bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermodynamic analysis of hybrid two-stage CO2 mechanical compression–ejector cooling cycle
Authors: Ierin Volodymyr , Chen Guangming , Hao Xinyue , Volovyk Oleksii
Published: July 2023

In the present study, the main results of thermodynamic analysis of the hybrid two-stage carbon dioxide (CO2) transcritical mechanical compression–ejector cooling cycle using R245ca are provided. In the proposed cycle, an increase in the energy efficiency of a mechanical compression refrigeration machine (MCRM) is provided by additional supercooling of CO2 after the gas cooler due to the use of cold obtained in an ejector cooling machine (ECM). The ECM uses part of the superheated vapor heat after the high-pressure compressor and the intermediate pressure heat after the low-pressure compressor. This solution provides intermediate cooling of CO2 vapor without using an external cooling medium. The proposed method of computation makes it possible to determine the optimal parameters of the hybrid cooling cycle for the design conditions, ensuring the maximum possible MCRM efficiency. At the same time, the method considers the need to determine the optimal gas cooler pressure – a parameter that has a significant impact on efficiency growth. The effect of the intermediate pressure is extremely insignificant and is defined as the geometric mean value of the product of the gas cooler and evaporator pressures. The results show an increase in efficiency of the two-stage CO2 MCRM by up to 31.6% at high temperatures of the environment. In addition, as a result of the exergy analysis, components have been identified, the improvement of which can lead to an additional increase in the efficiency of the entire system. As follows from the data obtained, the greatest attention should be paid to improving the ejector and reducing throttle losses in the CO2 cycle.
Perioperative use of gabapentinoids in pediatric patients
Authors: Burjek Nicholas E. , Hafeman Michael , Guthrie David , Desai Amruta , Jin Zhaosheng , Brockel Megan , Moore Robert
Published: July 2023

Effective management of pediatric perioperative pain is typically goal-directed and multimodal, requiring various imperfect agents in combination to provide analgesia and support recovery. Gabapentinoids are one such class of agents often used in pediatric analgesic and enhanced recovery pathways. In adults, gabapentinoids have been associated with a modest reduction in pain scores but are often avoided due to undesired side effects. Children may be less susceptible to these unwanted effects, and the reduction in pain, agitation, and post-operative nausea and vomiting seen with these medications may confer significant benefit. While further studies are needed, to date there is no evidence to suggest a significantly increased risk of adverse effects in generally healthy children treated with gabapentinoids in the perioperative period. Although current evidence does not support their indiscriminate use, there appears to be a subset of pediatric surgical patients who stand to benefit from perioperative gabapentinoids. Pediatric use should not be abandoned, but rather further investigated to support thoughtful goal-directed application.

Graphical Abstract
Predicting risk of postpartum hemorrhage using machine learning approach: A systematic review
Authors: Ranjbar Amene , Rezaei Ghamsari Sepideh , Boujarzadeh Banafsheh , Mehrnoush Vahid , Darsareh Fatemeh
Published: July 2023

Background

Postpartum hemorrhage (PPH) could be avoided by identifying high-risk women. The objective of this systematic review is to determine PPH predictors using machine learning(ML) approaches.

Method

This strategy included searching for studies from inception through November 2022 through the database included: Cochrane Central Register, PubMed, MEDLINE, EMBASE, ProQuest, Scopus, WOS, IEEE Xplore, and the Google Scholar database. The search methodology employed the PICO framework (population, intervention, control, and outcomes). In this study, “P” represents PPH populations, “I” represents the ML approach as intervention, “C” represents the traditional statistical analysis approach as control, and “O” represents prediction and diagnosis outcomes. The quality assessment of each included study was performed using the PROBAST methodology.

Results

The initial search strategy resulted in 2048 citations, which were subsequently refined by removing duplicates and irrelevant studies. Ultimately, four studies were deemed eligible for inclusion in the review. Among these studies, three were classified as having a low risk of bias, while one was considered to have a low to moderate risk of bias. A total of 549 unique variables were identified as candidate predictors from the included studies. Nine distinct models were chosen as ML algorithms from the four studies. Each of the four studies employed different metrics, such as the area under the curve, false positive rate, false negative rate, and sensitivity, to report the accuracy of their models. The ML models exhibited varying accuracies, with the area under the curve (AUC) ranging from 0.706 to 0.979. Several weighted predictors were identified as significant factors in PPH risk prediction. These included pre-pregnancy maternal weight, maternal weight at the time of admission, fetal macrosomia, gestational age, level of hematocrit at the time of admission, shock index, frequency of contractions during labor, white blood cell count, pregnancy-induced hypertension, the weight of the newborn, duration of the second stage of labor, amniotic fluid index, body mass index, and cesarean delivery before labor. These factors were determined to have a notable influence on the prediction of PPH risk.

