bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization and molecular targeting of CFIm25 (NUDT21/CPSF5) mRNA using miRNAs
Authors: Khan Naazneen , Gupta Mahesh , Masamha Chioniso Patience 
Published: January 2025

AbstractChanges in protein levels of the mammalian cleavage factor, CFIm25, play a role in regulating pathological processes including neural dysfunction, fibrosis, and tumorigenesis. However, despite these effects, little is known about how CFIm25 (NUDT21) expression is regulated at the RNA level. A potential regulator of NUDT21 mRNA are small non‐coding microRNAs (miRNAs). In general, miRNAs bind to the 3′untranslated regions (3′UTRs) and can target the bound mRNA for degradation or inhibit translation thus affecting the levels of protein in cells. Interestingly, a mechanism known as alternative polyadenylation (APA) enables mRNAs to escape miRNA regulation by generating mRNAs with 3′UTRs of different sizes. As many miRNA target sites are located within the 3′UTR, shortening the 3′UTR allows mRNAs to evade miRNAs targeting this region. The differences in the lengths and the sequence composition of the 3′UTRs may also impact the mRNA's translatability and subcellular localization. APA has been reported to regulate over 70% of protein coding genes, thus increasing the transcript repertoire. Several proteins, including mammalian cleavage factor, CFIm25 (NUDT21), have been shown to regulate APA. In this study we wanted to determine whether CFIm25 (NUDT21), itself a regulator of APA, undergoes APA to evade miRNA regulation. We used the blood cancer mantle cell lymphoma (MCL) cells as a model and showed that in these cells, NUDT21 is relatively stable with a long half‐life. In addition, the NUDT21 pre‐mRNA undergoes alternative APA within the same terminal exon. The three different sized NUDT21 mRNAs have different 3′UTR lengths and they each use a different canonical polyadenylation signal, AAUAAA, for 3′end cleavage and polyadenylation. Use of miRNA mimics and inhibitors showed that miR‐23a, miR‐222, and miR‐323a play a significant role in regulating NUDT21 expression. Hence, these results suggest that NUDT21 mRNA is stable and the different 3′UTRs generated through APA of NUDT21 play an important role in evading miRNA regulation and offers insights into how levels of CFIm25 (NUDT21) may be fine‐tuned as needed under different physiological and pathological conditions.
SKP1‐CUL1‐F‐box: Key molecular targets affecting disease progression
Authors: Zeng Xiangrong , Cao Jiaying , Xu Juan , Zhou Zihua , Long Chen , Zhou Yanhong , Tang Jingqiong 
Published: January 2025

AbstractThe correct synthesis and degradation of proteins are vital for numerous biological processes in the human body, with protein degradation primarily facilitated by the ubiquitin‐proteasome system. The SKP1‐CUL1‐F‐box (SCF) E3 ubiquitin ligase, a member of the Cullin‐RING E3 ubiquitin ligase (CRL) family, plays a crucial role in mediating protein ubiquitination and subsequent 26S proteasome degradation during normal cellular metabolism. Notably, SCF is intricately linked to the pathogenesis of various diseases, including malignant tumors. This paper provides a comprehensive overview of the functional characteristics of SCF complexes, encompassing their assembly, disassembly, and regulatory factors. Furthermore, we discuss the diverse effects of SCF on crucial cellular processes such as cell cycle progression, DNA replication, oxidative stress response, cell proliferation, apoptosis, cell differentiation, maintenance of stem cell characteristics, tissue development, circadian rhythm regulation, and immune response modulation. Additionally, we summarize the associations between SCF and the onset, progression, and prognosis of malignant tumors. By synthesizing current knowledge, this review aims to offer a novel perspective for a holistic and systematic understanding of SCF complexes and their multifaceted functions in cellular physiology and disease pathogenesis.
Influence of remifentanil on the pharmacokinetics and pharmacodynamics of remimazolam in healthy volunteers
Authors: Vellinga Remco , Koomen Jeroen V. , Eleveld Douglas J. , Stöhr Thomas , Pesic Marija , Struys Michel M.R.F. , Colin Pieter J. 
Published: January 2025

Background:
Synergistic effects between opioids and remimazolam on bispectral index (BIS) and modified observer’s assessment of alertness and/or sedation (MOAAS) score were previously described. This study aimed to characterize the influence of remifentanil on the sedative properties of remimazolam as measured by MOAAS, BIS, tolerance to laryngoscopy or tetanic stimulation (TOL or TOTS) and to determine target concentrations that maximize MOAAS 2/3.

