bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Worksheets for Immunomodulator Shared Decision-Making to Facilitate Patient-Clinician Communication
Authors: Kumar Bharat , Iftekhar Ayesha , Ni Ruoning , Feng Alick , Gheriani Gatr-alnada , Oke Ibiyemi , Abidov Amir , Moy Lindsay , Morita Craig T. , Cobb Kristina , Sigwarth Erica , Swee Melissa 
Published: October 2024

Background
Shared decision-making (SDM) is a principle of humanistic, patient-centered health care within the field of rheumatology. However, clear communication between patients and their clinicians regarding the benefits and risks of immunomodulators may be challenging in a clinical setting. The design-thinking process is a human-centered approach to quality improvement that can help to identify insights to uphold high-quality communication.

Methods
The development process adhered to the Stanford design thinking process framework, encompassing 5 stages: (1) empathize, (2) define, (3) ideate, (4) prototype, and (5) test. During the empathy stage, quality improvement members spent 4 hours immersed in the clinical setting observing how patients and clinicians engage in SDM conversations. These observations were augmented by unstructured debriefing sessions to better understand the needs and drivers of high-quality SDM. Following this, a rapid ideation workshop was convened to generate creative solutions. These led to rapid prototyping and testing, yielding a final product.

Results
The iterative design process identified 4 critical needs: (1) ensuring comprehensibility of materials, (2) upholding accuracy of information, (3) balancing standardization with individualization, and (4) promoting retention of knowledge. During the rapid ideation workshop, the concept of a Worksheet for Immunomodulator Shared Decision-Making (WISDM) was introduced and selected for further elaboration. This led to the creation of 5 prototypes for methotrexate, which were subsequently tested. These were reconciled and modified to make a final product.

Conclusion
The WISDM template contains 7 elements that support SDM. Forty-five WISDMs were created for 23 immunomodulators. Further investigation will focus on how WISDMs exactly impact SDM.
Mycoplasma pneumoniae: not a typical respiratory pathogen
Authors: Rowlands Richard S. , Meyer Sauteur Patrick M. , Beeton Michael L. ,   On behalf of the ESCMID Study Group for Mycoplasma and Chlamydia Infections (ESGMAC)
Published: October 2024

Graphical abstract
(a). The classic ‘fried-egg’ colonies are commonly seen with the growth of Mycoplasma pneumoniae on agar. (b). Scanning electron micrograph of M. pneumoniae demonstrates spindle-shaped cells with attachment organelles. M. pneumoniae is equipped with a repertoire of virulence factors, which include the production of the community-acquired respiratory distress syndrome toxin, formation of H202 and H2S, the immunoglobulin-binding protein of Mycoplasma, adhesion and antigenic variability via the P1 adhesin and associated surface proteins and the ability to form biofilms on surfaces.
Seasonal cycles in a seaweed holobiont: A multiyear time series reveals repetitive microbial shifts and core taxa
Authors: Mudlaff Chantal Marie , Weinberger Florian , Düsedau Luisa , Ghotbi Marjan , Künzel Sven , Bonthond Guido 
Published: October 2024

ABSTRACTSeasonality is an important natural feature that drives cyclic environmental changes. Seaweed holobionts, inhabiting shallow waters such as rocky shores and mud flats, are subject to seasonal changes in particular, but little is known on the influence of seasonality on their microbial communities.In this study, we conducted a bi-monthly, three-year time series to assess the seasonality of microbial epibiota in the seaweed holobiontGracilaria vermiculophylla. Our results reveal pronounced seasonal shifts that are both taxonomic and functional, oscillating between late winter and early summer across consecutive years. While epibiota varied taxonomically between populations, they were functionally similar, indicating that seasonal variability drives functional changes, while spatial variability is more redundant.We also identified seasonal core microbiota that consistently (re)associated with the host at specific times, alongside a permanent core that is present year-round, independent of season or geography. These findings highlight the dynamic yet resilient nature of seaweed holobionts and demonstrate that their epibiota undergo predictable changes. Therewith, the research offers important insights into the temporal dynamics of seaweed-associated microbiota, and demonstrates that the relationship between seaweed host and its epibiota is not static, but naturally subject to an ongoing seasonal succession process.
In vitrometabolic interaction network of a rationally designed nasal microbiota community
Authors: Bonillo-Lopez L. , Rouam-el Khatab O. , Obregon-Gutierrez P. , Florez-Sarasa I. , Correa-Fiz F. , Sibila M. , Aragon V. , Kochanowski K. 
Published: October 2024

