bluuebunny/crossref_metadata_2025 huggingface dataset:
Accounting for Illiberalism in American Liberal Internationalism
Authors: Viola Lora Anne
Published: September 2024

In US foreign policy, a commitment to liberal principles coexists empirically with illiberal practices. Gaps between principles and practices can be costly, leading to legitimacy and credibility losses, provoking contestation among those committed to liberal principles, and allowing those who reject the principles to exploit the US’ apparent hypocrisy in order to delegitimize its leadership and the liberal international order. Costs create pressures for leaders to give explanations that rationalize or account for gaps between principles and practices. I develop three types of accounts that are logically available to leaders for explaining the gap between liberal principles and foreign policy practices: the aspirational, justificatory, and necessity accounts. Leaders use these accounts to manage political consequences, shape audience opinion, and mobilize political support. I discuss when and why each type is likely to be used, and with what effects for different kinds of contestations of the liberal script.
Aesthetic Appropriation
Authors: Lopes Dominic McIver
Published: September 2024

One form of cultural appropriation is the appropriation of aesthetic culture. A value-neutral account is given of aesthetic appropriation. Some aesthetic appropriation is weaponized aesthetics: it stems from and compounds social injustice through theft, misrepresentation, disrespect, or assimilation. The reception of Bill Reid’s sculpture, The Spirit of Haida Gwaii, is a potential case of aesthetic injustice. The argument is that the case illustrates how some aesthetic injustice stems from and contributes to weaponized aesthetics. In particular, it illustrates how practices of cultural outsiders subvert an interest in the social autonomy of an aesthetic culture.
Beauty Ideals and Ideologies
Authors: Lopes Dominic McIver
Published: September 2024

Recent work on beauty ideals is surveyed alongside Tommie Shelby’s theory of ideology, and a theory is proposed of ideological beauty ideals. Ideological beauty ideals are weaponized aesthetics: they stem from and compound social injustice around gender and race. They arguably figure in concepts of gender and race, and they licence and normalize discriminatory behaviours. A much-discussed passage in Toni Morrison’s novel The Bluest Eye is a potential case of aesthetic injustice. The passage illustrates how some aesthetic injustice stems from and contributes to weaponized aesthetics. In particular, it illustrates how ideological beauty ideals subvert an interest in the value diversity of aesthetic cultures of bodily beauty.
Islamic Perspectives on Gamete Donation and Surrogacy
Authors: Shabana Ayman
Published: September 2024

This chapter explores Islamic perspectives on assisted reproductive technologies (ARTs) with a particular focus on gamete donation and surrogacy. It investigates the scriptural as well as juristic foundations underlying Muslim attitudes on these issues. It surveys some of the important discussions concerning assisted reproduction, including key opinions and statements that were issued in the Muslim world both by leading religious institutions as well as prominent scholarly figures, with illustrative examples from Egypt and Iran. It touches on the Sunni-Shiite divide on some of the ART questions and highlights the main lines of arguments as well as important areas of agreement and disagreement.
Adopting Embryos
Authors: Berkman John
Published: September 2024

For over twenty-five years, the relatively rare but now growing practice of embryo adoption has engendered what at first glance appears to be an outsized moral debate amongst Catholic ethicists. In embryo adoption, a woman undergoes embryo transfer. A previously frozen human embryo is transferred to her uterus, and then she gestates it to delivery. A number of competing moral descriptions of the practice have been proposed and defended: rescue, adoption, surrogacy, or infidelity. One reason this question has received such extensive moral analysis (or “casuistry”) is that Catholic ethicists early on recognized that the question could not be readily resolved using existing moral categories within that tradition. In other words, a conclusive moral evaluation of the practice would entail a development of moral doctrine. The alternative moral descriptions constitute competing paradigms through which to see and evaluate the practice. This chapter provides a moral analysis of these competing paradigms, and suggests possible new directions.
Contraception
Authors: Fletcher David B.
Published: September 2024

The moral acceptability of the use of contraceptives is highly contested by some religious communities, but evangelicals have no official position on the matter. They typically endorse the idea that marriages should be “fruitful” and bear children, as well as the “pro-life” position that is highly protective of human embryos. The attitudes of evangelical laypersons and clergy seem to have moved with the rest of the society toward acceptance of the use of contraception, but strong opposition has emerged. Evangelical views of the moral acceptability of contraception vary significantly, from virtual endorsement even for single persons to a ban for even married couples. Their attitudes toward contraception are entwined with their understanding of the details of various methods, and in particular whether embryos might be destroyed. In addition, evangelicals endorse a strictly conservative position about the permissibility of sexual relations, and are concerned not to lend support to what they deem inappropriate sexual relationships.
Zambia and Its Peoples
Authors: Phiri Bizeck Jube
Published: September 2024

