bluuebunny/crossref_metadata_2025 huggingface dataset:
Revolution and the Question of Terror
Authors: Gill Graeme
Published: December 2023

Revolution is one of those phenomena that provoke heightened passion and significant polarization. For many it is seen as an uplifting experience, a means for the oppressed to throw off their shackles and achieve the freedom that has long been denied them. For others it is seen as a catastrophe, perhaps conducted in the quest to achieve high ideals, but in the result leading to widespread hardship, dictatorship, and terror. It is this latter view that provides the focus of this book, in particular the argument that terror is an inevitable result of revolution. The chapter discusses and defines the two principal concepts in this study: revolution and terror. In discussing revolution, it not only defines revolution as a concept, but surveys views about why revolution occurs and how it unfolds. Turning to terror, it introduces a tripartite typology of terror—revolutionary, transformational, and inverted—which will be the basis of the subsequent analysis. The structure of the book is outlined.
The French Revolution
Authors: Gill Graeme
Published: December 2023

The focus of this chapter is the course of the French Revolution from 1789 into 1794. It shows how all three types of terror overlapped temporally, reflecting the truncated nature of the revolutionary process in France. It also shows how, central to the French revolutionary process, was the politics of the streets—popular meetings, riots, demonstrations—and how this both interacted with the politics of the elite, and helped shape the unrolling of revolutionary and transformational terror. In contrast, inverted terror owed more to Robespierre than it did to popular mobilization. This chapter explores the impact of Robespierre’s on ‘The Terror’ of 1793–1794.
Orientalism-as-Discourse and Orientalism-as-Experience
Authors: Rahim Sana
Published: December 2023

Chapter 3 conceptualizes a methodological approach that recognizes the difference and complexity from the position of the Other. To understand the methods used in social science by postcolonial scholars the chapter looks at different tools that critical discourse analysis (CDA) provides to show how Pakistan is Othered in the Western security discourse. Using insights from ethnography the chapter then moves on to focus on the colonial subject and consciousness, with particular emphasis on the role of the voice applied to the case of Pakistan asking if the Subaltern can speak in the global nuclear discourse. And finally, with these conceptual tools, it explores the power relations involved in conducting such research and writing it up. This means understanding in detail the methods and the researcher’s reflexivity.
Living with Orientalism
Authors: Rahim Sana
Published: December 2023

In Chapter 5, the different experiences and perspectives of the individuals in the nuclear community are highlighted and analysed. The lived experiences of the participants and the implications of Orientalism on their opportunities are unpacked, as well as their identity and what this means for them. In everyday practices, Orientalism is pervasive, ever present, and frequently encountered. Individual stories, experiences, and concerns reveal the inner world of the participants, where they lose life chances and opportunities due to their ethnicity, identity, their religion, and their chosen careers. Participants are unable to travel, research using the latest technology and science, and progress in their careers, but, the feelings of inadequacy, the frustration, and the experiences of inequality are arguably worse.
Introduction
Authors: Whiting Jennifer
Published: December 2023

The Introduction offers general background to the questions about Aristotle’s conception of eudaimonia that are taken up in each of the chapters, especially questions about the roles played in his conception by the activities of theoretical and practical intellect and the quality of our relations with others. Subtle changes in view between earlier and later essays are described, especially changes concerning the way in which Aristotle takes eudaimonia to be “complete” and the extent to which he allows contemplation to play a dominant role in the eudaimonia of at least some subjects. And thematic connections are made to essays in two companion volumes: those in First, Second, and Other Selves: Essays on Friendship and Personal Identity, which are inspired by the conception of “character-friendship” defended here; and those in Body and Soul: Essays on Aristotle’s Hylomorphism, in which Aristotle’s conception of phronêsis as the proper form of human desire plays a prominent role.
Aristotle’s Function Argument
Authors: Whiting Jennifer
Published: December 2023

The chapter argues that common objections to Aristotle’s function argument rest on misunderstandings. He does not move from purely descriptive claims about human beings and what is “peculiar” to them to normative conclusions, either about what makes a human being good of its kind or about what is objectively good for human beings simply as such. He uses ‘idion’ in a technical sense tied to his essentialism and so ultimately to his natural teleology, in which the telos of an organism is its good. So the “proper” function of a human being is not like that of some instrument, or even some laborer, employed to serve ends other than its own. Rather, just as the nature of any living thing determines what constitutes health for members of its kind, so the human function determines what constitutes flourishing for (non-defective) members of the humankind.
Human Nature and Intellectualism in Aristotle
Authors: Whiting Jennifer
Published: December 2023

The chapter defends the internal consistency of the Nicomachean Ethics by arguing that EN X does not, despite appearances, break from the earlier books’ identification of eudaimonia at least partly with virtuous activity engaged in “for itself” and suddenly embrace the “intellectualist” identification of eudaimonia exclusively with contemplative activity. Many commentators suspect inconsistency, but John Cooper affirms it and hypothesizes that it is due to Aristotle’s changing views about the nature of human intellect, specifically his commitment to the De Anima account of “active intellect.” The chapter rebuts the alleged connection with the De Anima and defends a reading according to which EN X makes only a conditional claim—if a human being is identified exclusively with theoretical (as distinct from active) intellect, then eudaimonia consists exclusively in contemplation—but does not affirm the antecedent. Practical intellect belongs to the human essence, so its activities are components of eudaimonia.
Integrating body-worn cameras, drones, and AI: A framework for enhancing police readiness and response
Authors: Davies Amanda , Krame Ghaleb
Published: December 2023