AbstractMounting evidence suggests that metabolite exchange between microbiota members is a key driver of microbiota composition. However, we still know little about the metabolic interaction networks that occur within many microbiota. This is particularly true for the nasal microbiota, and current efforts towards this end are hampered by a lack of microbial consortia that would enable the mapping of metabolic interactions between nasal microbiota members underin vitroconditions. To tackle these issues, we developed the Porcine Nasal Consortium (PNC8), a rationally designed microbial consortium of eight strains representing the mostin vivoabundant genera in the nasal microbiota of healthy piglets. We used this consortium to systematically examine the metabolic capabilities of nasal microbiota members, as well as the metabolic interactions occurring between them. We found that PNC8 strains differ substantially in their metabolic pathway repertoire and ability to grow across variousin vitroconditions. Nevertheless, spent-media experiments revealed that most metabolic interactions between PNC8 strains are negative, and exometabolomics data pointed to co-depletion of sugars as a key driver of this interaction network. Finally, direct co-cultivation experiments showed that, as a result of this largely negative metabolic interaction network, competition is common among pairs of PNC8 strains and leads to a complex competition hierarchy in which only few strains are able to consistently outcompete all others. Overall, this work provides a valuable resource for studying the nasal microbiota under experimentally tractablein vitroconditions and is a key step towards mapping its metabolic interaction network.
Metabolism-oriented compound screen in physiological culture conditions identifies a NAMPT inhibitor highly effective against drug-naïve and -resistant melanoma cells
Authors: Preis Jasmin Renate , Rolvering Catherine , Kirchmeyer Mélanie , Kreis Stephanie , Behrmann Iris , Haan Claude 
Published: October 2024

AbstractMany melanoma patients do not respond to therapy or rapidly develop resistance to MAPK pathway inhibitors and immune checkpoint blockade treatments, highlighting the urgent need for additional therapeutic strategies for these patients.To identify compounds that target drug-naïve and -resistant melanoma cells (Encorafenib/Binimetinib-resistant), we performed a screen using a metabolism-oriented compound library in different cell culture media and growth conditions (2D and 3D).The efficacy of several compounds varied considerably under changing test conditions, but importantly, we also detected compounds that work across all tested conditions. In general, drug activity was reduced under hypoxia and in 3D spheroids. Thorough validation was performed for drugs showing potency in all conditions with a focus on efficacy in 3D spheroids grown in an in- house physiological culture medium. Using hydrogel matrix-embedded multi-cell type 3D models, we found that FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, is very potently suppressing melanoma cell growth while not affecting the growth of healthy cells such as fibroblasts and endothelial cells.
Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to prevent HER2+ breast cancer
Authors: Sharma Vandana , Fernando Veani , Zheng Xunzhen , Sweef Osama , Choi Eun-Seok , Thomas Venetia , Furuta Saori 
Published: October 2024

AbstractArginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing SEP, the endogenous precursor of BH4(the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we report that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively prevented tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention. These findings suggest the possible roles of the SEP/BH4/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.
Computer prediction and genetic analysis identifies retinoic acid modulation as a driver of conserved longevity pathways in genetically-diverseCaenorhabditisnematodes
Authors: Banse Stephen A. , Sedore Christine A. , Coleman-Hulbert Anna L. , Johnson Erik , Onken Brian , Hall David , Segerdell Erik , Jones E. Grace , Song Yuhua , Osman Hadley , Xue Jian , Battistoni Elena , Guo Suzhen , Foulger Anna C. , Achanta Madhuri , Sheikh Mustafa , Fitzgibbon Theresa , Willis John H. , Woodruff Gavin C. , Driscoll Monica , Lithgow Gordon J. , Phillips Patrick C. 
Published: October 2024