Conclusion

The findings from ML models used to predict PPH are highly encouraging.
Full Disclosure
Authors: Fung Archon , Graham Mary , Weil David
Published: July 2023

Governments employ public disclosure strategies to reduce risks, improve public and private goods and services, and reduce injustice. In the United States, these targeted transparency policies include financial securities disclosures, nutritional labels, school report cards, automobile rollover rankings, and sexual offender registries. They constitute a light-handed approach to governance that empowers citizens. However, these policies are frequently ineffective or counterproductive. Based on a comparative analysis of eighteen major policies, the authors suggest that transparency policies often produce information that is incomplete, incomprehensible, or irrelevant to the consumers, investors, workers, and community residents who could benefit from them. Sometimes transparency fails because those who are threatened by it form political coalitions to limit or distort information. To be successful, transparency policies must place the needs of ordinary citizens at centre stage and produce information that informs their everyday choices. This title is also available as Open Access on Cambridge Core.
Measuring in the Renaissance
Authors: Lugli Emanuele
Published: July 2023

During the Renaissance, measuring played a critical role in shaping trade, material production (ranging from architecture to tailoring), warfare, legal studies, and even our understanding of the heavens and hell. This study delves into the applications of measuring, with a particular emphasis on the Italian states, and traces its wide-ranging cultural effects. The homogeneization of measurements was endorsed as a means to achieve political unity. The careful retrieval of ancient standards instilled a sense of connection and ownership toward the past. Surveying was fundamental in the process of establishing colonies. This study not only examines the perceived advantages of measuring, but it also highlights the overlooked distorting aspect of this activity. Measuring was not just a neutral quantification process but also a creative one. By suppressing or emphasizing information about the material world, measuring influenced people's perceptions and shaped their ideas about what was possible and what could be accomplished.
Interrogating representations of transgressive women: Using critical information literacy and comic books in the Shakespeare classroom
Authors: Paterson Susanne F. , Gamtso Carolyn White
Published: July 2023

How can instructors and librarians collaborate to provide the interpretive scaffolds for students to critically engage with visual primary materials? The authors, an English faculty member and a faculty instruction librarian at the University of New Hampshire at Manchester (UNH Manchester), used graphic fiction as the textual basis of information literacy (IL) instruction, encouraging students to interpret primary and secondary sources using visual literacy heuristics and critical inquiry skills. Their student-centered, inquiry-based IL session for a Capstone Shakespearean Adaptations course focused on critical thinking and research question design. Using woodcuts from primary historical texts and images from contemporary graphic fiction adaptations of Macbeth, the instructors decentralized the classroom, empowering students to ask probing questions about illustrations of witches in early modern English source materials. Students used their questions to explore interpretations of visual depictions of powerful women in historical primary texts and contemporary graphic adaptations of Shakespeare's Macbeth. Guided by the instructors, students decoded images using the metadiscourse of graphic fiction; generated questions to inform their own inquiry into the topic; applied their IL skills to new texts; and interrogated the biases of received narratives about women who transgress societal norms and expectations, both in the early modern period and in the contemporary world.
Use of Cognitive Aids to Augment Point of Care Hemorrhage Control Skills in Laypersons
Authors: Dadario Nicholas B. , Shleiwet Nicholas H. , Santana Felipes Rachel C. , Cook Brennan , Cooney Joseph V. , Stephenson Karen M. , Elsmore Michelle , Jafri Farrukh N.
Published: July 2023

Objective:

The Stop the Bleed course aims to improve bystander hemorrhage control skills and may be improved with point-of-care aids. We sought to create and examine a variety of cognitive aids to identify an optimal method to augment bystander hemorrhage control skills in an emergency scenario.

Methods:

Randomized trial of 346 college students. Effects of a visual or visual-audio aid on hemorrhage control skills were assessed through randomization into groups with and without prior training or familiarization with aids compared with controls. Tourniquet placement, wound packing skills, and participant comfortability were assessed during a simulated active shooter scenario.

Results:

A total of 325 (94%) participants were included in the final analyses. Participants who had attended training (odds ratio [OR], 12.67;P= 9.3 × 10−11), were provided a visual-audio aid (OR, 1.96;P= 0.04), and were primed on their aid (OR, 2.23;P= 0.01) were superior in tourniquet placement with less errors (P< 0.05). Using an aid did not improve wound packing scores compared with bleeding control training alone (P> 0.05). Aid use improved comfortability and likelihood to intervene emergency hemorrhage scenarios (P< 0.05).

Conclusions:

Using cognitive aids can improve bystander hemorrhage control skills with the strongest effects if they were previously trained and used an aid which combined visual and audio feedback that they were previously introduced to during the course training.
Evolution of an elastic blister in the presence of sloping topography
Authors: Tobin Sophie , Neufeld Jerome A.
Published: July 2023

The propagation of a finite blister of fluid beneath an elastic sheet is controlled by the local dynamics at the peeling periphery of the current. Previous works have described constant volume elastic blisters by considering the peeling due to curvature at these edges. Here, we show that an along-slope component of gravity fundamentally changes the dynamics by removing the role of curvature at the trailing, upslope edge. The local dynamics of this trailing edge is instead controlled by shear stress in the sheet, as in the elastic Landau–Levich problem, and thereby allows for a receding edge, in contrast to propagation by peeling for which only an advancing contact line is possible. Using an asymptotic analysis, we show that this receding edge condition allows for a new, nearly translating regime in which the body of the blister moves at an approximately constant speed, leaving behind a thin layer of fluid. This prediction is verified by detailed numerical modelling of the two-dimensional downslope spreading. We conclude by discussing the applicability of these results in the rapid spreading of subglacial meltwater.
Endangered maritime archaeology in North Africa – the MarEA Project
Authors: Nikolaus Julia , Westley Kieran , Breen Colin
Published: July 2023