The chapter examines and discusses the history of the peoples of Zambia and their contribution to the socio-economic development of the country from the colonial period to the present time. The themes examined are issues of ethnicity, regionalism, and religion. They are examined from the perspective of contributions or impediments to unifying the country and how they were handled to ensure continued unity and political, social, and economic development. Thus, in all the three republics, party politics, economic development, and security were deliberately designed to sustain national unity. This was particularly the case during the twenty-seven-year rule, from 1964 to 1991, of the United National Independence Party. Because well over half of the Zambian population now lives in urban areas following the rural–urban migration, particularly after independence when colonial restrictions on movement were removed, ethnic integration is very strong. This chapter interrogates the impact of high urbanization on the socio-economic and political environment of the rural areas. This discussion also focuses on the impact of ethnicity on politics and economic development in Zambia.
Group Decision-Making in Agent-Based Models of Organizations
Authors: Carneiro João , Alves Patrícia , Marreiros Goreti
Published: September 2024

In the field of computer science and artificial intelligence, dialogue games play a crucial role in enabling interactions among autonomous software agents. However, implementing these games in practical scenarios often involves dealing with complex challenges beyond the model’s explicit definitions, especially when striving for humanlike group interactions during in-person meetings. In our study, we introduce the Multi-Agent System for Group Decision-Making (MAS4GDM), a user-friendly multiagent system framework. MAS4GDM simplifies the implementation of dialogue games, specifically focusing on group decision-making scenarios where agents interact like humans in face-to-face discussions. By wrapping the JADE framework and abstracting intricate implementation details, MAS4GDM empowers developers and researchers, streamlining the incorporation of Prolog programs into agents. Our evaluation using a widely recognized deliberation dialogue model demonstrates that MAS4GDM maintains dialogue integrity, enhances code readability, facilitates error detection, and yields valuable outputs. This framework acts as a shield, enabling developers to navigate complexities that might otherwise impede the successful deployment of applications, ultimately bridging the gap between sophisticated dialogue models and practical, user-friendly implementation.
12‐HETE/GPR31 induces endothelial dysfunction in diabetic retinopathy
Authors: Chen Shuli , Qin Xinran , Sun Yu , Ma Zhenlin , Niu Chen , Xu Yi , Lu Lina , Zou Haidong
Published: September 2024

12‐hydroxyeicosatetraenoic acid (12‐HETE), a major metabolite of arachidonic acid, is converted by 12/15‐lipoxygenase and implicated in diabetic retinopathy (DR). Our previous study demonstrated a positive correlation between 12‐HETE and the prevalence of DR. However, reasons for the increased production of 12‐HETE are unclear, and the underlying mechanisms through which 12‐HETE promotes DR are unknown. This study aimed to elucidate the correlation between 12‐HETE and DR onset, investigate potential mechanisms through which 12‐HETE promotes DR, and seek explanations for the increased production of 12‐HETE in diabetes. We conducted a prospective cohort study, which revealed that higher serum 12‐HETE levels could induce DR. Additionally, G protein‐coupled receptor 31 (GPR31), a high‐affinity receptor for 12‐HETE, was expressed in human retinal microvascular endothelial cells (HRMECs). 12‐HETE/GPR31‐mediated HRMEC inflammation occurred via the p38 MAPK pathway. 12‐HETE levels were significantly higher in the retina of mice with high‐fat diet (HFD)‐ and streptozotocin (STZ)‐induced diabetes than in those with only STZ‐induced diabetes and healthy controls. They were positively correlated with the levels of inflammatory cytokines in the retina, indicating that HFD could induce increased 12‐HETE synthesis in patients with diabetes in addition to hyperglycemia. Conclusively, 12‐HETE is a potential risk factor for DR. The 12‐HETE/GPR31 axis plays a crucial role in HRMEC dysfunction and could be a novel target for DR prevention and control. Nevertheless, further research is warranted to provide comprehensive insights into the complex underlying mechanisms of 12‐HETE in DR.
Preliminary Validation of Measures of Experienced, Perceived, and Internalized Stigma Among Adults Who Are d/Deaf or Hard of Hearing in the United States and Ghana
Authors: Stelmach Rachel D. , Stockton Melissa A. , Kraemer John D. , Nyarko Marco S. , Troutman Adams Elizabeth , Boafo Neal , Owusu Nana Akua V. , Saalim Khalida , Alberg Joni , Tang Bowen , Musa Lawrence G. , Wu Ching-Heng , Gyamera Emma , Nyblade Laura
Published: September 2024

Objectives:

In this article, we examine the psychometric performance of 3 scales measuring experienced, perceived, and internalized d/Deaf or hard of hearing (d/DHH) stigma among adult (18 and older) populations of individuals who are d/DHH, including those who have been d/DHH since before they developed language (lifelong) and those who became d/DHH after they developed language (acquired) in the United States and Ghana.

Design:

The preliminary validation study took place in the Greater Accra and Eastern regions of Ghana and across the United States. In the United States, all data were collected online via self-administered surveys in English. In Ghana, trained interviewers who are d/DHH and fluent in Ghanaian Sign Language conducted interviews with participants who are lifelong d/DHH using a video survey. Ghanaian participants with acquired d/DHH status were surveyed by trained hearing interviewers. We calculated polychoric correlation matrices between the measures to remove redundant and unrelated items and used exploratory factor analysis to create the final scales. We also tested the association between the factor scores and a simple summing method for calculating the scale.

