bluuebunny/crossref_metadata_2025 huggingface dataset:
John Vesey and the ‘Revolution’ of 1688
Authors: Ward Matthew
Published: January 2024

This chapter establishes the significance of their engagements with Hobbes to the responses of Irish Anglicans to the rule of James II and the ‘Revolution’ of 1688. Though the focus remains on Vesey, the chapter also examines the responses of Vesey’s contemporaries, including William King. Vesey’s own discourse was eclectic in this period. He initially responded to James’s reign by defending his ecclesiastical authority as king. However, a dispute with James’s government over the privileges of urban corporations and the church turned him against James and prompted his departure to London in 1689. In London’s public prints, Vesey associated James’s approach to the church and his treatment of Protestants with ‘Hobbian principles’. Following William III’s victory over James in Ireland, however, Vesey resumed his sympathy for the crown and, this chapter suggests, for Hobbes. Vesey produced a distinctively Hobbesian version of the ‘de facto’ argument for allegiance to William.
Introduction
Authors: Carruthers Peter
Published: January 2024

This short opening chapter introduces the topic of the book, drawing distinctions and elucidating the main claims that are at stake. It explains what motivational egoism and motivational hedonism are, and how they contrast with motivational pluralism (including altruism), as well as with the everyday sense in which people can be described as hedonists. The chapter also explains why these issues matter for issues of moral responsibility, as well as for our understanding of the sources of motivation quite generally. Finally, the appropriate methodology for resolving the issue is outlined (theorizing the science rather than common-sense intuitions), and the sequence of topics covered in the book is described.
Traditional Critiques Critiqued
Authors: Carruthers Peter
Published: January 2024

This chapter shows that the scientifically informed version of motivational hedonism that emerged from the discussion in Chapter 3 is impervious to all of the main arguments that have been advanced previously against hedonism and in support of altruism, by both philosophers and psychologists. These include: evolutionary arguments; arguments from the fact that people sometimes sacrifice themselves for others in full knowledge of the consequences; the argument that pleasure is caused by the satisfaction of desires for things other than pleasure, and so is not itself the object of all desires; the famous “experience machine” argument; and an extensive body experimental evidence concerning the role of empathy in producing altruistic behavior. The final section of the chapter then shows that experience-directed imperative theories of valence (discussed in Chapter 6) can also evade standard critiques.
Indicatives Versus Imperatives
Authors: Carruthers Peter
Published: January 2024

This chapter has two main goals. One is to defend the value-representing theory of valence outlined in Chapter 5, comparing it with accounts that construe valence, not as indicative (representing—correctly or incorrectly—properties of the world), but rather as a kind of imperative. While developed initially to provide theories of the painfulness of pain, imperative accounts have now been extended into theories of pleasure and displeasure more generally. It is these generalized accounts that are considered here. The second main goal of the chapter is to articulate and then critique forms of imperativism about valence that entail motivational hedonism (in fact, only experience-directed kinds of imperativism do). The upshots of the chapter are twofold: the value-representing account provides the best overall theory of valence, and pluralism rather than hedonism provides the best account of human (and animal) motivation, thus making room for altruism.
Conceptual Engineering: Ambitious or Anodyne?
Authors: Ball Derek
Published: January 2024

A number of philosophers have suggested that we ought to change the way we approach discussions about matters of definition. On their view, we ought to adopt the novel methodology of conceptual engineering, which involves evaluating and trying to improve the meanings of our words. OI consider one prominent defencse of this claim is considered: Herman Cappelen’s “Master Argument”. TI reject the argument is rejected on the grounds that there is can be no novel and distinctive methodology of evaluating and improving the meanings of words. TI motivate this claim is motivated by evaluating the Master Argument in the context of the Ramsey-Carnap-Lewis method of defining theoretical terms, and it is showning that the feature of this method that makes conceptual engineering impossible generalises to the temporal externalist view defended in this book.
Why Are Paradoxes Hard?
Authors: Ball Derek
Published: January 2024

One motivation for thinking that our practice of engaging in definitional disputes, including many philosophical discussions, is in need of revision is that it can seem like we have made little progress on the issues. This line of thinking is especially prominent in recent work on paradoxes such as the Liar, where a number of philosophers have suggested that the attraction of paradoxical reasoning is due to the inconsistency of certain words or concepts. It is shown that appeals to inconsistent concepts cannot explain why we are attracted to paradoxical reasoning: the most plausible attempt at explanation is circular. It is suggested that the fact that paradoxes are hard to solve is not qualitatively different than the hardness of problems in other fields, such as the problem of curing the common cold.
The Metaphysics and Epistemology of Backwards Determination
Authors: Ball Derek
Published: January 2024