Increasing pressure – such as from conflict, climate change and urbanisation – on maritime cultural heritage in the Middle East and North Africa (MENA) led to the establishment of the Maritime Endangered Archaeology (MarEA) Project in 2019. This five-year programme aims to assess rapidly and comprehensively the vulnerability of maritime and coastal heritage in the MENA region and assist in its management in the face of the aforementioned challenges. The two case studies discussed in this article highlight some of the main aspects of MarEA's current work in North Africa by focusing on two different aspects of the methodological approach used: first, the generalised but comprehensive damage and threat assessment, as applied to all sites, and demonstrated for the historic port of Suakin (Sudan); second, site-specific shoreline change assessment for the purpose of assessing the impact of coastal erosion, as demonstrated for the World Heritage Site of Sabratha (Libya).
Truth without truths: Grim's Cantorian paradox and the ontology of the objects of omniscience
Authors: Catterson Troy T.
Published: July 2023

I argue that Grim's diagonalization argument against the possibility of omniscience is not sound by arguing that the properties of being a proposition or a truth are not legitimate sortal properties. Thus, the fact that there can be no set corresponding to the extension of these properties does not imply that there is no completed totality of the things possessing it. First, I demonstrate that a correspondence theory of truth implies that propositions are non-linguistic representations of a type that resist determinate and uniform individuation into units and allow for arbitrary division into parts that are also propositions. The property is, therefore, an abstract mass property with no determinate cardinality of individuals that possess it. I then sketch a new theory of omniscience with this as its basis.
Predictors of executive function trajectories in adolescents with and without ADHD: Links with academic outcomes
Authors: Shroff Delshad M. , Dunn Nicholas C. , Green Cathrin D. , Breaux Rosanna , Becker Stephen P. , Langberg Joshua M.
Published: July 2023

Changes in executive function (EF) occur during adolescence with several factors (e.g., parenting styles, socioeconomic status) influencing the development of EF abilities. These changes are important as EF has been strongly linked with a range of outcomes including academic achievement, job performance, and social–emotional well-being. However, few studies have examined variability in EF trajectories during this critical developmental period, or trajectories in samples known to have specific impairments with EF, such as adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD). The present study examined differential trajectories of three domains of parent-rated EF in 302 adolescents (167 males; Mage = 13.17 years) with and without ADHD (53.6% with ADHD) from grade 8 to 10. The study also explored whether adolescent ADHD, parent ADHD, and parents’ own EF predicted EF trajectories in addition to the longitudinal relation between trajectories and academic outcomes. Findings suggest that adolescence is marked by significant variability in EF development due to factors such as ADHD status, parent ADHD, and parent EF ability. Additionally, adolescents who displayed poor EF abilities throughout middle and high school had significantly lower grade point averages and poorer parent-, teacher-, and self-reported academic outcomes. Implications for interventions targeting EF deficits among adolescents with and without ADHD are discussed.
What are the experiences of nurses delivering research studies in primary care?
Authors: Ballintine Azaria , Potter Rachel
Published: July 2023

Background:

Clinical research provides evidence to underpin and inform advancements in the quality of care, services and treatments. Primary care research enables the general patient population access and opportunities to engage in research studies. Nurses play an integral role in supporting the delivery of primary care research, but there is limited understanding of nurses’ experiences of this role and how they can be supported to facilitate the delivery of research.

Aim:

To explore the experiences of nurses delivering research studies in primary care settings.

Methods:

We identified studies published between 2002 and June 2021 from key electronic databases. A two-level inclusion/exclusion and arbitration process was conducted based on study selection criteria. Data extraction and quality appraisal were performed simultaneously. Data were analysed in the form of a narrative synthesis.

Findings:

The key themes identified included: (1) what nurses value about primary care research and their motivations for study engagement, (2) the role of nurses in research, (3) working with research teams, (4) study training, (5) eligibility screening, data collection and study documentation, (6) nurse/participant dynamic, (7) gatekeeping, (8) relationships with colleagues and impact on recruitment, (9) time constraints and workload demands, and (10) health and safety.

Conclusions:

Nurses are integral to the delivery of research studies in primary care settings. The review highlights the importance of good communication by study teams, timely and study-specific training, and support from colleagues to enable nurses to effectively deliver research in primary care.
Nurses’ models of spiritual care: A cross-sectional survey of American nurses
Authors: Mascio Rita , Lynch Sandra , Phillips Jane L. , Hosie Annmarie , Best Megan
Published: July 2023

Objectives

Despite there being many models for how spiritual care should be provided, the way nurses actually provide spiritual care often differs from these models. Based on the premise that the way a person enacts their work role is related to how they understand that role, this study aims to describe the qualitatively different ways that nurses understand their spiritual care role.

Methods

A convenience sample of 66 American nurses completed an anonymous, online questionnaire about what spiritual care means for them and what they generally do to provide spiritual care. Their responses were analyzed phenomenographically.

Results

Four qualitatively different ways of understanding emerged: active management of the patient’s experience, responsive facilitation of patient’s wishes, accompaniment on the patient’s dying journey, and empowering co-action with the patient. Each understanding was found to demonstrate a specific combination of 5 attributes that described the spiritual care role: nurse directivity, the cues used for spiritual assessment, and the nurse’s perception of intimacy, the patient, and the task.

