bluuebunny/crossref_metadata_2025_split huggingface dataset:
HMGB1 mediates macrophage recruitment and regional intervertebral disc tissue functional and mechanical property changes following injury
Authors: Burt Kevin G. , Kim Min Kyu M. , Viola Dan C. , Genualdi Joseph R. , Marciano Gerard F. , Chahine Nadeen O. 
Published: November 2024

AbstractObjectiveFrequently evaluated in musculoskeletal disease, damage associated molecular patterns (DAMPs) respond to tissue damage and cellular stress by facilitating an inflammatory response via macrophage activation and broad inflammatory pathway activation. In the context of disc degeneration (DD), high mobility group box 1 (HMGB1), a potent intracellular DAMP, is seen to be increased within severely degenerated human IVDs and to directly mediate inflammatory responses within disc cellsin vitro. To further understand how HMGB1 mediated inflammation influences DD, this study evaluated the possible protective effect of an HMGB1 knockout on DD pathology following injury.MethodsUsing a needle puncture injury model in murine caudal IVDs we evaluated DD pathology within an IVD specificHmgb1knockout (KO) model. Structural and compositional changes in IVD cellularity, histopathology, disc height, and biomechanics were evaluated in addition to an assessment of disc inflammation via gene expression and macrophage presence throughout the course of degeneration.ResultsHMGB1 expression robustly increased shortly following needle puncture injury and elevated levels were sustained up to 28-days post injury both in injured IVDs and in the IVDs adjacent to the level of injury. IVD specificHmgb1KO mice had an increased disc height following injury both at the injured and adjacent to injury level compared to injured WT IVDs. Hmgb1 KO also protected against tissue mechanical property losses at both the injured (dynamic modulus) and adjacent to injury level (dynamic modulus, creep, and equilibrium modulus) compared to injured WT IVDs, however there was no significant effect on histopathologic scores post injury.Hmgb1KO resulted in alterations in macrophage (F4/80+) recruitment to the IVD post injuryin vivo.A lower macrophage migration was also observedin vitroin response to the secretome of an injuredHmgb1KO IVD compared to injured WT IVDs.Hmgb1KO had no effect on inflammatory gene expression changes following injury within adjacent to injury level or injury level IVDs.ConclusionOverall findings indicate that HMGB1 is upregulated regionally, at both the injured level and at the level adjacent to injury. Results suggest that HMGB1 plays a role in mediating structural, biomechanical, and inflammatory responses to IVD injury and serves as a potent chemoattractant, mediating macrophage recruitment to the IVD and overall migratory function.
A novelin-vitromodel of the bone marrow microenvironment in AML identifies CD44 and Focal Adhesion Kinase as therapeutic targets to reverse cell adhesion-mediated drug resistance
Authors: Ladikou Eleni Ε. , Sharp Kim , Simoes Fabio A. , Jones John , Burley Thomas , Stott Lauren , Vareli Aimilia , Kennedy Emma , Vause Sophie , Chevassut Timothy , Devi Amarpreet , Ashworth Iona , Ross David , Hartmann Tanja Nicole , Mitchell Simon , Pepper Chris , Best Giles , Pepper Andrea G.S. 
Published: November 2024

AbstractAcute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, disruption of the BMME, releasing tumour cells into the peripheral circulation, has therapeutic potential. Using both primary donor AML cells and cell lines, we developed anin-vitroco-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistanc E. We identified anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signalling as a contributing factor; adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing adhesion of the most primitive CD34highAML cells in primary autologous co-cultures. Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanised monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials.
Unanchored ubiquitin chains promote the non-canonical inflammasome via UBXN1
Authors: Yang Duomeng , Cahoon Jason G. , Geng Tingting , Wang Chengliang , Harrison Andrew G. , Teran Evelyn , Wang Yanlin , Vella Anthony T. , Rathinam Vijay A. , Ruan Jianbin , Wang Penghua 
Published: November 2024

