bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human inborn errors of long‐chain fatty acid oxidation show impaired inflammatory responses to TLR4‐ligand LPS
Authors: Mosegaard Signe , Twayana Krishna S. , Denis Simone W. , Kroon Jeffrey , Schomakers Bauke V. , van Weeghel Michel , Houtkooper Riekelt H. , Olsen Rikke K. J. , Holm Christian K. 
Published: August 2024

AbstractStimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro‐inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS‐induced formation of IL‐1β. If enzymes involved in beta‐oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long‐chain fatty acid oxidation disorders (lcFAOD), we report that disease‐causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl‐CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro‐inflammatory cytokines such as IL‐6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss‐of‐function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta‐oxidation, and patients with these deficiencies cannot sufficiently metabolize long‐chain fatty acids. We report that genes important for beta‐oxidation of long‐chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs.
GSK805 inhibits alpha‐smooth muscle expression and modulates liver inflammation without impairing the well‐being of mice
Authors: Nierath Wiebke‐Felicitas , Leitner Emily , Reimann Sabrina , Schwarz Rico , Hinz Burkhard , Bleich André , Vollmar Brigitte , Zechner Dietmar 
Published: August 2024

AbstractCholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell‐line LX‐2 and in vivo using male bile duct‐ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha‐smooth muscle actin expression in LX‐2 cells. In vivo, GSK805 significantly decreased IL‐23R, TNF‐α, and IFN‐γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well‐being.
Nurses' Experiences of the Prerequisites for Implementing Family-Centered Care to Prevent Pediatric Delirium
Authors: Saarenpää Tiina , Jansson Miia , Kerimaa Heli , Alanko Riitta , Peltoniemi Outi , Tervonen Miikka , Lahtela Tiina , Pölkki Tarja 
Published: August 2024

Purpose
The aim of this study was to describe nurses' experiences of the prerequisites for implementing family-centered care to prevent pediatric delirium.

Design
The research employed a qualitative, descriptive study design.

Methods
A total of 10 nurses working in the pediatric intensive care unit at 1 university hospital participated in the study. The quality data were collected using individual semistructured interviews, and the data were then analyzed by inductive content analysis.

Results
The prerequisites for implementing family-centered care to prevent delirium among pediatric patients consisted of 30 subcategories that were grouped into 11 generic categories. The generic categories were further grouped into 5 main categories: (1) an environment that supports family presence, (2) psychosocial support for the family, (3) individual family involvement, (4) family participation in shared decision-making, and (5) nurses' professional competence.

Conclusions
According to the nurses' experiences, the implementation of a family-centered approach to preventing delirium in pediatric patients requires creating a supportive environment for families, providing psychosocial support, encouraging family involvement in decision-making, and ensuring that all nurses have the necessary skills.
Efficacy of Calcium Sulfate Antibiotic Carriers in the Treatment of Severe Infections of the Temporal Bone
Authors: Müller-Goebel Justus M. , Bächinger David , Röösli Christof , Huber Alexander , Dalbert Adrian 
Published: August 2024

Objective:
To study the additional use of topical antibiotic-loaded calcium sulfate pellets in difficult-to-treat cases of temporal bone infections.

Patients:
Four patients with advanced and pretreated temporal bone disease.

Intervention:
Application of topical antibiotic-loaded calcium sulfate pellets following surgical debridement in infections of the temporal bone.

Main Outcome Measures:
Reinfection- and revision-free follow-up analysis and assessment of audiometric data.

Results:
A total of 4 patients were included (3 females and 1 male, mean age of 29.5 years [SD 19.8]). All patients (4/4) had a revision-free follow-up during a mean of 24.5 (SD, 6.19) months. Reinfections (n = 3) were observed in 2 patients (2/4) occurring 1 and 15, as well as 8 months after surgery. Reinfections could be successfully treated using topically and/or orally applied antibiotic therapy. No change in air-conducted pure-tone average was observed after treatment (mean change 1.3 dB; P = 0.99).