Significance of results

The findings of this study may explain why nurses vary in their spiritual care role and can be used to assess and develop competence in spiritual care.
Performant web-based interactive visualization tool for spatially-resolved transcriptomics experiments
Authors: Sriworarat Chaichontat , Nguyen Annie , Eagles Nicholas J. , Collado-Torres Leonardo , Martinowich Keri , Maynard Kristen R. , Hicks Stephanie C.
Published: July 2023

High-resolution and multiplexed imaging techniques are giving us an increasingly detailed observation of a biological system. However, sharing, exploring, and customizing the visualization of large multidimensional images can be a challenge. Here, we introduce Samui, a performant and interactive image visualization tool that runs completely in the web browser. Samui is specifically designed for fast image visualization and annotation and enables users to browse through large images and their selected features within seconds of receiving a link. We demonstrate the broad utility of Samui with images generated with two platforms: Vizgen MERFISH and 10x Genomics Visium Spatial Gene Expression. Samui along with example datasets is available at https://samuibrowser.com.
Exploring Pathways and Obstacles to Well-Being in Victims of Terrorism: A Qualitative Approach
Authors: Pemau Andrés , Marín-Martín Carolina , Hervás Gonzalo , Gómez-Gutiérrez María del Mar , Crespo María
Published: July 2023

On March 11, 2004, Madrid suffered one of the worst terrorist attacks in the history of Spain, leaving more than 190 dead and 2,000 injured. For years, the psychological consequences of the attacks have been studied; however, its long-term effects on symptomatology and especially on well-being remains unknown. This study aims to explore, through a qualitative approach, pathways and obstacles to the well-being of those affected directly or indirectly by the attacks of March 11 in Madrid. Two focus groups were held, one for indirect victims and one for direct victims. Subsequently, a thematic analysis of the materials obtained was carried out. More than 10 years after the attacks, most of the participants reported great difficulty in achieving well-being. Acceptance and victims’ associations seemed to act as key facilitators, while symptoms, political institutions and the media were the main obstacles. Direct and indirect victims presented similar data although aspects such as guilt and family relationships played a different role in their well-being.
Null Effects of Pro-Democracy Speeches by U.S. Republicans in the Aftermath of January 6th
Authors: Wuttke Alexander , Sichart Florian , Foos Florian
Published: July 2023

How can political elites strengthen citizen commitment to democratic norms when democracy is under imminent assault? We report results from a pre-registered survey experiment on the persuasive effects of actual speeches given by prominent Republican politicians (Schwarzenegger, McConnell) shortly after the January 2020 insurrection at the U.S. capitol. Although both speeches were widely considered effective at the time, in a survey experiment among Republican voters, we find no impact of one-time exposure to these speeches on the endorsement of democracy, the acceptance of election losses, the rejection of political violence, or the relevance of democratic norms in hypothetical vote choices.
Phanerozoic Tectonic and Sedimentation History of the Arctic: Constraints From Deep‐Time Low‐Temperature Thermochronology Data of Ellesmere Island and Northwest Greenland
Authors: Spiegel Cornelia , Sohi Mohammad S. , Reiter Wolfgang , Meier Katrin , Ventura Barbara , Lisker Frank , Estrada Solveig , Piepjohn Karsten , Berglar Kai , Koglin Nikola , Klügel Andreas , Monien Patrick , Gerdes Axel , Linnemann Ulf
Published: July 2023

Rocks exposed along both sides of the Smith Sound in Ellesmere Island and NW Greenland record the tectono‐sedimentary evolution of the whole Phanerozoic, including two periods of mountain building—the Palaeozoic Ellesmerian Orogeny and the Palaeogene Eurekan Orogeny—and the formation of two major sedimentary basins, the Franklinian and the Sverdrup Basins. We used geo‐ and thermochronology and apatite chemistry data to unravel this evolution. Apatite fission track and (U‐Th)/He dates vary strongly from >600 to <100 Ma. We present internally consistent thermal history models, which allow to explain the data variations by a unitized exhumation and burial history. Our models suggest that the cratonic areas were buried beneath a several km‐thick succession of Franklinian Basin deposits. During the Ellesmerian Orogeny, the craton acted as sediment source, as also suggested by the composition of apatite and by U‐Pb ages of zircon contained in Devonian foreland sediments. The Ellesmerian foreland was buried by up to 4–5 km thick strata on top of the preserved sedimentary rocks. During the Triassic, the Sverdrup Basin strongly widened and extended at least ∼370 km further toward the east, as compared with previous reconstructions of the basin based on the preservation of Triassic deposits. Thermal history modeling suggests Late Cretaceous to early Cenozoic reheating, which may be caused by deposition associated with the Eurekan Orogeny and/or enhanced heat flow associated with continental breakup. Our data also show that low‐temperature thermochronology is not suitable for resolving potential strike‐slip movements along the Wegener Fault.
A Lagrangian Estimate of the Mediterranean Outflow's Origin
Authors: Vecchioni G. , Cessi P. , Pinardi N. , Rousselet Louise , Trotta F.
Published: July 2023

