bluuebunny/crossref_metadata_2025 huggingface dataset:
The Doctrine of Salvation
Authors: McGrath Alister E.
Published: January 2024

This final chapter explores how Christian doctrine offers a theological mapping of the transformative potential of the Christian faith, affirming and exhibiting both the coherence and comprehensiveness of the Christian idea of salvation. After noting the problems with over-intellectualization when theorizing the atonement, the chapter explores the theological virtues of coherence and comprehensiveness in more detail, considering how theological reflection on the ‘Benefits of Christ’ discloses a coherent reality that is partly disclosed through individual concepts of salvation. This allows both the coherence and complexity of salvation to be affirmed. This point is explored in more detail by considering four models of salvation: the restoration and reinterpretation of cultic purity; the restoration of wholeness; deliverance from bondage; and familial relocation, expressed in the metaphor of ‘adoption’.
Conclusion
Authors: McGrath Alister E.
Published: January 2024

The conclusion considers the general implications of the approach developed in this book, which indicates that doctrine is an inevitable, legitimate, and necessary development, which both preserves and articulates the illuminating and transformative aspects of the Christian faith. While some suggest that the future of Christianity lies in the marginalization of doctrine, the arguments presented here suggest that the forms of Christianity that will survive in the future will probably be those with a strong sense of doctrinal commitment. Perhaps more importantly, this analysis has implications for how Christian doctrine should be taught—not as verbal formulae to be memorized, but rather as the articulation of a grand and transformative vision of reality, which demands (but cannot be reduced to) verbal expression.
Introduction
Authors: Ward Matthew
Published: January 2024

This Introduction opens at the end of our period with the claim of Edward Synge that Irish Anglicans resorted habitually to ‘Hobbian’ arguments. This claim has implications for the histories of the geography of Hobbes’s reception and of political thought in Ireland, both of which are then reviewed. These reviews establish the book’s debt to a certain conception of the history of ‘British’ political thought more widely: one which studies the interactions between the public discourses of different places in the British world and appreciates that the conditions of discourse varied between places. The conditions of the public discourse in which Hobbes was received in Ireland are characterized, and the term ‘thinking with Hobbes’ is coined to describe the distinctive engagements with Hobbes that the book uncovers in the works of Petty, Vesey, and Synge. The Introduction concludes by summarizing these works and the book’s contribution to their histories.
Edward Synge and ‘Hobbian’ Discourse in Early Eighteenth-Century Ireland
Authors: Ward Matthew
Published: January 2024

The final chapter returns to where the book started: Edward Synge’s claim about the reliance of Irish Anglicans on ‘Hobbian’ arguments. By now, the reader should have a clearer idea of what Synge was talking about. Synge made his claim in The Case of Toleration, which, having rejected as ‘Hobbian’ the Anglican claim that the right of civil authority to enforce religious uniformity derived from natural law, made a proposal for Catholic toleration. This chapter disputes the popular interpretation of The Case as a confident expression of Enlightenment values. Along with his father—Edward Syge the elder—and his clerical coterie—his fellow chaplains of Lord John Carteret, the lord lieutenant—Synge had recently employed the very arguments that he characterized as ‘Hobbian’ in The Case. Synge thus focussed more on this characterization than on his proposal for toleration, which he ultimately diluted and modified in response to Hobbes.
Human Motives
Authors: Carruthers Peter
Published: January 2024

Motivational hedonism (often called “psychological hedonism”) claims that everything we do is done in pursuit of pleasure (in the widest sense) and to avoid pain and displeasure (again, in the widest sense). Although perennially attractive, many philosophers and experimental psychologists have claimed to refute it. This work shows how decision-science and the recent science of affect can be used to construct a form of motivational hedonism that evades all previous critiques. On this view, we take decisions by anticipating and responding affectively to the alternatives, with the pleasure/displeasure component of affect constituting the common currency of decision-making. But we do not have to believe that the alternatives will bring us pleasure or displeasure in the future. Rather, those feelings get bound into and become parts of the future-directed representation of the options, rendering the latter attractive or repulsive. Much then depends on what pleasure and displeasure really are. If they are intrinsically good or bad properties of experience, for example, then motivational hedonism results. The author argues, in contrast, that the best account is a representational one: pleasure represents its object (nonconceptually, in a perception-like manner) as good, and displeasure represents it (nonconceptually) as bad. The result is pluralism about human motivation, making room for both genuine altruism and intrinsic motives of duty.
Kant's Impact on Moral Philosophy
Authors: Guyer Paul
Published: January 2024