The combined use of body-worn cameras (BWCs), drones, and artificial intelligence (AI) within the context of policing represents a significant advancement in policing methodology. This article presents a comprehensive framework for (a) the integrated use of these technologies to promote real-time situational awareness, heightened evidence collection, enhanced officer and public safety, improved operational efficiency, cognizant of compliance with ethical and privacy standards; and (b) an evaluation approach to the combined technology application. Illustration of the framework application to historical high-profile events presents a unique lens to assess potential outcomes and advantages, fostering and informing on a comprehensive discussion on future policing policies. This examination aims to offer a practical approach for implementing a synergistic BWCs, drones, and AI framework to leverage policing initiatives.
Precision cardiac targeting: empowering curcumin therapy through smart exosome-mediated drug delivery in myocardial infarction
Authors: Chen Ming , Wang Shengnan , Chen Yihuan , Shen Han , Chen Lei , Ding Liang , Tang Qingsong , Yang Ziying , Chen Weiqian , Shen Zhenya
Published: December 2023

Nanoparticle-mediated drug delivery has emerged as a highly promising and effective therapeutic approach for addressing myocardial infarction. However, clinical translation tends to be a failure due to low cardiac retention as well as liver and spleen entrapment in previous therapies. Herein, we report a two-step exosome delivery system, which precludes internalization by the mononuclear phagocyte system before the delivery of therapeutic cardiac targeting exosomes (ExoCTP). Importantly, curcumin released by ExoCTP diminishes reactive oxygen species over-accumulation in ischemic myocardium, as well as serum levels of lactate dehydrogenase, malonyldialdehyde, superoxide dismutase and glutathione, indicating better antioxidant capacity than free curcumin. Finally, our strategy was proven to greatly potentiate the delivery and therapeutic efficacy of curcumin without systemic toxicity. Taken together, our smart exosome-mediated drug delivery strategy can serve either as therapeutics alone or in combination with other drugs for effective heart targeting and subsequent wound healing.
Outcomes After Respiratory Extracorporeal Life Support in Teens and Young Adults: An Extracorporeal Life Support Organization Registry Analysis*
Authors: Brown Stephanie R. , Assy Jana , Anderson Michael P. , Thiagarajan Ravi R. , Brogan Thomas V.
Published: December 2023

OBJECTIVES:

A recent study from Germany found that survival after respiratory extracorporeal life support (ECLS) was lower among patients 10–20 years old than 20–30 years old. The objective of this study was to compare survival between teenage and young adult patients who receive respiratory ECLS.

DESIGN:

Retrospective cohort study.

SETTING:

Extracorporeal Life Support Organization registry, an international prospective quality improvement database.

PATIENTS:

All patients ages 16–30 years cannulated for respiratory indications from 1990 to 2020 were included. Patients were divided into two groups, teens (16–19 yr old) and young adults (20–30 yr old).

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Primary outcome was survival to discharge. Variables were considered for the multivariate logistic regression model if there was both a statistically significant difference (p ≤ 0.05) and a clinically meaningful absolute difference between the groups. A total of 5,751 patients were included, of whom 1,653 (29%) were teens and 4,098 (71%) were young adults. Survival to discharge was higher in young adults than teens, 69% versus 63% (p < 0.001). Severity of illness was higher among teens; however, survival within each stratum defined by Pao
2/Fio
2 ratio was higher in young adults than in teens. Use of venoarterial ECLS was higher in teens than in young adults, 15% versus 7%, respectively. Teens were more likely to receive high-frequency oscillatory ventilation and this therapy was associated with a longer time from admission to ECLS initiation. After adjusting for variables that differ significantly between the groups, the odds ratio for survival in young adults compared with teens was 1.14 (95% CI, 1.004–1.3).

CONCLUSIONS:

In this large multicenter retrospective study, mortality was higher in teens than in young adults who received respiratory ECLS. This difference persisted after adjusting for multiple variables and the mechanism underlying these findings remains unclear.
Hybrid Email and Outpatient Clinics to Optimize Maintenance Therapy in Acute Lymphoblastic Leukemia
Authors: Mungle Tushar , Mahadevan Ananya , Das Parag , Mehta Amit K. , Gogoi Manash P. , Jana Bishwaranjan , Ghara Niharendu , Ghosh Debjani , Saha Vaskar , Krishnan Shekhar
Published: December 2023