Conclusion:
Local application of antibiotic-loaded calcium sulfate pellets in combination with surgical debridement represents an effective treatment for local infection control in difficult-to-treat cases of temporal bone infections.
Physician Assistants in Plastic Surgery
Authors: Bautista Catherine H. , Chen Joanna , Bhagat Neel D. , Moss Whitney D. , Walzer Norelle K. , Bruza-Augatis Mirela , Puckett Kasey , Agarwal Jayant P. , Kwok Alvin C. 
Published: August 2024

Abstract
Physician assistants (PAs) play a vital role in the US health care system, particularly amid the persistent surgeon shortage and escalating health care demands. We aim to characterize the current cohort of PAs in plastic surgery by comparing them to PAs in all other specialties. Using a cross-sectional analysis of the 2022 National Commission on Certification of PAs dataset, we examined demographic and practice characteristics of PAs in plastic surgery with those in all other specialties. Analysis included descriptive and bivariate statistics. In 2022, 1.0% of PAs worked in plastic surgery, with the specialty's numbers nearly doubling from 2015 (n = 647) to 2022 (n = 1186). Bivariate analysis among PAs in plastic surgery and those in other settings revealed several important attributes (all P's < 0.001); PAs in plastic surgery were younger (median age, 36 vs 39), identified as female (91.0% vs 69.4%), resided in urban locations (97.6% vs 92.5%), and performed a higher proportion of clinical procedures (66.5% vs 33.9%). Furthermore, a statistically significant higher percentage of PAs in plastic surgery reported high job satisfaction and was more likely to report no symptoms of professional burnout. The expanding PA profession amid the scarcity of surgeons presents an ideal prospect for enhanced collaboration. In an era where surgeon burnout is increasingly common and PAs express a readiness to function at an advanced level, expanding PAs' role becomes desirable and imperative. This collaborative approach has the potential to address workforce challenges, elevate patient care, and enhance provider satisfaction.
Double-Flap Elevation From the Ipsilateral Lower Extremity
Authors: Tsuge Itaru , Yamanaka Hiroki , Katsube Motoki , Sakamoto Michiharu , Morimoto Naoki 
Published: August 2024

Abstract
The free fibular flap has been elevated by a “lateral approach” from the posterior edge of the peroneal muscle for more than 40 years. However, in this approach, the surgical view is limited because flap elevation in mandibular reconstruction is performed simultaneously with tumor resection in the supine position, even when using positioning pillows. We herein propose an “anterior approach” as a new surgical method. We retrospectively investigated free fibular flap surgeries performed using the anterior approach, which consists of three anterior approaches, over a seven-year period. First, to avoid the course of the superficial peroneal nerve, the crural fascia was incised 1–2 cm posterior to the anterior edge of the peroneal muscle. The anterior edge of the peroneus muscle is detached from the anterior intermuscular septum. After performing osteotomies distal and proximal to the fibula, the interosseous membrane was incised from the anterior view. Pulling out the fibula to the anterior space between the anterior intermuscular septum and the peroneal muscle made the surgical field shallow. No postoperative superficial or deep peroneal nerve palsies were found in the 55 patients. Only one tourniquet was used in 31 of the 55 cases (56.4%), with an average of 95 min. Twenty-four patients (43.6%) required a second tourniquet 38 min after an interval. Only one tourniquet was used in 25 of the 30 (83.3%) cases in the last 3 years. Moreover, double flaps were used in 21 cases (38.2%), all of which involved ipsilateral ALT flaps. In 18 cases, double-flap elevation and prefabrication were successfully finished before the completion of tumor resection by otorhinolaryngologists.
Successful Resuscitation of Porcine Hearts After 12 and 24 h of Static Cold Storage With Normothermic Ex Situ Perfusion
Authors: Johnson Matthew D. , Urrea Kristopher A. , Spencer Brianna L. , Singh Jasnoor , Niman Joseph B. , Owens Gabe E. , Haft Jonathan W. , Bartlett Robert H. , Drake Daniel H. , Rojas-Peña Alvaro 
Published: August 2024