Results:

The study sample included people who have been d/DHH since before they developed language (Ghana: n = 171, United States n = 100) and people who became d/DHH after they developed language (Ghana: n = 174, United States: n = 219). The final experienced, perceived, and internalized scales included six, seven, and five items, respectively. All three scales performed well as unidimensional measures across all four samples. Across the four samples, the experienced, perceived, and internalized stigma scales yielded ordinal αs ranging from 0.725 to 0.947, 0.856 to 0.935, and 0.856 to 0.935, respectively. It would be acceptable to operationalize all stigma scales as sum-of-item scores.

Conclusions:

The scales performed well and appear to provide a valid means of measuring different types of stigma among diverse groups of people who are d/DHH. Future work should refine and validate these scales in additional contexts.
Application of transformers in stomatological imaging: A review
Authors: Gao Yu , Zhang Peng , Xie Yunyi , Han Jie , Zeng Li , Ning Nan , Zheng Qianhan , Li Huimin , Chen Xuepeng , Chen Zhuo
Published: September 2024

Stomatology extensively utilizes detailed imaging to assist clinicians, traditionally requiring labor-intensive manual analysis, which significantly adds to their workload. Transformers are revolutionary neural network in deep learning, gaining substantial momentum in computer vision tasks. Their introduction into medical imaging, particularly in processing large image datasets, has been marked by remarkable precision and efficiency, establishing them as a pivotal tool in emerging research. However, the application of Transformers in stomatological imaging is still in its infancy. Current studies primarily focus on segmenting specific anatomical features such as teeth and jawbones, with some clinical implementations. Yet, the comprehensive analytical potential of Transformers in this field remains largely untapped. This paper presents an introductory examination of Transformers, coupled with an initial synthesis and assessment of its dental applications across various areas. It will highlight the observed advantages and limitations in dental contexts and conclude with a discussion on future research directions. This serves as a foundational guide for in-depth future investigations in this area.
Riding the gene therapy wave: challenges and opportunities for rare disease patients and clinicians
Authors: Alexander Matthew S. , Robin Nathaniel H.
Published: September 2024

Purpose of review

A growing number of gene therapies are getting FDA-approved for pediatric rare disorders to treat once incurable diseases. Opportunities for preventing lifetime illness and improving quality of life for these patients is now becoming a reality. Challenges exist in navigating the complexities of determining which patients will benefit from these new gene therapies and how to effectively deliver them as a standard of care.

Recent findings

Gene therapies have been approved for pediatric hematological, neuromuscular, cancer, and other disorders that have improved the quality of life for rare disease patients. FDA approval of these drugs has been on a case-by-case basis leading towards gaps in drug approval, physician and patient knowledge of new gene therapies, and ultimate delivery of these drugs. Identifying patients that would benefit from these drugs and other coordination of care issues have arisen with each unique gene therapy product. These gene therapies have unique requirements and patient indications that require a knowledgeable group of physicians and hospital administrators to incorporate their use as a standard of care. With more gene therapies on the near horizon for FDA approval, multidisciplinary teams may improve patient access to these drugs by streamlining approaches towards adapting gene therapies into clinical use.

The rapid increase in the number of FDA-approved gene therapies has not only created a number of challenges but also opportunities to improve the lives of pediatric patients with rare disorders. The adaptability of physicians, hospitals, and governmental regulatory boards is essential for delivering these new gene therapies safely and efficiently to these rare disease patients. Challenges still remain as to future requirements for additional gene therapy dosing and how to best manage financial burdens placed on the patient and providing institution.
Ethical issues in organ procurement: donation after normothermic regional perfusion in liver transplantation
Authors: Nguyen Brian M.
Published: September 2024

Purpose of review

With ongoing organ shortages, new perfusion technologies are being embraced to help fill the unmet requirement. Improvement in utilization of donation after cardiac death (DCD) donors has the potential to greatly expand the pool of usable liver allografts. Normothermic regional perfusion (NRP) has been shown to increase usage of DCD donors and improve recipient outcomes. Yet, there remains heterogeneity in its usage worldwide.

Recent findings

Results from the first US multicenter study show improved biliary outcomes with NRP, consistent with prior data from Europe. Internationally, there are wide variations in DCD and NRP usage, highlighting the opportunities for improvement and increased utilization. The ethics of this technique continue to be considered.

NRP is a sound technique that can improve utilization for DCD donors, thereby increasing organ supply. Its usage is increasing worldwide. New data continue to show the benefit of this procurement strategy. NRP agrees with the principles of ethics.
CellKine clinical trial: first report from a phase 1 trial of allogeneic bone marrow–derived mesenchymal stem cells in subjects with painful lumbar facet joint arthropathy
Authors: Yan Dan , Zubair Abba C. , Osborne Michael D. , Pagan-Rosado Robert , Stone Jeffrey A. , Lehman Vance T. , Durand Nisha C. , Kubrova Eva , Wang Zhen , Witter Drew M. , Baer Meghan M. , Ponce Gabriela C. , Quiñones-Hinojosa Alfredo , Qu Wenchun
Published: September 2024

Background:

Lumbar facet joint arthropathy (LFJA) is a major cause of low back pain (LBP), with current treatments offering limited long-term benefits. Bone marrow–derived mesenchymal stem cells (BM-MSCs) show promise due to their immunomodulatory and trophic effects, potentially addressing underlying degenerative processes in LFJA.

