Search Results (199)

Pancreatic cancer is frequently accompanied by cancer-associated cachexia, a debilitating metabolic syndrome marked by progressive skeletal muscle wasting and systemic metabolic dysfunction. This study presents a systems biology framework to simultaneously identify therapeutic targets for both pancreatic ductal adenocarcinoma (PDAC) and its associated cachexia (PDAC-CX), using cell-specific genome-scale metabolic models (GSMMs). The human metabolic network Recon3D was extended to include protein synthesis, degradation, and recycling pathways for key inflammatory and structural proteins. These enhancements enabled the reconstruction of cell-specific GSMMs for PDAC and PDAC-CX, and their respective healthy counterparts, based on transcriptomic datasets. Medium-independent metabolic biomarkers were identified through Parsimonious Metabolite Flow Variability Analysis and differential expression analysis across five nutritional conditions. A fuzzy multi-objective optimization framework was employed within the anticancer target discovery platform to evaluate cell viability and metabolic deviation as dual criteria for assessing therapeutic efficacy and potential side effects. While single-enzyme targets were found to be context-specific and medium-dependent, eight combinatorial targets demonstrated robust, medium-independent effects in both PDAC and PDAC-CX cells. These include the knockout of SLC29A2, SGMS1, CRLS1, and the RNF20–RNF40 complex, alongside upregulation of CERK and PIKFYVE. The proposed integrative strategy offers novel therapeutic avenues that address both tumor progression and cancer-associated cachexia, with improved specificity and reduced off-target effects, thereby contributing to translational oncology. Full article

Background/Objectives： Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a prevalent Mendelian disorder caused by mutations in the NOTCH3 gene, primarily impacting cerebral small blood vessels. This review aims to explore the involvement of large intracranial arteries in CADASIL, particularly focusing on the association with RNF213 polymorphisms, especially in Asian populations. Methods： A comprehensive literature review was conducted to gather data on the morphological features of both small and large intracranial arteries in CADASIL, examining clinical manifestations, imaging findings, and genetic associations. Results： The findings indicate that while CADASIL is predominantly characterized by small vessel disease, a significant number of patients also exhibit large artery involvement, particularly Asian populations where RNF213 polymorphisms may play a critical role. The review highlights the evidence of intracranial stenosis and the potential implications of traditional vascular risk factors, such as hypertension and diabetes mellitus, which are prevalent in these populations. Conclusions： The involvement of larger intracranial arteries in CADASIL underscores the complexity of the disease, suggesting that both genetic predispositions and environmental factors contribute to vascular abnormalities. Further research is needed to clarify these relationships and improve diagnostic and therapeutic strategies for CADASIL patients. Full article

Greenhouse gas (GHG) emissions evaluations from agroecosystems are critical, particularly as technology improves. Consistent GHG measurement methods are essential to the evaluation of GHG emissions. The objective of the study was to evaluate potential differences in gas-flux-determination (GFD) options and carbon dioxide (CO₂), methane (CH₄), and nitrous oxide (N₂O) fluxes and growing-season-long emissions estimates from furrow-irrigated cotton (Gossypium hirsutum) in southeast Arkansas. Four GFD methods were evaluated [i.e., linear (L) or exponential (E) regression models, with negative fluxes (WNF) included in the dataset or replacing negative fluxes (RNF)] over the 2024 growing season using a LI-COR field-portable chamber and gas analyzers. Exponential regression models were influenced by abnormal CO₂ and N₂O gas concentration data points, indicating the use of caution with E models. Season-long CH₄ emissions differed (p < 0.05) between the WNF (−0.51 kg ha⁻¹ season⁻¹ for L and−0.54 kg ha⁻¹ season⁻¹ for E) and RNF (0.01 kg ha⁻¹ season⁻¹ for L and E) GFD methods, concluding that RNF options over-estimate CH₄ emissions. Gas concentration measurements following chamber closure should remain under 300 s, with one concentration measurement obtained per second. The choice of GFD method needs careful consideration to result in accurate GHG fluxes and season-long emission estimates. Full article

