Search Results (21,772)

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) possesses dual enzymatic functions, i.e., kinase and E3 ubiquitin ligase activities, orchestrating proliferation, survival, apoptosis, DNA damage response, and immune modulation. Recent genomic and mechanistic studies have revealed MAP3K1’s paradoxical, context-dependent roles as both an oncogene and a tumor suppressor. We discuss MAP3K1’s multidomain architecture, featuring an N-terminal RING and PHD domain (E3 ligase activity), a TOG domain (microtubule dynamics), and a C-terminal kinase domain, enabling the integration of c-jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor kappa B (NF-κB) signaling pathways. MAP3K1 functions as a molecular switch balancing survival and apoptosis, with caspase-3 cleavage at Asp878 activating pro-apoptotic JNK/p38 signaling. Genomic analyses across >35 cancer types reveal MAP3K1 alterations at frequencies of <1–14%, highest in breast and endometrial cancers. These alterations show tissue specificity: loss-of-function mutations predominate in hormone receptor-positive breast cancer with a favorable prognosis, whereas gain-of-function mutations in melanoma activate oncogenic ERK signaling. MAP3K1 mutations predict response to mitogen-activated protein kinase kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors, with mutant cancers showing higher MEK inhibitor response than wild-type tumors. Despite substantial progress, critical gaps remain regarding MAP3K1’s E3 ligase substrates, context-dependent activity determinants, and therapeutic strategies. Addressing these through inhibitor development, biomarker validation, and mechanistic studies will accelerate potential clinical translation of MAP3K1 biology. Full article

Drought stress severely limits the growth and productivity of Morus alba, yet the molecular mechanisms underlying its adaptation remain poorly understood. Trehalose, an important osmoprotectant and signaling molecule, plays a key role in plant responses to abiotic stress, and its biosynthesis is primarily regulated by trehalose-6-phosphate synthase (TPS). However, the characteristics and potential functions of TPS genes in M. alba have not been systematically investigated. In this study, we identified 11 TPS genes (MaTPSs) in the M. alba genome and performed comprehensive analyses, including phylogenetic relationships, gene structures, conserved motifs, cis-regulatory elements, and expression profiles. Phylogenetic analysis classified MaTPSs into TPS I and TPS II subfamilies, with closer evolutionary relationships to Populus trichocarpa than to Arabidopsis thaliana. Promoter analysis revealed the presence of multiple stress- and hormone-responsive elements, suggesting their potential involvement in abiotic stress regulation. Physiological measurements showed that drought stress significantly increased trehalose accumulation, with a 1.6-fold increase in leaves and a 2.2-fold increase in roots. Expression profiling further demonstrated that six MaTPS genes were upregulated under drought stress, among which MaTPS4, MaTPS9, MaTPS10, and MaTPS11 exhibited significant induction (approximately 5-, 5-, 8-, and 10-fold, respectively). Correlation analysis further indicated that trehalose accumulation was positively associated with all upregulated MaTPS genes (p < 0.05). Taken together, these results suggest that MaTPS genes may be involved in drought-responsive regulation of trehalose metabolism in M. alba. This study provides a valuable foundation for future functional validation and the genetic improvement of drought tolerance in mulberry. Full article

Diapause hormone (DH) is an important endocrine substance capable of influencing diapause in Lepidoptera moths that is encoded by the neuropeptide hormone DH-PBAN gene. Imidazole derivative KK-42 is a synthetic insect growth regulator that can affect diapause in Lepidoptera moths, and appears to have an opposite physiological function to DH. To test the hypothesis that KK-42 may be operating through DH to affect diapause, here, we used two Lepidoptera species Bombyx mori L. and Antheraea pernyi that enter egg and pupal diapause, respectively, through examining whether KK-42 can influence DH-PBAN and some associated mRNA expression. We found that the protein sequences of DH-PBAN in insects were highly variable, although the PRXamide C-terminus was conserved. We also found that KK-42 induced significant up-regulation and prolonged expression duration of DH-PBAN in both A. pernyi and B. mori pupae, as well as in trimolter larvae of B. mori that were induced by the application of KK-42 from the normal tetramolter larvae. In addition, KK-42 can significantly upregulate glutamic acid decarboxylase (GAD) expression in B. mori in transcriptome data. Our findings suggested that KK-42 influences diapause by upregulating GAD expression, promoting DH accumulation to prolong the secretion time of DH-PBAN. Full article