Objectives:

This initial report describes the outcomes of the first treated patient in an ongoing mutidisciplinary phase 1 clinical trial evaluating the safety and feasibility of intra-articular allogeneic BM-MSCs for painful LFJA.

Methods:

Following enrollment in our IRB-approved protocol, symptomatic LFJA was confirmed through double blocks on L4 and L5 medial branches. Two 1-mL syringes, each containing 10 million BM-MSCs, were prepared in the cGMP facility and administered bilaterally to the patient’s L4-L5 lumbar facet joints. The patient underwent standardized follow-ups, including clinical examinations and functional and imaging assessments for 2 years, utilizing patient-reported outcomes measurement information system—computer adaptive tests (PROMIS CATs), visual analogue scale, Oswestry disability index, work functional status and opioid pain medication use, and MR imaging Fenton–Czervionke score.

Results:

The patient tolerated the procedure well, with no drug-related adverse events during the study period. Pain, spine function, and work functional status improved at multiple follow-ups. This patient also reported improvements in mental and social health, along with a notable improvement in the grade of facet synovitis observed at the one-year follow-up MRI evaluation.

Conclusions:

This case report suggests the safety and feasibility of administering intra-articular allogeneic BM-MSCs, offering therapeutic benefits for pain management and functional activities.
Ferroptosis Inhibition: A Key Opportunity for the Treatment of Ischemia/Reperfusion Injury in Liver Transplantation
Authors: Eggenhofer Elke , Proneth Bettina
Published: September 2024

The outcome after liver transplantation has improved in recent years, which can be attributed to superior storage and transportation conditions of the organs, as well as better peri- and postoperative management and advancements in surgical techniques. Nevertheless, there is an increasing discrepancy between the need for organs and their availability. Consequently, the mortality rate on the waiting list is high and continues to rise. One way of counteracting this trend is to increase the use of “expanded criteria donors.” This means that more and more donors will be included, especially those who are older and having additional comorbidities (eg, steatosis). A major complication of any transplantation is the occurrence of ischemia/reperfusion injury (IRI), which often leads to liver dysfunction and failure. However, there have been various promising approaches to minimize IRI in recent years, but an effective and clinically applicable method to achieve a better outcome for patients after liver transplantation is still missing. Thereby, the so-called marginal organs are predominantly affected by IRI; thus, it is crucial to develop suitable and effective treatment options for patients. Recently, regulated cell death mechanisms, particularly ferroptosis, have been implicated to play a major role in IRI, including the liver. Therefore, inhibiting this kind of cell death modality presents a promising therapeutic approach for the management of this yet untreatable condition. Thus, this review provides an overview of the role of ferroptosis in liver IRI and transplantation and discusses possible therapeutic solutions based on ferroptosis inhibition to restrain IRI in marginal organs (especially steatosis and donation after circulatory death organs).
Prevention and management of allergic-like reactions to iodine contrast media: a best practice implementation project
Authors: Liping Liu , Yanni Wu , Xuejie Bai , Zhou Chunlan , Xueting Du
Published: September 2024

Introduction:

With the wide application of iodine contrast media (ICM), the occurrence of allergic-like reactions to iodine contrast media (ALR-ICM) has increased. Strategies for the prevention and management of ALR-ICM need to be identified to provide quality care to patients undergoing enhanced computed tomography.

Aim:

The overarching aim of this project was to improve the prevention and management of ALR-ICM at a medical imaging center of a nearly 5,000-bed tertiary hospital in China.

Methods:

This project was guided by the JBI Evidence Implementation Framework, which is grounded in an audit, feedback, and re-audit strategy. A baseline audit was conducted to measure current practices against recommended best practices. Feedback from the audit was used to identify barriers and design strategies to improve practice. A follow-up audit was conducted to measure changes in compliance with best practices.

Results:

The results revealed a positive change in compliance with best practices. More than 60% compliance with the four audit criteria was observed. The overall ALR-ICM rate decreased from 0.56% to 0.19%, while emergency equipment management dramatically increased from 37.50% to 100%. The smallest improvement was observed for pre-procedure prophylactic treatment of high-risk patients (27.66%).

Conclusions:

Most audit criteria showed moderate improvements in compliance with best practices. Further testing of this program in more hospitals is needed.

