bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermoneutral temperature exposure enhances slow-wave sleep with a correlated improvement in amyloid pathology in a triple-transgenic mouse model of Alzheimer’s disease
Authors: Wang Jun , Huffman Dillon , Ajwad Asma’a , McLouth Christopher J , Bachstetter Adam , Kohler Katarina , Murphy M Paul , O’Hara Bruce F , Duncan Marilyn J , Sunderam Sridhar
Published: March 2024

Accumulation of amyloid-β (Aβ) plays an important role in Alzheimer’s disease (AD) pathology. There is growing evidence that disordered sleep may accelerate AD pathology by impeding the physiological clearance of Aβ from the brain that occurs in normal sleep. Therapeutic strategies for improving sleep quality may therefore help slow disease progression. It is well documented that the composition and dynamics of sleep are sensitive to ambient temperature. We therefore compared Aβ pathology and sleep metrics derived from polysomnography in 12-month-old female 3xTg-AD mice (n = 8) exposed to thermoneutral temperatures during the light period over 4 weeks to those of age- and sex-matched controls (n = 8) that remained at normal housing temperature (22°C) during the same period. The treated group experienced greater proportions of slow wave sleep (SWS)—i.e. epochs of elevated 0.5–2 Hz EEG slow wave activity during non-rapid eye movement (NREM) sleep—compared to controls. Assays performed on mouse brain tissue harvested at the end of the experiment showed that exposure to thermoneutral temperatures significantly reduced levels of DEA-soluble (but not RIPA- or formic acid-soluble) Aβ40 and Aβ42 in the hippocampus, though not in the cortex. With both groups pooled together and without regard to treatment condition, NREM sleep continuity and any measure of SWS within NREM at the end of the treatment period were inversely correlated with DEA-soluble Aβ40 and Aβ42 levels, again in the hippocampus but not in the cortex. These findings suggest that experimental manipulation of SWS could offer useful clues into the mechanisms and treatment of AD.
The Treatment of Refractory Vitiligo With Autologous Cultured Epithelium Grafting: A Real-World Retrospective Cohort Study
Authors: Li Jian , Zeng Xuanhao , Chen Shujun , Tang Luyan , Zhang Qi , Lv Minzi , Lian Weiling , Wang Jinqi , Lv Haozhen , Liu Yating , Shen Jiayi , Uyama Taro , Wu Fuyue , Wu Jinfeng , Xu Jinhua
Published: March 2024

Background

Surgical intervention is the main therapy for refractory vitiligo. We developed a modified autologous cultured epithelial grafting (ACEG) technique for vitiligo treatment. Between January 2015 and June 2019, a total of 726 patients with vitiligo underwent ACEG in China, with patient characteristics and clinical factors being meticulously documented. Using a generalized linear mixed model, we were able to assess the association between these characteristics and the repigmentation rate.

Results

ACEG demonstrated a total efficacy rate of 82.81% (1754/2118) in treating 726 patients, with a higher repigmentation rate of 64.87% compared to conventional surgery at 52.69%. Notably, ACEG showed a better response in treating segmental vitiligo, lesions on lower limbs, age ≤ 18, and stable period > 3 years. A keratinocyte:melanocyte ratio below 25 was found to be advantageous too. Single-cell RNA sequencing analysis revealed an increase in melanocyte count and 2 subclusters of keratinocytes after ACEG, which remained higher in repigmented sites even after 1 year.

Conclusions

ACEG is a promising therapy for refractory vitiligo. Patient age, clinical type, lesion site, and stability before surgery influence repigmentation in ACEG. The mechanism of repigmentation after ACEG treatment is likely not confined to the restoration of melanocyte populations. It may also involve an increase in the number of keratinocytes that support melanocyte function within the affected area. These keratinocytes may aid the post-transplant survival and function of melanocytes by secreting cytokines and extracellular matrix components.

Trial registration

registered with Chictr.org.cn (ChiCTR2100051405).
Transitioning into retirement: the interplay of self and life structure
Authors: Crary Marcy , Hall Douglas T. (Tim) , Kram Kathy E , Amabile Teresa M , Bailyn Lotte
Published: March 2024

This paper explores the psychological, social, and behavioral ways in which professionals end their corporate careers and reorient themselves and their lives in the transition from employment to retirement. Framed within life course theory, specifically the adult development literature, this study leverages Levinson’s construct of life structure in relation to the self as a lens for understanding the developmental work undertaken in different phases (“phase-tasks”) of the retirement process. We define life structure as a person’s system of contexts—the roles, relationships, activities, groups, organizations, and physical settings in the person’s life—and the dynamic interconnections among them. Our research focused on the underlying micro processes of the interplay between self and life structure. This qualitative study followed 14 knowledge workers through their retirement transitions, using multiple in-depth, semi-structured interviews. Data analyses revealed that the self and the life structure co-evolve, exerting mutual influence across the four phase-tasks of the retirement transition, driven by the individual’s desire for a life structure that is both suitable for the self and viable for the foreseeable future. Two in-depth case studies and data from the other 12 participants illustrate the interplay, throughout the transition, between moves made by the self on the life structure and claims and changes from the life structure influencing the self. We present an induced process model of this reciprocal influence between self and life structure across the retirement transition, and discuss our contributions to the retirement, adult development, and identity literatures, as well as practical implications.
Private Equity Investment in Health Care Soars—But at What Cost?
Authors: Roush Karen
Published: March 2024