We conducted this experiment with the aim of investigating the effects of different noise levels from ventilation fans on the growth and slaughter performance, meat quality, blood parameters, and feeding behavior of geese from 21 to 70 days of age. A total of 108 male geese (21-day-old) were randomly assigned to one of three conditions: a control group (no additional fan noise), low-noise treatment (65–75 dB), and high-noise treatment (85–95 dB). Each treatment included six replicates, with six geese per replicate. The results showed that neither ventilation fan noise level significantly affected growth performance, feeding behavior, slaughter performance, or major meat quality traits (p > 0.05). Compared with the control group, noise exposure significantly reduced circulating adrenocorticotropic hormone and corticosterone concentrations (p < 0.05), and the low-noise group exhibited significantly reduced cortisol concentrations (p < 0.05), while the high-noise group had increased cortisol concentrations. Under noise exposure conditions, no statistically significant effects were observed on superoxide dismutase, total antioxidant capacity, malondialdehyde concentration, catalase, and glutathione peroxidase activities compared with the control group (p > 0.05). Overall, prolonged noise stimulation (65–75 dB and 85–95 dB) alleviated stress responses in commercial geese aged 21–70 days, without negatively affecting their growth performance, slaughter performance, meat quality, or feeding behavior. Full article

Background: Polycystic ovary syndrome (PCOS) is characterized by substantial inter-individual variability in ovarian sensitivity to recombinant follicle-stimulating hormone (rFSH) during controlled ovarian stimulation (COS). Clinically applicable tools for personalized dosing in this population remain limited. Methods: This retrospective single-center study (2013–2024) analyzed 369 PCOS patients undergoing GnRH antagonist protocols who achieved optimal ovarian responses (10–20 oocytes with at least 40% of follicles ≥ 16 mm in diameter on trigger day). The final retrospective dataset was randomly split into modeling (n = 258) and validation (n = 111) groups. A multivariate linear regression model incorporating age, BMI, basal FSH, basal LH, AMH, and AFC was developed to estimate the average daily rFSH dose. Model performance was evaluated using correlation analysis, prediction error metrics, and calibration assessment. Results: Age, BMI, and basal FSH were positively associated with average daily rFSH dose, whereas basal LH, AMH, and AFC were negatively associated. The model explained 40.4% of the variability in average daily rFSH dose. In the modeling cohort, 77.9% of estimated doses fell within ±20% of the observed values, with a moderate correlation between predicted and observed doses (ρ = 0.646). In the validation cohort, 67.6% of estimates met the predefined accuracy threshold (ρ = 0.676). Calibration analyses demonstrated robust agreement between predicted and observed doses. Conclusions: By integrating endocrine markers, ovarian reserve indicators, and clinical characteristics, this study provides a practical example of personalized medicine in COS in women with PCOS. The internally validated approach may support individualized rFSH dosing during COS and serve as a basis for future development of decision support tools in this specific population. Full article

The common carp (Cyprinus carpio) kidney uniquely integrates excretory nephrons, renal hematopoietic tissue, and hormonally active thyroid follicles, positioning it as a candidate “multipurpose biomarker organ” for pollutants like perfluorooctanoic acid (PFOA), a prototype long-chain PFAS and persistent organic pollutant exhibiting nephrotoxic, immunotoxic, and thyroid-disrupting effects. Building on prior histological, ultrastructural, and morphometric analyses from carp exposed to waterborne PFOA (0, 200 ng L⁻¹, 2 mg L⁻¹ for 56 days), a hierarchical multipurpose index comprising nephrotoxic, immunotoxic, and thyrotoxic subindices was developed from z-scored light-, electron-microscopy, and morphometric features, enabling cross-scale integration; proximal tubule vesiculations and effete rodlet cells (RCs) were newly quantified from archival electron micrographs. The subindices captured PFOA-induced glomerular hyperfiltration with proximal protein reabsorption and collecting duct RCs recruitment (nephrotoxic); hematopoietic tissue RCs recruitment, clustering, and exocytosis (immunotoxic); and increased thyroid follicle abundance/vesiculation, cross-sectional area, and perimeter (thyrotoxic). Quantification of previously only qualitatively assessed features provided statistical validation, while radar plot integration rendered results more intuitively evident—particularly highlighting the non-monotonic thyroid response—condensing organ-level complexity into a coherent framework supporting carp kidney as a translational One Health model for multi-endpoint waterborne pollutant assessment. Full article

