Search Results (141)

The progression of inflammation during sepsis represents a multifaceted biological cascade that requires effective therapeutic interventions to improve survival. In septic neonatal foals, oxidative stress (OS) arises due to a compromised antioxidant defense system. Oxidative stress may disrupt the functionality of redox-sensitive organelles, such as the endoplasmic reticulum (ER). Endoplasmic reticulum stress disorder affects multiple cellular signaling pathways, including redox balance, inflammation, and apoptosis, and contributes to the pathogenesis of sepsis. The study aimed to elucidate whether OS conditions in sepsis influenced gene expression associated with ER stress. Blood samples were collected from 7 healthy and 21 hospitalized neonatal foals and processed for RNA extraction. RNA sequencing was employed to identify ER stress-responsive genes. Novel findings reported here indicate activation of the ER stress pathway in foals with sepsis. Several genes associated with ER stress, such as clusterin (CLU), BCL2-like 1 (BCL2L1), ubiquitin specific peptidase 14 (USP14), bifunctional apoptosis regulator (BFAR), and optic atrophy 1 (OPA1), were upregulated and positively correlated with sepsis scores and negatively correlated with the combined activities of antioxidant enzymes. In contrast, X-box binding protein 1 (XBP1), homocysteine inducible ER protein with ubiquitin-like domain 1 (HERPUD1), leucine-rich repeat kinase 2 (LRRK2), and selenoprotein S (SELENOS) were negatively correlated with sepsis scores and were downregulated in sepsis and positively correlated with the combined activities of antioxidant enzymes. Furthermore, a positive correlation was observed between cAMP responsive element binding protein 3 like 2 (CREB3L2) and BCL2L1, as well as between the expressions of USP14 and YOD1 deubiquitinase (YOD1) in sepsis. Similarly, the expression levels of XBP1 and Herpud1 demonstrated a positive correlation with each other in sepsis. Additionally, the downregulation of genes with protective function against OS, such as XBP1, HERPUD1, and SELENOS, in septic foals also highlights their significance in mitigating OS in sepsis treatment. The study reported here highlights the potential of ER stress as a promising therapeutic target and prognostic marker in septic foals. Full article

Conidiobolus coronatus (Entomophthorales), a fungal pathogen with a broad insect host range, is a promising candidate for biocontrol applications. We sequenced a C. coronatus strain isolated from a Rhopalomyia sp. cadaver using PacBio long-read sequencing to elucidate the molecular basis of its wide host adaptability. The newly assembled 44.21 Mb genome exhibits high completeness (BUSCO score: 93.45%) and encodes 11,128 protein-coding genes, with 23.1% predicted to mediate pathogen–host interactions. Comparative genomics with the aphid-obligate pathogen C. obscurus revealed significant expansions in gene families associated with host adaptation mechanisms, including host recognition, transcriptional regulation, degradation of host components, detoxification, and immune evasion. Functional annotation highlighted enrichment in cellular component organization and energy metabolism. Pfam annotation identified one hundred twenty-five seven-transmembrane receptors (putative GPCRs), sixty-seven fungus-specific transcription factors, three hundred sixty-one peptidases (one hundred ninety-eight serine proteases and one hundred three metalloproteases), one hundred twenty-seven cytochrome P450 monooxygenases (P450s), thirty-five cysteine-rich secretory proteins, and fifty-five tyrosinases. Additionally, four hundred thirty carbohydrate-active enzymes (CAZymes) across six major modules were characterized. Untargeted metabolomics detected 22 highly expressed terpenoids, consistent with terpenoid biosynthesis gene clusters in the genome. Collectively, these expansions underpin the broad host range of C. coronatus by enabling cross-host signal decoding and gene expression reprogramming, breaching diverse host physicochemical barriers, and expanding its chemical ecological niche. This study provides genomic insights into broad host adaptability in entomopathogenic fungi, facilitating further understanding of pathogen–host interactions. Full article