The origin of the Mediterranean Outflow is investigated by deploying six millions virtual Lagrangian parcels at the Strait of Gibraltar, and tracing them backward in time using velocity estimates from an eddy‐permitting reanalysis. The Lagrangian parcels are followed until they intercept one of three sections. The hypothesis is that each section is associated with distinct water masses: the Gulf of Lions, related to Western Mediterranean Deep Water and Western Intermediate Water, carries 86% of the Outflow's transport; the Northern Tyrrhenian, related to Tyrrhenian Deep and Intermediate Waters, carries 1% of the transport; the Strait of Sicily, related to Levantine Intermediate Waters, carries 13% of the transport. The median transit times from the sections to the Strait of Gibraltar range from 5 years (Gulf of Lions) to 8 years (Strait of Sicily).
WWLLN Energetic Lightning Events Are Different From Optical Superbolts
Authors: Peterson Michael
Published: July 2023

The most powerful optical emissions from lightning have been described as “superbolts” since the 1970s. Holzworth et al. (2019, https://doi.org/10.1029/2019jd030975) recently applied the superbolt label to the most energetic Radio Frequency emissions recorded by the World Wide Lightning Location Network (WWLLN). We compare the WWLLN energies to optical measurements by the photodiode detector on the Fast On‐orbit Recording of Transient Events satellite and the Geostationary Lightning Mappers on NOAA's Geostationary Operational Environmental Satellites to assess whether these energetic WWLLN events coincide with optical superbolts. We find no overlap between optical and WWLLN superbolts. Moreover, extreme WWLLN events occur in a contrasting meteorological context to optical superbolts. Despite similarities in their overall global patterns of occurrence, WWLLN superbolts correspond to a different phenomenon.
Engineering prostate cancer in vitro: what does it take?
Authors: Buskin Adriana , Scott Emma , Nelson Ryan , Gaughan Luke , Robson Craig N. , Heer Rakesh , Hepburn Anastasia C.
Published: July 2023

A key challenge in the clinical management and cause of treatment failure of prostate cancer (PCa) is its molecular, cellular and clinical heterogeneity. Modelling systems that fully recapitulate clinical diversity and resistant phenotypes are urgently required for the development of successful personalised PCa therapies. The advent of the three-dimensional (3D) organoid model has revolutionised preclinical cancer research through reflecting heterogeneity and offering genomic and environmental manipulation that has opened up unparalleled opportunities for applications in disease modelling, high-throughput drug screening and precision medicine. Despite these remarkable achievements of organoid technology, several shortcomings in emulating the complex tumor microenvironment and dynamic process of metastasis as well as the epigenome profile limit organoids achieving true in vivo functionality. Technological advances in tissue engineering have enabled the development of innovative tools to facilitate the design of improved 3D cancer models. In this review, we highlight the current in vitro 3D PCa models with a special focus on organoids and discuss engineering approaches to create more physiologically relevant PCa organoid models and maximise their translational relevance that ultimately will help to realise the transformational power of precision medicine.
Colorectal cancer detected by liquid biopsy 2 years prior to clinical diagnosis in the HUNT study
Authors: Brenne Siv S. , Madsen Poul Henning , Pedersen Inge Søkilde , Hveem Kristian , Skorpen Frank , Krarup Henrik Bygum , Giskeødegård Guro F. , Laugsand Eivor A.
Published: July 2023

Background

Colorectal cancer (CRC) is often diagnosed in advanced stages. Circulating tumour DNA (ctDNA) has been proposed as an early diagnostic biomarker. However, as a screening tool, ctDNA has mainly been studied in selected populations at the time of clinical diagnosis. The aim of this study was to detect CRC by known ctDNA markers up to 2 years prior to clinical diagnosis.

Methods

In this case–control study, methylated ctDNA markers were detected in plasma samples from 106 healthy controls and 106 individuals diagnosed with CRC within 24 months following participation in The Trøndelag Health Study.

Results

The most specific single markers were BMP3, FLI1, IKZF1, SFRP1, SFRP2, NPTX2, SLC8A1 and VIM (specificity >70%). When combining these into a panel, the CRC sensitivity was 43% (95% CI 42.7–43.4) and the CRC specificity was 86% (95% CI 85.7–86.2). The findings were reproduced in an independent validation set of samples.

Conclusions

Detection of known methylated ctDNA markers of CRC is possible up to 2 years prior to the clinical diagnosis in an unselected population resembling the screening setting. This study supports the hypothesis that some patients could be diagnosed earlier, if ctDNA detection was part of the CRC screening programme.
Transcriptome profiling and network enrichment analyses identify subtype-specific therapeutic gene targets for breast cancer and their microRNA regulatory networks
Authors: Elango Ramesh , Rashid Sameera , Vishnubalaji Radhakrishnan , Al-Sarraf Reem , Akhtar Mohammed , Ouararhni Khalid , Decock Julie , Albagha Omar M. E. , Alajez Nehad M.
Published: July 2023