Immanuel Kant’s Groundwork for the Metaphysics of Morals in 1785, followed by his Critique of Practical Reason in 1788, Religion within the Boundaries of Mere Reason in 1793, and Metaphysics of Morals in 1798, introduced a new paradigm into modern moral philosophy. For Kant, the fundamental goal of morality is not the realization of the greatest happiness for the greatest number, but the realization of human autonomy governed by pure reason through the “categorical imperative.” Kant’s ideal of autonomy is nothing less than the greatest possible freedom of each human being to set his or her own ends compatible with the equal freedom of every other human being to do the same. Kant’s work immediately drew the attention of both critics and supporters. While some argued that Kant’s categorical imperative was an “empty formalism,” that he left no room for happiness in his morality, that he could not explain responsibility for evil, and that he allowed no room for moral feeling in morally worthy motivation, others have found inspiration in his underlying idea that maximal but equal freedom is the “inner worth of the world.” This book examines the response to Kant by philosophers from Fichte, Schelling, and Hegel through T. H. Green, Josiah Royce, and Friedrich Nietzsche, to John Rawls, Onora O’Neill, Christine Korsgaard, and Derek Parfit, with many stops along the way. It argues that the most profound responses to Kant have been precisely those that have developed in their own way Kant’s ideal of freedom as the inner worth of the world.
The Development of Kant’s Moral Philosophy from 1764–5 to 1781
Authors: Guyer Paul
Published: January 2024

This chapter examines the development of Kant’s moral philosophy prior to the publication of the Critique of Pure Reason in 1781. The primary sources for this chapter are student transcriptions of Kant’s lectures in his class on moral philosophy, notes in his own hand for these lectures, and brief comments in some of his early publications. The argument is that Kant gradually evolved his underlying conception of freedom itself as our fundamental moral value, but freedom as intra- and interpersonal, that is, the greatest possible consistency in one’s own use of freedom and between one’s own use of freedom and that of all others. The chapter also examines Kant’s development of an argument for this position that was gradually transformed from a psychological into a more purely logical argument.
Kant in Cambridge
Authors: Guyer Paul
Published: January 2024

This chapter examines the responses to Kant’s moral philosophy from two famous Cambridge philosophers, Henry Sidgwick and his student G. E. Moore. Sidgwick defended “egoistic” and “universalistic” versions of utilitarianism, without being able to choose between them, against Kant’s categorical imperative. His criticism is basically a form of the “empty formalism” objection, and he did not recognize the substantive value of freedom as the basis of Kant’s moral philosophy. He also famously objected that Kant failed to distinguish between “moral” or “neutral” freedom and “rational” freedom, i.e., between freedom of the will and freedom as a value to be realized, although this distinction is precisely what Kant’s later treatment of freedom aims at. In one of his earliest papers, Moore soundly criticized Kant’s transcendental idealist theory of freedom of the will, and few have attempted to defend that since. Moore’s chief work Principia Ethica attacks both earlier forms of utilitarianism and Kantianism as examples of the “naturalistic fallacy,” the view that moral goodness can be defined in any way rather than simply grasped in the intuition of a synthetic rather than analytic proposition. This rejection of all previous moral philosophy has itself led to obscure forms of “intuitionism” and “moral realism.”
Kant in Oxford
Authors: Guyer Paul
Published: January 2024

The early twentieth-century Oxford “intuitionists” Harold Prichard and David Ross accepted what they took to be Kant’s “deontological” rather than “teleological” approach to moral philosophy (using terminology originally introduced by Jeremy Bentham and revived by the Cambridge Philosopher C. D. Broad). But while Kant had held that there could never be such a thing as a conflict of duties, only conflicting “grounds of obligation,” they rejected his single categorical imperative (even if it had multiple formulations) in favor of a non-reducible plurality of “prima facie” or “pro tanto” duties, conflict among which cannot be resolved by any higher-order principle. We know what we should do only by “intuition.” (Broad developed a similar view in Cambridge.) Later Elizabeth Anscombe advocated a similar view, while Bernard Williams went further, in conscious opposition to Kant, in arguing that ethical duties do not automatically outweigh personal “projects.” All of these philosophers rejected what they saw as Kantian universalism in favor of some form of what has come to be known as particularism.
Adoption intentions of smart weeding technologies—A lab-in-the-field experiment with German crop farmers
Authors: Feisthauer Philipp , Hartmann Monika , Börner Jan
Published: January 2024