Background: There is growing evidence suggesting that SARS-CoV-2 may contribute to metabolic dysfunction. SARS-CoV-2 infection is associated with systemic inflammation, oxidative stress, and metabolic dysregulation, all of which may impair liver function and promote glucose intolerance. This study investigated the role of SARS-CoV-2, specifically its Main Protease (M^pro), in accelerating insulin resistance and metabolic dysfunction in HepG2 cells in vitro. Methods: HepG2 cells were treated with varying concentrations of M^pro (2.5, 5, 10, 20, 40, 80, and 160 nmol/mL) for 24 h to assess cytotoxicity and glucose uptake. Based on initial findings, subsequent assays focused on higher concentrations (40, 80, and 160 nmol/mL). The effects of M^pro on cell viability, protein kinase B (AKT) expression, matrix metallopeptidase-1 (MMP1), dipeptidyl peptidase 4 (DPP4), interleukin-6 (IL-6) expression, and lipid peroxidation were investigated. Results: Our findings reveal that the SARS-CoV-2 M^pro treatment led to a concentration-dependent reduction in glucose uptake in HepG2 cells. Additionally, the M^pro treatment was associated with reduced insulin-stimulated AKT activation, particularly at higher concentrations. Inflammatory markers such as IL-6 were elevated in the extracellular medium, while DPP4 expression was decreased. However, extracellular soluble DPP4 (sDPP4) levels did not show a significant change. Despite these changes, cell viability remained relatively unaffected, suggesting that the HepG2 cells were able to maintain overall metabolic functions under M^pro exposure. Conclusions: This study demonstrated the concentration-dependent impairment of hepatic glucose metabolism, insulin signaling, and inflammatory pathways in HepG2 cells acutely exposed to the SARS-CoV-2 M^pro. These findings warrant further investigation to explore the long-term metabolic effects of SARS-CoV-2 and its proteases in the liver and to develop potential therapeutic approaches for post-viral metabolic complications. Full article

Carboxypeptidase A4 (CPA4) is an exopeptidase that cleaves peptide bonds at the C-terminal domain within peptides and proteins. It preferentially cleaves peptides with terminal aromatic or branched chain amino acid residues such as phenylalanine, tryptophan, or leucine. CPA4 was first discovered in prostate cancer cells, but it is now known to be expressed in various tissues throughout the body. Its physiologic expression is governed by latexin, a noncompetitive endogenous inhibitor of CPA4. Nevertheless, the overexpression of CPA4 has been associated with the progression and aggressiveness of many malignancies, including prostate, pancreatic, breast and lung cancer, to name a few. CPA4’s role in cancer has been attributed to its disruption of many cellular signaling pathways, e.g., PI3K-AKT-mTOR, STAT3-ERK, AKT-cMyc, GPCR, and estrogen signaling. The dysregulation of these pathways by CPA4 could be responsible for inducing epithelial--mesenchymal transition (EMT), tumor invasion and drug resistance. Although CPA4 has been found to regulate cancer aggressiveness and poor prognosis, no comprehensive review summarizing the role of CPA4 in cancer is available so far. In this review, we provide a brief description of peptidases, their classification, history of CPA4, mechanism of action of CPA4 as a peptidase, its expression in various tissues, including cancers, its role in various tumor types, the associated molecular pathways and cellular processes. We further discuss the limitations of current literature linking CPA4 to cancers and challenges that prevent using CPA4 as a biomarker for cancer aggressiveness and predicting drug response and highlight a number of future strategies that can help to overcome the limitations. Full article

Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults, but no effective disease-modifying therapies are currently available. Here, we identify glucagon-like peptide-1 (GLP-1) signaling as a novel therapeutic target for NPH through a systematic drug repurposing screen in zebrafish. By simultaneously depleting nphp1 and nphp4, we developed a robust zebrafish model that reproduces key features of human NPH, including glomerular cyst formation. Our screen revealed that dipeptidyl peptidase-4 (DPP4) inhibitors (Omarigliptin and Linagliptin) and GLP-1 receptor agonists (Semaglutide) significantly reduce cystogenesis in a dose-dependent manner. Genetic analysis demonstrated that GLP-1 receptor signaling is important for maintaining pronephros integrity, with gcgra and gcgrb (GLP-1 receptor genes) playing a particularly important role. Transcriptomic profiling identified adenosine receptor A2ab (adora2ab) as a key downstream effector of GLP-1 signaling, which regulates ciliary morphology and prevents cyst formation. Notably, nphp1/nphp4 double mutant zebrafish exhibited the upregulation of gcgra as a compensatory mechanism, which might explain their resistance to cystogenesis. This compensation was disrupted by the targeted depletion of GLP-1 receptors or the inhibition of adenylate cyclase, resulting in enhanced cyst formation, specifically in the mutant background. Our findings establish a signaling cascade from GLP-1 receptors to adora2ab in terms of regulating ciliary organization and preventing cystogenesis, offering new therapeutic opportunities for NPH through the repurposing of FDA-approved medications with established safety profiles. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Urinary extracellular vesicles (U-EVs) are gaining increasing interest as non-invasive liquid biopsy tools for clinical use. Prostate cancer (PCa) is amongst the highest cancer-related cause of death in men, and therefore, the identification of non-invasive robust biomarkers is of high importance. This study assessed U-EV profiles from individuals affected by PCa at Gleason scores 6–9, compared with healthy controls. U-EVs were characterised and assessed for proteomic cargo content by LC-MS/MS analysis. The U-EV proteomes were compared for enrichment of gene ontology (GO), KEGG, and Reactome pathways, as well as disease–gene associations. U-EVs ranged in size from 50 to 350 nm, with the majority falling within the 100–200 nm size range for all groups. U-EV protein cargoes from the PCa groups differed significantly from healthy controls, with 16 protein hits unique to the GS 6–7 and 88 hits to the GS 8–9 U-EVs. Pathway analysis showed increased enrichment in the PCa U-EVs of biological process GO (5 and 37 unique to GS 6–7 and GS 8–9, respectively), molecular function GO (3 and 6 unique to GS 6–7 and GS 8–9, respectively), and cellular component GO (10 and 22 unique to GS 6–7 and GS 8–9, respectively) pathways. A similar increase was seen for KEGG pathways (11 unique to GS 8–9) and Reactome pathways (102 unique to GS 8–9). Enrichment of disease–gene associations was also increased in the PCa U-EVs, with highest differences for the GS 8–9 U-EVs (26 unique terms). The pathway enrichment in the PCa U-EVs was related to several key inflammatory, cell differentiation, cell adhesion, oestrogen signalling, and infection pathways. Unique GO and KEGG pathways enriched for the GS 8–9 U-EVs were associated with cell–cell communication, immune and stress responses, apoptosis, peptidase activity, antioxidant activity, platelet aggregation, mitosis, proteasome, mRNA stability oxytocin signalling, cardiomyopathy, and several neurodegenerative diseases. Our findings highlight U-EVs as biomarkers to inform disease pathways in prostate cancer patients and offer a non-invasive biomarker tool for clinical use. Full article