AbstractAging is a pan-metazoan process with significant consequences for human health and society—discovery of new compounds that ameliorate the negative health impacts of aging promise to be of tremendous benefit across a number of age-based co-morbidities. One method to prioritize a testable subset of the nearly infinite universe of potential compounds is to use computational prediction of their likely anti-aging capacity. Here we present a survey of longevity effects for 16 compounds suggested by a previously published computational prediction set, capitalizing upon the comprehensive, multi-species approach utilized by theCaenorhabditisIntervention Testing Program (CITP). While eleven compounds (aldosterone, arecoline, bortezomib, dasatinib, decitabine, dexamethasone, erlotinib, everolimus, gefitinib, temsirolimus, and thalidomide) either had no effect on median lifespan or were toxic, five compounds (all-trans retinoic acid, berberine, fisetin, propranolol, and ritonavir) extended lifespan inCaenorhabditis elegans. These computer predictions yield a remarkable positive hit rate of 30%. Deeper genetic characterization of the longevity effects of one of the most efficacious compounds, the endogenous signaling ligand all-trans retinoic acid (atRA, designated tretinoin in medical products), which is widely prescribed for treatment of acne, skin photoaging and acute promyelocytic leukemia, demonstrated a requirement for the regulatory kinases AKT-1 and AKT-2. While the canonical Akt-target FOXO/DAF-16 was largely dispensable, other conserved Akt-targets (Nrf2/SKN-1 and HSF1/HSF-1), as well as the conserved catalytic subunit of AMPK AAK-2, were all necessary for longevity extension by atRA. Evolutionary conservation of retinoic acid as a signaling ligand and the structure of the downstream effector network of retinoic acid combine to suggest that the all-trans retinoic acid pathway is an ancient metabolic regulatory system that can modulate lifespan. Our results highlight the potential of combining computational prediction of longevity interventions with the power of nematode functional genetics and underscore that the manipulation of a conserved metabolic regulatory circuit by co-opting endogenous signaling molecules is a powerful approach for discovering aging interventions.
Bystander base editing interferes with visual function restoration in Leber congenital amaurosis
Authors: Lee Seok-Hoon , Wu Jun , Im Dongjoon , Hwang Gue-ho , Jeong You Kyeong , Jiang Hui , Lee Seok Jae , Jo Dong Hyun , Goddard William A. , Kim Jeong Hun , Bae Sangsu 
Published: October 2024

AbstractBase editors (BEs) have emerged as a powerful tool for gene correction with high activity. However, bystander base editing, a byproduct of BEs, presents challenges for precise editing. Here, we investigated the effects of bystander edits on phenotypic restoration in the context of Leber congenital amaurosis (LCA), a hereditary retinal disorder, as a therapeutic model. We observed that inrd12of LCA model mice, the highest editing activity version of an adenine base editors (ABEs), ABE8e, generated substantial bystander editing, resulting in missense mutations despite RPE65 expression, preventing restoration of visual function. Through AlphaFold-based mutational scanning and molecular dynamics simulations, we identified that the ABE8e-driven L43P mutation disrupts RPE65 structure and function. Our findings underscore the need for more stringent requirements in developing precise BEs for future clinical applications.
Phenotypic impact of individual conserved neuronal microexons and their master regulators in zebrafish
Authors: Lopez-Blanch Laura , Rodríguez-Marin Cristina , Mantica Federica , Iñiguez Luis P. , Permanyer Jon , Kita Elizabeth M. , Mackensen Tahnee , Codina-Tobias Mireia , Romero-Ferrero Francisco , Fernandez-Albert Jordi , Cuadrado Myriam , Bustelo Xosé R. , de Polavieja Gonzalo G. , Irimia Manuel 
Published: October 2024