Atherosclerosis, the leading global cause of death, is a chronic inflammatory vascular disease with higher prevalence and earlier onset in men than in women. This study aims to investigate sex differences in the atherogenic endothelial phenotype during early atherosclerosis processes by providing the first comprehensive analysis of hormone-independent responses in human umbilical vein endothelial cells (HUVECs) from opposite-sex twins. HUVECs underwent pro-inflammatory stimulation with TNF-α and supernatant from activated pro-inflammatory THP-1 cells, revealing distinct sex-specific patterns: mRNA expression of focal adhesion proteins talin-I, vinculin, FAK, and α1-actinin increased significantly only in male cells, while paxillin showed elevated mRNA and protein levels in both sexes. Male HUVECs exhibited stronger induction of cell adhesion molecule VCAM-1, pro-inflammatory cytokine IL-1β, and proangiogenic factors Flt-3L, G-CSF, and PDGF-AA, whereas IL-22 secretion was exclusively upregulated in female cells. These sex differences in levels of focal adhesion, adhesion molecules, and cytokine profiles uncover the mechanistic backgrounds of the atherogenic endothelial phenotype, independent of systemic hormones. The findings emphasize cellular sex as a critical biological variable in early atherosclerosis and vascular inflammation. Full article

Thyroid disorders are among the most common endocrine disorders worldwide and are classified as noncommunicable diseases. These disorders are associated with significant morbidity, impaired quality of life, and considerable socioeconomic burden. Like other noncommunicable diseases, thyroid disorders arise from complex interactions between genetic susceptibility and environmental factors, including diet and lifestyle. Despite growing interest in lifestyle-based approaches to noncommunicable disease prevention and management, thyroid disorders have received comparatively limited attention in this context. Graves’ disease, the most common cause of hyperthyroidism, is a relevant condition for exploring dietary interventions. Current treatment strategies—anti-thyroid drugs, radioactive iodine and thyroidectomy—have remained largely unchanged for decades. Long-term remission following drug therapy is achieved in no more than approximately 50% of patients, while all treatment modalities carry potential adverse effects. These limitations underscore the need for alternative or adjunctive therapeutic strategies. Iodine intake plays a central role in thyroid hormone synthesis. Indeed, observational studies have shown inverse associations between iodine intake and remission rates, as well as achievement of euthyroidism, medication requirements and thyroid autoantibody titers. These findings suggest that dietary iodine restriction may enhance treatment efficacy and reduce medication-related risks. Beyond its direct effects on thyroid hormone synthesis, iodine may influence Graves’ disease through indirect mechanisms involving the lipid profile and the gut–thyroid axis. Autoimmune thyroid diseases are associated with a dyslipidemic profile and with gut microbiota dysbiosis; the latter characterized by increased potentially pathogenic bacteria and reduced beneficial bacteria such as Lactobacillus and Bifidobacterium. Full article

NIN-like protein (NLP) transcription factors are key regulators of plant nitrate signaling and stress responses. Although extensively studied in Arabidopsis thaliana and various crops, it has rarely been reported in woody plants, particularly in drought-tolerant tree species. In this study, 10 PeNLP genes were identified in the drought-tolerant tree Populus euphratica Oliv. through comparative genomics. These genes were unevenly distributed across seven chromosomes, and the gene-family expansion was mainly driven by whole-genome duplication (WGD). Analysis of conserved domains showed that PeNLPs contained 4–10 characteristic motifs, and most members possessed the typical RWP-RK and PB1-related domains. Collinearity analysis identified 18 NLP orthologous gene pairs between P. euphratica and its relatives (Populus pruinosa and Salix sinopurpurea), which exceeded the 15 pairs detected between P. euphratica and A. thaliana, indicating that the NLP family is more conserved within the Salicaceae. Phylogenetic analysis divided PeNLPs into three subfamilies, and their promoter regions harbored diverse cis-acting elements associated with hormone signaling, environmental stress, growth, and light response. Transcriptome and qRT-PCR analyses further demonstrated that PeNLPs were generally downregulated under drought stress. Overall, this study systematically characterized the evolution, structure, and drought responsiveness of the PeNLPs, providing a theoretical basis and genetic resources for improving nitrogen use efficiency and drought resistance in trees. Full article

The utilization of microalgae for bioremediation presents a highly promising and cost-effective approach, offering advantages of simultaneous pollutant removal and biomass recovery. However, pollutants may adversely affect microalgal growth, potentially compromising both pollutant removal efficiency and biomass yield. In this study, the plant hormone indoleacetic acid was employed to enhance the tolerance to pollutants and lipid production capability of Chlorella vulgaris (C. vulgaris). Compared to the non-treated group, the addition of indoleacetic acid resulted in increased biomass, pigment content, sedimentation performance, lipid productivity and content, as well as antibiotic removal capacity in C. vulgaris. Furthermore, the effects of indoleacetic acid on C. vulgaris growth were elucidated through changes in antioxidant enzymes and fatty acid saturation. Overall, this study reveals the potential of plant hormones in enhancing microalgal tolerance and lipid productivity, providing a theoretical basis for the effective utilization of microalgae in achieving simultaneous pollutant removal and biofuel production. Full article