Study finds more hospital-acquired adverse events after acquisitions.
How Nurses Influence the Patient Experience
Authors: George Nicole
Published: March 2024

This article is one in a series from Press Ganey—a health care performance improvement organization—that will discuss the many facets of the human experience in health care. Using the latest national data, the series will explore the intersections of safety, reliability, experience, and service, and their impact on engagement, work culture, and nurse-sensitive outcomes. Each installment will be designed as a “deep dive” into the most recent thinking and evidence-based approaches to improvement of the patient experience with a particular focus on practical and implementable tactics in each of the above subject areas.
Technical challenges in small animal models for mimicking human ischemic cardiovascular diseases
Authors: Hu Kai , Ertl Georg
Published: March 2024

Animal models are essential for exploring pathophysiology and testing novel therapy options of human metabolic cardiovascular diseases. Several small animal models have been developed during the last decades to study effects on myocardial infarct size, healing or cardiac remodeling and thus outcome after ligation of a left coronary artery. The present review describes the value and limitations of small animal models mimicking human ischemic myocardial insult and offers technical tips for using them. A perspective on future improved small animal models mimicking human cardiovascular diseases is also given.
How Agent Orange impacts prostate cancer risk, pathology, and treatment outcomes
Authors: Paracha Awais , Siddiqui Zohair , Abid Ali , Deol Ekamjit , Waheed Fatima , Hamilton Zachary
Published: March 2024

Between 2.6 and 3.8 million veterans served in Vietnam while the US military dispersed Agent Orange (AO), although the exact number of exposed individuals is unknown. Agent Orange, an herbicide, is a known risk factor for various cancers, including sarcoma and leukemia, but less is known about its link with prostate cancer (PC). Prostate cancer is the most commonly diagnosed malignancy in men and the fifth most common cause of cancer-related death in men worldwide. In 2023, approximately 288,300 patients will be given a diagnosis of PC, and an estimated 34,700 fatalities will occur in the United States. However, whether the pathologic characteristics of PC among those exposed to AO differ from those in the general population remains unclear. Our review synthesizes the literature regarding the impact of AO exposure on PC incidence and disease course. A comprehensive PubMed literature search of articles published beginning in 1950 was performed using the primary search terms “Agent Orange,” “TCDD,” and “tetrachlorodibenzodioxin” and the secondary search terms “prostate cancer” or “prostate neoplasm.” The search was limited to studies that focused on human participants and were published in English. Four authors thoroughly reviewed the retrieved articles for relevancy to the study aims: discussion of PC diagnosis, prognosis, or management among patients exposed to AO. Of 108 studies identified in our search, 13 were included in this systematic review. Findings within studies concerning AO exposure with relation to PC incidence, age at diagnosis or treatment initiation, and PC severity seemed to be mixed and generally conflicting. However, the literature seems to indicate that there are no significant differences in survivorship between exposed and unexposed veterans who are given a diagnosis of PC. Given these heterogeneous outcomes, the evidence does not encourage a significantly different approach to the diagnosis and management of PC for veterans exposed to AO. Clinicians should make case-by-case decisions regarding PC screening and potential treatment options for this patient group, weighing clinical suspicion against the harms of diagnostic workup and treatment.
Leptomeningeal metastases in prostate cancer: A review of the current literature
Authors: Durrani Umar , Rifai Kasem , Arshad Maha , Paracha Awais , Deol Ekamjit , Paracha Maria , Waheed Fatima , Siddiqui Zohair , Abid Ali , Mustafic Esed , Rodriguez Wilson , Hamilton Zachary
Published: March 2024

Leptomeningeal metastasis/leptomeningeal carcinomatosis (LMC; terms used interchangeably) is an inflammatory complication of primary tumors that involves the spread of the disease to the meninges (specifically the arachnoid and pia maters) and spinal cord. In the United States, approximately 110,000 new cases are diagnosed each year, and the prognosis is usually poor. Complications of LMC include cognitive impairment, cranial nerve dysfunction, ischemic stroke, and mortality. The survival times of untreated and treated LMC are approximately 4–6 weeks and 2–4 months, respectively. Leptomeningeal carcinomatoses are usually metastatic cancers that spread to the central nervous system. Although lung and breast cancers have a clearly defined relationship with LMC, it remains unclear whether prostate cancer (PC) is also directly associated with LMC. To determine whether such association exists, we conducted a PubMed review of the literature on patients with PC with coexisting LMCs. Our search yielded 23 case reports of patients with preexisting PC who developed LMC. In addition, 2 retrospective cohort studies were examined.