Smart weeding technologies (SWT) enable substantial herbicide savings via precise sensor-based application. This can enhance agrobiodiversity and make modern agriculture more sustainable. Currently, our knowledge about what will determine SWT adoption at the farm level is limited because few mature and economically viable prototype systems are available. We conduct a pre-registered and incentive-compatible online lab-in-the-field experiment with a convenience sample of 334 active German crop farmers to assess whether pro-environmental attitude, innovativeness, and trust in farming data privacy explain hypothetical SWT adoption. We further test if an environmentally motivated subsidy, a green nudge, and a combination thereof affect adoption intentions. While attitudinal measures clearly modulate hypothetical adoption decisions in our sample, we detect no effect for the nudge and subsidy. Our findings have implications for policy and future research. Substantial policy support may be needed as long as environmentally beneficial smart farming technology remains privately less competitive than conventional alternatives. Moreover, targeting criteria for early adopters include pro-environmental attitudes and innovativeness.
Diversity in enrollment to clinical trials for cataract medicine and surgery: meta-analysis
Authors: Tao Brendan Ka-Lok , Xie Jim Shenchu , Xia Manvis , Marzban Sahand , Vosoughi Amir R. , Ahuja Nina , Rocha Guillermo
Published: January 2024

Purpose:

To investigate sex, racial, and ethnic disparities in patient enrollment across cataract trials registered in the United States.

Setting:

Participants enrolled in high-quality (reduced risk of bias), U.S.-registered (on ClinicalTrials.gov), cataract-related randomized controlled trials (RCTs). RCTs must be completed, have used double or greater masking, and have published results through the registry or a scholarly journal.

Design:

Cross-sectional database study.

Methods:

Trial (study sponsor country, study site location, trial initiation year, study phase, and study masking) and demographic data (sex, race, and ethnicity according to U.S. reporting guidelines) were collected. The Global Burden of Disease database provided sex-based cataract disease burdens. Pooled participation-to-prevalence ratios (PPRs) with 95% CIs were calculated for female sex, with values between 0.8 and 1.2 constituting sufficient study enrollment. Kruskal-Wallis tests (α = 0.05) with subsequent post hoc comparisons were used to evaluate demographic representations stratified by trial characteristics.

Results:

From 864 records, 100 clinical trials (N = 67 874) were identified, of which 97 (N = 67 697) reported sex demographics with a pooled female PPR of 0.89 (95% CI, 0.85-0.94). Of the 67 697 total participants, the absolute female enrollment was 19 062 (28.16%). Ethnicity and race were reported in 9 (N = 1792) and 26 trials (N = 23 181), respectively. Among trials that reported race, most were White (N = 19 574; 84.44%).

Conclusions:

High-quality, U.S.-registered, cataract trials enrolled acceptable proportions of women. However, the absolute number of female and racialized participants was low. Race and ethnicity were underreported. Disparity trends predominately held across secondary variables. To promote generalizability, future trials should pursue equitable demographic enrollment.
Neonatal Diet Type and Associations With Adverse Feeding Outcomes in Neonates With Critical Congenital Heart Defects
Authors: Davis Jessica A. , Baumgartel Kelley , Baust Tracy , Conley Yvette P. , Morowitz Michael J. , Ren Dianxu , Demirci Jill R.
Published: January 2024

Background:

Neonates with critical congenital heart defects (CCHD neonates) experience high rates of feeding intolerance, necrotizing enterocolitis (NEC), and malnutrition. The benefits of human milk and direct chest/breastfeeding are well known, but research is limited in CCHD neonates. Therefore, the purpose of this study is to examine the impact of neonatal diet and feeding modality on the incidence of feeding intolerance, NEC, and malnutrition among a cohort of CCHD neonates.

Methods:

A single-center retrospective study was conducted using electronic health record data of CCHD neonates admitted to a cardiac intensive care unit between April 2016 and April 2020. Regression models were fit to analyze associations between neonatal diet, feed modality, and adverse feeding outcomes.

Results:

Seventy-four CCHD neonates were included. Increased days of direct chest/breastfeeding were associated with fewer signs of gastrointestinal distress (P = .047) and bloody stools (P = .021). Enteral feeding days of “all human milk” were associated with higher growth trajectory (P < .001).

Conclusions:

Human milk and direct chest/breastfeeding may be protective against some adverse feeding outcomes for CCHD neonates. Larger, multicenter cohort studies are needed to continue investigating the effects of neonatal diet type and feeding modality on the development of adverse feeding outcomes in this unique population.
Effect of an Education Intervention on Nursing Students' Knowledge of and Attitudes Toward Caring for Transgender and Nonbinary People
Authors: Carmichael Tanya N. , Copel Linda Carman , McDermott-Levy Ruth
Published: January 2024

Background:

Transgender and nonbinary (TGNB) people experience inequities in health care access, quality, and outcomes. Health care professionals' lack of knowledge and biased attitudes toward gender minorities contribute to inequitable care.

Purpose:

This study examined the effect of TGNB health education on nursing students' knowledge and attitudes about caring for TGNB clients.

Methods:

A quasi-experimental study using a one-group pretest/posttest design was conducted with 46 nursing students at 2 private baccalaureate nursing programs.

Results:

A paired-samples t test found a significant increase in knowledge about caring for TGNB clients at posttest (P = .02). Attitudes toward caring for TGNB clients showed a significant improvement in the Sex and Gender Beliefs subscale at posttest (P = .014).