Spanish abstract:

http://links.lww.com/IJEBH/A269
Evaluation of commercial RNA extraction kits for long-read metatranscriptomics in soil
Authors: Barber Daniel G. , Davies Christian A. , Hartley Iain P. , Tennant Richard K.
Published: September 2024

Metatranscriptomic analysis of the soil microbiome has the potential to reveal molecular mechanisms that drive soil processes regulated by the microbial community. Therefore, RNA samples must be of sufficient yield and quality to robustly quantify differential gene expression. While short-read sequencing technology is often favoured for metatranscriptomics, long-read sequencing has the potential to provide several benefits over short-read technologies. The ability to resolve complete transcripts on a portable sequencing platform for a relatively low capital expenditure makes Oxford Nanopore Technology an attractive prospect for addressing many of the challenges of soil metatranscriptomics. To fully enable long-read metatranscriptomic analysis of the functional molecular pathways expressed in these diverse habitats, RNA purification methods from soil must be optimised for long-read sequencing. Here we compare RNA samples purified using five commercially available extraction kits designed for use with soil. We found that the Qiagen RNeasy PowerSoil Total RNA Kit performed the best across RNA yield, quality and purity and was robust across different soil types. We found that sufficient sequencing depth can be achieved to characterise the active community for total RNA samples using Oxford Nanopore Technology, and discuss its current limitations for differential gene expression analysis in soil studies.
Quality characteristics and antioxidant activity of rice muffins
added with Orostachys japonicus powder
Authors: Kim Ye-Ji , Choi Jin-Hee , Kim Soo-Bin , Hwang Jung-Min , Choi Hae-Yeon
Published: September 2024

This study aimed to suggest the usability and optimal amount of
Orostachys japonicus in foods. Orostachys
japonicus powder was added at 0% (Con), 3% (O3),
5% (O5), 7% (O7), and 9% (O9) to rice muffins and the
quality and antioxidant characteristics of the muffins were determined. The
moisture content and pH of the muffins decreased as the amount of
Orostachys japonicus powder added increased. The weight
increased as the amount of Orostachys japonicus powder added
increased, but the volume, specific volume, and baking loss rate decreased. The
L- and b-values of the muffins decreased as the a-value increased. The
texture, hardness, gumminess, and chewiness of muffins increased while
adhesiveness, springiness, and cohesiveness decreased. Polyphenol, flavonoid,
DPPH, and ABTS+ radical scavenging activity, as well as
reducing power, increased as the amount of Orostachys japonicus
powder added increased. In the sensory test, the 5-7% addition group
showed high scores in appearance, flavor, taste, texture, and overall
preference. The degree of flavor and astringency of muffins, which are
evaluation items for characteristic strength, increased as the amount of
Orostachys japonicus powder added increased, and the level
of moistness decreased. Therefore, the addition of 5-7% of Orostachys
japonicus powder is thought to have a positive effect on the muffins. The
purpose of this study was to suggest the usability and optimal addition amount
of Orostachys japonicus powder and to provide basic data on
foods with Orostachys japonicus added.
Rapid emergence of UV stabilizer Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (BTMPS) in the illicit fentanyl supply across the United States in July-August 2024: Results from drug and drug paraphernalia testing
Authors: Shover Chelsea L. , Godvin Morgan E. , Appley Meghan , Pyfrom Elise M. , Montero Castrillo Fernando , Hochstatter Karli , Nadel Talia , Garg Neil , Koncsol Adam , Friedman Joseph R. , Molina Caitlin A. , Romero Ruby , Harshberger Brendan , Spoliansky Jordan , Laurel Sarah , Jalayer Elham , Ruelas Juan , Gonzales John , Snakeoil Soma , Guerra Sonya , Arellano Oscar , Winstead Candace , Rybak Margaret , Champney Joanna , Waninger Brent , Sisco Edward
Published: September 2024

Background

Changes to the US drug supply historically unfold slowly with predictable patterns of geographic diffusion. Here we draw on drug checking results from around the United States to report a rapid shift in the illicit drug supply with important implications for public health. Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate, or “BTMPS” is a hindered amine light stabilizer with various industrial applications. Animal studies indicate multiple kinds of adverse health effects.

Methods

Drug samples collected by community-based drug checking programs in Los Angeles and Philadelphia, along with drug residue samples from other jurisdictions in California, Delaware, Maryland, and Washington, were submitted to the National Institute on Standards and Technology. Samples were qualitatively tested with Direct Analysis in Real Time mass spectrometry, with reflex to liquid chromatography mass spectrometry (LCMS) for confirmatory testing. Quantitation – percent by mass – was performed using LCMS. At both sites where drug samples were collected, participants were asked to respond to a survey that included questions about what the substance was sold as and any unexpected effects.

Results

Between June 1, 2024 and August 31, 2024, a total of 178 samples sold as fentanyl were tested. Of these, 43 (24%) contained BTMPS, with the proportion per month rising from 0% in June to more than a third in August. An additional 23 residue samples from sites doing residue testing contained BTMPS. Fentanyl samples with BTMPS also contained many other compounds, including local anesthetics and alpha-2 agonists. Average fentanyl purity was significantly lower in samples with BTMPS compared to samples without.