Previous studies have suggested that breast cancer (BC) from the Middle East and North Africa (MENA) is presented at younger age with advanced tumor stage, indicating underlying biological differences. Given the scant transcriptomic data on BC from the MENA region and to better understand the biology of this disease, we performed mRNA and microRNA (miRNA) transcriptomic profiling on a local cohort of BC (n = 96) from Qatar. Our data revealed the differentially expressed genes and miRNAs as function of BC molecular subtypes (HR+, HER2+, HER2+HR+, and TNBC), tumor grade (GIII vs GI-II), patients’ age (young (≤40) vs old (>40)), and ethnicity (MENA vs non-MENA). Our profiling data revealed close similarity between TNBC and HER2+, while the transcriptome of HER2+HR+tumor was resemblant of that from HR+tumors. Network analysis identified complex miRNA-mRNA regulatory networks in each BC molecular subtype, in highvslow grade tumors, in tumors from young vs old patients, and in tumors from MENA vs non-MENA, thus implicating miRNA-mediated gene regulation as an essential mechanism in shaping the transcriptome of BC. Integration of our transcriptomic data with CRISPR-Cas9 functional screen data and the OncoKB database identified numerous dependencies and therapeutic vulnerabilities in each BC molecular subtype, while CDC123 was functionally validated as potential therapeutic target for TNBC. Cox regression survival analyses identified mRNA and miRNA-based signatures predicative of worse and better relapse free survival (RFS), which were validated in larger BC cohorts. Our data provides comprehensive transcriptomic profiling and unraveled the miRNA-mRNA regulatory networks in BC patients from the region and identified novel actionable gene targets, employing integrated approach. Findings from the current study have potential implications to improve the current standard-of-care for BC from the MENA as well as patients from other ethnicities.
METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/β-catenin signaling
Authors: Yin Jianxing , Ding Fangshu , Cheng Zhangchun , Ge Xin , Li Yanhui , Zeng Ailiang , Zhang Junxia , Yan Wei , Shi Zhumei , Qian Xu , You Yongping , Ding Zhiliang , Ji Jing , Wang Xiefeng
Published: July 2023

Long noncoding RNAs (lncRNAs) are involved in glioma initiation and progression. Glioma stem cells (GSCs) are essential for tumor initiation, maintenance, and therapeutic resistance. However, the biological functions and underlying mechanisms of lncRNAs in GSCs remain poorly understood. Here, we identified that LINC00839 was overexpressed in GSCs. A high level of LINC00839 was associated with GBM progression and radiation resistance. METTL3-mediated m6A modification on LINC00839 enhanced its expression in a YTHDF2-dependent manner. Mechanistically, LINC00839 functioned as a scaffold promoting c-Src-mediated phosphorylation of β-catenin, thereby inducing Wnt/β-catenin activation. Combinational use of celecoxib, an inhibitor of Wnt/β-catenin signaling, greatly sensitized GSCs to radiation. Taken together, our results showed that LINC00839, modified by METTL3-mediated m6A, exerts tumor progression and radiation resistance by activating Wnt/β-catenin signaling.
IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype
Authors: Domínguez-Zorita Sonia , Romero-Carramiñana Inés , Santacatterina Fulvio , Esparza-Moltó Pau B. , Simó Carolina , del-Arco Araceli , Núñez de Arenas Cristina , Saiz Jorge , Barbas Coral , Cuezva José M.
Published: July 2023

ATPase Inhibitory Factor 1 (IF1) regulates the activity of mitochondrial ATP synthase. The expression of IF1 in differentiated human and mouse cells is highly variable. In intestinal cells, the overexpression of IF1 protects against colon inflammation. Herein, we have developed a conditional IF1-knockout mouse model in intestinal epithelium to investigate the role of IF1 in mitochondrial function and tissue homeostasis. The results show that IF1-ablated mice have increased ATP synthase/hydrolase activities, leading to profound mitochondrial dysfunction and a pro-inflammatory phenotype that impairs the permeability of the intestinal barrier compromising mouse survival upon inflammation. Deletion of IF1 prevents the formation of oligomeric assemblies of ATP synthase and alters cristae structure and the electron transport chain. Moreover, lack of IF1 promotes an intramitochondrial Ca2+ overload in vivo, minimizing the threshold to Ca2+-induced permeability transition (mPT). Removal of IF1 in cell lines also prevents the formation of oligomeric assemblies of ATP synthase, minimizing the threshold to Ca2+-induced mPT. Metabolomic analyses of mice serum and colon tissue highlight that IF1 ablation promotes the activation of de novo purine and salvage pathways. Mechanistically, lack of IF1 in cell lines increases ATP synthase/hydrolase activities and installs futile ATP hydrolysis in mitochondria, resulting in the activation of purine metabolism and in the accumulation of adenosine, both in culture medium and in mice serum. Adenosine, through ADORA2B receptors, promotes an autoimmune phenotype in mice, stressing the role of the IF1/ATP synthase axis in tissue immune responses. Overall, the results highlight that IF1 is required for ATP synthase oligomerization and that it acts as a brake to prevent ATP hydrolysis under in vivo phosphorylating conditions in intestinal cells.
Differential associations between body composition indices and neurodevelopment during early life in term-born infants: findings from the Pakistan cohort: Multi-Center Body Composition Reference Study
Authors: Ariff Shabina , Aamir Almas , Young Aneurin , Sikanderali Laila , Rizvi Arjumand , Shaheen Fariha , Khan Gul Nawaz , Soofi Sajid , Fernandes Michelle
Published: July 2023

Objective

We examined associations between fat free mass (FFM) and fat mass (FM) accretion during the first 1000 days of life and neurodevelopment in term-born, low-risk infants from Karachi, Pakistan.