AbstractMicroexons exhibit striking evolutionary conservation and are subject to precise, switch-like regulation in neurons, orchestrated by the splicing factorsSrrm3andSrrm4. Disruption of these regulators in mice leads to severe neurological phenotypes, and their misregulation is linked to human disease. However, the specific microexons involved in these phenotypes and the effects of individual microexon deletions on neurodevelopment, physiology, and behavior remain poorly understood. To explore this, we generated zebrafish lines with deletions of 18 individual microexons, alongsidesrrm3andsrrm4mutant lines, and conducted comprehensive phenotypic analyses. We discovered that while loss ofsrrm3, alone or together withsrrm4, resulted in significant alterations in neuritogenesis, locomotion, and social behavior, individual microexon deletions typically produced mild or no noticeable effects. Nonetheless, we identified specific microexons associated with defects in neuritogenesis (evi5b,vav2,itsn1,src) and social behavior (vti1a,kif1b). Additionally, microexon deletions triggered coordinated transcriptomic changes in neural pathways, suggesting the presence of molecular compensatory mechanisms. Our findings suggest that the severe phenotypes caused bySrrm3/4depletion arise from the combined effects of multiple subtle disruptions across various cellular pathways, which are individually well-tolerated.
Computational Identification of Migrating T cells in Spatial Transcriptomics Data
Authors: Zhong Lin , Li Bo , Zhang Siyuan , Li Qiwei , Xiao Guanghua 
Published: October 2024

AbstractT cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide novel insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T-cell trafficking display an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix (ECM) remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce a novel approach for studying T cell migration and interactions within the tumor microenvironment (TME), offering valuable insights into tumor-immune dynamics.
Apelin-13 in the paraventricular nucleus protects myocardium from ischemia via V1a receptor of the paraventricular nucleus and GABAA receptor γ2 of the nucleus tractus solitarii in rats
Authors: Yan Wen , Wang Dan , Zhang Xinmin , Xuan Chengluan 
Published: October 2024

AbstractBackgroundApelin system plays a significant role in central blood pressure regulation, but its role in neural control of myocardial injury protection is poorly understood. Thus, this study was undertaken to evaluate the effects of apelin-13 in the paraventricular nucleus (PVN) on myocardial infarction (MI) and ischemia/reperfusion (I/R).MethodsThe cardiac functions were assessed after microinjecting or transferring the apelin-13 gene into the paraventricular nucleus (PVN) of rat models with myocardial infarction (MI) or ischemia/reperfusion (I/R).ResultsIn MI rats, we showed that apelin-13 expression decreased in PVN, V1a receptor expression increased in PVN and nucleus tractus solitarii (NTS), and GABAA receptor (GAR) γ2 expression increased in NTS. In primary cultured hypothalamus and medulla oblongata neurons, V1a receptor expression was downregulated by APJ receptor antagonist or GAR agonist, indicating that there are interactions between these receptors in neurons. Apelin-13 overexpression in PVN significantly improved cardiac function of MI and I/R rats, including left-ventricular end-diastolic diameter, left-ventricular end-systolic diameter, left-ventricular ejection fraction, and left-ventricular fractions shortening, accompanied by decreased noradrenaline and increased vasopressin plasma levels. Myocardial ischemia–related apoptotic and inflammatory pathway markers (Bcl-1, Bax, TGF-β1, CCR5, Smad2) were downregulated and four neuropeptides of the parasympathetic endocrine system (somatostatin, cholecystokinin, glucagon-like peptide 1, vasoactive intestinal peptide) were increased in serum correspondingly with cardiac function improving. V1a receptor antagonist in PVN or NTS and GAR agonist in NTS decreased the effects of apelin-13 overexpression on cardiac function of MI and I/R rats.ConclusionsOverexpression of apelin-13 in PVN leads to cardiac function improvement via V1a receptor in PVN and NTS, and GARγ2 in NTS. Parasympathetic endocrine system and myocardial ischemia–related apoptotic and inflammation signaling pathways are involved in apelin-13 in PVN–mediated cardiac function regulation, which provides evidence for neural regulation of cardiovascular diseases.
Unraveling transposable element-mediated regulatory landscape in diverse human immune cells
Authors: Du Cui , Fan Hairui , Jiang Jiayao , Yang Juan , Chen Shuai , Vorobyeva Nadezhda E , Zhu Congrui , Mao Liming , Li Chenxi , Li Yanhua , Bao Wenbin , Sun Ming-an 
Published: October 2024