Acute lymphoblastic leukemia treatment includes an outpatient (OP)-based 2-year maintenance therapy (MT). Over an 8-year period, patients were transited from only OP to a hybrid e-clinic/OP-clinic model. Electronic and patient-held medical records of acute lymphoblastic leukemia patients 1 to 18 years old during MT were used to analyze demographics, drug doses, treatment response and cost. A survey evaluated family satisfaction with the hybrid service. Four hundred and seventy-eight children, all with at least 1 year of MT from March 13, 2014 to March 24, 2022 were grouped into 4 treatment eras, representing the transition from all OP (era 1) to the current hybrid MT practice (era 4). Cohort demographics were similar across all eras. With transition to era 4, OP visits decreased to a third (16 to 18/48 visits). Practice optimization in era 2 resulted in higher MT dose intensity in subsequent eras (era 1: median 82% [interquartile range, 63 to 97]; era 2: 93% [73 to 108]; era 3: 88% [68 to 106]; era 4: 90% [74 to 114], P<0·0001), with no differences in absolute neutrophil count or neutropenia-related toxicity (P=0.8). The hybrid service reduced MT expenses by ~50% and families (133/156, 85%) reported being very satisfied. Our experience indicates that a hybrid model is feasible, effective and less burdensome for patients and families.
Proposal of a modified classification for hilar cholangiocarcinoma
Authors: Xiang Shuai , Chen Xiao-Ping
Published: December 2023

Hilar cholangiocarcinoma is a malignant tumor that originates from the left and right hepatic ducts and their confluence. It is highly malignant and associated with a poor prognosis. Surgical resection is the only available curative treatment option. A scientific classification system can aid in the preoperative assessment of resectability and guide the development of appropriate surgical strategies. Several classification systems are available, with the Bismuth-Corlette (BC) classification being the earliest and most widely used. Similar to many other classifications, the BC classification relies on the secondary branching of the bile ducts as an important anatomical landmark, making it unsuitable for cases with variations in the bile duct anatomy. With advances in understanding the hepatic plate and anatomical structures at the hilum, the secondary bile ducts are no longer considered important anatomical landmarks. Therefore, modifications to the BC classification are needed to align with modern anatomical improvements and advancements in surgical techniques. Herein, we propose a modification to the BC classification. In this new system, the boundary of the hilar plate is considered as limit of the proximal ductal margin and used as an anatomical landmark, rather than the concept of “secondary bile ducts” in the BC classification.
Transcriptomic and Proteomic Characterization of the Immune Response to Elective Spinal Reconstructive Surgery: Impact of Aging and Comparison with Traumatic Injury Response
Authors: Bonaroti Jillian W , Ozel Mehves , Chen Tianmeng , Darby Jennifer L , Sun Xuejing , Moheimani Hamed , Reitz Katherine M , Kar Upendra K , Zuckerbraun Brian S , Das Jishnu , Okonkwo David O , Billiar Timothy R
Published: December 2023

BACKGROUND:

Major surgery triggers trauma-like stress responses linked to age, surgery duration, and blood loss, resembling polytrauma. This similarity suggests elective surgery as a surrogate model for studying polytrauma immune responses. We investigated stress responses across age groups and compared them with those of polytrauma patients.

STUDY DESIGN:

Patients undergoing major spinal reconstruction surgery were divided into older (age >65 years, n = 5) and young (age 18 to 39 years, n = 6) groups. A comparison group consisted of matched trauma patients (n = 8). Blood samples were collected before, during, and after surgery. Bone marrow mononuclear cells and peripheral blood mononuclear cells were analyzed using cellular indexing of transcriptomes and epitopes sequencing or single-cell RNA sequencing. Plasma was subjected to dual-platform proteomic analysis (SomaLogic and O-link).

RESULTS:

Response to polytrauma was highest within 4 hours. By comparison, the response to surgery was highest at 24 hours. Both insults triggered significant changes in cluster of differentiation 14 monocytes, with increased inflammation and lower major histocompatibility complex-class 2 expression. Older patient’s cluster of differentiation 14 monocytes displayed higher inflammation and less major histocompatibility complex-class 2 suppression; a trend was also seen in bone marrow mononuclear cells. Although natural killer cells were markedly activated after polytrauma, they were suppressed after surgery, especially in older patients. In plasma, innate immunity proteins dominated at 24 hours, shifting to adaptive immunity proteins by 6 weeks with heightened inflammation in older patients. Senescence-associated secretory phenotype proteins were higher in older patients at baseline and further elevated during and after surgery.

CONCLUSIONS:

Although both major surgery and polytrauma initiate immune and stress responses, substantial differences exist in timing and cellular profiles, suggesting major elective surgery is not a suitable surrogate for the polytrauma response. Nonetheless, distinct responses in young vs older patients highlight the utility of elective spinal in studying patient-specific factors affecting outcomes after major elective surgery.
AN OVERVIEW OF THE IMPACT OF SOCIAL SUPPORT ON NURSE BURN OUT IN HOSPITALS
Authors: Riu Silvia Dewi Mayasari , Pandin Moses Glorino Rumambo
Published: December 2023

Introduction

The nursing profession is one of the most difficult and stressful occupations. Nurses have a great responsibility in providing health care to clients, which often involves emotional, complex, and high-risk situations. Social support is emotional, informational and practical assistance provided by individuals or groups to others in certain situations. Burnout syndrome is a chronic stress condition that affects many individuals including nurses. This condition often arises as a result of excessive workload, high physical and emotional demands and imbalance between work and personal life plus the occurrence of a global pandemic.

Method

The author used the literature review method by searching for references via the internet. The literature search used Sciencedirect, Pubmed, and Medline and Google Scholar with keywords in English: “social support”, “burnout”. The inclusion criteria in this research were articles that discussed social support on burnout, were in English, published in the last 5 years (2018-2023), explored in the article was the influence of social support on burnout, and a comprehensive examination of the full article is provided. Exclusion criteria were articles that did not discuss social support on burnout.