Design

Prospective, observational study nested within the larger Multi-Center Body Composition Reference Study. FFM, FM, and fat% were estimated using measured deuterium dilution method. Neurodevelopmental outcomes were assessed at 24 months on the INTER-NDA (INTERGROWTH-21st Project Neurodevelopment Assessment) (n = 132).

Results

Children with gross motor delays had significantly lower FFM at 18 months (8.01 ± 0.97 kg vs. 7.55 ± 0.20 kg). Children with positive and negative behavior problems had significantly higher fat% at 24 months (20.62 ± 4.30% vs. 18.23 ± 5.46%) and 20.89 ± 4.24% vs. 18.54 ± 5.38%). No associations remained significant after adjusting for covariates. Trajectory modeling showed that between 12 and 18 months, negative behavior scores changed by 13.8 points for every standard deviation change in fat accretion.

Conclusions

Our findings highlight the importance of balancing neurodevelopment and metabolic risk when designing nutritional interventions for young children.
Mixed strain pathogen populations accelerate the evolution of antibiotic resistance in patients
Authors: Diaz Caballero Julio , Wheatley Rachel M. , Kapel Natalia , López-Causapé Carla , Van der Schalk Thomas , Quinn Angus , Shaw Liam P. , Ogunlana Lois , Recanatini Claudia , Xavier Basil Britto , Timbermont Leen , Kluytmans Jan , Ruzin Alexey , Esser Mark , Malhotra-Kumar Surbhi , Oliver Antonio , MacLean R. Craig
Published: July 2023

Antibiotic resistance poses a global health threat, but the within-host drivers of resistance remain poorly understood. Pathogen populations are often assumed to be clonal within hosts, and resistance is thought to emerge due to selection for de novo variants. Here we show that mixed strain populations are common in the opportunistic pathogenP. aeruginosa. Crucially, resistance evolves rapidly in patients colonized by multiple strains through selection for pre-existing resistant strains. In contrast, resistance evolves sporadically in patients colonized by single strains due to selection for novel resistance mutations. However, strong trade-offs between resistance and growth rate occur in mixed strain populations, suggesting that within-host diversity can also drive the loss of resistance in the absence of antibiotic treatment. In summary, we show that the within-host diversity of pathogen populations plays a key role in shaping the emergence of resistance in response to treatment.
AI-designed NMR spectroscopy RF pulses for fast acquisition at high and ultra-high magnetic fields
Authors: Manu V. S. , Olivieri Cristina , Veglia Gianluigi
Published: July 2023

Nuclear magnetic resonance (NMR) spectroscopy is a powerful high-resolution tool for characterizing biomacromolecular structure, dynamics, and interactions. However, the lengthy longitudinal relaxation of the nuclear spins significantly extends the total experimental time, especially at high and ultra-high magnetic field strengths. Although longitudinal relaxation-enhanced techniques have sped up data acquisition, their application has been limited by the chemical shift dispersion. Here we combined an evolutionary algorithm and artificial intelligence to design 1H and 15N radio frequency (RF) pulses with variable phase and amplitude that cover significantly broader bandwidths and allow for rapid data acquisition. We re-engineered the basic transverse relaxation optimized spectroscopy experiment and showed that the RF shapes enhance the spectral sensitivity of well-folded proteins up to 180 kDa molecular weight. These RF shapes can be tailored to re-design triple-resonance experiments for accelerating NMR spectroscopy of biomacromolecules at high fields.
Expanded quantum vortex liquid regimes in the electron nematic superconductors FeSe1−xSx and FeSe1−xTex
Authors: Čulo M. , Licciardello S. , Ishida K. , Mukasa K. , Ayres J. , Buhot J. , Hsu Y.-T. , Imajo S. , Qiu M. W. , Saito M. , Uezono Y. , Otsuka T. , Watanabe T. , Kindo K. , Shibauchi T. , Kasahara S. , Matsuda Y. , Hussey N. E.
Published: July 2023

The quantum vortex liquid (QVL) is an intriguing state of type-II superconductors in which intense quantum fluctuations of the superconducting (SC) order parameter destroy the Abrikosov lattice even at very low temperatures. Such a state has only rarely been observed, however, and remains poorly understood. One of the key questions is the precise origin of such intense quantum fluctuations and the role of nearby non-SC phases or quantum critical points in amplifying these effects. Here we report a high-field magnetotransport study of FeSe1−xSx and FeSe1−xTex which show a broad QVL regime both within and beyond their respective electron nematic phases. A clear correlation is found between the extent of the QVL and the strength of the superconductivity. This comparative study enables us to identify the essential elements that promote the QVL regime in unconventional superconductors and to demonstrate that the QVL regime itself is most extended wherever superconductivity is weakest.
The MOM1 complex recruits the RdDM machinery via MORC6 to establish de novo DNA methylation
Authors: Li Zheng , Wang Ming , Zhong Zhenhui , Gallego-Bartolomé Javier , Feng Suhua , Jami-Alahmadi Yasaman , Wang Xinyi , Wohlschlegel James , Bischof Sylvain , Long Jeff A. , Jacobsen Steven E.
Published: July 2023