Methods:
A three-period, cross-over, dose-ranging clinical trial was performed in 24 healthy volunteers. In all periods, remimazolam was administered using a step-up and step-down TCI protocol (50 – 2000 ng/mL). Stable remifentanil target concentrations of 0.5 ng/mL and 0.1 to 4.0 ng/mL were maintained in periods 2 and 3, respectively. Remifentanil, remimazolam and CNS7054 (metabolite) concentrations and, MOAAS, BIS, TOL and TOTS were collected in each step of the TCI protocol. Data were analyzed using non-linear mixed-effects models, where p≤0.01 was considered significant.

Results:
Remifentanil reduced the apparent clearance of CNS7054 with a half-maximum inhibition at 8.0 ng/mL (95% CI 5.5 to 13.4 ng/mL). A pharmacodynamic interaction was detected on all endpoints. Simulations indicate that the probability of observing a MOAAS 2/3 is highest at remimazolam target concentration of 275, 250 or 200 ng/mL combined with 0, 0.1, or 0.5 ng/mL remifentanil resulting in probabilities of 45%, 45% and 44%, respectively. Additionally, simulations indicate that the highest probability of observing TOTS and TOL was 93.3% and 85.5%, respectively, at the highest studied target concentrations.

Conclusions:
A pharmacokinetic and pharmacodynamic drug-drug interaction between remimazolam and remifentanil was quantified in this clinical trial. Appropriate target concentrations for MOAAS and BIS could be estimated, but, for TOL and TOTS, the trial design did not allow to fully characterize the exposure-response relationship.
Comparison of clinical outcomes in patients with refractory ascites treated with either TIPS, tunneled peritoneal catheter, or ascites pump
Authors: Schütte Sarah L. , Tiede Anja , Mauz Jim B. , Rieland Hannah , Kabelitz Martin , Iker Robin , Richter Nicolas , Meyer Bernhard , Heidrich Benjamin , Wedemeyer Heiner , Maasoumy Benjamin , Tergast Tammo L. 
Published: January 2025

Background:
Refractory ascites (RA) remains a serious complication in patients with cirrhosis. Currently, the insertion of a TIPS is considered the standard of care in these patients. To achieve symptom control in those with TIPS contraindications, tunneled peritoneal catheters (PeCa) or ascites pumps were introduced. However, data comparing the available treatment options are scarce. This study aims to compare outcomes among patients with RA treated either with TIPS, PeCa, or ascites pump.

Methods:
All patients with RA and cirrhosis treated at Hannover Medical School between 2009 and 2023 were evaluated. Endpoints included mortality, acute kidney injury (AKI), hyponatremia, peritonitis, and rehospitalization rate. Propensity score matching was conducted to adjust for group differences.

Results:
First, 31 patients with ascites pump were compared to 62 patients with a PeCa after propensity score matching. There were no differences regarding mortality nor incidences of AKI, hyponatremia, or rehospitalization. However, incidences of peritonitis and explantation were lower in those with ascites pump (HR 0.32, 95% CI: 0.15–0.70, and HR 0.32, 95% CI: 0.14–0.71, respectively). Second, 35 ascites pump patients were matched with 70 individuals with TIPS. No differences regarding mortality or peritonitis incidence were observed. Ascites pump patients showed higher incidences of AKI (HR 4.55, 95% CI: 2.53–8.18) and hyponatremia (HR 4.13, 95% CI: 2.08–8.22). Last, 129 patients with TIPS were compared to 129 with PeCa. Mortality was comparable, while incidences of AKI (HR 5.01, 95% CI: 3.36–7.47), hyponatremia (HR 4.64, 95% CI: 3.03–7.12), and peritonitis (HR 2.19, 95% CI: 1.41–3.41) were higher in those with PeCa.

Conclusions:
While ascites pump was associated with lower incidences of device infections and explantations, TIPS was associated with the lowest incidence of clinical complications in patients with RA.
Rural Culture and Diabetes Self-Management Beliefs, Behaviors and Health Outcomes
Authors: Pullyblank Kristin 
Published: January 2025

Abstract

Background
Rural populations in the United States face a diabetes mortality penalty. Self-management is a core component of treatment for type 2 diabetes, but there is low uptake of self-management education and support interventions in rural areas. Rural structural barriers to diabetes self-management have been described, yet the role of rural culture has not been extensively explored.

Objective
The purpose was to examine the relationships among rural culture, diabetes beliefs, self-management behaviors and health outcomes.