Background.Heart transplantation is always an emergency because the transplant needs to occur within 6 h after procurement to prevent primary graft dysfunction. Static cold storage (SCS) is the gold-standard preservation method. This study describes the outcomes of hearts preserved after prolonged SCS (12 and 24 h); those are then resuscitated with a novel normothermic ex situ heart perfusion (NEHP) system.Methods.Anesthetized piglets (n = 10) were used as heart donors. Hearts were procured and stored at 5 °C CoStorSol following standard SCS protocols. Two groups were studied: SCS-12 h and SCS-24 h. After SCS, 8 h of NEHP (37 °C blood-based perfusate) was performed at 0.7–1.0 mL/min/g of cardiac tissue. NEHP parameters were monitored continuously. Results were corroborated with 3 additional hearts transplanted orthotopically in healthy recipients (n = 3) after SCS (24 h) + NEHP (5 h). Recipients were observed for 90 min after weaning off cardiopulmonary bypass support.Results.All hearts (after 12 and 24 h of SCS) regained normal function and metabolism within 10 min and retained it throughout 8 h of NEHP. No differences were observed in NEHP parameters and histopathology between groups. Three hearts were successfully transplanted after a total ~30 h of preservation (24 h of SCS + 5 h of NEHP + 1 h of second cold ischemia time). The 3 recipients were weaned off cardiopulmonary bypass with mild vasopressor support.Conclusions.NEHP has the potential to routinely resuscitate porcine hearts that have undergone SCS for up to 24 h, restoring them to viable function. By objectively assessing heart function before transplant, NEHP may enhance the success rate of transplants. If these resuscitated hearts can be successfully transplanted, it would support the effectiveness of NEHP in ensuring heart viability.
Soluble IL-2R contributes to impaired muscle cell mitochondrial respiration in fatigued individuals with post-acute sequelae of COVID
Authors: Brown Laura P. , Joshi Jai , Kosmac Kate , Long Douglas E. , Montgomery-Yates Ashley A. , Kalema Anna G. , Sturgill Jamie L. , Vekaria Hemendra , Sullivan Patrick , Wilburn Dylan , Koutakis Panagiotis , Latham Christine M. , Fry Christopher S. , Kern Philip A. , Miller Benjamin , Dupont-Versteegden Esther E. , Ismaeel Ahmed , Mayer Kirby P. , Wen Yuan 
Published: August 2024

AbstractPost-acute sequelae of COVID (PASC) persist in many patients for weeks and months after recovery from initial SARS-CoV-2 infection. Recent evidence suggests that pathological changes in skeletal muscle may contribute significantly to ongoing pain and fatigue, particularly post-exertional malaise. This study aimed to investigate the underlying mechanisms of PASC-related fatigue by examining skeletal muscle function and circulating factors in affected individuals.We conducted a cross-sectional case-control study of patients with fatigue-associated PASC who had experienced mild to moderate COVID-19 without hospitalization. Skeletal muscle biopsies revealed reduced mitochondrial respiration and content in PASC participants compared to healthy controls. This lower respiratory capacity was accompanied by markedly elevated circulating levels of soluble IL-2 receptor alpha subunit (sIL2R), a T cell-specific receptor.In vitroexperiments demonstrated that sIL2R directly impairs mitochondrial oxygen consumption and reduces mitochondrial complex III subunit protein levels in cultured muscle cells. These findings suggest a mechanism linking systemic immune dysregulation to muscle-specific mitochondrial dysfunction in PASC.This work provides new insights into the pathophysiology of PASC identifying sIL2R as a promising therapeutic target for addressing mitochondrial deficits in PASC-related fatigue and opening avenues for developing targeted interventions.
Immune checkpoint inhibitor treatment does not impair ovarian or endocrine function in a mouse model of triple negative breast cancer
Authors: De La Cruz Payton , Woodman-Sousa Morgan F. , McAdams Julia N. , Sweeney Ellia , Hakim Lola , Aquino Melanie Morales , Grive Kathryn J. 
Published: August 2024