Result

From the literature search, it was obtained 16 journal articles that were relevant with the research objectives.

Conclusion

Social support has an important role as a protective factor that can reduce the risk of burnout in individuals, especially among professionals or workers who experience high workloads. Good social support can provide the emotional, instrumental, and informational resources needed to cope with daily stress and pressure.

Suggestion

Social support can be considered a form of “natural protection” against burnout, and efforts to strengthen social support networks can be an effective strategy in preventing and coping burnout at various levels of life and professions.
Clinical utility of plasma Aβ42/40 ratio by LC-MS/MS in Alzheimer’s disease assessment
Authors: Weber Darren M. , Taylor Steven W. , Lagier Robert J. , Kim Jueun C. , Goldman Scott M. , Clarke Nigel J. , Vaillancourt David E. , Duara Ranjan , McFarland Karen N. , Wang Wei-en , Golde Todd E. , Racke Michael K.
Published: December 2023

INTRODUCTION

Plasma Aβ42/40 ratio can be used to help predict amyloid PET status, but its clinical utility in Alzheimer’s disease (AD) assessment is unclear.

METHODS

Aβ42/40 ratio was measured by LC-MS/MS in 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and 6,192 consecutive clinical specimens submitted for Aβ42/40 testing.

RESULTS

High diagnostic sensitivity and negative predictive value (NPV) for Aβ-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients’ cognitive impairment and help reduce PET evaluation by about 40%.

DISCUSSION

Using high-throughput plasma Aβ42/40 LC-MS/MS assays can help reduce PET evaluations in patients with low likelihood of AD pathology, allowing for cost savings.

Highlights

A new plasma LC-MS/MS assay for the Aβ42/Aβ40 ratio has clinical utility in AD assessment.

Performance was assessed using specimens with a moderate prevalence of Aβ-PET positivity.

Analysis was extrapolated to 6,192 consecutive clinical specimens submitted for ratio testing.

Assay cutpoints were proposed to help suggest clinical management decisions.

Based on the assay’s high NPV, costly PET evaluations may be avoided for many individuals.

Research in Context

Systematic Review

Aβ42/Aβ40 ratio data were analyzed from 250 ADRC cohort participants and 6,192 plasma specimens submitted for Aβ42/40 ratio testing by LC-MS/MS at Quest Diagnostics.

Interpretation

Based on its high NPV, the assay identifies individuals likely to have negative amyloid PET results. Higher discriminatory power and larger fold-changes between PET-positive and negative individuals were observed compared with previous studies. Our “real-world” data set, combined with known performance characteristics, allows us to suggest cutpoints and clinical decisions based on plasma Aβ42/40 ratios.

Future Directions

Longitudinal plasma specimens from individuals who convert from PET-negative to positive, or that transition from cognitively normal to MCI and AD, will improve understanding of the prognostic utility of the Aβ42/40 ratio. Using Aβ42/40 ratio alone or combined with other biomarkers, to follow patients with cognitive impairment may yield insights regarding their disease conditions and progression and who may benefit from disease-modifying therapeutics.
Racial and Ethnic Disparities in Healthcare Utilization and Mortality by Neighborhood Poverty among Individuals with Congenital Heart Defects, four U.S. Surveillance Sites, 2011-2013
Authors: Raskind-Hood Cheryl L. , Kancherla Vijaya , Ivey Lindsey C. , Rodriguez Fred H. , Sullivan Anaclare M. , Lui George K. , Botto Lorenzo , Feldkamp Marcia , Li Jennifer S. , D’Ottavio Alfred , Farr Sherry L. , Glidewell Jill , Book Wendy M.
Published: December 2023

BACKGROUND

Socioeconomic factors may lead to a disproportionate impact on healthcare utilization and mortality among individuals with congenital heart defects (CHD) by race, ethnicity, and socio-economic factors. How neighborhood poverty affects racial and ethnic disparities in healthcare utilization and mortality among individuals with CHD across the lifespan is not well described.

METHODS

Individuals, 1-64 years, with at least one CHD-related ICD-9-CM code were identified from healthcare encounters between 01/01/2011-12/31/2013 from four U.S. sites. Residence was classified into lower or higher poverty neighborhoods based on ZCTA from the 2014 American Community Survey 5-Year Estimates. Multivariable logistic regression models, adjusting for site, sex, CHD anatomic severity, and insurance evaluated associations between race and ethnicity, and healthcare utilization and mortality, stratified by neighborhood poverty.

RESULTS

Of 31,542 individuals, 22.2% were non-Hispanic Black (nHB) and 17.0% Hispanic. In high poverty neighborhoods, nHB (44.4%) and Hispanic (47.7%) individuals, respectively, were more likely to be hospitalized (aOR)=1.2 [95%CI=1.0-1.3] and aOR=1.3 [95%CI=1.2-1.5]) and have ED visits (aOR=1.3 [95%CI=1.2-1.5] and aOR=1.7 [95%CI=1.5-2.0]) compared to non-Hispanic White (nHW) individuals. In high poverty neighborhoods, nHB individuals with CHD had 1.7 times the odds of mortality compared to nHW individuals in high poverty neighborhoods (95%CI=1.1-2.7). Racial and ethnic disparities in healthcare utilization were similar in low poverty neighborhoods, but disparities in mortality were attenuated (aOR for nHB=1.2 [95%CI=0.9-1.7]).