This chapter addresses metaphysical and epistemological issues raised by temporal externalism. How can the future make a difference to the past? It is suggested that thereir are innocent analogues of the temporal externalist’s commitments. How does temporal externalism relate to questions about the metaphysics of time? It is argued that it is compatible with a wide range of metaphysical views. What should temporal externalists say about mental causation and self-knowledge? These issues are no different for temporal externalists than for other forms of externalism. How can the temporal externalist view that isI endorsed, which emphasises cases in which meaning does not change over time, make sense of cases in which meaning does change? AI develop a view is developed of meaning continuity, and discuss how this view relates to similar questions about the persistence of physical objects is discussed.
The Categorical Imperative, Empty Formalism, and Happiness
Authors: Guyer Paul
Published: January 2024

This chapter focuses on issues raised in the first reviews of Kant’s first two books in moral philosophy. Of special interest are the reviews of the Groundwork and Critique of Practical Reason by Herman Andreas Pistorius, the first published quickly in 1786 while the second, although apparently written in timely fashion, did not appear until 1794. Pistorius developed the charge that the categorical imperative is an “empty formalism,” and more generally argued that a conception of what is right must presuppose an account of the good, and that morality must be founded on the recognition that happiness is the natural end of human beings, not merely an incidental object of morality. Kant’s amplification of the conception of the highest good in the Critique of Practical Reason is already a response to Pistorius’s criticism of the Groundwork, while the “empty formalism” objection would be repeated by Hegel in both 1802 and 1821, and by many since.
Moral Feelings in Kantian Ethics
Authors: Guyer Paul
Published: January 2024

This chapter reviews the debate between Kant and Friedrich Schiller over whether morally worthy motivation allows, requires, or excludes moral feeling, for example feelings of benevolence and sympathy. The debate was triggered by Schiller’s 1793 essay “On Grace and Dignity,” which was itself as much a response to the treatment of grace in Lord Kames’s 1762 Elements of Criticism as it was a response to Kant. The 1793–4 debate between Kant and Schiller is somewhat of a comedy of errors, as Kant thinks that Schiller is criticizing him when he is not and ends up taking the position—that morally worthy action must always also be graceful, without any sign of having had to overcome resistance (which is mere dignity)—that Schiller never took, and which Kant otherwise did not defend either. If anything, Kant generally thought that we ordinary humans would always experience some degree of resistance to the demands of morality. Kant took a better position four years later in the Metaphysics of Morals when he argued that moral action requires the refinement and strengthening of a complex of “aesthetic preconditions of the mind’s susceptibility to concepts of duties”—or moral feelings (and conscience).
Fichte
Authors: Guyer Paul
Published: January 2024

This is the first of three chapters on the reception of Kant’s moral philosophy in German idealism. Johann Gottlieb Fichte, who initially thought of himself as a Kantian, thought that the categorical imperative needed both more content and a better proof or “deduction” than Kant had provided. He argued that conceiving of oneself as a conscious agent at all required recognition the existence and “summons” of others, thus that the basic demand of morality—to treat others as one would treat oneself—is built into the very basis of self-consciousness itself. Fichte also thought that he could give a transcendental and not merely empirical argument for the existence of moral feeling. He also tried to demonstrate the spontaneity and thus freedom of human choice without resorting to Kant’s distinction between how things appear and how they may be “in themselves” (for Kant, possibly free according to theoretical reason, actually and necessarily free according to practical reason).
Herbart and Schopenhauer
Authors: Guyer Paul
Published: January 2024

This chapter briefly considers Johann Friedrich Herbart’s unusual use of Kant’s conception of aesthetic judgment as a model for moral judgment, but is primarily concerned with Arthur Schopenhauer’s response to Kant’s moral philosophy. Schopenhauer based his metaphysics on Kant’s distinction between phenomena and noumena, appearances and things in themselves, but rejected Kant’s premise of the underlying rationality of human nature and the human will. Instead, he argued that reality is fundamentally non-rational and that human will and conduct are too. The non-rationality of existence is exemplified by the endless frustration of human desire, in which we are always miserable either because we do not get what we want or because we do, and therefore quickly become bored, starting the cycle all over again. The ultimate remedy to this is the “ascetic attitude,” in which we realize that it is all mere and meaningless appearance. But on the way to that, recognizing that beneath the level of appearance we are all one, we should treat each other with compassion. This is Schopenhauer’s version of sympathy as an appropriate moral feeling in Kant (indeed, their word is the same, Mitleid), although Schopenhauer reduces all moral feeling and indeed any moral principle to compassion, while for Kant it is only one of several morally appropriate feelings, to be strengthened but also governed by our recognition of the moral law.
Kant and Anglophone Idealism
Authors: Guyer Paul
Published: January 2024

