We aim to explore the factors that influence the varying prognostic outcomes of itraconazole treatment in patients with onychomycosis. A prediction model for treatment failure of onychomycosis to itraconazole was developed and validated. This study is a prospective, case-cohort study of observational cases. Patient information meeting the inclusion criteria will be grouped and compared based on their outcomes six months after treatment. A total of 437 patients were enrolled in our study, and the following factors were correlated with prognosis: patient ages, duration of illness, number of affected nails, fungal species, clinical classification, nail thickness, nail involvement, and bathing frequency. Based on these variables, we constructed a predictive model for treatment failure in onychomycosis. The accuracy and precision of the prediction model for itraconazole treatment failure in onychomycosis were 0.936 and 0.924. First, this study validated that multiple factors are associated with the prognosis of itraconazole pulse therapy for onychomycosis, suggesting that early treatment of the disease and attention to bathing habits can lead to better therapeutic outcomes. Second, based on the contribution of representative variables to the predictive power of the binary multivariate logistic regression model, it can help clinicians better understand the characteristics of patients with onychomycosis who experience treatment failure. These characteristics mainly include a longer disease duration, non-dermatophyte infections, multiple nail involvement, and significant psychological impact. Based on these features, it provides a reliable basis for determining the optimal treatment course of itraconazole pulse therapy for onychomycosis and whether additional treatment is needed.

Letter to the Editor – “Relevant factors for the cardiovascular responses to dietary nitrate and nitrite”

Sex-differences in influenza vaccine efficacy and immunogenicity among Canadian Hutterite children.

Protein CoAlation is regulated by and integrated with growth factor signalling and the cellular antioxidant response.

MdARF18-like, a member of Auxin response factor gene family, promotes adventitious root elongation in apple.

Cheatgrass (Bromus tectorum L.) is a problematic weed species in the wheat cropping systems in the rainfed crop production areas of the inland Pacific Northwest (PNW) and now is becoming resistant to multiple modes of action. To identify mechanisms of non-target site acetohydroxy-acid/acetolactase synthase (AHAS/ALS) inhibitor resistance, 123 B. tectorum accessions were treated with three sulfosulfuron treatments (3.5, 35 and 350 g ha-1). A genome-wide association study (GWAS) was performed using the results from the spray trials to unravel the mechanisms underlying sulfosulfuron resistance in B. tectorum. A single nucleotide polymorphism (SNP) explained up to 48% of observed phenotypic variation of sulfosulfuron resistance in B. tectorum but was not located near the AHAS/ALS gene in the genome. Candidate genes included members of the cytochrome P450 (CYP450) 71 gene family, heat shock-related proteins and a regulator of a heat shock-related protein. Additionally, the analysis revealed hormonal regulators, and genes involved in abiotic stress response as candidate genes. Non-target site resistance for sulfosulfuron is present in B. tectorum populations of the inland PNW. A heat shock-related protein 70 regulator and an auxin response factor gene was near the SNP that explained 48% of the variation in the GWAS, indicating auxin regulation and stress response pathways are involved in the resistance of B. tectorum populations to sulfosulfuron. The heat shock-factor protein 70 regulated by the heat shock-related protein 70 regulator was found on another significant SNP and the SNPs those two genes were on have a significant interaction. Additionally, the GWAS analysis indicated CYP450 genes are likely involved in resistance. © 2025 Society of Chemical Industry.

Identification of ARF members in Fragaria vesca and the role of FvARF2 in auxin-induced early-stage fruit development.

A novel prohibitin inhibitor acts as a dual inhibitor of angiogenesis and fibrosis.

Ensuring safety of patients using pharmaceuticals and medical devices through chemical characterization requires accurate estimation of extractables and leachables to ensure tolerable risk from unintentional exposure to these chemicals. However, this is complicated by variability in chemical responses, particularly with mass spectrometry methods. High quality relative response factor predictions provide the opportunity for both expedited and more accurate quantitation in extractables and leachables analyses. In-silico prediction models were developed to test a wide variety of compounds, selected utilizing a physicochemical property coverage approach. Three neural network models, and associated sub-models, were applied to both positive and negative ionization modes for Liquid Chromatography Mass Spectrometry, and Gas Chromatography Mass Spectrometry methods. Mean absolute errors across all methods for training data was 0.47 and 0.65 for out-of-sample data, indicating high predictability of response factors for the compounds chosen by the model and a low likelihood that the data was overfit.Model performance was evaluated using a series of chemicals outside the training data set. When tested, predictive accuracy was greater than 60% of known values for 44 of the 49 chemicals tested (90%). This proof-of-concept work shows that sophisticated neural network modeling of response factor data is a potential solution for response factor variation.