Conclusions:

The findings suggest that TGNB health education is effective for inclusion in nursing curricula to better prepare nurses to care for gender-diverse clients.
Chromosome-level genome assembly of the common chiton,Liolophura japonica(Lischke, 1873)
Authors:   Hong Kong Biodiversity Genomics Consortium,   Project Coordinator and Co-Principal Investigators, Hui Jerome H.L. , Chan Ting Fung , Chan Leo L. , Cheung Siu Gin , Cheang Chi Chiu , Fang James K.H. , Gaitan-Espitia Juan D. , Lau Stanley C.K. , Sung Yik Hei , Wong Chris K.C. , Yip Kevin Y.L. , Wei Yingying ,   DNA extraction, library preparation and sequencing, Au Franco M.F. , So Wai Lok ,   Genome assembly and gene model prediction, Nong Wenyan ,   Gene family annotation, Franco Au Ming Fung ,   Samples collectors, Hui Tin Yan , Leung Brian K.H. , Williams Gray A.
Published: January 2024

Chitons (Polyplacophora) are marine molluscs that can be found worldwide from cold waters to the tropics, and play important ecological roles in the environment. Nevertheless, there remains only two chiton genomes sequenced to date. The chitonLiolophura japonica(Lischke, 1873) is one of the most abundant polyplacophorans found throughout East Asia. Our PacBio HiFi reads and Omni-C sequencing data resulted in a high-quality near chromosome-level genome assembly of ∼609 Mb with a scaffold N50 length of 37.34 Mb (96.1% BUSCO). A total of 28,233 genes were predicted, including 28,010 protein-coding genes. The repeat content (27.89%) was similar to the other Chitonidae species and approximately three times lower than in the genome of the Hanleyidae chiton. The genomic resources provided in this work will help to expand our understanding of the evolution of molluscs and the ecological adaptation of chitons.
MassDash: A Web-based Dashboard for Data-Independent Acquisition Mass Spectrometry Visualization
Authors: Sing Justin C. , Charkow Joshua , AlHigaylan Mohammed , Horecka Ira , Xu Leon , Röst Hannes L.
Published: January 2024

With the increased usage, diversity of methods and instruments being applied to analyze Data-Independent Acquisition (DIA) data, visualization is becoming increasingly important to validate automated software results. Here we present MassDash, a cross-platform, DIA mass spectrometry visualization and validation software for comparing features and results across popular tools. MassDash provides a web-based interface and Python package for interactive feature visualizations and summary report plots across multiple automated DIA feature detection tools including OpenSwath, DIA-NN, and dreamDIA. Furthermore, MassDash processes peptides on the fly, enabling interactive visualization of peptides across dozens of runs simultaneously on a personal computer. MassDash supports various multidimensional visualizations across retention time, ion mobility, m/z, and intensity providing additional insights into the data. The modular framework is easily extendable enabling rapid algorithm development of novel peak picker techniques, such as deep learning based approaches and refinement of existing tools. MassDash is open-source under a BSD 3-Clause license and freely available athttps://github.com/Roestlab/massdash, and a demo version can be accessed athttps://massdash.streamlit.app.
DepoScope: accurate phage depolymerase annotation and domain delineation using large language models
Authors: Concha-Eloko Robby , Stock Michiel , De Baets Bernard , Briers Yves , Sanjuan Rafael , Domingo-Calap Pilar , Boeckaerts Dimitri
Published: January 2024

Bacteriophages (phages) are viruses that infect bacteria. Many of them produce specific enzymes called depolymerases to break down external polysaccharide structures. Accurate annotation and domain identification of these depolymerases are challenging due to their inherent sequence diversity. Hence, we present DepoScope, a machine learning tool that combines a fine-tuned ESM-2 model with a convolutional neural network to precisely identify depolymerase sequences and their enzymatic domains. To accomplish this, we curated a dataset from the INPHARED phage genome database, created a polysaccharide-degrading domain database, and applied sequential filters to construct a high-quality dataset, which are subsequently used to train DepoScope. Our work is the first approach that combines sequence-level predictions with amino-acid-level predictions for an accurate depolymerase detection and functional domain identification. In that way, we believe that DepoScope can enhance our understanding of phage-host interactions at the level of depolymerases.

Summary with Key Messages

Phage depolymerases are proteins that play a crucial role in the first step of a phage replication cycle. As a result, they are both important from a biological perspective and a therapeutical perspective.

Current methods to accurately annotate phage depolymerases and their associated enzymatic domains remains challenging due to their inherent high sequence diversity.

We have developed DepoScope, a language-based artificial intelligence model that can accurately identify phage depolymerases and their specific enzymatic domains.