Drought stress severely limits plant growth and productivity, yet the molecular basis of drought tolerance and post-drought recovery remains incompletely understood in many forage legumes. Medicago ruthenica is a perennial legume native to arid and cold regions and exhibits strong drought resilience. Results: We integrated key physiological traits related to stomatal regulation, photosynthesis, osmotic adjustment and antioxidant defense with RNA-seq across four stages (well-watered control, CK; drought for 9 days, D9; drought for 12 days, D12; and rewatering for 4 days, RW). Drought triggered stage-dependent physiological shifts, and transcriptome profiling identified >3000 drought- and rewatering-responsive genes enriched in primary metabolism, redox homeostasis and hormone signaling. WGCNA highlighted two drought-associated modules (MEcyan and MEcoral1) and prioritized three hub transcription factors for functional validation: 861 (AP2/ERF), 22 (WRKY) and 89 (bZIP). Overexpression of each gene in tobacco improved drought tolerance, as indicated by enhanced growth/root traits, increased osmolyte accumulation and antioxidant enzyme activities, and reduced membrane damage. Conclusions: Together, these results provide an integrated view of drought stress response and recovery in M. ruthenica and identify 861, 22 and 89 as candidate regulatory genes for engineering drought resilience in legumes. Full article

A rare clinical condition associated with numerous diagnostic and treatment challenges, pregnancy-associated melanoma (PAM), is defined as melanoma diagnosed either during pregnancy or within the first year postpartum. The physiological changes in pregnancy (hormonal changes and immune modulation), along with the normal changes in the pregnant woman’s skin (skin color changes, etc.), may all hinder early detection of this disease and create concerns regarding the advancement of melanoma and the well-being of both the mother and her fetus. The purpose of this review article was to summarize the current literature on the incidence, biology, diagnostic methods and treatments of PAM, with an emphasis on comparison between the two forms of melanoma. More recent research indicates that pregnancy itself is not typically associated with decreased melanoma-specific survival rates. However, when worse results are reported, it appears that this may be more due to delays in initial diagnoses (diagnosis of cancer after delivery) or detection of cancer postpartum, as well as the increased number of stages of melanoma at which women were diagnosed at the time of their first evaluation compared to non-pregnant controls, rather than being a result of enhanced biologic aggressiveness in melanoma driven by pregnancy itself. The preclinical and translational models have suggested that pregnancy may influence melanoma biology through the mechanisms of hormonal signaling, immune system modulation and vascular remodeling; however, these mechanisms remain hypothesis-generating, and current clinical evidence does not indicate that changes in hormone levels during pregnancy negatively affect melanoma survival. Surgical excision is the mainstay of treatment and can be performed safely during pregnancy. In select patients, a sentinel lymph node biopsy may also be performed. Due to the risk of fetal harm, systemic therapy (targeted agents and/or immune checkpoint inhibitors) cannot be used for the treatment of PAM during pregnancy. Post-pregnancy treatment of PAM will follow standard melanoma treatment guidelines; however, the treatment options will need to take into consideration whether or not the patient is breastfeeding and if she desires to become pregnant again in the future. In summary, PAM will require a multidisciplinary, individualized approach to maximize oncologic outcomes while protecting the health of both the mother and her fetus. Awareness of this disease and timely diagnosis are critical to maximizing the prognosis. Full article