ABSTRACTUbiquitination is a major posttranslational covalent modification that regulates numerous cellular processes including inflammasome signaling. Cells also contain unanchored ubiquitin chains (polyUb) that bind protein targets non-covalently, but their physiological functions in immunity have been appreciated only recently. Here, we report that ubiquitin regulatory x domain-containing protein 1 (UBXN1) activates the noncanonical inflammasome via unanchored Lysin (K) 48- or 63-linked polyUb. UBXN1 deficiency impairs the activation of caspase-4/11, secretion of inflammasome-dependent cytokines and pyroptosis in response to intracellular lipopolysaccharide (LPS). UBXN1-deficient mice are protected from LPS- and cecal-ligation-and-puncture-induced sepsis, evidenced by reduced mortality and systemic inflammation, compared to UBXN1-sufficient littermates. Mechanistically, UBXN1 together with unanchored K48/63-linked polyUb bind caspase-4/11, the intracellular sensors of LPS, and promote their assembly and activation. Depleting cellular unanchored polyUb with recombinant ubiquitin-specific proteinase 5 (USP5) reduces UBXN1 binding to caspase-4/11 and inflammasome signaling, while USP5 inhibitors enhance pyroptosis in an UBXN1-dependent manner. Thus, this study identifies a critical UBXN1-dependent posttranslational mechanism involved in noncanonical inflammasome activation and UBXN1 as a potential therapeutic target for sepsis and advances a fundamental understanding of unanchored polyUb biology.
N-Aldehyde-Modified Phosphatidylethanolamines generated by lipid peroxidation are robust substrates ofN-Acyl Phosphatidylethanolamine Phospholipase D
Authors: Fadaei Reza , Bernstein Annie C. , Jenkins Andrew N. , Pickens Allison G. , Zarrow Jonah E. , Alli-Oluwafuyi Abdul-Musawwir , Tallman Keri A. , Davies Sean S. 
Published: November 2024

ABSTRACTN-acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) hydrolyzes phosphatidylethanolamines (PE) where the headgroup nitrogen has been enzymatically modified with acyl chains of four carbons or longer (N-acyl-PEs or NAPEs). The nitrogen headgroup of PE can also be non-enzymatically modified by reactive lipid aldehydes, thus formingN-aldehyde modified-PEs (NALPEs). Some NALPEs such asN-carboxyacyl-PEs are linked to PE via amide bonds similar to NAPEs, but others are linked by imine, pyrrole, or lactam moieties. Whether NAPE-PLD can hydrolyze NALPEs was unknown. We therefore characterized the major NALPE species formed during lipid peroxidation of arachidonic acid and linoleic acid and generated various NALPEs for characterization of their sensitivity to NAPE-PLD hydrolysis by reacting synthesized aldehydes with PE. We found that NAPE-PLD could act on NALPEs of various lengths and linkage types including those derived from PE modified by malondialdehyde (N-MDA-PE), butane dialdehyde (N-BDA-PE), 4-hydroxynonenal (N-HNE-PE), 4-oxo-nonenal (N-ONE-PE), 9-keto-12-oxo-dodecenoic acid (N-KODA-PE), and 15-E2-isolevuglandin (N-IsoLG-PE). To assess the relative preference of NAPE-PLD for various NALPEs versus its canonical NAPE substrates, we generated a substrate mixture containing roughly equimolar concentrations of the seven NALPEs as well as two NAPEs (N-palmitoyl-PE andN-linoleoyl-PE) and measured their rate of hydrolysis. Several NALPE species, including theN-HNE-PE pyrrole species, were hydrolyzed at a similar rate asN-linoleoyl-PE and many of the other NALPEs showed intermediate rates of hydrolysis. These results significantly expand the substrate repertoire of NAPE-PLD and suggest that it may play an important role in clearing products of lipid peroxidation in addition to its established role in the biosynthesis ofN-acyl-ethanolamines.
A novel miniaturized filamentous phagemid as a gene delivery vehicle to target mammalian cells
Authors: Wong Shirley , Jimenez Salma , Pushparajah Deborah , Prakash Rohini , Slavcev Roderick 
Published: November 2024