Various findings were identified in the revised cases and studies. The first 3 findings were related to the progression of the disease: patients presenting with neurological disease symptoms were in remission from PC for 7 years on average, LMCs tended to occur after other cancer diagnoses, and the disease had already rapidly progressed by the time the symptoms were present. Regarding diagnosis, the major finding was that most LMCs were detected by magnetic resonance imaging (which does not detect early dissemination), and it was suggested that single-photon emission computed tomography or positron emission tomography imaging could be used for earlier detection. Finally, in terms of treatment, the main finding was that treatment was palliative rather than curative and that prognosis remained poor despite treatment. On the basis of these results, we recommend for individuals with risk factors, such as high-grade PC and hormonal PC, to be evaluated on a case-by-case basis for increased surveillance of LMC development.
The surging cholera epidemic in Africa: a review of the current epidemiology, challenges and strategies for control
Authors: Lawal Lukman , Amosu Opeyemi P. , Lawal Abdulwahab O. , Wada Yusuf Hassan , Abdulkareem Ahmed O. , Shuaib Abdulrahman K. , Jaji Tawakalitu A. , Mogaji Abdulazeez B. , Abdul-Rahman Toufik , Adeoti Sodiq G. , Buhari Ahmad O.
Published: March 2024

Africa, a known region with abundant warm coastal waters and a natural reservoir for Vibrio cholera, is known to bear the highest burden of cholera morbidity and mortality globally. Malawi is currently experiencing the deadliest cholera outbreak in two decades, and neighbouring countries, Mozambique and Zambia, have also reported significant numbers of cases. If the current trend of cholera transmission is sustained, the number of fatalities recorded in 2021, Africa’s deadliest year for cholera over the past decade, might be exceeded. This article aims to review the current epidemiology, prevention and control strategies, and treatment of cholera in Africa to highlight context-specific challenges and recommend possible solutions. The authors found out that cholera outbreaks in Africa are taking place in the midst of epidemics (measles, mumps, etc.) and natural disasters like cyclones and flooding (Mozambique, Malawi), drought (Kenya, and Ethiopia), and conflict (Cameroon, the DR Congo, Nigeria, and Ethiopia). The shortages of medical supplies like cholera kits and oral cholera vaccines in many countries due to constrained and limited resources and antibiotic resistance further make management and control difficult. The outbreak is spreading throughout the region because of poor sanitation, unsafe water supplies, and increased cross-border travel. Cholera in Africa follows a seasonal pattern, suggesting specific periods for heightened outbreak preparedness and response. The authors suggest a targeted multisectorial approach and a coordinated mechanism to respond to the epidemic through sustained political will, formidable partnerships, resource mobilisation, and the provision of technical support and advocacy at sub-national, national, and international levels.
Muslim Women's Experiences with Infertility
Authors: Abdelnabi Samia Jamal
Published: March 2024

Objective:

Infertility affects one in six women worldwide, playing a large role on an individual's psychosocial wellbeing and quality of life. The purpose of this review was to examine the experiences of Muslim women with infertility.

Methods:

A Prisma-guided literature review was conducted in Scopus, CINAHL, PubMed, Embase, PsychInfo, and Google Scholar. Sample inclusion criteria included research that examined the psychosocial consequences of infertility in women, used a qualitative design, were from a Muslim majority country or specified participants were Muslim, and were published in the English-language since 2013. Thematic analysis was used to synthesize the findings into themes.

Results:

Fourteen qualitative studies that explored the experiences of Muslim women with infertility were included for analysis. Women's responses were categorized into three focus areas: (1) emotional responses, (2) interpersonal relationships, and (3) social relationships. From these focus points, six overarching themes were identified that illustrated the challenges faced by Muslim women experiencing infertility: (1) identity crisis, (2) low self-esteem and depression, (3) abuse and harassment, (4) a weakened marital bond, (5) stigma, and (6) social exclusion and isolation.

Clinical Implications:

Review of the literature provided an initial entrée into understanding the experiences of Muslim women with infertility. Understanding the unique role of infertility within a religious community equips nurses and other providers with the knowledge that discussions surrounding infertility must be conducted with cultural sensitivity. Further research should be conducted to explore and offer culturally tailored educational materials that align with the religious preferences of Muslim women.
Empowering Nurses for High-Value Healthcare
Authors: Kapu April
Published: March 2024