CONCLUSIONS

Racial and ethnic disparities in healthcare utilization were found among individuals with CHD in low and high poverty neighborhoods, but mortality disparities were larger in high poverty neighborhoods. Understanding individual- and community-level social determinants of health, including access to healthcare, may help address racial and ethnic inequities in healthcare utilization and mortality among individuals with CHD.
Changes in the structure of spontaneous speech predict the disruption of hierarchical brain organization in first-episode psychosis
Authors: He Rui , Alonso-Sánchez Maria Francisca , Sepulcre Jorge , Palaniyappan Lena , Hinzen Wolfram
Published: December 2023

Psychosis implicates changes across a broad range of cognitive functions. These functions are cortically organized in the form of a hierarchy ranging from primary sensorimotor (unimodal) to higher-order association cortices, which involve functions such as language (transmodal). Language has long been documented as undergoing structural changes in psychosis. We hypothesized that these changes as revealed in spontaneous speech patterns may act as readouts of alterations in the configuration of this unimodal-to-transmodal axis of cortical organization in psychosis. Results from 29 patients with first-episodic psychosis (FEP) and 29 controls scanned with 7T resting-state fMRI confirmed a compression of the cortical hierarchy in FEP, which affected metrics of the hierarchical distance between the sensorimotor and default mode networks, and of the hierarchical organization within the semantic network. These organizational changes were predicted by graphs representing semantic and syntactic associations between meaningful units in speech produced during picture descriptions. These findings unite psychosis, language, and the cortical hierarchy in a single conceptual scheme, which helps to situate language within the neurocognition of psychosis and opens the clinical prospect for mental dysfunction to become computationally measurable in spontaneous speech.
Steady-state neuron-predominant LINE-1 encoded ORF1p protein and LINE-1 RNA increase with aging in the mouse and human brain
Authors: Bonnifet Tom , Sinnassamy Sandra , Massiani-Beaudoin Olivia , Mailly Philippe , Monnet Héloïse , Loew Damarys , Lombard Berangère , Servant Nicolas , Joshi Rajiv L. , Fuchs Julia
Published: December 2023

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-1 encoded proteins can induce cell toxicity implicated in aging and neurodegenerative diseases. However, our knowledge of the expression and localization of LINE-1-encoded proteins in the central nervous system is limited. Using a novel approach combining atlas-based brain mapping with deep-learning algorithms on large-scale pyramidal brain images, we unveil a heterogeneous, neuron-predominant and widespread ORF1p expression throughout the murine brain at steady-state. In aged mice, ORF1p expression increases significantly which is corroborated in human post-mortem dopaminergic neurons by an increase in young LINE-1 elements including those with open reading frames. Mass spectrometry analysis of endogenous mouse ORF1p revealed novel, neuron-specific protein interactors. These findings contribute to a comprehensive description of the dynamics of LINE-1 and ORF1p expression in the brain at steady-state and in aging and provide insights on ORF1p protein interactions in the brain.
Structured dynamics in the algorithmic agent
Authors: Ruffini G. , Castaldo F. , Vohryzek J.
Published: December 2023

In the Kolmogorov Theory of Consciousness, algorithmic agents utilize inferred compressive models to track coarse-grained data produced by simplified world models, capturing regularities that structure subjective experience and guide action planning. Here, we study the dynamical aspects of this framework by examining how the requirement of tracking natural data drives the structural and dynamical properties of the agent. We first formalize the notion ofgenerative modelusing the language of symmetry from group theory, specifically employing Lie pseudogroups to describe the continuous transformations that characterize invariance in natural data. Then, adopting a generic neural network as a proxy for the agent dynamical system and drawing parallels to Noether’s theorem in physics, we demonstrate that data tracking forces the agent to mirror the symmetry properties of the generative world model. This dual constraint on the agent’s constitutive parameters and dynamical repertoire enforces a hierarchical organization consistent with the manifold hypothesis in the neural network. Our findings bridge perspectives from algorithmic information theory (Kolmogorov complexity, compressive modeling), symmetry (group theory), and dynamics (conservation laws, reduced manifolds), offering insights into the neural correlates of agenthood and structured experience in natural systems, as well as the design of artificial intelligence and computational models of the brain.

Highlights

Lie generative models are formalized using Lie pseudogroups, linking algorithmic simplicity, recursion, and compositionality with symmetry.

Neural networks inherit structural constraints reflecting the symmetries in Lie-generated data.

Similarly, agents, instantiated as neural networks tracking world Lie-generated data, reflect Lie structure and reduced-dimensional dynamical manifolds.

Compositional structure in world data induces coarse-grained constraints, resulting in reduced manifolds that reflect the underlying generative process.

Mutual Algorithmic Information (MAI) between the agent and the world emerges as shared symmetries in their dynamical interactions.