This chapter examines responses to Kant’s moral philosophy in British and American idealism, represented by the English philosophers Francis Herbert Bradly and Thomas Hill Green, the Scots Edward Caird and Herbert James Paton, and the American Josiah Royce. Bradley argued that abstract distinctions are characteristic of mere appearance and that ultimate reality is essentially unitary; in moral philosophy he thus rejected what he took to be Kant’s conception of “duty for duty’s sake” in favor of a more Hegelian conception our “station and its duties.” But his view that morality is a form of self-realization remained Kantian. Green followed Kant’s emphasis on the value of freedom but argued that our selves are constituted only in society and that we must therefore find ways to express our freedom that are compatible with society. In the course of a large commentary on all of Kant’s works, Caird continued the theme that individual consciousness is only fully realized in an interpersonal community. Royce changed the terms if not the substance of the idealist approach to Kantian morality by arguing that individuals must have loyalty to their own causes (their own ends) but at the same time must have loyalty to their idea of loyalty, that is, to the idea that individuals must pursue their own causes in ways compatible with others doing the same. Finally, inspired by Plato as well as Kant, Paton argued that the moral will aims at interpersonal coherence in action just as we aim at coherence in cognition.
Beatrice's Last Smile
Authors: Pegg Mark Gregory
Published: January 2024

Beatrice's Last Smile outlines the history of the Middle Ages from the fourth to the sixteenth centuries, while encompassing the Eurasian landmass. It discusses how Christianity and Islam evolved out of a shared cultural and religious ferment. Interweaving the history of Muslims with the histories of Christians and Jews helps build the narrative on the relationship of the human and the divine within individuals and their societies between 950 and 1550. Beatrice's Last Smile places Islamic history at the center of the story of Western civilization, which is similar to European Christianity in the West. It also raises the awareness that medieval Latin Christendom was arguably the marginal cultural phenomenon for most of the centuries.
Hermits in Mail
Authors: Pegg Mark Gregory
Published: January 2024

The chapter elaborates on Rodulfus Glaber's theory about the religious difference between the East and the West. It starts with farmer Leutard’s sorrowful tale of millennial prophecy, heresy, and suicide that involved God. The First Crusade epitomized the radical blending of early medieval apocalypticism with an ardent reforming millennialism that was first articulated by Rodulfus and other Latin Christian intellectuals. Moreover, the crusade transformed the long tradition of pilgrimage and penitential redemption going back to Columbanus at the end of the sixth century. The chapter also mentions how Rodulfus was unusual in his hatred of the Jews in the early eleventh century.
One From the Many
Authors: Meissner Christopher M.
Published: January 2024

This book is a brief introduction to the economic history of the global economy and the process of globalization since 1850. Key indicators of globalization, also known as economic integration, are the ratios of trade to world production, the ratio of global foreign assets relative to world production, and the share of foreign-born in the population. This book tracks the evolution of these indicators over time. All indicators of globalization rose between 1850 and 1914, during the first wave of globalization. Between 1918 and 1939, the global economy stagnated, suffering a momentous collapse during the Great Depression of the 1930s. After World War II, the global economy re-emerged, and integration deepened. A long-run view suggests that the global economy generates economic benefits and raises welfare. Humans tend to prefer more globalization to less as revealed by the very long-run historical record. Of course, there are costs to globalization, and certain groups may lose in economic terms from globalization. Going forward, with an eye on the lessons from this long-run view, the global economy will almost surely survive, and integration will continue to grow. However, globalization can only survive if humanity continues to recognize its common interests and the adverse effects of greater integration are mitigated and minimized.
The Global Economy in the Post-War Era
Authors: Meissner Christopher M.
Published: January 2024

In the three decades after 1945, the global economy was reconstructed. By the 1970s, trade integration had regained the level it had achieved in the late 19th century. The fundamental drivers of higher trade integration were, of course, lower trade costs. New technologies, higher incomes, and a new, multilateral approach to trade policy drove these declines. The global economy also witnessed a resurgence of economically motivated migration in the 1950s and 1960s. Western European nations were especially dependent on inflows of manufacturing workers. In the Americas, migration restrictions remained, although by the 1960s the United States and several other “new world” nations began to see modest increases in the numbers of foreign-born. Nevertheless, during the 1950s and 1960s, migration rates would never attain the levels they had prior to World War II in these former “receiving” nations.
Mind the gap: Epigenetic regulation of chromatin accessibility in plants
Authors: Candela-Ferre Joan , Diego-Martin Borja , Pérez-Alemany Jaime , Gallego-Bartolomé Javier
Published: January 2024