Conclusions

The introduction of an industrial chemical to the illicit drug supply at this speed and scale is unprecedented and concerning. Further research is urgently needed to determine why it is present in the fentanyl supply and characterize effects on human health.
DIFFERENTIAL REGULATION OF GENES IN ENTORHINAL CORTEX AND HIPPOCAMPUS IN LATE ONSET AD
Authors: Biswas Moumita , Basu Soumalee
Published: September 2024

Amyloidogenic processing of APP mediated by increased BACE1 activity resulting in Aβ production and accumulation of hyperphosphorylated tau cause neuronal degeneration in AD. Pathological changes occur early in the EC and the hippocampus, much before neurodegeneration sets in. Here, using 500 and 303 differentially expressed genes from the EC and hippocampus respectively, we observed impairment of several cellular functions owing to either disrupted transcription or post-translational regulation, through functional enrichment, PPI network, miRNA and convergent functional genomic analysis. In EC, functional enrichment analysis highlighted several processes of which the Oncostatin-M-mediated pathway is related in the disease pathogenesis by increasing BACE1 transcription through STAT3 activation. Hub genes, BRD4 and PIN1, involved in Aβ and tau pathology are downregulated probably through the concerted action of hsa-miR-3613-3p and hsa-miR-4674, upregulated miRNAs in AD. In the hippocampus, upregulated FXR1 and downregulated RTN3 being involved in post-transcriptional processing of BACE1, result in increased Aβ production. For the disruption observed in the autophagy-lysosomal pathway, neurotransmitter synthesis and Aβ clearance, YWHAH, a downregulated hub gene is instrumental. Regulation of YWHAH expression is probably mediated at the post-transcriptional level through hsa-miR-455-3p and hsa-miR-4674, known to be heavily upregulated in AD. In both the regions, similar pattern of disrupted cellular pathways emerge, although the key players, differ. Whereas dysfunctional proteasomal degradation is mediated by SKP1-CUL1 in EC, it is CUL3 mediated in hippocampus. Thus, similar disease pathology develops through dysregulation of pathways that are evidently different in EC and hippocampus implying failure of therapeutics based on single target.
Trajectory-guided dimensionality reduction for multi-sample single-cell RNA-seq data reveals biologically relevant sample-level heterogeneity
Authors: Zhuang Haotian , Gai Xin , Zhang Anru R , Hou Wenpin , Ji Zhicheng , Shi Pixu
Published: September 2024

The analysis of single-cell RNA-sequencing (scRNA-seq) data with multiple biological samples remains a pressing challenge. We presentMUSTARD, a trajectory-guided dimension reduction method for multi-sample multi-condition scRNA-seq data. This all-in-one decomposition reveals major gene expression variation patterns along the trajectory and across multiple samples simultaneously, providing opportunities to discover sample endotypes along with associated genes and gene modules. In data-driven simulation,MUSTARDachieves high accuracy in distinguishing sample-level group differences that existing methods fail to capture.MUSTARDalso demonstrates a robust ability to capture gene markers and pathways associated with phenotypes of interest across multiple real-world case studies.
Functional MRI reveals regional changes of brain activity after five days of focal high-density theta burst stimulation (hdTBS) of the rat brain
Authors: Li Charlotte Qiong , Hoffman Samantha , Nguyen Hieu , Carney Aidan , Duan Ying , Ma Zilu , Zhang Nanyin , Yang Yihong , Lu Hanbing
Published: September 2024

Background

The therapeutic effects of transcranial magnetic stimulation (TMS) likely stem from neuroplasticity induced by repeated sessions over time. While animal models offer insights into TMS-induced plasticity, a rodent model that faithfully replicates prolonged TMS conditions in humans is still lacking.

Objective/Hypothesis

Develop a rat model that mimics the spatial and temporal patterns of TMS in humans.

Methods

Experiments were conducted on two cohorts of healthy adult rats (N=33). In cohort 1, rats underwent surgical implantation of microelectrodes for motor evoked potential (MEP) recording. With a rodent-specific coil and the high-density theta burst stimulation (hdTBS) paradigm, under awake condition, rats received daily TMS at 100% motor threshold for five days (days 1-5) to the hindlimb motor cortex. Cortical excitability was measured by input-output (I-O) curves on Day 0 (pre-hdTBS baseline) and Day 6 (post-hdTBS). The second cohort received identical TMS and underwent fMRI to map cerebral blood volume (CBV) on Days 0 and 6.

Results

Daily hdTBS session for 5 days significantly up-shifted I-O curves only in the TMS group (N=9), not in the sham group (N=7), indicating enhanced cortical excitability. fMRI data showed that, compared to sham group (N=9), rats receiving hdTBS (N=8) had increased basal CBV in several brain regions proximal and distal to the stimulation site, suggesting enhanced basal metabolism.

Conclusion(s)

Daily hdTBS session for 5 days focally delivered to the motor cortex of naïve rats significantly altered basal brain activity in a network of brain regions, opening a novel platform for further investigating TMS-induced plasticity.
DuReS: An R package for denoising experimental tandem mass spectrometry-based metabolomics data
Authors: Banerjee Shayantan , Nakrani Prajval , Singh Aviral , Wangikar Pramod P.
Published: September 2024