Methods
A stratified random sample of 500 adults with type 2 diabetes were recruited from a rural integrated health care system and invited to participate in this non-experimental cross-sectional study. Participants completed a survey that included validated measures of rural identity, self-reliance, perceived diabetes threat, and diabetes self-management behaviors. The most recent A1c was collected from the medical record. Descriptive, bivariate, multivariate and moderation analyses were conducted.

Results
128 participants returned completed surveys. Having an A1c < 8% was associated with better diabetes self-management behaviors, lower perceived threat, being female, and older age. Better diabetes self-management behaviors were associated with lower self-reliance, lower perceived threat, and older age. The combined moderation effect of both self-reliance and rural identity on the relationship between perceived threat and self-management behaviors was significant.

Discussion
Findings highlight the complex relationship between diabetes beliefs and behavior in rural populations and demonstrate that components of the rural culture have both direct and moderating effects on diabetes beliefs and self-management behaviors. These findings have important ramifications for nurses practicing in rural settings.
Diagnosis and Treatment Options for Cirrhosis With Unexplained Upper Gastrointestinal Bleeding: An Observational Study Based on Endoscopic Ultrasonography
Authors: Bai Yuchuan , Wang Zhihong , Shi Chen , Chen Lihong , Mei Xuecan , Kong Derun 
Published: January 2025

Objective:
To investigate the role of endoscopic ultrasonography (EUS) in the diagnosis and treatment of upper gastrointestinal bleeding of unknown origin in liver cirrhosis, focusing on patients with recurrent treatment of esophageal and gastric varices who failed to identify the bleeding site under direct endoscopy.

Background:
Esophagogastric variceal bleeding is one of the severe complications of decompensated liver cirrhosis, and serial endoscopic therapy can improve the long-term quality of life of patients. Most acute bleeding can be detected under direct endoscopy with thrombus or active bleeding, but there are still some patients with recurrent bleeding after repeated treatments, and it is difficult to find the bleeding site, especially in gastric variceal bleeding. Therefore, it is of great significance to identify the bleeding site.

Patients and Methods:
A total of 88 patients with liver cirrhosis bleeding diagnosed and treated under EUS were collected in this study, including 26 patients who failed to identify the bleeding site under direct endoscopy. EUS was used to scan the bleeding site, and EUS-guided treatment was performed. The characteristics of the bleeding site under direct endoscopy and EUS and the follow-up results after surgery were analyzed.

Results:
Among the 26 patients, 16 patients (16/26, 61.5%) showed red color signs of gastric fundus mucosa under direct endoscopy, 5 patients (5/26, 19.2%) showed punctate erosion, and the remaining 5 patients (5/26, 19.2%) showed no abnormal mucosal manifestations. All patients could find anechoic blood vessels under EUS, and blood flow signals could be detected within. Among them, 23 patients (23/26, 88.5%) chose EUS-guided treatment, and no rebleeding occurred after surgery. Another 3 patients (3/26, 11.5%) were given endoscopic variceal ligation due to small esophageal and gastric varices and inability to perform intravascular injection. The median follow-up time was 86 days. Adverse reactions included 5 cases of retrosternal pain (5/23, 21.7%), and 1 case of fever (1/23, 4.3%).

Conclusion:
EUS can detect submucosal varices in the gastric mucosa, and these bleeding sites may present as red color signs or punctate erosion under direct endoscopy.
The Acceptability of a Tobacco Dependency Treatment for NHS Staff in the North East of England: A Mixed-Methods Study
Authors: Thompson Caitlin , Brennan-Tovey Kerry , Robinson Caitlin , McIlvenna Rachel , Kaner Eileen FS , Ramsay Sheena E , Aquino Maria Raisa Jessica 
Published: January 2025