We provide full public access to the DepoScope code and database to give broad access to the research community and promote further research.
Mapping resources available for early identification and recovery-oriented intervention for people with psychosis in Addis Ababa, Ethiopia
Authors: Tsehay Mekonnen , Kelkile Teshome Shibre , Fekadu Wubalem , Cohen Alex , Misganaw Eleni , Hanlon Charlotte
Published: January 2024

Background

There is a pressing need to reduce the long duration of untreated illness and improve care and outcomes for people with psychosis in Ethiopia. This study aimed to map community resources that have the potential to be leveraged to achieve earlier and more recovery-oriented interventions for people with psychosis in Addis Ababa, Ethiopia.

Method

A strength-based resource mapping exercise was undertaken in two sub-cities, covering an estimated population of half a million people. We identified the types of resources to be mapped, based on their importance for multi-sectoral care in mental health: healthcare facilities, religious organisations, traditional and faith healers, non-governmental organisations (NGOs), and social/community organisations. The lead investigator traversed the study sites to gather information on community resources, recorded the Global Positioning System (GPS) coordinates of the resources, and consulted with key informants. The information obtained was complemented by a participatory Theory of Change workshop attended by 30 stakeholders.

Results

We identified 124 health facilities, of which only 16 health centres and nine hospitals currently provide mental health services. We identified three registered traditional healers, 38 religious organisations, 104 non-governmental organisations, and other charitable/community-based organisations. In addition, three health facilities, six holy water religious healing sites, and four traditional healers were identified as out-of-site resources that were popular and frequently visited by people living in the sub-cities. The two sub-cities also had six feeding centres each providing meals for 1000 people in need. There were extensive networks of social organisations and community-based associations. Existing care pathways are complex but commonly include traditional and religious healing sites as places of first contact.

Conclusions

We identified important available resources that provide a wealth of opportunities for improving the early identification and outcomes of people with psychosis.
Enolase inhibitors as therapeutic leads forNaegleria fowleriinfection
Authors: Milanes Jillian E. , Yan Victoria C. , Pham Cong-Dat , Muller Florian , Kwain Samuel , Rees Kerrick C. , Dominy Brian N. , Whitehead Daniel C. , Millward Steven W. , Bolejack Madison , Abendroth Jan , Phan Isabelle Q. , Staker Bart , Moseman E. Ashley , Zhang Xiang , Ma Xipeng , Jebet Audriy , Yin Xinmin , Morris James C.
Published: January 2024

Infections with the pathogenic free-living amoebaeNaegleria fowlerican lead to life-threatening illnesses including catastrophic primary amebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate that these agents are potent inhibitors ofN. fowleriENO (NfENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC50value of 0.14 ± 0.04 µM) that was toxic to trophozoites (EC50value of 0.21 ± 0.02 µM) while the reported CC50was >300 µM. Molecular docking simulation revealed that HEX binds strongly to the active site ofNfENO with a binding affinity of –8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream ofNfENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the conclusion of the experiment, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. Brains of six of the eight survivors were positive for amoebae, suggesting the agent at the tested dose suppressed, but did not eliminate, infection. These findings suggest that HEX is a promising lead for the treatment of PAM.
Evidence of interplays between the vascular and nociceptive systems revealed by changes in capsaicin pain caused by limb position change
Authors: Courtin Arthur S. , Knaepen Clara , Mouraux André , van Neerven Sabien Geraldine Antonia
Published: January 2024

This experiment aimed at confirming our incidental observation that, when capsaicin is applied on the volar forearm, raising the arm to a vertical position leads to a dramatic increase in capsaicin-evoked pain and to explore possible underlying mechanisms.

Twenty healthy volunteers received a 2% capsaicin patch on one forearm and a vehicle patch on the other. Patches were kept in place for 60 minutes. The sensation caused by the patch was assessed repeatedly -in resting position and when the arm was raised vertically-before, during and after patch application. In addition, capsaicin-induced secondary hyperalgesia was assessed using mechanical pinprick stimuli. Half of the participants were seated upright while the other half were lying supine, to assess whether the effect of limb position was due to gravity.

After a few minutes of patch application, raising the capsaicin treated arm (but not the vehicle treated arm) led to a strong increase of the pain experienced at the patch. This effect of raising the arm did not differ between participants in the supine and seated groups and is therefore likely related to the position of the arm relative to the ground (gravity) rather than to the body. Mechanical secondary hyperalgesia and the arm raising effect were strongly decorrelated at the last time point after patch removal, indicating different underlying mechanisms.