AbstractThe filamentous phage M13 is a single-stranded DNA phage with several attractive characteristics for gene delivery, including a capsid amenable to the display of foreign peptides, and a simple well-characterized genome that is easy to genetically modify. Previously, we constructed a DNA minivector based on M13 (a miniphagemid), which minimized the inflammatory bacterial and phage DNA content in the vector. In general, DNA minivectors, devoid of their prokaryotic components have shown improved gene transfer and safety. We examined the miniphagemid’s capacity forin vitrotransgene delivery to target cells through phage display of epidermal growth factor to target its cognate receptor. The absence of the prokaryotic backbone and smaller vector size conferred by the miniphagemid was associated with improved transgene expression for purified single-stranded phagemid DNA and phagemid virion particles. We further engineered this system to enhance packaging of DNA minivectors by deletion of the packaging signal within the helper plasmid, used to produce miniphagemids, and observed improved phage-mediated gene expression in mammalian cells. Overall, here, we present a set of novel transgene delivery vectors that combine cell-targeting ligand display and vector minimization. This platform showcases the flexibility of M13 as a gene delivery tool with immense therapeutic potential.
AnE. coli-based platform for the production and assembly of anellovirus vectors
Authors: Prakash Rohini , Slavcev Roderick 
Published: November 2024

AbstractGene therapy offers immense potential for treating various diseases, including cancer, immunodeficiencies, and cardiovascular conditions. The efficacy of gene therapy (GT) largely depends on the vector used for gene delivery. Viral vectors, while effective, pose risks including insertional mutagenesis, immune responses, and high manufacturing costs. Non-viral vectors, although safer and easier to produce, often exhibit lower transfection efficiency and weaker transgene expression. This highlights the need for novel, more efficient vectors. Among emerging strategies, bacteriophages are gaining attention as promising GT delivery vehicles due to their adaptability and safety profile. Filamentous phages like M13 have demonstrated potential as targeted gene delivery vectors. This study proposes constructing a single-stranded DNA (ssDNA) phage-based vector incorporating a eukaryotic gene cassette. By leveraging Ff phage replication mechanisms inE. coli, the study explores encapsidating ssDNA within anellovirus capsids. These small, ssDNA viruses, known for their ability to transfect diverse tissues, offer a safer alternative to conventional viral vectors. Through successful expression and assembly of anellovirus capsid proteins, ssDNA viral particles were producedex vivo. This innovativeE. coli-based anellovirus-phagemid system provides a promising, cost-effective platform for developing next-generation viral vectors in gene therapy.
Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm
Authors: Wang Hui , Kazaleh Mattew , Gioscia-Ryan Rachel , Millar Jessica , Temprano-Sagrera Gerard , Wood Sherri , Van Den Bergh Fran , Blin Muriel G. , Wragg Kathleen M. , Luna Adrian , Hawkins Robert B. , Soleimanpour Scott A. , Sabater-Lleal Maria , Shu Chang , Beard Daniel A. , Ailawadi Gorav , Deng Jane C. , Goldstein Daniel R. , Salmon Morgan 
Published: November 2024

AbstractAbdominal aortic aneurysms (AAAs) are a degenerative aortic disease and associated with hallmarks of aging, such as mitophagy. Despite this, the exact associations among mitophagy, aging, and AAA progression remain unknown. In our study, gene expression analysis of human AAA tissue revealed downregulation of mitophagy pathways, mitochondrial structure, and function-related proteins. Human proteomic analyses identified decreased levels of mitophagy mediators PINK1 and Parkin. Aged mice and, separately, a murine AAA model showed reduced mitophagy in aortic vascular smooth muscle cells (VSMCs) and PINK1 and Parkin expression. Parkin knockdown in VSMCs aggravated AAA dilation in murine models, with elevated mitochondrial ROS and impaired mitochondrial function. Importantly, inhibiting USP30, an antagonist of the PINK1/Parkin pathway, increased mitophagy in VSMCs, improved mitochondrial function, and reduced AAA incidence and growth. Our study elucidates a critical mechanism that proposes AAAs as an age-associated disease with altered mitophagy, introducing new potential therapeutic approaches.
Olfactory Training: Recommendation Frequency Amongst Rhinologists
Authors: Thomas Sherina R. , Nguyenkhoa Vincent L. , Mattos Jose L. , Munger Steven D. 
Published: November 2024