Chromatin plays a crucial role in genome compaction and is fundamental for regulating multiple nuclear processes. Nucleosomes, the basic building blocks of chromatin, are central in regulating these processes, determining chromatin accessibility by limiting access to DNA for various proteins and acting as important signaling hubs. The association of histones with DNA in nucleosomes and the folding of chromatin into higher-order structures are strongly influenced by a variety of epigenetic marks, including DNA methylation, histone variants, and histone post-translational modifications. Additionally, a wide array of chaperones and ATP-dependent remodelers regulate various aspects of nucleosome biology, including assembly, deposition, and positioning. This review provides an overview of recent advances in our mechanistic understanding of how nucleosomes and chromatin organization are regulated by epigenetic marks and remodelers in plants. Furthermore, we present current technologies for profiling chromatin accessibility and organization.
Unraveling the complex dynamics of signaling molecules in cellular signal transduction
Authors: Wang Shenqing , Zhang Yi , Zhang Liangwei , Huang Yan , Zhang Jie , Zhang Kena , Huang Yujie , Su Gaoxing , Chen Lingxin , Yan Bing
Published: January 2024

Signaling molecules in cellular responses to foreign stimuli are described as static up- or down-concentration changes during signal transduction. This is because analytical methods for transducing molecules are much slower than the signaling events. In this study, we develop a dynamic cell model and reveal the temporal regulation of signal transduction events in response to reactive oxygen species (ROS). The model contained a set of 10 batches of redox-modified cells that mimic the temporal ROS accumulation events. Validating this dynamic cell model, we discover that cells survive early ROS attacks by activating the Nrf2/polysulfide/p62/CDK1 pathway. Nearly all signaling molecules exhibit time-dependent V-shape or inverse V-shape activation/feedback regulation dynamics in response to ROS accumulation. The results show that the dynamic cell model approach is invaluable for revealing complex signal intensity- and time-dependent cell signaling events.
Poor statistical reporting: do we have a reason for concern? A narrative review and recommendations
Authors: Ordak Michal
Published: January 2024

Purpose of review

The aim of the review conducted was to present recent articles indicating the need to implement statistical recommendations in the daily work of biomedical journals.

Recent findings

The most recent literature shows an unchanged percentage of journals using specialized statistical review over 20 years. The problems of finding statistical reviewers, the impractical way in which biostatistics is taught and the nonimplementation of published statistical recommendations contribute to the fact that a small percentage of accepted manuscripts contain correctly performed analysis. The statistical recommendations published for authors and editorial board members in recent years contain important advice, but more emphasis should be placed on their practical and rigorous implementation. If this is not the case, we will additionally continue to experience low reproducibility of the research.

There is a low level of statistical reporting these days. Recommendations related to the statistical review of submitted manuscripts should be followed more rigorously.
Health Care Professional Distress and Mental Health: A Call to the Continuing Professional Development Community
Authors: Turco Mary G. , Sockalingam Sanjeev , Williams Betsy
Published: January 2024

COVID-19 unleashed a maelstrom of distress on health care professionals. The pandemic contributed to a host of stressors for workers because of the need for rapid acquisition of new knowledge and skills to provide best treatment while simultaneously dealing with personal safety, limited resources, staffing shortages, and access to care issues. Concurrently, problems with systemic racial inequality and discrimination became more apparent secondary to difficulties with accessing health care for minorities and other marginalized groups. These problems contributed to many health care professionals experiencing severe moral injury and burnout as they struggled to uphold core values and do their jobs professionally. Some left or disengaged. Others died. As continuing professional development leaders focused on all health professionals, we must act deliberately to address health care professionals' distress and mental health. We must incorporate wellness and mental health as organizing principles in all we do. We must adopt a new mental model that recognizes the importance of learners' biopsychosocial functioning and commit to learners' wellness by developing activities that embrace a biopsychosocial point of view. As educators and influencers, we must demonstrate that the Institute for Healthcare Improvement's fourth aim to improve clinician well-being and safety (2014) and fifth aim to address health equity and the social determinants of health (2021) matter. It is crucial that continuing professional development leaders globally use their resources and relationships to accomplish this imperative call for action.
Evaluating minority representation across health care settings in hidradenitis suppurativa and psoriasis
Authors: Greif Charlotte , Gibson Ruby S. , Kimball Alexa B. , Holcomb Zachary E. , Porter Martina L.
Published: January 2024

Background:

Females and minorities have been underrepresented in clinical research despite legislative efforts, including in hidradenitis suppurativa (HS) and psoriasis (PsO) clinical trials.

Objective:

To identify differences in demographic breakdowns of HS and PsO patients between health care settings to uncover any causative health disparities.

Methods:

This study reports racial, ethnic, and sex of HS and PsO patient populations across the emergency department (ED), inpatient, clinical trial, and registry settings. In addition, 95% confidence intervals are used as proxies of statistical significance to compare demographics between settings.