Recognizing the positive impact of clinical data outcomes and patient care experiences, coupled with the growing preference for advanced practice RNs among patients, it is imperative that nurse leaders propel legislative reforms and infrastructure support from health systems. This strategic approach is crucial for maximizing the potential of nurses in improving patient care experience and outcomes, as well as increasing accessibility to healthcare in every community.
Pao 2 and Mortality in Neonatal Extracorporeal Membrane Oxygenation: Retrospective Analysis of the Extracorporeal Life Support Organization Registry, 2015–2020*
Authors: Brohan Orlane , Chenouard Alexis , Gaultier Aurélie , Tonna Joseph E. , Rycus Peter , Pezzato Stefano , Moscatelli Andrea , Liet Jean-Michel , Bourgoin Pierre , Rozé Jean-Christophe , Léger Pierre-Louis , Rambaud Jérôme , Joram Nicolas
Published: March 2024

OBJECTIVES:

Extracorporeal life support can lead to rapid reversal of hypoxemia but the benefits and harms of different oxygenation targets in severely ill patients are unclear. Our primary objective was to investigate the association between the Pao2after extracorporeal membrane oxygenation (ECMO) initiation and mortality in neonates treated for respiratory failure.

DESIGN:

Retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry data, 2015–2020.

PATIENTS:

Newborns supported by ECMO for respiratory indication were included.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Pao224 hours after ECMO initiation (H24 Pao2) was reported. The primary outcome was 28-day mortality. We identified 3533 newborns (median age 1 d [interquartile range (IQR), 1–3]; median weight 3.2 kg [IQR, 2.8–3.6]) from 198 ELSO centers, who were placed on ECMO. By 28 days of life, 731 (20.7%) had died. The median H24 Pao2was 85 mm Hg (IQR, 60–142). We found that both hypoxia (Pao2< 60 mm Hg) and moderate hyperoxia (Pao2201–300 mm Hg) were associated with greater adjusted odds ratio (aOR [95% CI]) of 28-day mortality, respectively: aOR 1.44 (95% CI, 1.08–1.93),p= 0.016, and aOR 1.49 (95% CI, 1.01–2.19),pvalue equals to 0.045.

CONCLUSIONS:

Early hypoxia or moderate hyperoxia after ECMO initiation are each associated with greater odds of 28-day mortality among neonates requiring ECMO for respiratory failure.
A core genome multi-locus sequence typing scheme for Streptococcus uberis: an evolution in typing a genetically diverse pathogen
Authors: Whiley Daniel , Jolley Keith , Blanchard Adam , Coffey Tracey , Leigh James
Published: March 2024

Streptococcus uberis is a globally endemic and poorly controlled cause of bovine mastitis impacting the sustainability of the modern dairy industry. A core genome was derived from 579 newly sequenced S. uberis isolates, along with 305 publicly available genome sequences of S. uberis isolated from 11 countries around the world and used to develop a core genome multi-locus sequence typing (cgMLST) scheme. The S. uberis core genome comprised 1475 genes, and these were used to identify 1447 curated loci that were indexed into the cgMLST scheme. This was able to type 1012 of 1037 (>97  %) isolates used and differentiated the associated sequences into 932 discrete core genome sequence types (cgSTs). Analysis of the phylogenetic relationships of cgSTs revealed no clear clustering of isolates based on metadata such as disease status or year of isolation. Geographical clustering of cgSTs was limited to identification of a UK-centric clade, but cgSTs from UK isolates were also dispersed with those originating from other geographical regions across the entire phylogenetic topology. The cgMLST scheme offers a new tool for the detailed analysis of this globally important pathogen of dairy cattle. Initial analysis has re-emphasized and exemplified the genetically diverse nature of the global population of this opportunistic pathogen.
Using Large Language Models for sentiment analysis of health-related social media data: empirical evaluation and practical tips
Authors: He Lu , Omranian Samaneh , McRoy Susan , Zheng Kai
Published: March 2024

Health-related social media data generated by patients and the public provide valuable insights into patient experiences and opinions toward health issues such as vaccination and medical treatments. Using Natural Language Processing (NLP) methods to analyze such data, however, often requires high-quality annotations that are difficult to obtain. The recent emergence of Large Language Models (LLMs) such as the Generative Pre-trained Transformers (GPTs) has shown promising performance on a variety of NLP tasks in the health domain with little to no annotated data. However, their potential in analyzing health-related social media data remains underexplored. In this paper, we report empirical evaluations of LLMs (GPT-3.5-Turbo, FLAN-T5, and BERT-based models) on a common NLP task of health-related social media data: sentiment analysis for identifying opinions toward health issues. We explored how different prompting and fine-tuning strategies affect the performance of LLMs on social media datasets across diverse health topics, including Healthcare Reform, vaccination, mask wearing, and healthcare service quality. We found that LLMs outperformed VADER, a widely used off-the-shelf sentiment analysis tool, but are far from being able to produce accurate sentiment labels. However, their performance can be improved by data-specific prompts with information about the context, task, and targets. The highest performing LLMs are BERT-based models that were fine-tuned on aggregated data. We provided practical tips for researchers to use LLMs on health-related social media data for optimal outcomes. We also discuss future work needed to continue to improve the performance of LLMs for analyzing health-related social media data with minimal annotations.
Reduced STMN2 and pathogenic TDP-43, two hallmarks of ALS, synergize to accelerate motor decline in mice
Authors: Krus Kelsey L. , Morales Benitez Ana , Strickland Amy , Milbrandt Jeffrey , Bloom A. Joseph , DiAntonio Aaron
Published: March 2024

Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients.Stathmin2(Stmn2)is a key target of TDP-43 regulation and aberrantly splicedStmn2mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer’s Disease. STMN2 participates in the axon injury response and its depletionin vivopartially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murineStmn2splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy ofStmn2and express one mutant TDP-43Q331Kknock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration.
Persistent homology centrality improves link prediction performance in Pubmed co-occurrence networks
Authors: Brown Chase Alan , Wren Jonathan D.
Published: March 2024

Abstract

This paper provides a novel approach to understanding the nature of innovation and scientific progress by analyzing large-scale datasets of scientific literature. A new measure of novelty potential or disruptiveness for a set of scientific entities is proposed, based in the mathematical formalism of algebraic topology via a method calledpersistent homology. In this framework, understanding where academic ideas depart from the existing body of knowledge tofill knowledge gapsis key to scoring a set of entities and their potential for filling future knowledge gaps. This framework is motivated by the assumption that scientific discovery has underlying regularities that can be modeled and predicted.

Our method uses afiltration, which is a type of ranking of hypergraph components along a chosen parameter. In this work two different axes are used, which constructs a growing grid of sub-hypergraphs. The axes of time (scientific knowledge evolution) and normalized point-wise mutual information (network structure) affords the ability to succinctly represent the entire dynamic structure of the scientific literature network. We then find that using very simple and interpretable measures of centrality derived from this crudebifiltrationorvineyardaffords the ability to predict links within the dynamic scientific network.

While several different methods of link prediction have been proposed in the past, the method presented hereextendsthe notion of link prediction to a higher dimension, as the boundary of the knowledge gap may be more than just 0-dimensional nodes.

The system presented here not only suggests a mathematical basis, consistent with observations in cognitive neurosciences regarding early childhood language acquisition, but additionally provides useful applications for the scientific community in predicting and ranking hypothesis for scientific discovery.
Integrin conformation-dependent neutrophil slowing obstructs the capillaries of the pre-metastatic lung in a model of breast cancer
Authors: Fercoq Frédéric , Cairns Gemma S. , Donatis Marco De , Mackey John B. G. , Floerchinger Alessia , McFarlane Amanda , Raffo-Iraolagoitia Ximena L. , Whyte Declan , Arnott Lindsey W. G. , Nixon Colin , Wiesheu Robert , Kilbey Anna , Brown Leah , Al-Khalidi Sarwah , Norman Jim C. , Roberts Edward W. , Blyth Karen , Coffelt Seth B. , Carlin Leo M.
Published: March 2024

Neutrophils are thought to be critical to the process whereby breast cancers establish an immunosuppressive and tumour cell nurturing ‘pre-metastatic’ niche before overt metastasis can be detected. However, the spatial localization of neutrophils and their interaction with other cell types in the lung pre-metastatic niche is not well described. We used a spontaneously metastatic mammary cancer model combined with a multiplexed three- and four-dimensional imaging approach to investigate the behaviour of neutrophils in the pre-metastatic niche. Volume fixed tissue three-dimensional imaging showed that approximately 40% of CD8+T cells are adjacent to neutrophils at this stage. In live tissue, we found neutrophils with impaired intravascular motility congested the capillaries of pre-metastatic lungs potentially obstructing CD8+T cells. Slowed neutrophil transit was dependent on the conformation of β2-integrin and could be recapitulated by treating non-tumour bearing mice with G-CSF, a potent systemic mediator of granulopoiesis. We found a decrease in L-selectin (CD62L) on neutrophils in the lungs of both mammary tumour bearing and G-CSF treated mice. Finally, we observed differential accumulation of intravenously injected micro-beads in the lung, suggestive of transient circulatory dead spaces which were also dependent on β2-integrin inactivation. Overall, our study proposes that integrin-mediated neutrophil congestion of the alveolar capillaries could contribute to the generation of the pulmonary pre-metastatic niche.
Atomistic Characterization of Beta-2-Glycoprotein I Domain V Interaction with Anionic Membranes
Authors: Hasdemir Hale S. , Pozzi Nicola , Tajkhorshid Emad
Published: March 2024

Background

Interaction of beta-2-glycoprotein I (β2GPI) with anionic membranes is crucial in antiphospholipid syndrome (APS), implicating the role of it’s membrane bind-ing domain, Domain V (DV). The mechanism of DV binding to anionic lipids is not fully understood.

Objectives

This study aims to elucidate the mechanism by which DV ofβ2GPI binds to anionic membranes.