Our results indicate that capsaicin-evoked pain can be strongly modulated by limb posture and that this effect may be caused by an interplay between vascular and nociceptive systems.
Exploring human rare disease variants from a multidimensional perspective illuminates receptor – G protein coupling diversity
Authors: Redfern-Nichols Theo , O’Brien Shannon L , Huang Xianglin , Medel-Lacruz Brian , Calebiro Davide , Selent Jana , Ladds Graham , Marti-Solano Maria
Published: January 2024

G protein-coupled receptors (GPCRs) are transmembrane proteins capable of detecting signals as diverse as odours, neurotransmitters, and hormones. Upon activation, receptor signalling converges onto four Gα protein subtypes to regulate intracellular responses. Therefore, variation in a single Gα protein gene can potentially impact the function of numerous receptors. In this work, we have performed a multidimensional study of rare disease mutations in Gαs, a prototypical Gα protein. By integrating data from 3D structures, GPCR / G protein functional pairings, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modelling, our results reveal why mutations impairing receptor / Gαs coupling result in highly specific context-based signalling defects. Furthermore, we show that mutations leading to the same rare disease can alter different signal transduction steps, highlighting the importance of patient-specific treatment strategies. By closely dissecting G protein coupling, our study provides a blueprint to interrogate GPCR pathway signalling diversity in different (patho)physiological contexts.
RareACTN2Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation
Authors: Ranta-aho Johanna , Felice Kevin J. , Jonson Per Harald , Sarparanta Jaakko , Palmio Johanna , Tasca Giorgio , Sabatelli Mario , Yvorel Cédric , Harzallah Ines , Touraine Renaud , Pais Lynn , Austin-Tse Christina A. , Ganesh Vijay , O’Leary Melanie C. , Rehm Heidi L. , Hehir Michael K. , Subramony Sub , Wu Qian , Udd Bjarne , Savarese Marco
Published: January 2024

Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene,ACTN2, have been shown to cause distal myopathy.ACTN2, a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. NewACTN2variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations inACTN2-related diseases, actininopathies, persists.

Objective

The objective of the study is to characterize the pathomechanisms underlying actininopathies.

Methods

Functional characterization in C2C12 cell models of severalACTN2variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants.

Results

The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates.

Interpretation

The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants inACTN2should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.
Identifying compounds to treat opiate use disorder by leveraging multi-omic data integration and multiple drug repurposing databases
Authors: Stratford Jeran K. , Carnes Megan Ulmer , Willis Caryn , Minto Melyssa S. , Elnimeiry Logain , Mathur Ravi , Schu Matthew , Quach Bryan C. , Carter Javan , Nolen Tracy , Vandergrift Nathan , Kosten Thomas , Johnson Eric Otto , Webb Bradley T.
Published: January 2024

Genes influencing opioid use disorder (OUD) biology have been identified via genome-wide association studies (GWAS), gene expression, and network analyses. These discoveries provide opportunities to identifying existing compounds targeting these genes for drug repurposing studies. However, systematically integrating discovery results and identifying relevant available pharmacotherapies for OUD repurposing studies is challenging. To address this, we’ve constructed a framework that leverages existing results and drug databases to identify candidate pharmacotherapies.

For this study, two independent OUD related meta-analyses were used including a GWAS and a differential gene expression (DGE) study of post-mortem human brain. Protein-Protein Interaction (PPI) sub-networks enriched for GWAS risk loci were identified via network analyses. Drug databases Pharos, Open Targets, Therapeutic Target Database (TTD), and DrugBank were queried for clinical status and target selectivity. Cross-omic and drug query results were then integrated to identify candidate compounds.

GWAS and DGE analyses revealed 3 and 335 target genes (FDR q<0.05), respectively, while network analysis detected 70 genes in 22 enriched PPI networks. Four selection strategies were implemented, which yielded between 72 and 676 genes with statistically significant support and 110 to 683 drugs targeting these genes, respectively. After filtering out less specific compounds or those targeting well-established psychiatric-related receptors (OPRM1andDRD2), between 2 and 329 approved drugs remained across the four strategies.

By leveraging multiple lines of biological evidence and resources, we identified many FDA approved drugs that target genes associated with OUD. This approach a) allows high-throughput querying of OUD-related genes, b) detects OUD-related genes and compounds not identified using a single domain or resource, and c) produces a succinct summary of FDA approved compounds eligible for efficient expert review. Identifying larger pools of candidate pharmacotherapies and summarizing the supporting evidence bridges the gap between discovery and drug repurposing studies.
Genetic Association and Transferability for Urinary Albumin-Creatinine Ratio as a Marker of Kidney Disease in four Sub-Saharan African Populations and non-continental Individuals of African Ancestry
Authors: Brandenburg Jean-Tristan , Chen Wenlong Carl , Boua Palwende Romuald , Govender Melanie Ann , Agongo Godfred , Micklesfield Lisa K. , Sorgho Hermann , Tollman Stephen , Asiki Gershim , Mashinya Felistas , Hazelhurst Scott , Morris Andrew P , Fabian June , Ramsay Michèle ,   as members of AWI-Gen and the H3Africa Consortium
Published: January 2024

Background

Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts.