Mass spectrometry-based untargeted metabolomics is a powerful technique for profiling small molecules in biological samples, yet accurate metabolite identification remains challenging. One of the primary obstacles in processing tandem mass spectrometry data is the prevalence of random noise peaks, which can result in false annotations and necessitate labor-intensive verification. A common method for removing noise from MS/MS spectra is intensity thresholding, where low-intensity peaks are discarded based on a user-defined cutoff or by analyzing the top “N” most intense peaks. However, determining an optimal threshold is often dataset-specific and may retain many noisy peaks. In this study, we hypothesize that true signal peaks consistently recur across replicate MS/MS spectra generated from the same precursor ion, unlike random noise. An optimal recurrence frequency of 0.12 (95% CI: 0.087-0.15) was derived using an open-source metabolomics dataset, which enhanced the dot product score between the experimental and library spectra by 66% post-denoising and resulted in a median signal and noise reduction of 5.83% and 99.07%, respectively. Validated across multiple metabolomics datasets, our denoising workflow significantly improved spectral matching metrics, leading to more accurate annotations and fewer false positives. Available freely as an R package, Denoising Using Replicate Spectra (DuReS) (https://github.com/BiosystemEngineeringLab-IITB/dures) is designed to remove noise while retaining diagnostically significant peaks efficiently. It accepts mzML files and feature lists from standard global untargeted metabolomics analysis software as input, enabling users to seamlessly integrate the denoising pipeline into their workflow without additional data manipulation.
Whole Genome Sequencing and single-cell transcriptomics identifyKMT2Das a potential new driver for pituitary adenomas
Authors: Brunner Maxime , Meylan-Merlini Jenny , Muriset Maude , Oreshkov Sergey , Messina Andrea , Messerer Mahmoud , Daniel Roy , Hewer Ekkehard , Brouland Jean Phillipe , Santoni Federico
Published: September 2024

The pituitary gland is a main component of the endocrine system and a master controller of hormone production and secretion. Unlike neoplastic formation in other organs, Pituitary Neuroendocrine Tumors (PitNETs) are frequent in the population (16%) and, for unknown reasons, almost exclusively benign. So far, few genes have been identified as drivers for PitNETs, such asGNASin somatotroph tumors andUSP8in corticotroph tumors. Using whole genome sequencing, we uncover a potential novel driver, the histone methyltransferaseKMT2D, in a patient in his 50s suffering from a mixed somato-lactotroph tumor. Coverage ratio between germline and tumor revealed extensive chromosomal alterations. Single-cell RNA sequencing of the tumor shows up-regulation of known tumorigenic pathways compared to a healthy reference, as well as a different immune infiltration profile compared to other PitNETs, more closely resembling the profile of carcinomas than adenomas. Genome-wide DNA methylation analysis identified 792 differentially methylated regions, including notable hypomethylation in the promoter ofSPON2, an immune-related gene. Our results show that tumors considered as quiet and non-aggressive can share drivers, features, and epigenetic alterations with metastatic forms of cancer, raising questions about the biological mechanisms controlling their homeostasis.
Acute Viral Infection Accelerates Neurodegeneration in a Mouse Model of ALS
Authors: Marzok Art , Mapletoft Jonathan P. , Cowbrough Braeden , Celeste Daniel B. , D’Agostino Michael R. , Ang Jann C. , Chen Andrew T. , Surendran Vithushan , Dvorkin-Gheva Anna , Zhang Ali , Stacey Hannah D. , Lam Mannie , Kollar Yasmine , Milnes Kevin R. , Afkhami Sam , Miller Matthew S.
Published: September 2024

While several viral infections have been associated with amyotrophic lateral sclerosis (ALS), the mechanism(s) through which they promote disease has remained almost entirely elusive. This study investigated the impact of common, acute viral infections prior to disease onset on ALS progression in the SOD1G93Amouse model. A single sublethal infection prior to onset of ALS clinical signs was associated with markedly accelerated ALS disease progression characterized by rapid loss of hindlimb function. Prior infection resulted in gliosis in the lumbar spine and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis with an anti-inflammatory small molecule, or administration of a direct-acting antiviral, was associated with significantly improved ALS clinical signs, akin to what was observed in uninfected animals. This study provides causal and mechanistic evidence that the immune response elicited by acute viral infections may be an important etiological factor that alters ALS disease trajectory, and provides insight into novel therapeutic and preventative strategies for ALS.

One Sentence Summary

Acute viral infection with influenza A virus and SARS-CoV-2 accelerates the progression of ALS in SOD1G93Amice.
Obstetric anal sphincter injuries detection by digital rectal examination and impedance spectroscopy: post-hoc analysis of the results from a prospective, comparative, multicentre clinical study
Authors: Salvatore Stefano , Borycka Katarzyna , Ruffolo Alessandro , Młyńczak Marcel , Rosoł Maciej , Korzeniewski Kacper , Iwanowski Piotr , Spinelli Antonino , de Tayrac Renaud , Ratto Carlo , Athanasiou Stavros , Rizk Diaa Essameldin Ali , Stuart Andrea , Baekelandt Jan , Heřman Hynek , Janku Petr , Rosenblat Peter , Franco Rita , Grzesiak Mariusz , Dziki Adam , Fernando Ruwan
Published: September 2024

Objective

To evaluate the clinical performance of digital rectal examination (DRE) and machine learning-assisted impedance spectroscopy (ONIRY) for detecting obstetric anal sphincter injuries (OASI) compared to three-dimensional endoanal ultrasound (EAUS).

Design

A post-hoc analysis of data from a prospective, comparative, multicentre, international study (NCT04903977).

Setting

Poland, Czech Republic, Slovakia, and Spain.

Population

152 vaginally delivered women to 8 weeks post-partum.