This study identified genomic variants and potential candidate genes associated with 11 primal cut traits (back fat, belly fat, total fat, loin fat, ham fat, picnic fat, butt fat, loin intramuscular fat content, ham side fat, shoulder dorsal fat, and belly side fat thicknesses) in Canadian commercial crossbred pigs. Genome-wide association studies using whole genome sequencing data were conducted using genotyping data from 1118 commercial crossbred pigs. This analysis revealed multiple QTLs across chromosomes SSC1, 2, 3, 6, 7, 9, 14, 15, and 17, associated with fat traits. Notably, an SNP at position 160,230,075 bp on SSC1 was significantly associated with multiple fat traits, including belly fat, butt fat, ham fat, loin fat, picnic fat, and side fat. Common genes in windows associated with multiple traits, such as MC4R, RNF152, and CDH20 were shared across these traits, suggesting pleiotropic effects. Some of the QTLs were near previously identified QTLs or candidate genes that have been reported to be linked to meat quality traits associated with backfat and intramuscular fat. Other candidate genes identified in the study include TNFRSF11A, LEPR, and genes from the SERPINB family, highlighting their roles in fat deposition and composition. Additional candidate genes were also implicated in regulation of fat metabolism, adipogenesis, and adiposity. These findings offer valuable insights into the genetic architecture of fat traits in pigs, which could inform breeding strategies aimed at improving the pork quality. Full article

RNA-binding E3 ubiquitin ligases (RBULs) provide a link between RNA metabolic processes and the ubiquitin proteasome system (UPS). In humans, RBULs are involved in various biological processes, such as cell proliferation and differentiation, as well as sexual development. To date, little is known about their role in the protozoan parasite Plasmodium falciparum, the causative agent of malaria tropica. We previously identified a novel P. falciparum RBUL, the RING finger E3 ligase PfRNF1, which is highly expressed during gametocyte development. Here, we conducted BioID-based proximity interaction studies to unveil the PfRNF1 interactome. We show that in immature gametocytes, PfRNF1 forms an interaction network that is mainly composed of RNA-binding proteins, including the translational repressors DOZI and CITH and members of the CCR4-NOT complex, as well as UPS-related proteins. In particular, PfRNF1 interacts with recently identified regulators of sexual development like the zinc finger protein PfMD3, with which it shares the majority of interactors. The common interactome of PfRNF1 and PfMD3 comprises several uncharacterized proteins predominantly expressed in male or female gametocytes. Our results demonstrate that PfRNF1 engages with RNA-binding proteins crucial for sex determination in gametocytes, thereby linking posttranscriptional regulation with the UPS. Full article

RNF213 encodes a unique protein with AAA+ ATPase and E3 ubiquitin ligase activities that are critical for its diverse roles, which range from involvement in human vasculopathies, such as Moyamoya disease, to ubiquitination of viral and bacterial pathogens. Nevertheless, its primary functions in human signaling remain unclear due to the limited identification of direct substrates. Here, we investigated the interaction between RNF213 and caveolin-1 (Cav-1), a small scaffolding protein vital for caveolae formation and the regulation of a plethora of cellular processes. Cav-1 specifically binds within the two functional AAA+ domains of RNF213 in an ATP-dependent manner, highlighting the influence of cellular energy status on this interaction. Consequently, RNF213 ubiquitinates Cav-1 at several N-terminal lysine residues through K48 and K63 linkages, although several Moyamoya disease-associated RNF213 mutations greatly reduce this polyubiquitination. Moreover, RNF213 activity inhibits phosphorylation of a key regulatory residue of Cav-1, as RNF213 knockdown under oxidative stress markedly enhances Cav-1 Tyr14 phosphorylation and modifies nitric oxide bioavailability in endothelial cells. Collectively, our results indicate that RNF213 functions as a molecular switch modulating Cav-1 signaling based on RNF213 functionality and cellular conditions. These findings offer new insights into vascular pathogenesis and the vast signal pathways along the RNF213–Cav-1 axis. Full article

Background: Macrocephaly can be a component manifestation of several monogenic conditions, in association with intellectual disability/developmental delay (ID/DD) behaviour abnormalities, including autism spectrum disorders (ASD), and variable additional features. On the other hand, idiopathic ASD can present with developmental delay and macrocephaly. Methods: We carried out a retrospective analysis of a cohort of 78 patients who were tested from February 2017 to December 2024 by high-throughput sequencing of a panel of 27 genes (ABCC9, AKT1, AKT2, AKT3, BRWD3, DIS3L2, DNMT3A, EZH2, GPC3, GPC4, HERC1, MED12, MTOR, NFIA, NFIX, NSD1, PDGFRB, PIK3CA, PIK3R1, PIK3R2, PPP2R1A, PPP2R5D, PTEN, RAB39B, RNF135, SETD2, and TBC1D7) because of neurodevelopmental impairment, including ID/DD, ASD/behaviour abnormalities associated with macrocephaly, mimicking to a large extent idiopathic ASD. Results: Pathogenic variants leading to the diagnosis of monogenic conditions were detected in 22 patients (28%), including NSD1 (2), PTEN (16), and PPP2R5D (4). Distinctive of the PTEN-associated phenotype were true macrocephaly (100%), ASD or behaviour abnormalities (92%), mild/borderline ID (79%), and no facial dysmorphisms. Typical of the PPP2R5D-associated phenotype were relative macrocephaly (75%), a few unspecific peculiar facial characteristics (50%), and a more variable presentation of the neurodevelopmental phenotype. Conclusions: Pathogenic variants in PTEN and PPP2R5D are the most recurrent gene mutations in a patient-oriented procedure for the genetic diagnosis of apparently idiopathic ASD and behaviour abnormalities associated with macrocephaly. The clinical applicability of the presented diagnostic strategy is discussed. Full article