These findings provide new insights for neuroscience, AI design, and computational brain modeling, emphasizing the interplay between data structure and agent dynamics.
Keratinocyte Piezo1 drives paclitaxel-induced mechanical hypersensitivity
Authors: Mikesell Alexander R , Isaeva Elena , Schulte Marie L , Menzel Anthony D , Sriram Anvitha , Prahl Megan M , Shin Seung Min , Sadler Katelyn E , Yu Hongwei , Stucky Cheryl L
Published: December 2023

Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown if keratinocytes contribute to touch evoked pain and hypersensitivity following tissue injury. Here, we used inhibitory optogenetic and chemogenetic techniques to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapeutic treatment. We found that keratinocyte inhibition largely alleviates paclitaxel-induced mechanical hypersensitivity. Furthermore, we found that paclitaxel exposure sensitizes mouse and human keratinocytes to mechanical stimulation through the keratinocyte mechanotransducer Piezo1. These findings demonstrate the contribution of non-neuronal cutaneous cells to neuropathic pain and pave the way for the development of new pain-relief strategies that target epidermal keratinocytes and Piezo1.

Sensitization of the keratinocyte mechanotransducer Piezo1 drives paclitaxel-induced touch pain.
Shared features underlying compact genomes and extreme habitat use in chironomid midges
Authors: Nell Lucas A. , Weng Yi-Ming , Phillips Joseph S. , Botsch Jamieson C. , Book K. Riley , Einarsson Árni , Ives Anthony R. , Schoville Sean D.
Published: December 2023

Non-biting midges (family Chironomidae) are found throughout the world in a diverse array of aquatic and terrestrial habitats, can often tolerate harsh conditions such as hypoxia or desiccation, and have consistently compact genomes. Yet we know little about the shared molecular basis for these attributes and how they have evolved across the family. Here, we address these questions by first creating high-quality, annotated reference assemblies forTanytarsus gracilentus(subfamily Chironominae, tribe Tanytarsini) andParochlus steinenii(subfamily Podonominae). Using these and other publicly available assemblies, we created a time-calibrated phylogenomic tree for family Chironomidae with outgroups from order Diptera. We used this phylogeny to test for features associated with compact genomes, as well as examining patterns of gene family evolution and positive selection that may underlie chironomid habitat tolerances. Our results suggest that compact genomes evolved in the most recent common ancestor of Chironomidae and Ceratopogonidae, and that this occurred mainly through reductions in non-coding regions (introns, intergenic sequences, and repeat elements). Gene families that significantly expanded in Chironomidae included biological processes that may relate to tolerance of stressful environments, such as temperature homeostasis, inflammatory response, melanization defense response, and trehalose transport. We identified a number of genes with evidence for positive selection in Chironomidae, notably sulfonylurea receptor, peroxiredoxin-1, and protein kinase D. Our results help to understand the genomic basis for the small genomes and extreme habitat use in this widely distributed group.

Significance Statement

Chironomid midges are known for having small genomes and being able to tolerate many forms of environmental stress, yet little is known of the shared features of their genomes that may underlie these traits. We found that reductions in non-coding regions coincide with small chironomid genomes, and we identified duplicated and/or selected genes that may equip chironomids to tolerate harsh conditions. These results describe the key genomic changes in chironomid midges that may explain their ability to inhabit a range of extreme habitats across the world.
Micro-DeMix: A mixture beta-multinomial model for investigating the fecal microbiome compositions
Authors: Liu Ruoqian , Wang Yue , Cheng Dan
Published: December 2023

Extensive research has uncovered the involvement of the human gut microbiome in various facets of human health, including metabolism, nutrition, physiology, and immune function. Researchers often study fecal microbiota as a proxy for understanding the gut microbiome. However, it has been demonstrated that this approach may not suffice to yield a comprehensive understanding of the entire gut microbial community. Emerging research is revealing the heterogeneity of the gut microbiome across different gastrointestinal (GI) locations in both composition and functions. While spatial metagenomics approach has been developed to address these variations in mice, limitations arise when applying it to human-subject research, primarily due to its invasive nature. With these restrictions, we introduce Micro-DeMix, a mixture beta-multinomial model that decomposes the fecal microbiome at compositional level to understand the heterogeneity of the gut microbiome across various GI locations and extract meaningful insights about the biodiversity of the gut microbiome. Moreover, Micro-DeMix facilitates the discovery of differentially abundant microbes between GI regions through a hypothesis testing framework. We utilize the Inflammatory Bowel Disease (IBD) data from the NIH Integrative Human Microbiome Project to demonstrate the effectiveness and efficiency of the proposed Micro-DeMix.

Key MessagesKey Messages

Micro-DeMix is a computational tool for understanding the heterogeneity of the gut microbiome across GI locations.

Micro-DeMix facilitates the detection of differentially abundant microbes along the GI tract.