Results:

Female, Hispanic, and Black patients were underrepresented in HS clinical trials compared to their population prevalence (female: 63.7% vs 73.5%; Hispanic: 3.8% vs 12.0%; Black: 9.1% vs 20.3%). Female and Black patients were underrepresented in PsO trials compared to their population prevalence (female: 33.0% vs 54.8%; Black: 2.2% vs 5.7%). Black patients were overrepresented in the inpatient and ED settings in HS (inpatient vs ED vs population prevalence: 49.9% vs 49.9% vs 20.3%) and in the inpatient setting in PsO (inpatient vs population prevalence: 19.8% vs 5.7%).

Limitations:

The main limitation is the reliability and generalizability of the published studies used to compare demographics across settings.

Conclusion:

Underrepresentation of females and minorities in HS and PsO clinical trials is consistent with published literature. Overrepresentation of Black patients in acute care settings is likely multifactorial.
The psychiatric-mental health nurse practitioner as coordinating practitioner in the Netherlands: A multiple case study
Authors: Boeijen Enzio R. K. , Sitvast Jan E. , Boonstra Nynke , Houtjes Wim , van Meijel Berno , Laurant Miranda G. H. , van Vught Anneke J. A. H.
Published: January 2024

Background:

Psychiatric-mental health nurse practitioners (PMHNPs) in the Netherlands have been allowed to perform the role of coordinating practitioner (CP) since 2018. This role is reserved for mental health care specialists who are trained and qualified at the master's degree level. Earlier studies have not addressed how PMHNPs perform that role and what mechanisms and contextual factors determine their performance. This understanding could help optimize their performance in this role and promote effective deployment of PMHNPs in mental health care.

Purpose:

To understand how PMHNPs perform this role and what mechanisms and contextual factors underlie that performance.

Methodology:

A multiple case study involving PMHNPs who work in various settings as CPs. Data were collected and analyzed using the realistic evaluation approach.

Results:

We identified four mechanisms related to the performance of PMHNPs in the role of CP: (1) autonomous performance; (2) unique expertise; (3) accessibility, availability, and professional involvement; and (4) additional roles. The extent to which these mechanisms are present is largely determined by organizational factors, team factors, and individual factors.

Conclusions:

Psychiatric-mental health nurse practitioners are seeking to identify and interpret the role of CP. This study helps to elucidate the mechanism of role performance by PMHNPs and what they should focus on to deliver effective and patient-centered mental health care.

Implications:

Policymakers, health care professionals, and educators should consider the mechanisms and contextual factors to facilitate and support PMHNPs' employment and training in the role of CP.
Bloodstream Infections in Pediatric Oncology Patients: Bacterial Pathogen Distribution and Antimicrobial Susceptibility at the University Hospital Centre Zagreb, Croatia—A 5-Year Analysis
Authors: Mareković Ivana , Vujnović Tajana , Radanović Jasna , Herljević Zoran , Kuliš Tomislav , Pavlović Maja , Mucavac Lucija , Dejanović-Bekić Sara , Bilić Ernest
Published: January 2024

The epidemiology of bacterial pathogens causing bloodstream infections (BSIs) in pediatric hematology/oncology patients is changing and resistance to antimicrobial agents is globally spread. We retrospectively assessed demographic, clinical, and microbiologic data of BSIs during a 5-year period at a pediatric hematology/oncology unit from January 1, 2017, to December 31, 2021, at the University Hospital Centre Zagreb, Zagreb, Croatia. In 66 pediatric patients with malignancies, 93 BSI episodes were registered and 97 bacterial isolates were cultured. The Gram-positive versus Gram-negative ratio was 67 (69.1%) versus 30 (30.9%). Coagulase-negative staphylococci (48; 49.6%) were the most frequent isolates, followed by Enterobacterales (17; 17.5%) and Staphylococcus aureus (6; 6.2%). Multidrug resistance isolates included extended spectrum β-lactamase producers (n=3). Resistance rates to piperacillin/tazobactam, cefepime, and meropenem in Gram-negative isolates were 15.4%, 14.3%, and 0.0%, respectively. Gram-positive bacteria are the most common cause of BSI in our patients. Resistance rates to piperacillin/tazobactam and cefepime in Gram-negative isolates make meropenem a better choice for empirical antimicrobial treatment. As national and hospital data may differ, the surveillance of pathogen distribution and antimicrobial susceptibility in pediatric hematology/oncology wards is necessary to adjust empirical treatment accordingly.
Student Reflections on Learning in a Doctoral-Level Writing Course
Authors: Anderson Jessica , Berryman Kristen , Dowd Jessica , Kenny Caitlin , Luib Patrick , Nkrumah Isaac , Reilly Laura , Retano-Anderson Angela , Ronquillo Khristine , Wadhawan Anju , Birnbaum Shira
Published: January 2024

Background:

Programs to improve student writing have been deployed widely in nursing graduate education, but few operational indicators exist for measuring their value.