Methods

Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations.

Results

Two genome-wide significant (P<5×10−8) UACR-associated loci were identified, one in theBMP6 regionon chromosome 6, in the meta-analysis of resident African individuals, and another in theHBBregion on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, includingTHB53,GATM,andARL15. PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained.

Conclusion

This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.
Titin-Truncating variants Predispose to Dilated Cardiomyopathy in Diverse Populations
Authors: DePaolo John , Bornstein Marc , Judy Renae , Abramowitz Sarah , Verma Shefali S. , Levin Michael G. , Arany Zoltan , Damrauer Scott M.
Published: January 2024

Importance

The effect of high percentage spliced in (hiPSI)TTNtruncating variants (TTNtvs) on risk of dilated cardiomyopathy (DCM) has historically been studied among population subgroups defined by genetic similarity to European reference populations. This has raised questions about the effect of TTNtvs in diverse populations, especially among individuals genetically similar to African reference populations.

Objective

To determine the effect of TTNtvs on risk of DCM in diverse population as measured by genetic distance (GD) in principal component (PC) space.

Design

Cohort study

Setting

Penn Medicine Biobank (PMBB) is a large, diverse biobank.

Participants

Participants were recruited from across the Penn Medicine healthcare system and volunteered to have their electronic health records linked to biospecimen data including DNA which has undergone whole exome sequencing.

Main Outcomes and Measures

Risk of DCM among individuals carrying a hiPSI TTNtv.

Results

Carrying a hiPSI TTNtv was associated with DCM among PMBB participants across a range of GD deciles from the 1000G European centroid; the effect estimates ranged from odds ratio (OR) = 3.29 (95% confidence interval [CI] 1.26 to 8.56) to OR = 9.39 (95% CI 3.82 to 23.13). When individuals were assigned to population subgroups based on genetic similarity to the 1000G reference populations, hiPSI TTNtvs conferred significant risk of DCM among those genetically similar to the 1000G European reference population (OR = 7.55, 95% CI 4.99 to 11.42,P<0.001) and individuals genetically similar to the 1000G African reference population (OR 3.50, 95% CI 1.48 to 8.24,P=0.004).

Conclusions and Relevance

TTNtvs are associated with increased risk of DCM among a diverse cohort. There is no significant difference in effect of TTNtvs on DCM risk across deciles of GD from the 1000G European centroid, suggesting genetic background should not be considered when screening individuals for titin-related DCM.

Key Points

Question

Do high percentage spliced in (hiPSI) titin truncating variants (TTNtvs) confer similar levels of risk for dilated cardiomyopathy (DCM) across diverse populations?

Findings

In a cohort study that comprised 43,731 individuals of diverse genetic background with electronic health records linked to whole exome sequencing data, hiPSI TTNtvs conferred increased risk of DCM across all individuals irrespective of genetic background as measured by genetic distance from the 1000 Genomes Project European centroid.

Meaning

The findings of this study suggest that TTNtvs increase risk of DCM among individuals independent of genetic background and that genetic similarity to a reference population should not play a role in screening for genetic causes of dilated cardiomyopathy.
Label-free virtual peritoneal lavage cytology via deep-learning-assisted single-color stimulated Raman scattering microscopy
Authors: Fang Tinghe , Wu Zhouqiao , Chen Xun , Tan Luxin , Li Zhongwu , Ji Jiafu , Fan Yubo , Li Ziyu , Yue Shuhua
Published: January 2024

Clinical guidelines for gastric cancer treatment recommend intraoperative peritoneal lavage cytology to detect free cancer cells. Patients with positive cytology require neoadjuvant chemotherapy instead of instant resection and conversion to negative cytology results in improved survival. However, the accuracy of cytological diagnosis by pathologists or artificial intelligence is disturbed by manually-produced, unstandardized slides. In addition, the elaborate infrastructure makes cytology accessible to a limited number of medical institutes. Here, we developed CellGAN, a deep learning method that enables label-free virtual peritoneal lavage cytology by producing virtual hematoxylin-eosin-stained images with single-color stimulated Raman scattering microscopy. A structural similarity loss was introduced to overcome the challenge of existing unsupervised virtual pathology techniques unable to present cellular structures accurately. This method achieved a structural similarity of 0.820±0.041 and a nucleus area consistency of 0.698±0.102, indicating the staining fidelity outperforming the state-of-the-art method. Diagnosis using virtually stained cells reached 93.8% accuracy and substantial consistency with conventional staining. Single-cell detection and classification on virtual slides achieved a mean average precision of 0.924 and an area under the receiver operating characteristic curve of 0.906, respectively. Collectively, this method achieves standardized and accurate virtual peritoneal lavage cytology and holds great potential for clinical translation.
Short-term outcomes of the digital combined lifestyle intervention CooL-MiGuide: a descriptive case series study
Authors: Philippens Nicole , Janssen Ester , Kremers Stef , Crutzen Rik
Published: January 2024