Micro-DeMix detects that in IBD populations, the lower GI tract exhibits a larger abun-dance of Firmicutes and Bacteroidetes, whereas the upper GI tract is predominated by Proteobacteria and Firmicutes.
AlphaFold2 has more to learn about protein energy landscapes
Authors: Chakravarty Devlina , Schafer Joseph W. , Chen Ethan A. , Thole Joseph R. , Porter Lauren L.
Published: December 2023

Recent work suggests that AlphaFold2 (AF2)–a deep learning-based model that can accurately infer protein structure from sequence–may discern important features of folded protein energy landscapes, defined by the diversity and frequency of different conformations in the folded state. Here, we test the limits of its predictive power on fold-switching proteins, which assume two structures with regions of distinct secondary and/or tertiary structure. Using several implementations of AF2, including two published enhanced sampling approaches, we generated >280,000 models of 93 fold-switching proteins whose experimentally determined conformations were likely in AF2’s training set. Combining all models, AF2 predicted fold switching with a modest success rate of ∼25%, indicating that it does not readily sample both experimentally characterized conformations of most fold switchers. Further, AF2’s confidence metrics selected against models consistent with experimentally determined fold-switching conformations in favor of inconsistent models. Accordingly, these confidence metrics–though suggested to evaluate protein energetics reliably–did not discriminate between low and high energy states of fold-switching proteins. We then evaluated AF2’s performance on seven fold-switching proteins outside of its training set, generating >159,000 models in total. Fold switching was accurately predicted in one of seven targets with moderate confidence. Further, AF2 demonstrated no ability to predict alternative conformations of two newly discovered targets without homologs in the set of 93 fold switchers. These results indicate that AF2 has more to learn about the underlying energetics of protein ensembles and highlight the need for further developments of methods that readily predict multiple protein conformations.
Loss-of-function mutation in the polyamine transporter geneOsLAT5as a selectable marker for genome editing
Authors: Schenstnyi Kyrylo , Zhang Zhengzhi , Liu Bo , Nakamura Masayoshi , Schepler-Luu Van , Loo Eliza P.I. , Yang Bing , Frommer Wolf B.
Published: December 2023

Genome editing by TALENs, CRISPR/Cas, base or prime editing have become routine tools. During stable plant transformation, the gene coding for the editing enzyme, e.g.,Cas9,the guide RNAs (gRNAs), alongside a selectable marker are integrated into the nuclear genome. Identification of successful transformants relies on selectable or screenable markers, typically genes providing resistance to antibiotics or herbicides. Selectable markers use a substantial portion of the T-DNA, hence reducing transfer efficiency by limiting the effective number of TALENs or guide/pegRNAs that can be used in parallel. Moreover, marker genes are frequently subject to gene silencing. Here, we generated loss-of-function mutations in PUT/LAT-type polyamine transporter family genes to confer resistance to the phytotoxin methylviologen (MV) as a method for selection. As a proof of concept, CRISPR/Cas9 vectors with gRNAs were constructed to target three close homologsOsLAT1,OsLAT5, andOsLAT7. We show that loss ofOsLAT5(also known asOsPUT3orOsPAR1) function was sufficient to confer resistance to MV in rice seeds, seedlings and calli, validating the editing approach ofOsLAT5to obtain a selectable marker. We discuss the potential of incorporating a gRNA cassette (forOsLAT5) as a selectable marker and a reporter for successful genome editing for optimizing editing protocols.
Short-term effects of “Yijinjing Wohu Pushi” posture-voice therapy on speech in Parkinson’s disease after STN-DBS
Authors: Sun Xin , Yang Mei , Yan Jin , Wang Linbin , Sun Yuxin , Wang Yong , Yan Shiqing , Li Dianyou , Niu Chuanxin M.
Published: December 2023

Hypokinetic dysarthria in Parkinson’s Disease (HD-PD) deteriorates patients’ quality of life by impeding communication and social engagement. Existing treatments like levodopa drugs and deep brain stimulation (DBS) can improve motor symptoms but fall short in addressing speech-related impairments; effective speech therapies tend not to mandate the posture, which potentially hinders vocal performance. Here we first proposed a therapeutic protocol that specified a lunging-and-clawing posture (Wohu Pushi method from Yijinjing) during vocalization training. The protocol aimed to ensure that PD patients could accomplish the training even with moderate motor impairments. A total of 20 HD-PD patients with implanted stimulators in subthalamic nuclei (STN-DBS) participated in one session of training, either following our posture-voice therapy (PVT) or the conventional voice therapy (CVT). Results indicated that the maximum phonation time was significantly elongated in PVT(3.85±2.81s) but not in CVT(0.46 ± 2.24s), and the formant-distance was significantly increased in PVT(95.80 ± 112.71Hz) compare to CVT(-47.10 ± 84.28Hz). Our results indicated that by demanding appropriate amount of postural maintenance during vocalization, it might facilitate the recovery of speech-related functions. This study warranted larger-scale clinical trials to understand the impact, limitation, and optimization of posture-voice therapy for HD-PD.
HIPTox – Hazard Identification Platform to Assess the Health Impacts from Indoor and Outdoor Air Pollutant Exposures, through Mechanistic Toxicology: A single-centre double-blind human exposure trial protocol
Authors: Faherty Thomas , Badri Huda , Hu Dawei , Voliotis Aristeidis , Pope Franics D. , Mudway Ian , Smith Jacky , McFiggans Gordon
Published: December 2023