Background/Objectives: The incidence of early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, has been rising at an alarming rate, with Hispanic/Latino (H/L) individuals experiencing the most significant increases in both incidence and mortality. Despite this growing public health concern, the molecular mechanisms driving EOCRC disparities remain poorly understood. Oncogenic pathways such as WNT, TGF-beta, and RTK/RAS are critical in colorectal cancer (CRC) progression, yet their specific roles in EOCRC across diverse populations have not been extensively studied. This research seeks to identify molecular alterations within these pathways by comparing EOCRC cases in H/L and non-Hispanic White (NHW) individuals. Furthermore, we explore the clinical significance of these findings to inform precision medicine strategies tailored to high-risk populations. Methods: To investigate mutation frequencies in genes associated with the WNT, TGF-beta, and RTK/RAS pathways, we conducted a bioinformatics analysis using publicly available CRC datasets. The study cohort consisted of 3412 patients, including 302 H/L and 3110 NHW individuals. The patients were categorized based on age (EOCRC: <50 years; late-onset CRC [LOCRC]: ≥50 years) and population group (H/L vs. NHW) to assess variations in mutation prevalence. Statistical comparisons of mutation rates between the groups were conducted using chi-squared tests, while Kaplan–Meier survival analysis was employed to evaluate overall survival differences associated with pathway alterations. Results: Notable molecular distinctions in the RTK/RAS pathway were identified between EOCRC and LOCRC among the H/L patients, with EOCRC exhibiting a lower frequency of RTK/RAS alterations compared to LOCRC (66.7% vs. 79.3%, p = 0.01). Within this pathway, mutations in CBL (p < 0.05) and NF1 (p < 0.05) were significantly more prevalent in the EOCRC cases (5.8% vs. 1.2% and 11.6% vs. 3.7%, respectively), whereas BRAF mutations were notably less frequent in EOCRC than in LOCRC (5.1% vs. 18.3%, p < 0.05). Comparisons between the EOCRC patients from the H/L and NHW populations revealed distinct pathway-specific alterations that were more common in the H/L individuals. These included RNF43 mutations (12.3% vs. 6.7%, p < 0.05) in the WNT pathway, BMPR1A mutations (5.1% vs. 1.8%, p < 0.05) in the TGF-beta pathway, and multiple RTK/RAS pathway alterations, such as MAPK3 (3.6% vs. 0.7%, p < 0.05), CBL (5.8% vs. 1.4%, p < 0.05), and NF1 (11.6% vs. 6.1%, p < 0.05). Survival analysis in the H/L EOCRC patients did not reveal statistically significant differences based on pathway alterations. However, in the NHW EOCRC patients, the presence of WNT pathway alterations was associated with significantly improved survival outcomes, suggesting potential ethnicity-specific prognostic implications. Conclusions: This study highlights the substantial molecular heterogeneity present in EOCRC, particularly among high-risk populations. The H/L EOCRC patients exhibited distinct genetic alterations, with a higher prevalence of CBL, NF1, RNF43, BMPR1A, and MAPK3 mutations compared to their NHW counterparts. Additionally, RTK/RAS pathway alterations were less frequent in EOCRC than in LOCRC. Despite these molecular differences, pathway alterations did not significantly impact survival outcomes in the H/L EOCRC patients. However, in the NHW EOCRC patients, the presence of WNT pathway alterations was associated with improved survival. These findings emphasize the necessity for further research to clarify the molecular mechanisms driving EOCRC disparities in high-risk populations and to inform precision medicine strategies for underrepresented groups. Full article