ABSTRACTBackgroundRepresenting 15-20% of all breast cancer cases, triple negative breast cancer (TNBC) is diagnosed more frequently in reproductive-age women and exhibits higher rates of disease metastasis and recurrence when compared with other subtypes. Few targeted treatments exist for TNBC, and many patients experience infertility and endocrine disruption as a result of frontline chemotherapy treatment. While they are a promising option for less toxic therapeutic approaches, little is known about the effects of immune checkpoint inhibitors on reproductive and endocrine function.ResultsOur findings in a syngeneic TNBC mouse model revealed that therapeutically relevant immunotherapies targeting PD-1, LAG-3, and TIM-3 had no effect on the quality and abundance of ovarian follicles, estrus cyclicity, or hormonal homeostasis. Similarly, in a tumor-free mouse model, we found that ovarian architecture, follicle abundance, estrus cyclicity, and ovulatory efficiency remain unchanged by PD-1 blockade.ConclusionsTaken together, our results suggest that immunotherapy may be a promising component of fertility-sparing therapeutic regimens for patients that wish to retain ovarian and endocrine function after cancer treatment.
LncRNA 3222401L13Rik Is Up-regulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3
Authors: Schroeder Sophie , Sakib M. Sadman , Krüger Dennis , Pena Tonatiuh , Burkhardt Susanne , Schütz Anna-Lena , Sananbenesi Farahnaz , Fischer André 
Published: August 2024

AbstractAging is linked to a decline in cognitive functions and significantly increases the risk of neurodegenerative diseases. While molecular changes in all central nervous system (CNS) cell types contribute to aging-related cognitive decline, the mechanisms driving disease development or offering protection remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as key regulators of cellular functions and gene expression, yet their roles in aging, particularly within glial cells, are not well characterized. In this study, we investigated lncRNA expression profiles in non-neuronal cells from aged mice. We identified 3222401L13Rik, a previously unstudied lncRNA enriched in glial cells, as being specifically upregulated in astrocytes during aging. Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes essential for neuronal support and synapse organization. This function was also conserved in human iPSC-derived astrocytes. Additionally, we found that 3222401L13Rik mediates its cellular effects through interaction with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and that overexpression of Npas3 effectively rescued the functional deficits observed in astrocytes lacking 3222401L13Rik. Our findings suggest that upregulation of 3222401L13Rik in aging astrocytes acts as a compensatory mechanism to enhance neuronal and synaptic support, potentially delaying the onset of molecular and structural changes in both astrocytes and neurons. Strategies to boost 3222401L13Rik expression earlier in life may help mitigate age-associated loss of neuronal plasticity.
Insect size responses to climate changes vary across elevations according to seasonal timing
Authors: Nufio César R. , Sheffer Monica M. , Smith Julia M. , Troutman Michael , Bawa Simran , Taylor Ebony , Schoville Sean D. , Williams Caroline M. , Buckley Lauren B. 
Published: August 2024