AbstractAimsHigh smoking rates and deprivation levels in North East of England led to an opportunity to pilot a tobacco dependency treatment offer for NHS Staff who smoke to make a supported quit attempt. The direct and indirect benefits to staff, patients, and NHS organisations are well documented. This study aimed to evaluate the acceptability of the service.MethodsThe service included up to 12 weeks of free Nicotine Replacement Therapy (NRT) and/or a refillable e-cigarette, motivational support, and premium access to the Smoke-Free App. Service evaluation used a mixed-methods design, combining the Theoretical Framework of Acceptability (TFA) questionnaire and semi-structured interviews with staff who had accessed the offer. Quantitative data were analysed using descriptive statistics and qualitative data via thematic analysis.Results68 survey responses (Mage= 43.92 years,SD= 12.27; Gender = 27.9% M and 72.1% F) reflected high acceptability (M= 4.59,Mdn= 5.00,SD= 0.72). Eighteen interviews (Mage= 40.67 years,SD= 12.22; Gender = 38.9% M and 81.1% F) revealed four themes relating to service familiarity and ease of access, suitability of the NRT/e-liquid ordering service, the vape kit, and behavioural support.ConclusionsThe service was deemed highly acceptable, and service users’ experiences informed recommendations for improving future tobacco dependency services. This is the first known application of the TFA to an evaluation of a smoking cessation intervention and contributes to a broader body of research on reducing tobacco dependence.
From Flies to Humans: Conserved Roles of CEBPZ, NOC2L, and NOC3L in rRNA Processing and Tumorigenesis
Authors: Rambaldelli Guglielmo , Manara Valeria , Vutera Cuda Andrea , Bertalot Giovanni , Penzo Marianna , Bellosta Paola 
Published: January 2025

AbstractNOC1, NOC2, and NOC3 are conserved nucleolar proteins essential for regulating ribosomal RNA (rRNA) maturation, a process critical for cellular homeostasis. NOC1, inDrosophilaand yeast, enhances nucleolar activity to sustain rRNA processing, whereas its depletion leads to impaired polysome formation, reduced protein synthesis, and apoptosis. These genes have vertebrate homologs called CEBPZ, NOC2L, and NOC3l. In this study, we demonstrated that the RNA-regulatory functions of CEBPZ are conserved in vertebrates, and we showed that CEBPZ leads to the accumulation of 45S-pre rRNA, with consequent reduction in protein synthesis. Gene Ontology and bioinformatic analyses of CEBPZ, NOC2L, and NOC3L in tumors highlight a significant correlation between their reduction and the processes that regulate rRNA and 60S ribosomal maturation. Comparative analysis of their expression in tumor databases revealed that CEBPZ, NOC2L, and NOC3L exhibit contrasting expression patterns across tumor types. This dual role suggests that their overexpression promotes tumor growth, whereas reduced expression may exert tumor-suppressive effects, uncovering unexpected regulatory functions exerted by these proteins in cancer.
An online GPCR drug discovery resource
Authors: Caroli Jimmy , Andreassen Søren N. , Lorente Javier Sánchez , Xiao Binghan , Pándy-Szekeres Gáspár , Gloriam David E. 
Published: January 2025

AbstractG protein-coupled receptors (GPCRs) have been targeted across all therapeutic areas, mediate the actions of 516 (36% of all) approved drugs and are being targeted by 337 agents in clinical trials. So far, 121 GPCRs are targets of approved drugs and 30 additional receptors have entered clinical trials and may expand the drugged GPCRome in the coming years. Here, we describe an online resource of GPCR drugs, clinical trial agents, targets and disease indications. This resource offers unique reference data, analysis and visualization, and is availed as a new section, ‘Drugs and Agents in trial’ integrated in the GPCR database, GPCRdb. Furthermore, it includes a target selection tool for prioritization of receptors for future drug discovery. This up-to-date knowledgebase will help identify strategies and trends in current GPCR drug discovery and give insights into which already drugged, or yet untapped targets have the largest potential in specific diseases.
Soil Carbon Sequestration inNothofagus obliquaForests with Different Canopy Cover Levels under Silvopastoral Management
Authors: Ramos Camila , Zagal Erick , Timmusk Salme , Dube Francis , Paulino Leandro , Ortiz Juan , Intriago Jean , Fuentes Juan Pablo 
Published: January 2025