AbstractTransposable elements (TEs) are key contributors to genetic novelty. Despite increasing evidence of their importance, their roles in shaping the regulatory landscape of diverse immune cell populations remain largely unclear. Using single-cell multiome data from human peripheral blood mononuclear cells, we annotated the cell-specific cis-regulatory elements for major immune cell populations and identified a highly cell-specific signature of the overrepresented TE families. Focusing on monocytes that bear fast-evolving transcriptomes, we found that high proportions of their enhancers are TE-derived and bound by multiple pioneer transcription factors. Among them, we confirmed that the core myeloid regulator SPI1 can bind and regulate hundreds of TE-derived enhancers, which further affect the expression of adjacent immune genes. Additionally, interspecies comparison reveals that non-conserved monocyte enhancers are frequently generated by lineage-specific TE insertions, and correlate with the evolved gene expression between human and mouse. Overall, our study supports the importance of TEs in shaping the regulatory landscape of diverse immune cell populations.
Expression pattern of the ST heat-stable enterotoxin gene cassettes inVibriossuperintegrons
Authors: Fonseca Érica L. , Freitas Fernanda S. , Morgado Sérgio M. , Vicente Ana Carolina P. 
Published: October 2024

AbstractBACKGROUNDVibrio mimicushas been associated with a cholera-like diarrhea and other gastroenteritis due to the presence of virulence factors such as the heat-stable ST enterotoxin. In spite of its relevant role inVibriopathogenesis, there is still a lack of information concerning ST expression dynamics and associated genomic context.OBJECTIVEthis study aimed to determine the prevalence, genomic context, and expression of thestgene found inV. choleraeandV. mimicusstrains.METHODSgenome sequencing, in silico analyses of st promoter region and genomic context, and relative quantification pf st expression by real time RT-PCR were applied.FINDINGSThestgene was found within the SI of bothVibriospecies, presenting variations in their amino acid sequences. Thein silicoanalysis of thest5’UTR identified different promoter versions among them. Significant differences were observed in thestexpression level, which varied from 10X to 640X-fold, correlating with the differences found in the promoter versions.MAIN CONCLUSIONSTherefore, the present study highlighted the link between the ST toxin gene and the superintegron, not only forV. cholerae, but also forV. mimicus. The differentialstexpression revealed that it is detrimental to the cognate promoter version, which would impact the toxin production and strain virulence.
Regulation of Sex-biased Gene Expression by the Ancestral X-Y Chromosomal Gene PairKdm5c-Kdm5d
Authors: Malcore Rebecca M. , Samanta Milan Kumar , Kalantry Sundeep , Iwase Shigeki 
Published: October 2024

SummaryConventionally, Y-linkedSryis thought to drive sex differences by triggering differential hormone production. Ancestral X-Y gene pairs, however, are hypothesized to drive hormone-independent sex differences. Here, we show that the X-Y gene pairKdm5c-Kdm5dregulates sex-biased gene expression in pluripotent mouse embryonic stem cells (ESCs). Wild-type (WT) XX female ESCs exhibit >2-fold higher expression of 409 genes relative to WT XY male ESCs. Conversely, WT XY male ESCs exhibit >2-fold higher expression of 126 genes compared to WT XX female ESCs. Loss ofKdm5cin female ESCs downregulates female-biased genes. In contrast, loss of eitherKdm5corKdm5din male ESCs upregulates female-biased genes and downregulates male-biased genes, effectively neutralizing sex-biased gene expression. KDM5C promotes the expression ofKdm5dand several other Y-linked genes in male ESCs. Moreover, ectopicKdm5dexpression in female ESCs is sufficient to drive male-biased gene expression. These results establishKdm5c-Kdm5das critical regulators of sex-biased gene expression.