Methods

We utilized molecular dynamics (MD) simulations to investigate the struc-tural basis of anionic lipid recognition by DV. To corroborate the membrane-binding mode identified in the HMMM simulations, we conducted additional simulations using a full mem-brane model.

Results

The study identified critical regions in DV, namely the lysine-rich loop and the hydrophobic loop, essential for membrane association via electrostatic and hydrophobic interactions, respectively. A novel lysine pair contributing to membrane binding was also discovered, providing new insights intoβ2GPI’s membrane interaction. Simulations revealed two distinct binding modes of DV to the membrane, with mode 1 characterized by the insertion of the hydrophobic loop into the lipid bilayer, suggesting a dominant mechanism for membrane association. This interaction is pivotal for the pathogenesis of APS, as it facilitates the recognition ofβ2GPI by antiphospholipid antibodies.

Conclusion

The study advances our understanding of the molecular interactions be-tweenβ2GPI’s DV and anionic membranes, crucial for APS pathogenesis. It highlights the importance of specific regions in DV for membrane binding and reveals a predominant bind-ing mode. These findings have significant implications for APS diagnostics and therapeutics, offering a deeper insight into the molecular basis of the syndrome.
Illuminating the Dark Cancer Phosphoproteome Through a Machine-Learned Co-Regulation Map of 26,280 Phosphosites
Authors: Jiang Wen , Jaehnig Eric J. , Liao Yuxing , Yaron-Barir Tomer M. , Johnson Jared L. , Cantley Lewis C. , Zhang Bing
Published: March 2024

Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, but limited knowledge about the regulation and function of most phosphosites restricts our ability to extract meaningful biological insights from phosphoproteomics data. To address this, we combine machine learning and phosphoproteomic data from 1,195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network mapping the co-regulation of 26,280 phosphosites. Integrating network features from CoPheeMap into a machine learning model, CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA reveals 24,015 associations between 9,399 phosphosites and 104 serine/threonine kinases, including many unannotated phosphosites and under-studied kinases. We validate the accuracy of these predictions using experimentally determined kinase-substrate specificities. By applying CoPheeMap and CoPheeKSA to phosphosites with high computationally predicted functional significance and cancer-associated phosphosites, we demonstrate the effectiveness of these tools in systematically illuminating phosphosites of interest, revealing dysregulated signaling processes in human cancer, and identifying under-studied kinases as putative therapeutic targets.
Inverse and Postponed Impacts of Extracellular Tau PHF on Astrocytes and Neurons’ Mitochondrial Function
Authors: Zufferey Valentin , Parietti Enea , Barve Aatmika , Espourteille Jeanne , Varisco Yvan , Fabbri Kerstin , Capotosti Francesca , Preitner Nicolas , Richetin Kevin
Published: March 2024

Background

Tauopathies encompass a spectrum of neurodegenerative disorders which are marked by the pathological aggregation of tau protein into paired helical filaments (PHF-tau), neurofibrillary tangles (NFTs) and Glial-fibrillary tangles (GFTs). These aggregates impair cellular, mitochondrial, and synaptic functions. The emergence of extracellular tau (ePHF-tau), featuring a myriad of isoforms and phosphorylation states, presents a challenge in comprehending its nuanced effects on neural cells, particularly concerning synaptic and mitochondrial integrity.

Methods

We studied the impact of ePHF-tau (2N4R) on different states and ages of primary cultures of rat neuroglia. Using confocal microscopy and proteomic analysis of synaptosomes, we studied the impact of ePHF-tau on neurite and synapse number. We monitored mitochondrial responses in neurons and astrocytes over 72 hours using advanced fluorescence microscopy for dynamic, high-throughput analysis.

Results

Treatment with ePHF-tau has a strong effect on the neurites of immature neurons, but its toxicity is negligible when the neurons are more mature. At the mature stage of their development, we observed a substantial increase in the density of the PSD-95/vGlut1 zone in neurite, suggesting altered synaptic connectivity and ePHF-tau excitotoxicity. Proteomics revealed significant changes in mitochondrial protein in synaptosomes following exposure to ePHF-tau. In the neuronal compartment, real-time imaging revealed rapid and persistent mitochondrial dysfunction, increased ATP production, and reduced mitochondrial turnover. In contrast, we observed increased mitochondrial turnover and filamentation after treatment in the astrocyte processes, indicating cell-specific adaptive responses to ePHF-tau.

Conclusions

This study sheds light on the intricate effects of extracellular tau aggregates on neuronal and astrocytic mitochondrial populations, highlighting how tau pathology can lead to mitochondrial disturbances and synaptic alterations. By delineating the differential responses of neurons and astrocytes to ePHF-tau, our findings pave the way for developing targeted therapeutic interventions to mitigate the detrimental impacts of tau aggregates in neurodegenerative diseases.
Thoracic discopathy and thoracic-chest related pain: a scoping review
Authors: Lucia Ferrulli , Martina Zaninetti , Michele Margelli , Filippo Maselli , Galeoto Giovanni
Published: March 2024

Background

Thoracic discopathy refers to the degeneration or herniation of one or more discs in the thoracic spine, which can cause thoracic-chest related pain. Thoracic-chest related pain can be challenging to diagnose and treat, as it can have various causes, including musculoskeletal, neurological, and visceral.