Methods

Participants were divided into two groups based on EAUS results: Group I (no OASI, including 1st and 2nd degree perineal tears per OASIS classification) and Group II (OASI, including 3rd and 4th-degree tears per OASIS classification). DRE and impedance measurements using the ONIRY system were performed. The machine learning (ML) model for ONIRY was trained and validated. The diagnostic outcomes of ONIRY and DRE were compared to EAUS.

Main Outcome Measures

Accuracy, sensitivity, and specificity.

Results

DRE’s performance versus EAUS was 67.8% for accuracy, 44.3% for sensitivity, and 83.5% for specificity. After completion of ML model training, impedance spectroscopy’s accuracy, sensitivity, and specificity were 87.0%, 90.6%, and 84.6%, respectively, compared with EAUS.

Conclusion

DRE is insufficient for OASI detection. The ML-assisted impedance spectroscopy demonstrated higher accuracy and could facilitate rapid OASI detection post-delivery.

Funding

The study was financed by the European Union’s Fast Track program through the Polish National Centre for Research and Development (POIR.01.01.01-00-0726/18)
Evaluating and Reducing Subgroup Disparity in AI Models: An Analysis of Pediatric COVID-19 Test Outcomes
Authors: Libin Alexander , Treitler Jonah T. , Vasaitis Tadas , Shao Yijun
Published: September 2024

Artificial Intelligence (AI) fairness in healthcare settings has attracted significant attention due to the concerns to propagate existing health disparities. Despite ongoing research, the frequency and extent of subgroup fairness have not been sufficiently studied. In this study, we extracted a nationally representative pediatric dataset (ages 0-17, n=9,935) from the US National Health Interview Survey (NHIS) concerning COVID-19 test outcomes. For subgroup disparity assessment, we trained 50 models using five machine learning algorithms. We assessed the models’ area under the curve (AUC) on 12 small (<15% of the total n) subgroups defined using social economic factors versus the on the overall population. Our results show that subgroup disparities were prevalent (50.7%) in the models. Subgroup AUCs were generally lower, with a mean difference of 0.01, ranging from -0.29 to +0.41. Notably, the disparities were not always statistically significant, with four out of 12 subgroups having statistically significant disparities across models. Additionally, we explored the efficacy of synthetic data in mitigating identified disparities. The introduction of synthetic data enhanced subgroup disparity in 57.7% of the models. The mean AUC disparities for models with synthetic data decreased on average by 0.03 via resampling and 0.04 via generative adverbial network methods.
Postnatal Development Of Dendritic Morphology And Action Potential Shape In Rat Substantia Nigra Dopaminergic Neurons
Authors: Moubarak Estelle M , Wernert Florian , Tell Fabien , Goaillard Jean-Marc
Published: September 2024

Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons are characterized by specific morphological and electrophysiological properties. First, in ~90% of the cases, their axon arises from an axon-bearing dendrite (ABD) at highly variable distances from the soma. Second, they display a highly regular pattern of spontaneous activity (aka pacemaking) and a broad action potential (AP) that faithfully back-propagate through the entire dendritic arbor. In previous studies (Moubarak et al., 2019; Moubarak et al., 2022), we demonstrated that the presence of a high density of sodium current in the ABD and the complexity of this dendrite played a critical role in the robustness of pacemaking and setting the half-width of the AP. In the current study, we investigated the postnatal development of both morphology and AP shape in SNc DA neurons in order to determine when and how the mature electrophysiological phenotype of these neurons was achieved. To do so, we performed electrophysiological recordings of SNc DA neurons at 4 postnatal ages (P3, P7, P14, P21) and fully reconstructed their dendritic and proximal axon morphology. Our results show that several morphological parameters, including the length of the ABD, display abrupt changes between P7 and P14, such that a mature morphology is reached by P14. We then showed that AP shape followed a similar timecourse. Using realistic multicompartment Hodgkin-Huxley modeling, we then demonstrated that the rapid morpho-electrical maturation of SNc DA neurons likely arises from synergistic increases in dendritic length and in somatodendritic sodium channel density.
DNFE: Directed-network flow entropy for detecting the tipping points during biological processes
Authors: Peng Xueqing , Li Peiluan , Luonan Chen
Published: September 2024

There generally exists a critical state or tipping point from a stable state to another in dynamic biological processes, beyond which a significant qualitative transition occurs. Identifying this tipping point and its driving network is essential to prevent or delay catastrophic consequences. However, most traditional approaches based on undirected networks still suffer from the problem of the robustness and effectiveness when applied to high-dimensional small sample data, especially for single-cell data. To address this challenge, we developed a directed-network flow entropy (DNFE) method which can transform measured omics data into a directed network. This method is applicable to both single-cell RNA-sequencing (scRNA-seq) and bulk data. By applying this method to five real datasets, including three single-cell datasets and two bulk tumor datasets, the method can not only successfully detect the critical states as well as their dynamic network biomarkers, but also help explore regulatory relationships between genes. Numerical simulation indicates that the DNFE method is robust and superior to existing methods. Furthermore, DNFE has predicted active transcription factors (TFs), and further identified ‘dark genes’, which are usually overlooked by traditional methods.