Problem:

The challenge of measuring outcomes reflects the complexity of what transpires when graduate students write. Better understanding is needed of what it means to students to “learn” from writing support.

Approach:

A full-semester writing course was implemented in a nursing science PhD program. In formative course assessment activities, students identified problems in early drafts of their work, which they subsequently learned to detect and resolve. In this article, students report what was learned.

Conclusion:

Writing skills, like clinical skills, are intertwined with intellectual maturation and sense of professional identity. Writing, like clinical learning, requires an investment of time and labor far beyond what is typical in didactic approaches to classroom-based graduate education. Our experience suggests a need to reconceptualize writing pedagogy in nursing.
Genomic evidence for supergene control of Darwin′s 'complex marriage arrangement' – the tristylous floral polymorphism
Authors: Xue Haoran , Gong Yunchen , Wright Stephen I. , Barrett Spencer C. H.
Published: January 2024

Tristyly is a sexual polymorphism characterized by three flower morphs with reciprocal stigma and anther heights controlled by two epistatically interacting diallelic loci (S and M), hypothesized to be supergenes. Chromosome-level genome assemblies of Eichhornia paniculata identified the S- and M-loci. The S-locus is a supergene consisting of two divergent alleles: The S-allele (2.51 Mb), with three S-allele specific genes hemizygous in most S-morph plants and the s-allele (596 kb) with five s-allele specific genes. Two of the S-allele specific genes, LAZY1-S and HRGP-S, were specifically expressed in styles and stamens, respectively, making them tristyly candidate genes. The M-locus contains one gene (LAZY1-M) present in the M-allele but absent from the m-allele and which is homologous to LAZY1-S. Estimates of allele age are consistent with theory predicting that the S-locus evolved before the M-locus. Re-use of the same gene family highlights the potential role of gene duplication in the evolution of epistatic multilocus polymorphisms.
Unraveling principles of thermodynamics for genome-scale metabolic networks using graph neural networks
Authors: Fan Wenchao , Ding Chuyun , Huang Dan , Zheng Weiyan , Dai Ziwei
Published: January 2024

The fundamental laws of thermodynamics determine the feasibility of all natural processes including metabolism. Although several algorithms have been developed to predict the most important thermodynamic parameter, the standard Gibbs free energy, for metabolic reactions and metabolites, their application to genome-scale metabolic networks (GEMs) with thousands of metabolites and reactions is still limited. Here, we develop a graph neural network (GNN)- based model dGbyG for predicting Gibbs energy for metabolites and metabolic reactions which outperforms all existing methods in accuracy, versatility, robustness, and generalization ability. By applying dGbyG to the human GEM, Recon3D, we identify a critical subset of reactions with substantial negative values of the standard Gibbs free energy change, which we name thermodynamic driver reactions. These reactions exhibit distinctive network topological characteristics akin to driver nodes defined in control theory and remarkable heterogeneity in enzyme abundance, implying evolutionary constraints on the selection of thermodynamic parameters of metabolic networks. We also develop a thermodynamics-based flux balance analysis (TFBA) approach to integrate reaction thermodynamics with GEMs to curate these models. Our work not only transcends the augmentation of accessible thermodynamic data to facilitate an enriched understanding of metabolism, but also enables refinement of metabolic reconstructions from a thermodynamic perspective, thereby underscoring the critical role of thermodynamics in the accurate modeling of biological systems.
MCLand: A Python program for drawing emerging shapes of Waddington’s epigenetic landscape by Monte Carlo simulations
Authors: Chong Ket Hing , Zhang Xiaomeng , Lin Zhu , Zheng Jie
Published: January 2024

Waddington’s epigenetic landscape is a powerful metaphor for illustrating the process of cell differentiation. Recently, it has been used to model cancer progression and stem cell reprogramming. User-friendly software for landscape quantification and visualization is needed to allow more modeling researchers to benefit from this theory.

Results

We present MCLand, a Python program for plotting Waddington’s epigenetic landscape with a user-friendly graphical user interface. It models gene regulatory network (GRN) in ordinary differential equations (ODEs), and uses a Monte Carlo method to estimate the probability distribution of cell states from simulated time-course trajectories to quantify the landscape. Monte Carlo method has been tested on a few GRN models with biologically meaningful results. MCLand shows better intermediate details of kinetic path in Waddington’s landscape compared to the state-of-the-art software Netland.