Objectives

This scoping review aims to provide an overview of the current scientific literature on the thoracic discopathy and the thoracic-chest related pain, by examining the available scientific research, as well as to identify any existing gaps in knowledge.

Eligibility criteria

The databases of Medline, Cinahl, Cochrane, Prospero were searched using key terms: “thoracic”, “chest”, “dorsal”, “disc”, “hernia”, “radiculopathy”, “myelopathy”, and “pain”.

We also have searched for Grey literature onclinicaltrial.govand google scholar.

Inclusion criteria

adult population (over 18 years old); thoracic discopathy or thoracic-chest related pain; Italian or English language; no context, geographical or temporal limits. Exclusion criteria: unspecified pathologies and symptoms (as non-specific back pain, low back pain) and specific pathologies without any interest of thoracic disc (as spinal synovial cysts, spinal arachnoid webs, lung herniation ecc).
Emergence and ongoing outbreak of ST80 vancomycin-resistantEnterococcus faeciumin Guangdong province, China from 2021 to 2023: a multicenter, time-series and genomic epidemiological study
Authors: Shen Cong , Luo Li , Zhou Hongyun , Xiao Yinglun , Zeng Jinxiang , Zhang Liling , Pu Jieying , Zeng Jianming , Zhang Ni , Jiang Yueting , Xu Lingqing , Chen Dingqiang , Li Gang , Wu Kuihai , Yu Hua , Wang Min , Guo Xuemin , Wang Juan , Huang Bin , Chen Cha
Published: March 2024

Abstract

Background

The surveillance system revealed that the prevalence of vancomycin-resistantEnterococcus faecium(VREfm) has increased. We aim to investigate the epidemiological and genomic characteristics of VREfm in China.

Methods

We collected 20747 non-redundantE. faeciumisolates from inpatients across 19 hospitals in six provinces between Jan 2018 and June 2023. VREfm was confirmed by antimicrobial susceptibility testing. The prevalence was analyzed using changepoint package in R. Genomic characteristics were explored by whole-genome sequencing and bioinformatic analysis.

Results

5.59% (1159/20747) ofE. faeciumisolates were resistant to vancomycin. The prevalence of VREfm increased in Guangdong province from 5% before 2021 to 20%-50% in 2023 (p<0.0001), but not in the other five provinces. The two predominant clones before 2021, ST17 and ST78, were substituted by an emerging clone, ST80, from 2021 to 2023 (88.63%, 195/220). All ST80 VREfm from Guangdong formed a single lineage (SC11) and were genetically distant from the ST80 VREfm from other countries, suggesting a regional outbreak. All ST80 VREfm in SC11 carried a new type of plasmid which harbored avanAcassette (vanRSHAXYZ) flanked by Tn1546/Tn3clusters. However, no conjugation-related gene was detected and no transconjugant was obtained in conjugation experiment, indicating that the outbreak of ST80 VREfm could be attributed to clonal transmission.

Conclusions

We revealed an ongoing outbreak of ST80 VREfm with a newvanA-harboring plasmid in Guangdong, China. This clone has also been identified in other provinces and countries, foreboding a risk of wider spreading shortly. Continuous surveillance is needed to inform public health interventions.
Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs
Authors: Auwerx Chiara , Moix Samuel , Kutalik Zoltán , Reymond Alexandre
Published: March 2024

Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carriers among unrelated white British UK Biobank participants, we performed a phenome-wide association study between the region’s copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for thirty, ten, four, and two phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, cognitive function, or socio-economic status as potential mediators, we found that sixteen testable deletion-driven associations (61%) – primarily with cardiovascular and metabolic traits – were BMI-dependent, with other mediators playing a more subtle role. Bidirectional Mendelian randomization supported that 13 out of these 16 associations (81%) were secondary consequences of the CNV’s impact on BMI. For the 22 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that eleven phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, pulmonary capacity, pneumonia, and acute kidney injury, remained associated under strict Bonferroni correction, with eight additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5’s pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV’s impact on BMI and cognition, acting through trait-specific dosage mechanisms.
Otoferlin requires a free intravesicular C-terminal end for synaptic vesicle docking and fusion
Authors: Dulon Didier , Boutet de Monvel Jacques , Plion Baptiste , Mallet Adeline , Condamine Steven , Bouleau Yohan , Safieddine Saaid
Published: March 2024