Background/Objectives: Secondary hyperparathyroidism (SHPT) is a common and clinically significant complication of advanced chronic kidney disease and may require surgical intervention when medical therapy fails. This study aimed to evaluate the association between parathyroid gland burden, defined by gland number and size parameters, and biochemical disease severity in patients undergoing parathyroidectomy for SHPT, and to assess the concordance between preoperative imaging findings and intraoperative observations. Although parathyroid gland enlargement is a hallmark of SHPT, the clinical relevance of parathyroid gland number and overall gland burden in relation to biochemical disease severity and the accuracy of preoperative imaging remains incompletely defined. Methods: This single-center, retrospective observational study included adult patients who underwent parathyroidectomy for secondary hyperparathyroidism between January 2015 and December 2020. Demographic, clinical, laboratory, imaging, intraoperative, and histopathological data were analyzed. Parathyroid gland burden was assessed based on gland number, largest gland diameter, and total gland burden. Associations between gland morphology and biochemical parameters were evaluated using correlation analyses and multivariable logistic regression. Agreement between preoperative imaging and intraoperative findings was assessed using diagnostic performance metrics, contingency analysis, and the weighted kappa coefficient. Results: A total of 101 patients were included. Patients with three or more enlarged parathyroid glands had significantly higher preoperative parathyroid hormone and alkaline phosphatase levels, higher serum phosphorus levels, and lower calcium and vitamin D levels (all p < 0.05). Total gland burden and largest gland diameter were positively correlated with parathyroid hormone and alkaline phosphatase levels. In multivariable analysis, higher parathyroid hormone levels, longer dialysis duration, and vitamin D deficiency were independently associated with high gland burden. Preoperative imaging demonstrated moderate agreement with intraoperative findings (weighted kappa = 0.46; 95% CI, 0.29–0.63). Separate evaluation of imaging modalities showed that both ultrasonography and scintigraphy had relatively high sensitivity but limited specificity for detecting extensive gland involvement. Conclusions: In patients undergoing parathyroidectomy for secondary hyperparathyroidism, increased parathyroid gland burden is associated with greater biochemical disease severity. Preoperative imaging shows limited concordance with intraoperative findings and should be interpreted cautiously, particularly in the presence of multiglandular disease. These findings support the integration of morphological parameters into comprehensive preoperative assessment while highlighting the need for larger prospective, multicenter studies with standardized imaging protocols and long-term follow-up. Full article

Growth, reproduction, and survival are fundamental biological priorities that animals balance by evaluating dietary cues. Cholesterol occupies a unique position among nutrients, serving both as a structural component of cellular membranes and as a precursor for steroid hormones, yet its regulation differs fundamentally across taxa. In mammals, cholesterol availability is buffered by endogenous synthesis and post-ingestive metabolic control. In contrast, insects have evolutionarily lost sterol biosynthesis and are therefore sterol auxotrophs that rely entirely on dietary sources. Here, we synthesize current understanding of cholesterol biology in Drosophila melanogaster, with a focus on sterol auxotrophy, life-stage–specific allocation, and endocrine and lifespan outcomes in a comparative framework. We highlight cholesterol not only as a metabolic substrate but also as a sensory-encoded nutrient that shapes feeding behavior. We further examine how lipophorin (Lpp)-mediated transport, Niemann–Pick type C proteins, ATP-binding cassette transporters, and the nuclear receptor DHR96 coordinate systemic sterol distribution and endocrine output in the absence of endogenous synthesis. By integrating these mechanisms across development, we illustrate how cholesterol availability governs larval growth, ecdysteroid production, adult reproduction, neural function, and lifespan through coupled endocrine and nutrient-signaling networks. This review positions cholesterol as a multifunctional signal linking sensory perception, metabolic regulation, and life-history strategy in sterol-auxotrophic insects, offering a framework for understanding how evolutionary loss of biosynthetic capacity reshapes nutrient sensing and homeostatic control. Full article

Background: Elevated levels of the C-3 epimer (3-epi-25(OH)D) of 25-hydroxyvitamin D (25(OH)D) have been identified in premature infants as compared to most adults, and an immature liver has been suggested as a possible cause. We hypothesised that patients with cirrhosis might present with elevated C-3 epimerisation due to impaired liver function. The aim was to assess whether 3-epi-25(OH)D levels differ in patients with chronic liver disease with cirrhosis vs. those without cirrhosis. Methods: A total of 309 patients were included (254 patients with cirrhosis vs. 55 without cirrhosis). Serum 25(OH)D and 3-epi-25(OH)D levels were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Patients with cirrhosis had significantly higher median relative 3-epi-25(OH)D concentrations, as compared to patients without cirrhosis (7.4% (5.5–10.4) vs. 4.8% (2.4–5.7), respectively; p < 0.001). They also had similar absolute 3-epi-25(OH)D levels (despite having lower 25(OH)D serum concentrations) than patients without cirrhosis. A progressive increase in relative 3-epi-25(OH)D levels was observed with more advanced cirrhosis (p < 0.001). An analysis of the ROC area under the curve determined 6% as the optimal cut-off for relative 3-epi-25(OH)D. All patients with Child–Pugh stage C and 88.6% with stage B were above the 6% cut-off and had significantly higher absolute serum 3-epi-25(OH)D concentrations (0.9 ng/mL vs. 0.6 ng/mL; p < 0.05) and lower serum 25(OH)D levels (9.3 vs. 14.1 ng/mL; p < 0.001) than patients <6% cut-off. Conclusions: These results reflect the marked increases in relative 3-epi-25(OH)D levels that occur with cirrhosis. The specific hepatic metabolic alterations still need to be unravelled, including whether cirrhosis might lead to reduced epimer clearance. Full article