Availability and implementation

The source code and user manual of MCLand can be downloaded fromhttps://mcland-ntu.github.io/MCLand/index.html.
A Worldwide Study of White Matter Microstructural Alterations in People Living with Parkinson’s Disease
Authors: Owens-Walton Conor , Nir Talia M. , Al-Bachari Sarah , Ambrogi Sonia , Anderson Tim J. , Aventurato Ítalo Karmann , Cendes Fernando , Chen Yao-Liang , Ciullo Valentina , Cook Phil , Dalrymple-Alford John C. , Dirkx Michiel F. , Druzgal Jason , Emsley Hedley C. A. , Guimarães Rachel , Haroon Hamied A. , Helmich Rick C. , Hu Michele T. , Johansson Martin E. , Kim Ho Bin , Klein Johannes C. , Laansma Max , Lawrence Katherine E. , Lochner Christine , Mackay Clare , McMillan Corey , Melzer Tracy R. , Nabulsi Leila , Newman Ben , Opriessnig Peter , Parkes Laura M. , Pellicano Clelia , Piras Fabrizio , Piras Federica , Pirpamer Lukas , Pitcher Toni L. , Poston Kathleen L. , Roos Annerine , Silva Lucas Scárdua , Schmidt Reinhold , Schwingenschuh Petra , Shahid Marian , Spalletta Gianfranco , Stein Dan J. , Thomopoulos Sophia I. , Tosun Duygu , Tsai Chih-Chien , van den Heuvel Odile A. , van Heese Eva , Vecchio Daniela , Villalón-Reina Julio E. , Vriend Chris , Wang Jiun-Jie , Wu Yih-Ru , Yasuda Clarissa Lin , Thompson Paul M. , Jahanshad Neda , van der Werf Ysbrand
Published: January 2024

Background

The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies, particularly regarding the involvement of white matter (WM) tracts. Here we performed the largest diffusion MRI study of PD to date, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of WM differences.

Methods

Diffusion-weighted MRI data from 1,654 participants diagnosed with PD (age range: 20-89 years; 33% female) and 885 controls (age range: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate regional microstructure in 21 white matter regions. Skeletonized maps of diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD) were analyzed and compared between Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter differences at different stages.

Results

We found an enhanced, more widespread pattern of microstructural differences with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest (ROIs): Cohen’sdeffect sizes reachedd=-1.01 for FA differences in the fornix by PD HY Stage 4/5. The early PD signature in HY stages 1 and 2 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with clinical metrics of motor and non-motor clinical dysfunction.

Conclusion

While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA in PD, which is consistent with early compensatory changes associated with the disorder.
Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival
Authors: Strauss Alexandra , Swann Peter , Kigar Stacey , Christou Rafailia , Yarkoni Natalia Savinykh , Murley Alexander , Chouliaras Leonidas , Savulich George , Bevan-Jones Richard , Surendranthan Ajenthan , O’Brien John , Rowe James , Malpetti Maura
Published: January 2024

The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g. cerebral microglia), peripheral innate immune cells (e.g. blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells, in n=148 people with Alzheimer’s disease (AD), Frontotemporal Dementia (FTD), Corticobasal syndrome (CBS), Progressive Supranuclear Palsy (PSP), Lewy Body Disease (LBD) as compared to n=37 healthy controls. To compare groups, we used Principal Component Analysis and multivariate Dissimilarity analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals’ immune profile weighting, positively to TREM2+ and nonclassical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies.
Concerted Transport and Phosphorylation of Diacylglycerol at ER-PM Contacts Sites Regulates Phospholipid Dynamics During Stress
Authors: García-Hernández Selene , Haslam Richard , Moya-Cuevas José , Catalá Rafael , Michaelson Louise , Amorim-Silva Vitor , Marković Vedrana , Salinas Julio , Napier Johnathan , Jaillais Yvon , Ruiz-Lopez Noemí , Botella Miguel A.
Published: January 2024

ABSTRACT

A universal response of plants to environmental stresses is the activation of plasma membrane (PM) phospholipase C (PLC) that hydrolyzes phosphatidylinositol phosphate (PIP) to produce soluble inositol phosphate (IP) and diacylglycerol (DAG). DAG produced in this way can be either phosphorylated by PM diacylglycerol kinases (DGKs) to produce the second messenger phosphatidic acid (PA) or transferred to the endoplasmic reticulum (ER) by the Synaptotagmin 1 (SYT1) protein at ER-PM Contact Sites (CS). In Arabidopsis, the clearance of DAG at the PM (avoiding deleterious accumulation) by the transfer activity of SYT is essential to maintain PM stability after stress. In this study we identify that DGK1 and DGK2 form a module with SYT1 at ER-PM CS through interaction of their C1 and C2 domains respectively. Global transcriptomic and metabolomic analyses confirms thatSYT1andDGK1/DGK2are functionally related and lipidomic analysis supports the hypothesis that DGK1 and DGK2 function at the ER by phosphorylating DAG transferred by SYT1 from the PM. DGK1 and DGK2 show structural similarity to human DGKε, the DGK isoform that function at ER-PM CS in the phosphoinositide (PI) cycle. Our data indicate that components of the PI cycle are conserved between animals and plants and provide a novel mechanism leading to an increase in the efficiency of the PI cycle by channeling the transport and hydrolysis of DAG at the ER-PM CS.
Single-Molecule Force Spectroscopy of Toehold-Mediated Strand Displacement
Authors: Walbrun Andreas , Wang Tianhe , Matthies Michael , Šulc Petr , Simmel Friedrich C. , Rief Matthias
Published: January 2024