Our understanding of how otoferlin, the major calcium sensor in inner hair cells (IHCs) synaptic transmission, contributes to the overall dynamics of synaptic vesicle (SV) trafficking remains limited. To address this, we generated a knock-in mouse model expressing an otoferlin-GFP protein, where GFP was fused to its C-terminal transmembrane domain. Similar to the wild type protein, the GFP-tagged otoferlin showed normal expression and was associated with IHC SV. Surprisingly, while the heterozygoteOtof+/GFPmice exhibited a normal hearing function, homozygoteOtofGFP/GFPmice were profoundly deaf attributed to severe reduction in SV exocytosis. Fluorescence recovery after photobleaching revealed a markedly increased mobile fraction of the otof-GFP-associated SV inOtofGFP/GFPIHCs. Correspondingly, 3D-electron tomographic of the ribbon synapses indicated a reduced density of SV attached to the ribbon active zone. Collectively, these results indicate that otoferlin requires a free intravesicular C-terminal end for normal SV docking and fusion.
Cell-Type Specific Reductions in Interneuron Gene Expression within Subregions of the Anterior and Posterior Cingulate Gyrus of Schizophrenia and Bipolar Disorder Subjects
Authors: Krolewski David M. , Waselus Maria , Bunney Blynn G. , Myers Richard M. , Barchas Jack D. , Lee Francis S.Y. , Schatzberg Alan F. , Bunney William E. , Akil Huda , Watson Stanley J.
Published: March 2024

Schizophrenia (SZ) and bipolar disorder (BP) patients share overlapping and distinct neurocognitive deficits. Neuroimaging of these patients and postmortem gene expression analyses suggest that compromised cingulate gyrus GABA-ergic interneurons may contribute to cognitive impairments in SZ and BP. Therefore, we investigated potential gene expression signatures for SZ and BP using interneuron cell-type specific markers including glutamic acid decarboxylase (GAD67), parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) within cingulate Brodmann’s areas (BA). We report reduced GAD67 mRNA in anterior midcingulate cortex (aMCC) of SZ and BP subjects with BA24c’ being most dysregulated across disorders, demonstrating reduced PV (SZ), SST (BP), and VIP mRNA (SZ and BP). Dorsal posterior cingulate (dPCC) displayed decreased SST (BP) whereas retrosplenial cortex (RSC) showed reduced PV (SZ and BP) and SST mRNA (BP). Our results show shared and unique transcription signatures of two disorders in specific cingulate gyrus regions and cell types. SZ and BP show a similar profile of aMCC gene expression reductions suggesting subregional dysregulation within areas associated with error/action monitoring and the saliency network. In dPCC/RSC, transcriptional changes are associated with disease-specific gene/subregion signatures, possibly underlying differential effects on allocation of attentional resources and visuospatial memory processing unique to each disorder.
Platelets induce cell apoptosis of cardiac cells via FasL after acute myocardial infarction
Authors: Krott Kim J. , Reusswig Friedrich , Dille Matthias , Krüger Evelyn , Gorressen Simone , Karray Saoussen , Polzin Amin , Kelm Malte , Fischer Jens-W. , Elvers Margitta
Published: March 2024

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Cell apoptosis in the myocardium plays an important role in ischemia and reperfusion (I/R) injury, leading to cardiac damage and dysfunction. Platelets are major players of hemostasis and play a crucial role in vessel occlusion, inflammation and cardiac remodeling after I/R. Here, we studied the impact of platelets on cell apoptosis in the myocardium using a close-chest mouse model of AMI. We found caspase-3 positive resident cardiac cells while leukocytes were negative for caspase-3. Using two different mouse models of thrombocytopenia, we detected a significant reduction of caspase-3 positive cells in the infarct border zone after I/R injury. Further, we identified platelet FasL to induce cell apoptosis via the extrinsic pathway of Fas receptor activation of target cells. Mechanistically, hypoxia triggers platelet adhesion to FasR suggesting that platelet induced apoptosis is elevated after I/R. Platelet-specific FasL knock-out mice showed reduced Bax and BcL-2 expression suggesting that platelets modulate the intrinsic and the extrinsic pathway of apoptosis leading to reduced infarct size after myocardial I/R injury. Therefore, platelet induced cardiac damage needs to be taken into account while optimizing antithrombotic/antiplatelet strategies for patients with AMI.
Ether lipids influence cancer cell fate by modulating iron uptake
Authors: Henry Whitney S. , Müller Sebastian , Yang Jia-Shu , Innes-Gold Sarah , Das Sunny , Reinhardt Ferenc , Sigmund Kim , Phadnis Vaishnavi V. , Wan Zhengpeng , Eaton Elinor , Sampaio Julio L. , Bell George W. , Viravalli Amartya , Hammond Paula T. , Kamm Roger D. , Cohen Adam E. , Boehnke Natalie , Hsu Victor W. , Levental Kandice R. , Rodriguez Raphaël , Weinberg Robert A.
Published: March 2024

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with a high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, leading directly to significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.