Sepsis, a severe infection, often leads to an overwhelming inflammatory response. Transfer RNA (tRNA)-derived small RNAs (tsRNAs), a emerging type of small RNAs, is crucial in various biological activities. Nevertheless, the connection between tsRNAs and sepsis is still unknown. We attempt to uncover the functions that these small RNAs play in sepsis. Our studies in humans, cells, and animal models revealed a significant downregulation of tiRNA-Glu-TTC-003 in the plasma of sepsis patients, in vitro macrophage inflammation models, and in the plasma and tissues of mice subjected to cecal ligation and puncture (CLP). Subsequent experiments revealed that the administration of tiRNA-Glu-TTC-003 agomir augmented the survival rate of CLP mice, mitigated organ damage, and attenuated inflammatory responses. In cellular experiments, we observed that overexpression of tiRNA-Glu-TTC-003 ameliorated the inflammatory state of cells and inhibited the expression of inflammation-related factors in M1 macrophages. Additionally, through target gene prediction and screening, we found that tiRNA-Glu-TTC-003 may interact with triggering receptor expressed on myeloid cells 2 (TREM2) to exert its functions. In THP-1 cells, the application of tiRNA-Glu-TTC-003 mimics resulted in an upregulation of TREM2 at both mRNA and protein levels, alongside a downregulation of Toll-like receptor 4 (TLR4) and its downstream effector, myeloid differentiation factor 88 (MyD88). In conclusion, tiRNA-Glu-TTC-003 demonstrates significant anti-inflammatory and protective effects in CLP mice and macrophage inflammation models. These findings suggest that tiRNA-Glu-TTC-003 may be a major factor in the inflammatory response of sepsis and provide a new idea for future treatment.

In intensive cropping systems, limited understanding of how residues with contrasting biochemical qualities decompose leads to nutrient immobilization, poor nutrient release synchrony and persistent residue burning challenges. The decomposition dynamics of various crop residues displayed unexpected variations at both the early and late stages, with the precise underlying factors for these differential responses to diversity remaining unclear. We hypothesized that the chemical composition and biochemical diversity of crop residues specifically difference in lignin, cellulose, hemicellulose, protein, phenol, nitrogen content and C: N ratio would substantially influence their decomposition dynamics and associated microbial and enzymatic responses at different time points. In an incubation experiment, we examined nine treatments, each with three replicates: maize stover (T1), rice straw (T2), cotton stalks (T3), redgram stalks (T4), greengram residue (T5), blackgram residue (T6), sunhemp residue (T7), soybean residue (T8), and sorghum stover (T9). We closely monitored the transformation of lignocellulose, total phenols and proteins in these crop residues using the litter bag method alongside measurements of soil enzyme activities and microbial population dynamics. Results revealed distinct decomposition patterns, where legume-based residues (sunhemp (T7), greengram (T5), blackgram (T6) and soybean (T8)) exhibited rapid degradation of lignocellulosic fractions and protein content within 60 days, associated with early peaks in microbial populations and enzyme activities (cellulase, xylanase, laccase and lignin peroxidase). In contrast, residues high in lignin, C:N ratio, lignin: N ratio and phenol: N ratio such as redgram stalks (T4), maize stover (T1), rice straw (T2), cotton stalks (T3) and sorghum stover (T9) decomposed more slowly, showing prolonged microbial activity and enzyme induction up to 120 days. Total phenol content initially declined (0-30 days after incorporation) and subsequently increased, reflecting the release and transformation of bound phenolics. Principal component analysis (PCA) revealed that residue biochemical traits, especially nitrogen content, lignin level and phenol content, strongly influenced microbial succession and enzymatic response. Overall, the decomposition sequence of biochemical components followed the order: lignin < cellulose < hemicellulose < proteins, and the enzyme activity followed the order: lignin peroxidase < cellulase < xylanase. These findings emphasize the importance of residue quality in regulating decomposition dynamics and offer actionable strategies for tailoring residue management to enhance nutrient cycling and soil health.

Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans(C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.

Abstract Understanding the genetic basis of grain yield and related traits in bread wheat under different water regimes is essential for improving moisture stress tolerance and water‐use efficiency. This study aimed to identify stable loci associated with these traits under rainfed conditions. A single‐nucleotide polymorphism (SNP)‐based multi‐locus genome‐wide association study (ML‐GWAS) was conducted using 22,962 polymorphic SNPs and six ML‐GWAS models in 220 bread wheat genotypes sourced from International Maize and Wheat Improvement Center, International Center for Agricultural Research in the Dry Areas, and Ethiopian breeding programs. Field trials were carried out across three environments using an alpha lattice design with two replications. Combined analysis revealed highly significant ( p &lt; 0.001) differences among genotypes for most traits. The ML‐GWAS identified seven stable quantitative trait nucleotides (QTNs) associated with four yield and yield‐related traits, spanning 21 chromosomes. Candidate genes near these QTNs encode key functional proteins, including serine‐rich protein, TF‐B3 domain protein, zinc finger GRF‐type protein, protein kinase domain protein, glycoside hydrolase family five proteins, cytochrome P450, polycomb VEFS‐box protein, and auxin response factor implicated in drought tolerance, nutrient remobilization, and developmental regulation. These results provide valuable genomic resources for future breeding programs, offering robust markers for marker‐assisted and genomic selection to accelerate the development of wheat varieties with improved resilience and yield stability under rainfed conditions.

ABSTRACTAimIntegration of locoregional treatments (LRTs) with atezolizumab plus bevacizumab (atezo/bev) has improved treatment outcomes, enabling an increasing number of patients with unresectable hepatocellular carcinoma (HCC) to achieve a complete response (CR). A comprehensive analysis of recurrence following CR may provide insights into prognosis. This study aimed to identify the factors associated with post‐CR recurrence in unresectable HCC.MethodsThis retrospective study included 15 patients with unresectable HCC who achieved CR with atezo/bev therapy. The incidence and characteristics of post‐CR recurrence were analyzed.ResultsTen patients achieved CR by combining LRT with atezo/bev, whereas five achieved CR with atezo/bev alone. The post‐CR recurrence rate was 53.3% (recurrence group, n = 8; non‐recurrence group, n = 7). No significant differences were observed between the recurrence and non‐recurrence groups in HCC treatment history prior to atezo/bev initiation, predictive factors for treatment response, including the neutrophil‐to‐lymphocyte ratio, hepatic functional reserve, and tumor burden at the initiation of atezo/bev, treatment progress, or frequency of atezo/bev maintenance therapy post‐CR. In multivariate analysis, a history of ≥ 2 HCC treatments prior to atezo/bev initiation was independently associated with post‐CR recurrence (hazard ratio, 6.744; 95% confidence interval, 1.189–38.25; p = 0.031); conversely, predictive factors for atezo/bev response, treatment progress, and maintenance therapy did not contribute to post‐CR recurrence.ConclusionsGiven the high post‐CR recurrence rate with atezo/bev in unresectable HCC, vigilant surveillance remains essential even after achieving CR, particularly in patients with ≥ 2 prior HCC treatments before atezo/bev initiation.

Potato transcription factor StMYB19 enhances drought tolerance by regulating ROS homeostasis and JA signalling pathway.

HER3 enhances ATF4 induction and survival in breast cancer cells during endoplasmic reticulum stress.