AbstractAgroforestry contributes to slowing deforestation, favouring ecosystem regeneration and improving land use sustainability. In this study, we evaluated the effect of agroforestry on the recovery of degraded soils in a native forest and its capacity to capture and stabilize carbon (C) and nitrogen (N) in the soil. We conducted the study in a native forest ofNothofagus obliqua(oak) located in Ranchillo Alto (37°04′52″ S, 71°39′14″ W), in the Ñuble region, Chile. This site includes three silvopastoral systems with different levels of forest degradation: open (Op), semi- open (SOp) and semi-closed (SC), together with a control treatment without silvopastoral treatment (Ctr). The analysis was conducted at four soil depths (0-10, 10-20, 20-30 and 30-60 cm). To evaluate carbon and nitrogen sequestration and fixation in relation to the different forest cover treatments, we performed chemical, physical and biological soil analyses. We also included a physical fractionation by particle size to separate soil organic matter (SOM) into meaningful fractions with different characteristics and dynamics: particulate organic matter (POM) and organic matter associated with the mineral matrix (MAOM). Our results indicated that Op, despite being the most degraded condition, showed the highest values of C, N and non- oxidizable carbon (Cnox). This condition could be associated with the history of potato burning in this sector, which generates stable pyrogenic carbon in the soil. Analyses of C and N, as well as Cnox in the MAOM fraction, and C stock revealed that the three silvopastoral systems showed higher values than the control treatment without silvopastoral treatment. This suggests that the adoption of silvopastoral practices can improve soil quality and contribute to long-term carbon sequestration. These results support the application of sustainable practices to mitigate soil degradation and enhance carbon sequestration in degraded ecosystems.
Assessment of developmental neurotoxicology-associated alterations in neuronal architecture and function usingCaenorhabditis elegans
Authors: Huayta Javier , Seay Sarah , Laster Joseph , Rivera Nelson A. , Joyce Abigail S. , Ferguson P. Lee , Hsu-Kim Heileen , Meyer Joel N. 
Published: January 2025

AbstractFew of the many chemicals that regulatory agencies are charged with assessing for risk have been carefully tested for developmental neurotoxicity (DNT). To speed up testing efforts, as well as to reduce the use of vertebrate animals, great effort is being devoted to alternate laboratory models for testing DNT. A major mechanism of DNT is altered neuronal architecture resulting from chemical exposure during neurodevelopment.Caenorhabditis elegansis a nematode that has been extensively studied by neurobiologists and developmental biologists, and to a lesser extent by neurotoxicologists. The developmental trajectory of the nervous system inC. elegansis easily visualized, normally entirely invariant, and fully mapped. Therefore, we hypothesized thatC. eleganscould be a powerfulin vivomodel to test chemicals for the potential to alter developmental patterning of neuronal architecture. To test whether this might be true, we developed a novelC. elegansDNT testing paradigm that includes exposure throughout development, examines all major neurotransmitter neuronal types for architectural alterations, and tests behaviors specific to dopaminergic, cholinergic, and glutamatergic functions. We used this paradigm to characterize the effects of early-life exposures to the developmental neurotoxicants lead, cadmium, and benzo(a)pyrene (BaP) on dopaminergic, cholinergic, and glutamatergic architecture. We also assessed whether exposures would alter neuronal specification as assessed by expression of reporter genes diagnostic of specific neurotransmitters. We identified no cases in which the apparent neurotransmitter type of the neurons we examined changed, but many in which neuronal morphology was altered. We also found that neuron-specific behaviors were altered duringC. elegansmid-adulthood for populations with measured morphological neurodegeneration in earlier stages. The functional changes were consistent with the morphological changes we observed in terms of type of neuron affected. We identified changes consistent with those reported in the mammalian DNT literature, strengthening the case forC. elegansas a DNT model, and made novel observations that should be followed up in future studies.
Debiasing Sinkhorn divergence in optimal transport of cellular dynamics
Authors: Cooper Jayshawn , Young Christina , Lee Pilhwa 
Published: January 2025

AbstractSingle-cell RNA-seq analysis characterizes developmental mechanisms of cellular differentiation, lineage determination, and reprogramming with differential conditioning of the microenvironment. In this article, the underlying dynamics are formulated via optimal transport with algorithms that calculate the transition probability of the state of cell dynamics over time. The algorithmic biases of optimal transport (OT) due to entropic regularization are balanced by Sinkhorn divergence, which normally de-biases the regularized transport by centering them. In the case of reprogramming mouse embryonic fibroblasts [1] with dense time points, Sinkhorn divergence is shown to improve the trajectories of targeted cell fates depending on the specific cell types. When the time points are filtered out with sparser 9 and 5 time points, some cell phenotypes show better outcomes from strong entropic regularization. For 9 time points with 2 days interval, Sinkhorn divergence shows a clear advantage with broad bandwith of optimal entropic regularization. For these derived time points, when the cell population is scaled down fromn= 8000ton= 2000, there comes no benefit from Sinkhorn divergence for some specific cell types. In the case of stratifying morphogenesis of the epidermis [2], the sparsity of time points makes it not significant to prescribe Sinkhorn divergence in the accuracy of transporting to the expected cell fates. Overall, whether to prescribe Sinkhorn divergence for the accurate prediction of lineages of single cells depends on temporal sparsity.