AbstractDespite the prevalence and health impact of olfactory dysfunction (OD), therapeutic options remain limited. One potential therapy is olfactory training (OT), where patients repeatedly sniff a small set of odors over several weeks with the goal of improving olfactory function. Although double-blinded, placebo-controlled clinical trials supporting the efficacy of OT are lacking, anecdotal evidence suggests that the procedure is widely recommended to patients with anosmia or other olfactory disorders. To better understand the adoption of OT in clinical practice, we recruited a convenience sample of 95 rhinologists and other otolaryngologists to complete an online survey that assessed how often, and under what conditions, they recommend OT to their patients with OD. Our survey revealed that the majority of responding otolaryngologists (93.7%) routinely recommend OT. Further, they recommend OT more often for quantitative than for qualitative disorders, and most frequently for post-viral and idiopathic OD etiologies. These findings support the perception that OT is commonly recommended in otolaryngological practice for the treatment of OD.Key PointsMost surveyed otolaryngologists routinely recommend olfactory training (OT).OT is recommended more often for quantitative than qualitative olfactory dysfunction (OD).OT is most often recommended for post-viral and idiopathic OD etiologies.
Utilizing artificial intelligence-driven virtual standardized pediatric patients to enhance the capabilities of primary healthcare doctors in China for managing common pediatric diseases: a study protocol for a randomized controlled trial
Authors: Mao Yanna , Luo Huanyuan , Cai Yiyuan , Huang Wanqing , Fang Fang , Lu Yue , Chen Xin , Zhao Qing , Wang Duolao , He Hua , Wang Xiaohui , Zhang Dexing , Li Guobao , Zhang Yichi , Xu Dong (Roman) , Zhao Yao 
Published: November 2024

AbstractBackgroundChina’s healthcare system for children faces significant challenges, particularly due to the limited pediatric service capacity of primary healthcare institutions. A shortage of effective and accessible training tools for primary care doctors further hinders progress in addressing this gap. Technological advancements, especially in artificial intelligence, offer a potential solution to improve pediatric care. Artificial intelligence-driven virtual standardized patients (VSPs), leveraging internet and virtual simulation technologies, simulate clinical cases with specific disease characteristics, providing an innovative, efficient, and flexible training method. VSPs are increasingly utilized in medical education, clinical reasoning, and licensure exams. This study focuses on using VSPs to improve the management of common pediatric conditions, which are major health concerns for children and impose significant psychological and financial burdens on families.MethodsThis study will involve a three-arm randomized controlled trial to evaluate the effectiveness of a virtual pediatric standardized patient platform in enhancing primary care doctors’ management of common pediatric diseases. At least 459 participants, including general practitioners, internal medicine practitioners, surgeons, and pediatricians from more than 10 provinces across China, will be randomly assigned to one of three groups: the virtual patient platform group, the case teaching manual group, or the case teaching video group. Five virtual patient cases covering pneumococcal pneumonia, rotavirus enteritis with hypovolemic shock, hand-foot-and-mouth disease, acute appendicitis, and respiratory failure will be developed, along with corresponding case teaching materials. After a two-week learning period, participants’ disease management abilities will be assessed using clinical vignettes. The primary outcome is adherence to best clinical practice guidelines, categorized into full adherence, partial adherence, and nonadherence.DiscussionThis study aims to leverage artificial intelligence for capacity enhancement, targeting the shortcomings of primary care pediatrics and using VSP to help enhance primary care pediatrics capacity. It is a randomized controlled trial involving over 300 primary healthcare institutions across more than 10 provinces in China, ensuring broad and representative participation from both developed and underdeveloped regions.Trial registrationChictr.org.cn,ChiCTR2400085808. Registered on 19 June 2024.
Monkeypox virus pangenomics reveals determinants of clade Ib
Authors: Sganzerla Martinez Gustavo , Kumar Anuj , Kiganda-Lusamaki Eddy , Dutt Mansi , Wawina Bokalanga Tony , Toloue Ali , Francisca Muyembe Mawete , Makangara-Cigolo Jean Claude , Kelvin Patricia , Adrienne Amuri Aziza , Richardson Christopher D , Lokilo Emmanuel , Luakanda Gradi , Ayouba Ahidjo , Rimoin Anne W. , Mukadi-Bamuleka Daniel , Delaporte Eric , Pilarowski Genay , Kindrachuk Jason , Liesenborghs Laurens , Hensley Lisa E. , Subissi Lorenzo , Peeters Martine , Hoff Nicole A. , Tshiani-Mbaya Olivier , Tessema Sofonias , Muyembe Tamfum Jean-Jaques , Ahuka-Mundeke Steve , Kelvin Alyson A , Archibald John M , Mbala-Kingebeni Placide , Flores-Giron Luis , Kelvin David J 
Published: November 2024