To elucidate the species-specific regulatory mechanisms of hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) in ruminant liver metabolism and to decipher the consequent metabolic-transcriptional network dysregulation using an integrated multiomics approach in a dairy cow hepatocyte model. A loss-of-function study was conducted using transfecting primary hepatocytes isolated from dairy cows with HADHA-targeting small interfering RNA (n = 6). LC-MS+GC-MS metabolomics and transcriptomics were integrated and analyzed via orthogonal partial least squares-discriminant analysis, differential and enrichment analysis, and multiomics network analysis. HADHA knockdown induced profound metabolic reprogramming, identifying 692 differentially abundant metabolites and 736 differentially expressed genes. Key dysregulated metabolomic pathways included upregulation of forkhead box O signaling, tricarboxylic acid cycle, and butanoate metabolism and downregulation of glycolysis/gluconeogenesis and ATP-binding cassette transporters. This was evidenced by suppression of primary bile acids and accumulation of glyceroneogenesis markers. Transcriptomic analysis revealed downregulation of insulin response and nuclear factor κ B signaling and upregulation of phosphatidylinositol and phosphatidylinositol 3-kinase-protein kinase B signaling. Multiomics integration confirmed disruption in core pathways, including arginine and proline metabolism, nicotinate and nicotinamide metabolism, and cAMP signaling. This study provides a comprehensive map of the HADHA-mediated regulatory network in the ruminant hepatocytes. Its depletion directly suppresses fatty acid oxidation and bile acid synthesis and rewires central carbon and lipid metabolism, leading to a state of metabolic imbalance. The elucidated mechanisms establish a foundational basis for future research aimed at developing nutritional or genetic strategies to improve metabolic health in the dairy industry.

Propranolol at 3 mg/kg/day is considered the gold standard for treating infantile haemangiomas. Nevertheless, the management of propranolol-resistant infantile haemangiomas (PRIH) remains challenging. This national multicentre retrospective observational study includes all PRIHs who received propranolol > 3 mg/kg/day. The study aims to investigate the pattern of PRIHs, assess the effects and tolerance of a higher dose, and identify predictive factors for response to this increased dosage. Fifteen PRIHs were included (prevalence 0.45%), mainly females, and most presented with a large lesion. Three distinct patterns of PRIH were identified: facial segmental lesions (47%), facial localized lesions with a subcutaneous component (40%), and body-localized mixed and ulcerated lesions (13%). Six PRIH (40%) responded to the higher dose (from 3.75 to 4 mg/kg/day). Three predictive factors were significantly associated with a good response: IGIc-IH1 at the end of 3 mg/kg/day regimen (OR = 22.9, 95% CI [1.2–1844.1]), a duration of 3.5 months or more at 3 mg/kg/day (OR = 17.5, 95% CI [1.22–250.37]), and 7 months or more at > 3 mg/kg/day (OR = 17.5, 95% CI [1.22–250.37]). Tolerance was generally good, although one patient experienced severe hypotension during dose escalation. Propranolol doses higher than 3 mg/kg/day may therefore be considered a potential treatment option for PRIHs.

Immunological phenotype as a predictor for response after isolated limb perfusion for patients with melanoma in-transit metastasis.

The JCOG1806 trial (jRCTs031190129) is underway to evaluate the omission of surgery in patients with human epidermal growth factor receptor (HER2)-positive early breast cancer who have a clinical complete response (cCR) after primary systemic therapy (PST). We aimed to assess the cCR rate in this trial and identify predictive factors. HER2-positivity was defined as an immunohistochemistry (IHC) score of 3 + or in situ hybridization-positivity. A cCR was defined as the absence of detectable lesions upon palpation, contrast-enhanced magnetic resonance imaging, and ultrasonography; biopsy-based confirmation was optional in hormone receptor (HR)-negative cases and mandatory in HR-positive cases. Multivariate logistic regression analyses were used to identify predictors of a cCR. The cCR rate was 57.6% (196/340 patients; 95% confidence interval [CI]: 52.2-63.0%). Strongly estrogen-receptor (ER)-positive tumors (≥ 10%) were significantly less likely to have a cCR than ER-negative tumors (odds ratio [OR], 0.41; 95% CI: 0.20-0.81). IHC 3 + tumors had higher cCR rates than IHC 1 + or 2 + tumors (OR, 2.19; 95% CI: 1.01-4.74). Compared with histological grade I tumors, cCR odds were higher in grade II (OR: 2.92; 95% CI: 1.07-7.93) and III (OR: 4.90; 95% CI: 1.76-13.7) tumors. Among patients without a cCR patients undergoing surgery, 22.2% were diagnosed with ypT0 tumors upon analysis of surgical specimens. ER-negativity, an IHC score of 3 + , and a higher histological grade were independent predictors of a cCR. Identifying these features may improve the feasibility and safety of surgery omission for patients with HER2-positive early breast cancer.