Porcine respiratory and reproductive syndrome is a viral disease that impacts the health and profitability of swine farms, largely due to significant variation in the vaccination response. The objective was to identify and validate molecular markers associated with the antibody response in gilts following vaccination against the PRRSV. The study included one hundred (n = 100) 6-month-old Yorkshire gilts that were negative for the PRRSV. Gilts were randomly assigned to one of two treatments, PRRS-vaccinated (n = 75) and control (n = 25) groups. Blood samples collected on day 21 were analyzed to evaluate the antibody response, as indicated by the sample-to-positive (S/P) ratio, to the PRRSV following vaccination. DNA was extracted and genotyped using a low-density chip containing 10,000 single nucleotide polymorphisms (SNPs). A genome-wide association study (GWAS) was conducted to identify candidate SNPs associated with the S/P ratio, which were validated in two independent gilt populations (n = 226). The SNPs rs707264998, rs708860811, and rs81358818 in the genes RNF144B, XKR9, and BMAL1, respectively, were significantly associated (p < 0.01) with the S/P ratio and demonstrated an additive effect. In conclusion, three SNPs are proposed as candidate markers for an enhanced immune response to vaccination against the PRRSV and may be beneficial in genetic selection programs. Full article

Diabetic kidney disease (DKD) is a prevalent complication associated with diabetes in which podocyte dysfunction significantly contributes to the development and progression of the condition. Ring finger protein 183 (RNF183) is an ER-localized, transmembrane ring finger protein with classical E3 ligase activity. However, whether RNF183 is involved in glomerular podocyte dysfunction, which is the mechanism of action of DKD, is still poorly understood. In this study, we first demonstrated that RNF183 expression in glomerular podocytes of patients with DKD decreased as the disease progressed. Additionally, our transcriptome sequencing analysis of kidney tissues from diabetic mice revealed a significant reduction in RNF183 expression within the kidney cortex. Similarly, the expression of RNF183 was significantly reduced both in the kidneys of diabetic mice and in human podocytes exposed to high glucose conditions. The downregulation of RNF183 resulted in a suppression of autophagic activity, an increase in apoptotic cell death, and reduced expression of cellular markers in HPC cells. We found that RNF183 was modified via N6-methyladenosine (m6A) RNA methylation. Meanwhile, treatment with meclofenamic acid 2 (MA2), an m6A demethylase inhibitor, resulted in the upregulation of RNF183 expression in HPC cells cultured in high glucose conditions. Furthermore, high glucose treatment decreased the transcription and protein levels in both the m6A writer methyltransferaselike3 (METTL3) and the m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). IGF2BP2 assisted with METTL3, which is jointly involved in the transcription of RNF183. Furthermore, we confirmed that RNF183 directly ubiquitinates M2 pyruvate kinase (PKM2) through co-immunoprecipitation (Co-IP) and liquid chromatography–mass spectrometry (LC-MS) experiments. The level of PKM2 ubiquitination was increased following RNF183 overexpression, leading to enhanced PKM2 protein degradation and subsequently alleviating high glucose-induced podocyte damage. The results of this study indicated that RNF183 was regulated via m6A methylation modification and that RNF183 expression was reduced in HPC cells treated with high glucose, which resulted in decreased PKM2 ubiquitination levels and subsequently aggravated podocyte injury. The findings suggest that RNF183 may serve as a potential therapeutic target for diabetic kidney injury, offering new insights into its role in the progression of DKD. Full article

Background: Pediatric radial neck fractures (pRNFs) can occur in isolation or in association with concomitant injuries. It is unknown whether the presence of associated injuries should influence the choice of treatment. The aim of this study is to assess the incidence of associated injuries in pRNF and their correlation with fracture angulation (Judet grade) or the patient’s age (under or over ten years of age). Methods: A systematic literature review was performed following PRISMA-IPD guidelines, including case series on pRNF with a minimum of five cases of children until 16 years of age. The quality assessment included a risk of bias analysis and evaluation using the MINORS criteria. Individual patient data on age, Judet classification and associated injuries were extracted from the included studies and pooled for the meta-analysis. The correlation between the presence of associated injury and the patient’s age or Judet classification was depicted in two forest plots. Results: A total of 20 articles published sufficient individual patient data (n = 371) on associated injuries. All but one were retrospective case series. Fifteen articles had MINORS scores of 8 or higher. The incidence of associated injuries was 33% (123 of 371 cases). Almost half of the associated injuries included an olecranon fracture (61/123). There was no correlation between Judet classification (p = 0.243) and incidence nor between patient age and the incidence of associated injuries (p = 0.694). Conclusions: Surgeons should be aware of potential associated injuries in over a third of pRNF cases, regardless of the patient’s age or fracture angulation. Deduction of the trauma mechanism may be a more useful tool for assessing the potential presence of associated injuries than the most frequently used fracture classification or the patient’s age. More research is needed regarding the requirements for enhanced diagnostic imaging, specific treatment or follow-up adaptations in children with pRNFs and associated injuries. Full article