AbstractMpox, formerly monkeypox, is a viral zoonotic disease caused by the monkeypox virus (MPXV). MPXV, which is taxonomically divided into clades I and II, was declared a Public Health Emergency of International Concern for the second time in August 2024 due to rapid geographic expansion of clade I viruses including the newly identified clade Ib [1]. With a unique set of genomic mutations and sustained human-to-human transmission, clade Ib has rapidly spread throughout the eastern Democratic Republic of the Congo as well as neighboring non-endemic regions outside the African continent [2–6]. Currently, there is a lack of comparative genomic data with which to address potential zoonotic transmissibility and pathobiology of clade Ib. Here we show MPXV clades I and II share a core genome composed of 68 protein-coding genes which are common in the genomes of other poxviruses such as camelpox, cowpox, and vaccinia. The first documented and all subsequently examined isolates of clade Ib lack the gene pairOPG032andOPG033, which encode the complement control protein (a vaccinia ortholog associated with virulence), and a Kelch-like protein, respectively. The genomic rearrangement of MPXV suggests a functional evolution that might play an important role in the pathobiology of the novel clade Ib virus. Our results lay the groundwork to exploit the genomic of elements of MPXV as potential targets for therapeutics development/repurposing, vaccine design, and molecular diagnostic expansion, as well as to uncover the viral diversity, and zoonosis of MPXV.
SCD-Tron: Leveraging Large Clinical Language Model for Early Detection of Cognitive Decline from Electronic Health Records
Authors: Guan Hao , Novoa-Laurentiev John , Zhou Li 
Published: November 2024

AbstractBackgroundEarly detection of cognitive decline during the preclinical stage of Alzheimer’s disease is crucial for timely intervention and treatment. Clinical notes, often found in unstructured electronic health records (EHRs), contain valuable information that can aid in the early identification of cognitive decline. In this study, we utilize advanced large clinical language models, fine-tuned on clinical notes, to improve the early detection of cognitive decline.MethodsWe collected clinical notes from 2,166 patients spanning the 4 years preceding their initial mild cognitive impairment (MCI) diagnosis from the Enterprise Data Warehouse (EDW) of Mass General Brigham (MGB). To train the model, we developed SCD-Tron, a large clinical language model on 4,949 note sections labeled by experts. For evaluation, the trained model was applied to 1,996 independent note sections to assess its performance on real-world unstructured clinical data. Additionally, we used explainable AI techniques, specifically SHAP values, to interpret the models predictions and provide insight into the most influential features. Error analysis was also facilitated to further analyze the model’s prediction.ResultsSCD-Tron significantly outperforms baseline models, achieving notable improvements in precision, recall, and AUC metrics for detecting Subjective Cognitive Decline (SCD). Tested on many real-world clinical notes, SCD-Tron demonstrated high sensitivity with only one false negative, crucial for clinical applications prioritizing early and accurate SCD detection. SHAP-based interpretability analysis highlighted key textual features contributing to model predictions, supporting transparency and clinician understanding.ConclusionSCD-Tron offers a novel approach to early cognitive decline detection by applying large clinical language models to unstructured EHR data. Pretrained on real-world clinical notes, it accurately identifies early cognitive decline and integrates SHAP for interpretability, enhancing transparency in predictions.
The Relationship Between Biological Aging with Interdisciplinary Health Indicators: A Scoping Review
Authors: Reeves Jennifer T. H. , Knock Emma , Gilson Zoë M. , Derry Leah , McGhee Miki C. , Taylor-Hood Katherine , Ziesel Alison , Jabbari Hosna , Newton Lorelei , Miller Jo Ann , Zhang Jie , Rhodes Ryan , Mallidou Anastasia , Paterson Theone S. E. 
Published: November 2024

AbstractObjectivesThis review aims to provide a comprehensive examination of biomarkers and interdisciplinary variables related to aging.MethodsThis scoping review included studies which involved adult participants, and which reported on the relationship between any biomarker or biological age with chronological age.ResultsAfter screening, 447 articles met the selection criteria. Results were categorized into 10 distinct categories through an iterative process.ConclusionsThis review contributes information regarding the interdisciplinary influences on the rate of aging. Telomere length was the most commonly examined biomarker, and Horvath’s 353-CpG Pan-Tissue clock was the most common clock, with both demonstrating a strong and consistent relationship with chronological age. The interdisciplinary variables demonstrated relationships with biological aging with varying strengths and consistencies.