Over the past decade, our understanding of the impact of air pollution on short- and long-term population health has advanced considerably, focusing on adverse effects on cardiovascular and respiratory systems. There is, however, increasing evidence that air pollution exposures affect cognitive function, particularly in susceptible groups. Our study seeks to assess and hazard rank the cognitive effects of prevalent indoor and outdoor pollutants through a single-center investigation on the cognitive functioning of healthy human volunteers aged 50 and above, with a familial predisposition to dementia. Participants will all undertake five sequential controlled exposures. The sources of the air pollution exposures are wood smoke, diesel exhaust, cleaning products, and cooking emissions, with clean air serving as the control. Pre- and post-exposure spirometry, nasal lavage, blood sampling, and cognitive assessments will be performed. Repeated testing pre- and post-exposure to controlled levels of pollutants will allow for the identification of acute changes in functioning as well as the detection of peripheral markers of neuroinflammation and neuronal toxicity. This comprehensive approach enables the identification of the most hazardous components in indoor and outdoor air pollutants and further understanding of the pathways contributing to neurodegenerative diseases. The results of this project have the potential to facilitate greater refinement in policy, emphasizing health-relevant pollutants and providing details to aid mitigation against pollutant-associated health risks.
Prevalence and determinants of evidence of silicosis and impaired lung function, among small scale tanzanite miners and the peri-mining community in northern Tanzania
Authors: Mbuya Alexander W. , Mboya Innocent B. , Semvua Hadija H. , Mamuya Simon H. , Howlett Patrick J. , Msuya Sia E.
Published: December 2023

Among mining communities in Tanzania, the limited data available suggests the prevalence of silicosis, obstructive lung diseases (OLD) and restrictive lung disease (RLD) to be around 1.6%, 1.9% and 8.8% respectively. Our study therefore aimed to determine the prevalence and factors associated with evidence of silicosis and ILF among tanzanite mining community in northern Tanzania.

We conducted a cross-sectional study, involving 330 randomly selected miners and 330 conveniently selected non-mine workers from the peri-mining community (PMC) in Mererani mines, northern Tanzania. Evidence of silicosis was defined based on study participants’ history of exposure to mining dust and digital chest radiological findings with reference to the 2011 ILO classification of pneumoconiosis. Impaired lung function was determined by spirometry using American Thoracic Society (ATS)/European Respiratory Society (ERS) recommended system 3. Association between evidence of silicosis/impaired lung function and presumed risk factors were determined using binary logistic regression analyses. The study found that 99/330 (30.0%) of miners had evidence of silicosis, of whom 97.0% had accelerated silicosis. Among miners and community members, 75 (11.4%) had ILF, of whom 30 (4.5%) had COPD, 9 (1.4%) had asthma, 29 (4.4%) had restrictive lung disease and 7 (1.1%) had mixed pattern of both obstructive and restrictive lung disease. We found that having a daily income of more than USD 4.3 was associated with lower odds of silicosis (aOR 0.57, 95% CI 0.37-0.89, p<0.05) while ILF was associated with being a miner (aOR 2.06, CI=1.38-3.07, p<0.001).

We found a concerningly high prevalence of evidence of silicosis despite short durations of exposure among small scale tanzanite miners. Immediate dust control measures including deployment of wet drilling, wearing of personal protective equipment (PPE) and regular monitoring of dust exposure need to be enforced by the OSHA (Tanzania).
The AMsh glia ofC. elegansmodulates the duration of touch-induced escape responses
Authors: Awe Temitope , Akinosho Aalimah , Niha Shifat , Kelly Laura , Adams Jessica , Stein Wolfgang , Vidal-Gadea Andrés
Published: December 2023

Once considered mere structural support cells in the nervous system, glia have recently been demonstrated to play pivotal roles in sensorimotor processing and to directly respond to sensory stimuli. However, their response properties and contributions to sensory-induced behaviors remain little understood. InCaenorhabditis elegans, the amphid sheath glia (AMsh) directly respond to aversive odorants and mechanical stimuli, but their precise transduction machinery and their behavioral relevance remain unclear.

We investigated the role of AMsh in mechanosensation and their impact on escape behaviors inC. elegans. We found that nose touch stimuli in immobilized animals induced a slow calcium wave in AMsh, which coincided with the termination of escape reversal behaviors. Genetic ablation of AMsh resulted in prolonged reversal durations in response to nose touch, but not to harsh anterior touch, highlighting the specificity of AMsh’s role in distinct escape behaviors.

Mechanotransduction in AMsh requires the α-tubulin MEC-12 and the ion channels ITR-1 and OSM-9, indicating a unique mechanosensory pathway that is distinct from the neighboring ASH neurons. We find that GABAergic signaling mediated by the GABA-A receptor orthologs LGC-37/8 and UNC-49 play a crucial role in modulating the duration of nose touch-induced reversals.

We conclude that in addition to aversive odorant detection, AMsh mediate mechanosensation, play a pivotal role in terminating escape responses to nose touch, and provide a mechanism to maintain high sensitivity to polymodal sensory stimuli.

Significance

Polymodal nociceptive sensory neurons have the challenge of multitasking across sensory modalities. They must respond to dangerous stimuli of one modality, but also adapt to repeated nonthreatening stimuli without compromising sensitivity to harmful stimuli from different modalities. Here we show that a pair of glia in the nematodeC. elegansmodulate the duration of nose-touch induced escape responses. We identify several molecules involved in the transduction of mechanical stimuli in these cells and show that they use the signaling molecule GABA to modulate neural function. We propose a mechanism through which these glia might function to maintain this polysensory neuron responsive to dangerous stimuli across different modalities.