Histone modifications serve as molecular switches controlling critical cellular processes. The ubiquitination of histone H2A at lysines 13 and 15 (H2AK13/15ub) is a crucial epigenetic modification that coordinates DNA repair and genome stability during the DNA damage response (DDR). This epigenetic mark is dynamically regulated by three functional protein groups: “writer” enzymes (e.g., E3 ubiquitin ligase RNF168 that catalyzes H2AK13/15ub formation), “reader” proteins (including 53BP1 and BRCA1-BARD1 that recognize the mark to guide DNA repair), and “eraser” deubiquitinases (such as USP3 and USP16 that remove the modification). Dysregulation of the precisely coordinated network of H2AK13/15ub is strongly associated with various diseases, including RIDDLE syndrome, neurodegenerative disorders, immune deficiencies, and breast cancer. This review systematically analyzes the dynamic regulation of H2AK13/15ub in DDR and explores its therapeutic potential for disease intervention. Full article

Poly(ADP-ribosyl)ation (PARylation) is a dynamic protein post-translational modification (PTM) mediated by ADP-ribosyltransferases (ARTs), which regulates a plethora of essential biological processes, such as DNA repair, gene expression, and signal transduction. Among these, PAR-dependent ubiquitination (PARdU) plays a pivotal role in tagging PARylated substrates for subsequent ubiquitination and degradation events through the coordinated action of enzymes, including the E3 ligase RNF146 and the ADP-ribosyltransferase tankyrase. Notably, this pathway has emerged as a key regulator of tumorigenesis, immune modulation, and cell death. This review elucidates the molecular mechanisms of the PARdU pathway, including the RNF146–tankyrase interaction, substrate specificity, and upstream regulatory pathways. It also highlights the biological functions of PARdU in DNA damage repair, signaling pathways, and metabolic regulation, with a focus on its therapeutic potential in cancer treatment. Strategies targeting PARdU, such as tankyrase and RNF146 inhibitors, synthetic lethality approaches, and immune checkpoint regulation, offer promising avenues for precision oncology. These developments underscore the potential of PARdU as a transformative therapeutic target in combating various types of human cancer. Full article

Moyamoya disease (MMD) is a rare progressive cerebrovascular disorder characterized by the stenosis or occlusion of the terminal segments of the internal carotid arteries, leading to the development of abnormal collateral vascular networks. These networks are a compensatory mechanism for reduced blood flow to the brain. Despite extensive research, the exact etiology of MMD remains unknown, although recent studies suggest that immune system dysfunction plays a critical role in its pathogenesis. In particular, the involvement of immune cells such as T cells, macrophages, and dendritic cells has been increasingly recognized. These immune cells contribute to the inflammatory process and vascular remodeling observed in MMD patients, further complicating the disease’s progression. Inflammation and immune-mediated damage to the vessel walls may accelerate the narrowing and occlusion of arteries, exacerbating ischemic events in the brain. Additionally, studies have revealed that certain genetic and environmental factors can influence immune system activation in MMD, linking these pathways to disease development. This review aims to provide a comprehensive overview of the immune mechanisms at play in MMD, focusing on how immune cells participate in vascular injury and remodeling. Understanding these immunological processes may offer new therapeutic targets to halt or reverse disease progression, potentially leading to more effective treatment strategies for MMD. Full article

Estimating the post mortem interval (PMI) is a crucial and contentious issue in forensic research, particularly in criminal cases. Traditional methods for PMI estimation are limited by constraints and inaccuracies. Circular RNA (circRNA), formed through exon or intron looping to create a complete circular structure without a 5′ end cap and a 3′ poly(A) tail, exhibits exceptional stability, abundance, and tissue-specific characteristics that make it potentially valuable for PMI estimation. However, research on the exploration or application of circRNA in PMI estimation has been limited. This study aims to investigate the correlation between circRNA and PMI. In this study, liver tissue samples were collected from mice at six different time points at 4 °C, 18 °C, 25 °C, and 35 °C, respectively. The reference gene 28S rRNA and the biomarker circRnf169 were successfully screened. Quantitative PCR was employed to examine the correlation between circRnf169 levels and PMI. At 4 °C, the level of circRnf169 decreased with prolonged PMI, whereas at 18 °C, 25 °C, and 35 °C, the circRnf169 RNA was degraded rapidly, indicating that circRnf169 is suitable for PMI estimation at low temperatures or early PMI. These findings suggest the establishment of mathematical model for early PMI based on circRnf169 using liver tissue, which may serve as a reliable marker. Further research is required in order to develop more markers in mice and/or to validate these mathematical models in human samples. Full article