MORPHEUS’ MOLECULE1 (MOM1) is an Arabidopsis factor previously shown to mediate transcriptional silencing independent of major DNA methylation changes. Here we find that MOM1 localizes with sites of RNA-directed DNA methylation (RdDM). Tethering MOM1 with an artificial zinc finger to an unmethylated FWA promoter leads to establishment of DNA methylation and FWA silencing. This process is blocked by mutations in components of the Pol V arm of the RdDM machinery, as well as by mutation of MICRORCHIDIA 6 (MORC6). We find that at some endogenous RdDM sites, MOM1 is required to maintain DNA methylation and a closed chromatin state. In addition, efficient silencing of newly introduced FWA transgenes is impaired in the mom1 mutant. In addition to RdDM sites, we identify a group of MOM1 peaks at active chromatin near genes that colocalized with MORC6. These findings demonstrate a multifaceted role of MOM1 in genome regulation.
Three-dimensional images reveal the impact of the endosymbiont Midichloria mitochondrii on the host mitochondria
Authors: Uzum Zerrin , Ershov Dmitry , Pavia Michael J. , Mallet Adeline , Gorgette Olivier , Plantard Olivier , Sassera Davide , Stavru Fabrizia
Published: July 2023

The hard tick, Ixodes ricinus, a main Lyme disease vector, harbors an intracellular bacterial endosymbiont. Midichloria mitochondrii is maternally inherited and resides in the mitochondria of I. ricinus oocytes, but the consequences of this endosymbiosis are not well understood. Here, we provide 3D images of wild-type and aposymbiotic I. ricinus oocytes generated with focused ion beam-scanning electron microscopy. Quantitative image analyses of endosymbionts and oocyte mitochondria at different maturation stages show that the populations of both mitochondrion-associated bacteria and bacterium-hosting mitochondria increase upon vitellogenisation, and that mitochondria can host multiple bacteria in later stages. Three-dimensional reconstructions show symbiosis-dependent morphologies of mitochondria and demonstrate complete M. mitochondrii inclusion inside a mitochondrion. Cytoplasmic endosymbiont located close to mitochondria are not oriented towards the mitochondria, suggesting that bacterial recolonization is unlikely. We further demonstrate individual globular-shaped mitochondria in the wild type oocytes, while aposymbiotic oocytes only contain a mitochondrial network. In summary, our study suggests that M. mitochondrii modulates mitochondrial fragmentation in oogenesis possibly affecting organelle function and ensuring its presence over generations.
Reconstructed Ir‒O‒Mo species with strong Brønsted acidity for acidic water oxidation
Authors: Chen Shiyi , Zhang Shishi , Guo Lei , Pan Lun , Shi Chengxiang , Zhang Xiangwen , Huang Zhen-Feng , Yang Guidong , Zou Ji-Jun
Published: July 2023

Surface reconstruction generates real active species in electrochemical conditions; rational regulating reconstruction in a targeted manner is the key for constructing highly active catalyst. Herein, we use the high-valence Mo modulated orthorhombic Pr3Ir1−xMoxO7 as model to activate lattice oxygen and cations, achieving directional and accelerated surface reconstruction to produce self-terminated Ir‒Obri‒Mo (Obri represents the bridge oxygen) active species that is highly active for acidic water oxidation. The doped Mo not only contributes to accelerated surface reconstruction due to optimized Ir‒O covalency and more prone dissolution of Pr, but also affords the improved durability resulted from Mo-buffered charge compensation, thereby preventing fierce Ir dissolution and excessive lattice oxygen loss. As such, Ir‒Obri‒Mo species could be directionally generated, in which the strong Brønsted acidity of Obri induced by remaining Mo assists with the facilitated deprotonation of oxo intermediates, following bridging-oxygen-assisted deprotonation pathway. Consequently, the optimal catalyst exhibits the best activity with an overpotential of 259 mV to reach 10 mA cmgeo−2, 50 mV lower than undoped counterpart, and shows improved stability for over 200 h. This work provides a strategy of directional surface reconstruction to constructing strong Brønsted acid sites in IrOx species, demonstrating the perspective of targeted electrocatalyst fabrication under in situ realistic reaction conditions.
Detecting diagnostic features in MS/MS spectra of post-translationally modified peptides
Authors: Geiszler Daniel J. , Polasky Daniel A. , Yu Fengchao , Nesvizhskii Alexey I.
Published: July 2023

Post-translational modifications are an area of great interest in mass spectrometry-based proteomics, with a surge in methods to detect them in recent years. However, post-translational modifications can introduce complexity into proteomics searches by fragmenting in unexpected ways, ultimately hindering the detection of modified peptides. To address these deficiencies, we present a fully automated method to find diagnostic spectral features for any modification. The features can be incorporated into proteomics search engines to improve modified peptide recovery and localization. We show the utility of this approach by interrogating fragmentation patterns for a cysteine-reactive chemoproteomic probe, RNA-crosslinked peptides, sialic acid-containing glycopeptides, and ADP-ribosylated peptides. We also analyze the interactions between a diagnostic ion’s intensity and its statistical properties. This method has been incorporated into the open-search annotation tool PTM-Shepherd and the FragPipe computational platform.