Introduction: The objective of this study is to investigate the changes over time in anthropometrics, behaviours and health perceptions after eight months of participation in the Combined Lifestyle Intervention (CLI) CooL-MiGuide, a digital version of the Coaching on Lifestyle (CooL) intervention with the add-on of a digital platform and an app.  Method: Longitudinal data were collected between January 2022 and December 2023 from adults, mainly in the South-Western area of the Netherlands, that meet the inclusion criteria for the CLI (i.e. being obese (Body Mass Index (BMI)>30) or being overweight (25<BMI<30) combined with comorbidity; and being sufficiently motivated). We collected a broad set of data at baseline (T0) and after eight months of participation (T1) on anthropometrics (self-reported weight, length, waist circumference), control and support (self-mastery, social support), physical activity (sedentary time on least/most active days, physical active minutes), diet attentiveness (attentiveness to meal composition, amounts of food and consuming), alcohol consumption, smoking, perceived fitness (perceived health, fitness when waking, fitness during daytime, impact daily stress), sleep and stress. Changes over time were analyzed using paired t-tests comparing T1 to baseline. Effect sizes were calculated using Cohen’s d. Results: The results show positive changes after eight months in anthropometrics, sedentary time, diet attentiveness, sleep, stress, fitness, and perceived health of the participants. Largest effect sizes were found for weight (Cohen’s d=0.62, average weight loss of 3.82kg), perceived health (Cohen’s d=0.58) and perceived fitness of the participants when waking and during daytime (Cohen’s d=0.41 and 0.52 respectively). Conclusion: CooL-MiGuide participants show relevant changes in the essential constructs perceived health and weight. The digital version of CooL can be a valuable alternative for people who prefer participation from a location of their choice.
Clinical Characteristics and Factors Associated with Long COVID in Zambia, August 2020 to January 2023: A Mixed Methods Design
Authors: Malambo Warren , Chanda Duncan , Besa Lily , Engamba Daniella , Mwiinga Linos , Mwitumwa Mundia , Matibula Peter , Naik Neil , Sivile Suilanji , Agolory Simon , Auld Andrew , Mulenga Lloyd , Hines Jonas Z. , Fwoloshi Sombo
Published: January 2024

Introduction

A number of seroprevalence studies in Zambia document the extent of spread of SARS-CoV-2, yet few have examined signs, symptoms and conditions that continue or develop after acute COVID-19 infection (long COVID). This is an important gap given the estimated prevalence of long COVID in other countries. We sought to examine characteristics of post-acute COVID-19 (PAC-19) clinics patients in Zambia and assess factors associated with long COVID at first visit to a PAC-19 clinic and longitudinally among a cohort of patients.

Methods

Long COVID was defined, initially in the Zambia PAC-19 clinical guidelines, as new, relapsing, or persistent symptoms lasting >4 weeks after an initial SARS-CoV-2 infection. Severe COVID-19 was defined as COVID-19 episode that required supplemental oxygen therapy, intensive care unit stay or treatment with steroids/remdesivir. We performed a cross-sectional and longitudinal analysis of PAC-19 clinic patients from August 2020 to January 2023 using logistic and mixed effects regression models and considered statistical significance at p<0.05.

Results

In total, 1,359 patients attended PAC-19 clinics of whom 548 (40.3%) with ≥2 visits were included in the longitudinal analysis. Patients’ median age was 53 (interquartile range [IQR]: 41-63) years, 919 (67.6%) were hospitalized for acute COVID-19, and of whom 686 (74.6%) had severe COVID-19. Patients with hospital length of stay ≥15 days (adjusted odds ratio [aOR]: 5.37; 95% confidence interval [95% CI]: 2.99-10.0), severe illness (aOR: 3.22; 95% CI: 1.68-6.73), and comorbidities (aOR:1.50; 95% CI: 1.02-2.21) had significantly higher likelihood of long COVID. Longitudinally, long COVID prevalence significantly (p<0.001) declined from 75.4% at the first PAC-19 visit to 26.0% by the fifth visit. The median follow-up time was 7 (IQR: 4-12) weeks.

Conclusion

Long COVID symptoms were common among patient presenting for care in PAC-19 clinics in Zambia, but most recovered within ∼2 months. Despite potentially substantial morbidity due to long COVID, few patients overall with COVID-19 attended a PAC-19 clinic. Scaling up PAC-19 services and integrating into routine clinical care could improve access by patients.