clusters, (ii) obtain the neighborhood network from Voronoi cells, and (iii) apply a fluctuation analysis along all shortest paths. We find that most European countries exhibit long-range correlations but in several cases these are anti-correlations. In an analogous way, we study a model inspired by Central Places Theory and find that it leads to positive long-range correlations, unless there is strong additional spatial disorder—contrary to intuition. We conclude that the interactions between cities extend over large distances reaching the country scale. Our findings have policy relevance as urban development or decline can affect cities at a considerable distance.
What is it to have an inquisitive attitude?
Authors: Gaultier Benoit
Published: August 2024

Following a common assumption, when one inquires into a question, one has an inquisitive attitude towards it. More precisely, I shall assume that there is an inquisitive attitude towards Q that all of those who inquire into Q have in common and in virtue of which they can be said to be in an inquisitive state of mind towards Q. This paper is about the nature of this attitude. I elucidate it by examining whether it boils down to doubt, curiosity, epistemic desire, or wondering. I shall do this by examining whether having these attitudes is necessary and sufficient for being in an inquisitive state of mind. The test will prove negative for the first three, but the case of wondering is more complex.