The Spodoptera litura, a Lepidopteran pest known for its high fecundity, undergoes a complete metamorphosis, including a distinctive process during which the male testes fuse from two separate organs into a single entity, significantly enhancing its fertility. To elucidate the molecular mechanisms underlying this testicular fusion, this study employed an integrated multi-omics approach to investigate concurrent changes at the transcriptomic and proteomic levels. We identified a series of synchronized alterations on the peritestic larval membrane, including heme binding, peptidase activity, hydrolase activity, metal ion transport, redox reactions, and chitin metabolism, all of which are substantially enriched at specific temporal points during testicular fusion. Nine genes/proteins co-expressed at the mRNA and protein levels were selected for targeted quantitative proteomics (PRM) and quantitative PCR (qPCR) validation, leading to the identification of five genes potentially involved in the testicular fusion process: Sl3030, ARCP, PSLRE, Obstructor-E, and Osris9B. Notably, the gene Sl3030, once knocked out, not only disrupted the normal fusion process but also resulted in reduced testis size, thickened peritestic membranes, and abnormal sperm development. Transcriptomic sequencing of the Sl3030 knockout mutant revealed its primary influence on the fusion process by affecting the assembly of the microtubule system and cytoskeleton. This research, for the first time, provides a multi-omics perspective on the response of key signaling pathways and molecular changes during the testicular fusion of S. litura and validates the role of the previously uncharacterized gene Sl3030 in this process, offering valuable insights into the complex mechanisms of testicular fusion in this species. Full article

Background: Camel milk is considered to be an important source of bioactive peptides with potential anti-diabetic effects. However, the mechanism by which these active peptides exert their anti-diabetic effects is not clear. The aim of this study was to systematically evaluate the in vivo anti-diabetic effects of Leucine-Leucine-Proline-Lysine (LLPK), a novel dipeptidyl peptidase-4 (DPP-4) inhibitory peptide identified from the in vitro gastrointestinal digestion product of camel milk. Methods: A db/db diabetic mouse model was used, and LLPK was administered to mice at doses of 50 mg/kg BW and 100 mg/kg BW as a daily oral gavage for 30 days. The effects of LLPK on fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and serum lipid levels were monitored, and possible mechanisms of action were elucidated using proteomics. Results: The results demonstrated that LLPK significantly improved diabetic symptoms, including FBG, OGTT, ITT, and serum lipid levels in db/db diabetic mice. Furthermore, significantly increased levels of serum glucagon-like peptide 1 (GLP-1) and reduced serum DPP-4 activity were observed in the LLPK-treated group compared to the control group. Hepatic proteomics indicated that LLPK improved glucose and lipid metabolism via the PPAR signaling pathway, where the key targets were Scd1, Acox1, Acaa1b, Slc27a1, Acsl1, and Ehhadh. Conclusions: In summary, this study provided new insights into the anti-diabetic mechanisms of camel milk and supported the development of camel milk-based anti-diabetic functional foods or nutraceuticals. Full article

Background/Objectives: The human kallikrein-related peptidase 6 (KLK6), a serine protease with trypsin-like properties, belongs to the 15-member kallikrein (KLK) gene family and is predominantly recognized for its role in oncogenesis, neurodegenerative disorders, and skin conditions. Aquaporins (AQPs) are integral membrane proteins that facilitate water transport across cell membranes. AQP1 is constitutively active in the kidneys and plays a crucial role in reabsorbing filtered water, while AQP2 is regulated by vasopressin and is essential for maintaining body fluid homeostasis. The primary objective of the present study is to investigate the spatio-temporal expression patterns of KLK6, AQP1, and AQP2 throughout normal human nephrogenesis and congenital kidney and urinary tract (CAKUT) abnormalities: duplex kidneys, horseshoe kidneys, and dysplastic kidneys. Methods: An immunofluorescence analysis of KLK6, AQP1, and AQP2 was performed on 37 paraffin-embedded fetal kidney samples. The area percentage of KLK6 in the kidney cortex was calculated in normal developing samples during developmental phases 2, 3, and 4 and compared with CAKUT samples. Results: KLK6 exhibits distinct spatiotemporal expression patterns during human kidney development, with consistent localization in proximal tubules. Its subcellular positioning shifts from the basolateral cytoplasm in early phases to the apical cytoplasm in later stages, which may be strategically positioned to act on its substrate in either the peritubular space or the tubular fluid. KLK6 expression followed a quadratic trajectory, peaking at Ph4. This marked increase in the final developmental phase aligns with its strong expression in mature kidneys, suggesting a potential role in proximal tubule differentiation and functional maturation through facilitating extracellular matrix remodeling and activating proteinase-activated receptors, modulating the signaling pathways that are essential for tubular development. In duplex kidneys, structural abnormalities such as ureteral obstruction and hydronephrosis may upregulate KLK6 as part of a reparative response, while its downregulation could impair epithelial remodeling and cytoskeletal integrity, exacerbating dysplastic phenotypes. Conclusions: These findings highlight the potential of KLK6 involvement in normal kidney development and the pathology of CAKUT. Full article