Toehold-mediated strand displacement (TMSD) is extensively utilized in dynamic DNA nanotechnology and is the foundation for a wide range of DNA or RNA-based reaction circuits. Previous studies have typically relied on bulk fluorescence measurements to investigate the kinetics of TMSD, which only provide effective, bulk-averaged reaction rates and do not resolve the process on the level of individual molecules or even base pairs. In this work, we addressed this limitation by exploring the dynamics of strand displacement processes at the single-molecule level using single-molecule force spectroscopy (SMFS) with an optical trap supported by state-of-the-art coarse-grained simulations.

By probing the ends of the hairpin of a toehold structure, we can trigger and observe TMSD in real time with microsecond and nanometer resolution. Using a microfluidic assay where we expose the hairpin to a solution of trigger strands, we find that under load, TMSD proceeds very rapidly, with single step times of 1 μs. Introducing mismatches into the invader sequence allows us to tune stability such that invasion and re-invasion occur in equilibrium, even under load. This allows us to study thousands of invasion/re-invasion events on a single molecule and analyze the kinetics of the invasion process. Extrapolating our findings to zero load, we find single step times for DNA invading DNA four times faster than for RNA invading RNA. Moreover, we used force to study the kinetics of DNA invading RNA, a process that in the absence of force would rarely occur. Our results reveal the importance of sequence effects for the TMSD process and have importance for a wide range of applications in nucleic acid nanotechnology and synthetic biology.
Ciliary length regulation by intraflagellar transport in zebrafish
Authors: Sun Yi , Chen Zhe , Jin Minjun , Xie Haibo , Zhao Chengtian
Published: January 2024

How cells regulate the size of their organelles remains a fundamental question in cell biology. Cilia, with their simple structure and surface localization, provide an ideal model for investigating organelle size control. However, most studies on cilia length regulation are primarily performed on several single-celled organisms. In contrast, the mechanism of length regulation in cilia across diverse cell types within multicellular organisms remains a mystery. Similar to humans, zebrafish contain diverse types of cilia with variable lengths. Taking advantage of the transparency of zebrafish embryos, we conducted a comprehensive investigation into intraflagellar transport (IFT), an essential process for ciliogenesis. By generating a transgenic line carrying Ift88-GFP transgene, we observed IFT in multiple types of cilia with varying lengths. Remarkably, cilia exhibited variable IFT speeds in different cell types, with longer cilia exhibiting faster IFT speeds. This increased IFT speed in longer cilia is likely not due to changes in common factors that regulate IFT, such as motor selection, BBSome proteins, or tubulin modification. Interestingly, longer cilia in the ear cristae tend to form larger IFT compared to shorter spinal cord cilia. Reducing the size of IFT particles by knocking down Ift88 slowed IFT speed and resulted in the formation of shorter cilia. Our study proposes an intriguing model of cilia length regulation via controlling IFT speed through the modulation of the size of the IFT complex. This discovery may provide further insights into our understanding of how organelle size is regulated in higher vertebrates.
A pathogenic variant in RAB32 causes autosomal dominant Parkinson’s disease andactivates LRRK2 kinase
Authors: Gustavsson Emil K. , Follett Jordan , Trinh Joanne , Barodia Sandeep K. , Real Raquel , Liu Zhiyong , Grant-Peters Melissa , Fox Jesse D. , Appel-Cresswell Silke , Stoessl A. Jon , Rajput Alex , Rajput Ali H. , Auer Roland , Tilney Russel , Sturm Marc , Haack Tobias B. , Lesage Suzanne , Tesson Christelle , Brice Alexis , Vilariño-Güell Carles , Ryten Mina , Goldberg Matthew S. , West Andrew B. , Hu Michele T. , Morris Huw R. , Sharma Manu , Gan-Or Ziv , Samanci Bedia , Lis Pawel , Tocino Teresa , Amouri Rim , Sassi Samia Ben , Hentati Faycel ,   Global Parkinson’s Genetics Program (GP2), Tonelli Francesca , Alessi Dario R. , Farrer Matthew J.
Published: January 2024

Background

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD.

Methods

Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed.

Findings

We foundRAB32c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families.RAB32Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably,RAB32Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase.

Interpretation

Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD.

Funding

National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson’s, the Michael J. Fox Foundation for Parkinson’s Research, and the UK Medical Research Council.