AbstractWidespread plastic and evolutionary responses to temperature have led to body size declines being proposed as a universal response to warming, but the high degree of variation in terrestrial ectotherms has challenged this view. We investigate whether temperature dependent development and growth rates in ectothermic organisms drive departures from universal size responses. Leveraging a long-term study of montane grasshoppers, we detect size shifts over recent decades that depend on elevation and species’ seasonal timing. Size shifts have been focused at low elevations with the earliest emerging species (those that overwinter as juveniles) getting bigger, and later season species getting smaller. The shifts correspond to warmer temperatures at low elevation increasing the sizes of the earliest season species but decreasing the sizes of the later season species. This is consistent with our hypothesis that the earliest season species may be able to take advantage of warmer conditions accelerating growth during early spring development, whereas warm temperatures may adversely impact later season species via mechanisms such as increased rates of energy use or thermal stress. Grasshoppers tend to capitalize on warm conditions by both getting bigger and reaching adulthood earlier. Our analysis further reinforces the need to move beyond expectations of universal responses to climate change to consider how environmental exposure and sensitivity varies across elevations and life histories.
Evaluation of search-enabled Pre-trained Large Language Models on retrieval tasks for the PubChem Database
Authors: Sze Ash , Hassoun Soha 
Published: August 2024

ABSTRACTDatabases are indispensable in biological and biomedical research, hosting vast amounts of structured and unstructured data, facilitating the organization, retrieval, and analysis of complex data. Database access, however, remains a manual, tedious, and sometimes overwhelming, task. We investigate in this study the current state of using pre-trained, search-enabled LLMs for data retrieval from biological databases. Equipped with internet search and code generation capabilities, LLMs promise to streamline database access through natural language, expedite search and knowledge retrieval, and provide coherent analytical summaries. As an example database, we focus on evaluating a current search-enabled LLMs (GPT-4o) for retrieval from the PubChem database, a flagship, heavily used database that plays a critical role in biological and biomedical research. As PubChem is an open archival repository, it provides a well-documented programmatic interface that can be exploited through LLM code generation capabilities. We evaluate retrieval tasks for eight common PubChem access protocols that were previously documented. The tasks include identifying interacting genes and proteins, finding drug-like compounds based on structural similarity, retrieving bioactivity data, and locating stereoisomers and isotopomers. We develop a methodology for adopting the protocols into an LLM-prompt, where we supplement the prompt with additional context through iterative prompt refinement as needed. To further evaluate the LLM capabilities, we instruct the LLM to perform the retrieval with and without using programmatic access. We compare the results (referred to as gold and silver answers) when using these retrieval modalities with two traditional retrieval baselines that include running the manual search steps for each reference protocol through the PubChem database web interface, and through the provided PUG (Power-User Gateway) programmatic access. We quantitatively and qualitatively summarize our results, showing that generating programmatic access is more likely to yield the correct answers. We highlight the value and limitations of using current search-based LLMs for database retrieval. We also provide guidance for the future development that can improve the accuracy and reliability of search-based LLMs.
Network-based representation learning enables the identification of risk genes and latent functional pathways in primary open-angle glaucoma
Authors: Cousins Henry C. , Altman Russ B. , Pasquale Louis R. 
Published: August 2024

ABSTRACTDespite the identification of hundreds of risk genes for primary open-angle glaucoma (POAG), a significant portion of the POAG genetic risk landscape remains unexplored. We hypothesized that unsupervised learning on large protein-protein interaction (PPI) networks could enable comprehensive characterization of the genetic pathways that underlie POAG risk. We used graph representation learning on a proteome-scale PPI network to generate embeddings capturing complex features of each protein’s interactions. Using these embeddings, we trained a model with POAG-associated genes from the DisGeNET database to output an inferred POAG risk score for over 12,000 gene products, which identified known POAG risk genes with an area under the receiver operating characteristic curve of 0.739 (95% CI 0.686-0.792). These included well-known POAG risk genes such asRHOAandMMP3, as well as genes with significant contributions to other ocular diseases. Pathway analysis on the proteome-wide risk scores implicated 20 biological processes in POAG pathogenesis. Furthermore, cluster analysis of embeddings for POAG risk genes revealed 5 distinct functional neighborhoods, including cytokine signaling, coagulation response, collagen biosynthesis, extracellular matrix development, and fatty acid metabolism. Our results suggest that representation learning can recognize important patterns of protein interaction that allowin silicoprioritization of POAG risk genes and pathways.