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the small intestine upon food intake. GLP-1 enhances insulin secretion, suppresses glucagon release, and promotes satiety, resulting in reduced food consumption and subsequent weight loss. Endogenous GLP-1 has a very short half-life and is rapidly degraded by the enzyme dipeptidyl-peptidase-IV (DPP-4). To address this limitation, GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4is) were developed and have demonstrated potency in clinical practice. In recent years, GLP-1RA and DPP4-i therapies are known to have pleiotropic effects, such as a reduction in oxidative stress, autophagy regulation, metabolic reprogramming, enhancement of anti-inflammatory signaling, regulation of gene expression, and being neuroprotective. These effects imply a therapeutic perspective for GLP-1RA and DPP-4i therapies in neuropathic pain treatment. Preclinical and clinical studies increasingly support the hypothesis that these therapies may alleviate neuropathic pain by targeting multiple mechanisms that induce neuropathic pain, such as inflammation, oxidative stress, and mitochondrial dysfunction. This review explores the mechanisms by which GLP-1RAs and DPP-4is alleviate neuropathic pain. It also highlights current advancements in incretin research, focusing on the therapeutic effects of GLP-1RAs and DPP-4-is for neuropathic pain. Full article

The genes that encode the universal stress protein (USP) family domain (pfam00582) aid the survival of bacteria in specific host or habitat-induced stress conditions. Genome sequencing revealed that the genome of Helicobacter pylori, a gastric cancer pathogen, typically contains one USP gene, while related helicobacters have one or two distinct USP genes. However, insights into the functions of Helicobacteraceae (Helicobacter and Wolinella) USP genes are still limited to inferences from large-scale genome sequencing. Thus, we have combined bioinformatics and visual analytics approaches to conduct a more comprehensive data investigation of a set of 1045 universal stress protein sequences encoded in 1014 genomes including 785 Helicobacter pylori genomes. The study generated a representative set of 183 USP sequences consisting of 180 Helicobacter sequences, two Wolinella succinogenes sequences, and a sequence from a related campylobacteria. We used the amino acid residues and positions of the 12 possible functional sites in 1030 sequences to identify 25 functional sites patterns for guiding studies on functional interactions of Helicobacteraceae USPs with ATP and other molecules. Genomic context searches and analysis identified USP genes of gastric and enterohepatic helicobacters that are adjacent or in operons with genes for proteins responsive to DNA-damaging oxidative stress (ATP-dependent proteases: ClpS and ClpA); and DNA uptake proteins (natural competence for transformation proteins: ComB6, ComB7, ComB8, ComB9, ComB10, ComBE, and conjugative transfer signal peptidase TraF). Since transcriptomic evidence indicates that oxidative stress and the presence of virulence-associated genes regulate the transcription of H. pylori USP gene, we recommend further research on Helicobacter USP genes and their neighboring genes in oxidative stress response and virulence of helicobacters. To facilitate the reuse of data and research, we produced interactive analytics resources of a dataset composed of values for variables including phylogeography of H. pylori strains, protein sequence features, and gene neighborhood. Full article

Background: Diabetic ketoacidosis (DKA), a life-threatening complication, can occur in individuals with type 2 diabetes during illness, stress, or medication use. This study examines DKA signals in type 2 diabetes, focusing on sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors. Methods: DKA reports from Q1 2019 to Q3 2024 were retrieved from the FDA Adverse Event Reporting System (FAERS). Associations between primary exposure and outcomes were ascertained using four key metrics: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Component (IC). Results: SGLT2 inhibitors exhibited the higher DKA risk in 2019–2021 (ROR: 314.86 [95% CI 301.76–328.53], PRR of 245.69 [95% CI 235.47–256.36], IC of 6.90, and EBGM of 120), declining in 2022–2024. GLP-1 receptor agonists showed an ROR increase from 2.88 [95% CI 2.56–3.25] in 2019–2021 to 4.64 [95% CI 4.06–5.29] in 2022–2023, slightly declining to 3.95 [95% CI 3.27–4.74] in 2024. DPP-4 inhibitors exhibited a steady ROR rise from 6.81 [95% CI 5.52–8.40] in 2019–2021 to 8.57 [95% CI 6.24–11.76] in 2022–2023 and further to 11.02 [95% CI 6.71–18.10] in 2024. PRR, EBGM, and IC values followed similar trends. The age groups 41–60 and 61–91 years were the most affected, with hospitalization at its highest rate for DPP4-inhibitors in Q1–Q3 of 2024. Hospitalizations were also observed with GLP-1 receptor agonists and SGLT2 inhibitors. Life-threatening events and fatalities were also reported, with physicians contributing to most reports. Conclusions: DKA signals were observed for all three drug classes, particularly among elderly patients, highlighting the need for careful monitoring, especially during periods of illness or stress. However, the risk was higher in the SGLT2 inhibitor group than in the other groups. Full article

Cytophaga is a genus of Gram-negative bacteria occurring in soil and the gut microbiome. It is closely related to pathogenic Flavobacterium spp. that cause severe diseases in fish. Cytophaga strain L43-1 secretes cytophagalysin (CPL1), a 137 kDa peptidase with reported collagenolytic and gelatinolytic activity. We performed highly-confident structure prediction calculations for CPL1, which identified 11 segments and domains, including a signal peptide for secretion, a prosegment (PS) for latency, a metallopeptidase (MP)-like catalytic domain (CD), and eight immunoglobulin (Ig)-like domains (D3–D10). In addition, two short linkers were found at the D8–D9 and D9–D10 junctions, and the structure would be crosslinked by four disulfide bonds. The CPL1 CD was found closest to ulilysin from Methanosarcina acetivorans, which assigns CPL1 to the lower-pappalysin family within the metzincin clan of MPs. Based on the structure predictions, we aimed to produce constructs spanning the full-length enzyme, as well as PS+CD, PS+CD+D3, and PS+CD+D3+D4. However, we were successful only with the latter three constructs. We could activate recombinant CPL1 by PS removal employing trypsin, and found that both zymogen and mature CPL1 were active in gelatin zymography and against a fluorogenic gelatin variant. This activity was ablated in a mutant, in which the catalytic glutamate described for lower pappalyins and other metzincins was replaced by alanine, and by a broad-spectrum metal chelator. Overall, these results proved that our recombinant CPL1 is a functional active MP, thus supporting the conclusions derived from the structure predictions. Full article

To identify new ubiquitin-related functions using yeast, we searched for mutants conferring a temperature-sensitivity phenotype that could be rescued through ubiquitin overexpression. Screening of mutants using this overexpression strategy identified SPC2, which encodes a subunit of the endoplasmic reticulum (ER) signal peptidase complex (SPC). Ubiquitin overexpression rescued a high-temperature sensitivity of spc2 deletion mutant, suggesting that ubiquitin could compensate for Spc2 loss-of-function at high temperatures. The double mutant of Spc2 and Hrd1, an ER E3 ubiquitin ligase, showed a synergistic growth defect at higher temperatures. A weak genetic interaction was also observed between spc2Δ and cdc48-3 mutation. The results suggest a close functional relationship between SPC and the ubiquitin–proteasome system in yeast and further provide proof-of-principle for this ubiquitin overexpression approach to identify novel ubiquitin-related genes and associated cellular processes. Full article