Glucosinolates (GSLs) are sulfur- and nitrogen-containing secondary metabolites that serve as defense compounds in Arabidopsis and other members of the Brassicales. Although the enzymatic pathway that produces GSLs is well-studied, the upstream mechanisms that control their tissue-specific synthesis are poorly understood. We identified a novel repression module that transcriptionally regulates GSL levels in sepals, the modified leaves that protect reproductive tissues within the floral bud. GLABRA2 (GL2) INTERACTING REPRESSOR1 (GIR1) interacts directly with Arabidopsis thaliana MERISTEM LAYER1 (ATML1), an HD-Zip IV transcription factor known to be required for giant cell formation in the sepal epidermis. This interaction requires a predicted Zn finger of GIR1 and the C-terminal START adjacent domain (STAD) of ATML1. The gir1 loss-of-function mutants exhibit excess giant cells, in contrast to atml1 mutants which display fewer giant cells, supporting the role of GIR1 as a negative regulator of ATML1. We confirmed that GIR1 interacts with TOPLESS (TPL) and TOPLESS-RELATED (TPR) corepressors, and coimmunoprecipitation demonstrated that GIR1 acts as an adaptor protein connecting ATML1 and TPL/TPR. RNA sequencing revealed that numerous genes involved in GSL biosynthesis, including the key transcriptional regulator MYB29, are upregulated in gir1 mutants. Consistent with the transcriptomic data, chemical analysis revealed that gir1 mutants display elevated GSL levels in sepals. Mass spectrometry imaging confirmed high GSL accumulation in gir1 sepals compared to wild type and atml1 . Overall, our findings uncover a previously unrecognized link between cell expansion and GSL metabolism, suggesting strategies for engineering plants with cell-type specific GSL profiles. Plants belonging to the order Brassicales produce sulfur-containing glucosinolate (GSL) metabolites that serve in defense against herbivory. In cruciferous vegetables such as broccoli and kale, these compounds contribute to their unique flavors and health-promoting attributes. In agriculturally important oilseed crops, they affect the palatability of animal feeds. Here, we identified a novel transcriptional regulatory module that controls GSL biosynthesis in the epidermis of the sepal, the floral organ that protects the reproductive tissues. This regulatory module also controls cell expansion of specific cell types in the sepal, demonstrating a surprising connection between cell growth and a chemical defense pathway in plants. Our results suggest strategies for engineering crops with tissue-specific GSL profiles to fit agronomic needs.
Reproductive aging in females is characterized by the irreversible depletion of ovarian follicles, yet the structure and function of the post-reproductive ovary remain poorly defined. Using paired histological and bulk transcriptomic analyses of ovaries from reproductively young (2 m), reproductively old (18 m), and post-reproductive (24 m) mice, we mapped how ovarian identity evolves beyond follicle exhaustion. As expected, follicle loss, stromal remodeling, and increased collagen deposition were observed in the reproductively old and post-reproductive cohorts. Transcriptomic analyses revealed a shift from reproductive functionality to an immune-dominant signature with age. Correspondingly, post-reproductive ovaries exhibited increased infiltration of T cells, macrophages, and multinucleated giant cells. Although old and post-reproductive ovaries diverged substantially from young ovaries, they also showed discrete transcriptomic differences, indicating that the ovary continues to undergo molecular changes after reproductive senescence. Lastly, age-dependent changes in ovarian factors that are predicted to be secreted suggest that the post-reproductive ovary could be a source of pro-inflammatory signaling mediators with the potential to modulate extra-ovarian tissues. These findings challenge the assumption that the post-reproductive ovary is inert, instead indicating that it acquires an immune identity with potential endocrine and paracrine influence on whole-body aging.
Assessing disease activity in giant cell arteritis (GCA) remains challenging, as existing clinical, laboratory and imaging biomarkers lack specificity. This proof-of-concept study explored the diagnostic potential of vascular adhesion protein-1 (VAP-1) targeting [68Ga]Ga-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) DOTA-sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) positron emission tomography-CT (PET/CT) as an inflammation-specific molecular imaging biomarker in newly diagnosed and relapsing GCA. Patients with newly diagnosed GCA underwent [68Ga]Ga-DOTA-Siglec-9 PET/CT and vascular ultrasound. Tracer uptake (SUVmean/SUVmax) was quantified in aortic, supra-aortic and extravascular (shoulder/hip) regions and compared with relapsing patients. Levels of soluble VAP-1 (sVAP-1) and matrix metalloproteinase (MMP)2/MMP3/MMP9 were measured in patients and controls as potential biomarkers related to vascular inflammation. Eight patients with newly diagnosed GCA were compared with eight relapsing patients, alongside eight controls. Imaging revealed a positive association between ultrasound-assessed subclavian artery intima-media thickness and tracer uptake (r=0.67, p=0.035). Prednisolone exposure was inversely associated with vascular uptake across various vascular regions, with SUVmean showing a stronger overall negative association than SUVmax (SUVmean r=-0.51, p=0.043; SUVmax r=-0.62, p=0.010). Levels of sVAP-1 were reduced in newly diagnosed GCA compared with relapsing patients (p=0.0145) and controls (p=0.0446), and inversely associated with MMP2 (r=-0.56, p=0.037) and MMP9 (r=-0.47, p=0.089). Notably, MMP2 and MMP3 were negatively associated with vascular uptake (eg, aortic arch: r=-0.59, p=0.027). This first-in-human study demonstrates that [68Ga]Ga-DOTA-Siglec-9 PET/CT detects vascular inflammation in GCA and shows attenuation with prednisolone exposure. Reduced sVAP-1 levels and inverse associations between MMP2/MMP3 and tracer uptake support a functional VAP-1/MMP axis underlying the imaging signal. Our findings further position [68Ga]Ga-DOTA-Siglec-9 PET/CT as a promising potential molecular imaging biomarker in GCA.
Sporadic cervicothoracic dumbbell neurofibromas are rare and surgically challenging when large. A 44-year-old male presented with left cervical swelling, cervicobrachial pain, and C8-T1 deficits with hypothenar atrophy. Magnetic resonance imaging revealed a 6.4 × 6.6 × 11 cm C4-D3 dumbbell mass without invasion. A single-stage posterior C6-D1 laminectomy with microsurgical excision and Cavitron Ultrasonic Surgical Aspirator-assisted debulking achieved complete resection. Postoperatively, pain resolved with marked neurological recovery. Histopathology confirmed WHO Grade I neurofibroma. This case shows that even giant lesions can be safely managed with meticulous microsurgical planning.
Patients on low-dose prednisolone may develop adrenal insufficiency causing reduced health-related quality of life (HRQoL) and increased risk of adrenal crisis. This study examines whether supplemental hydrocortisone during mild to moderate stress improves HRQoL in patients with polymyalgia rheumatica/giant cell arteritis (PMR/GCA) with adrenal insufficiency on low-dose prednisolone. A multicentre, randomised, double-blinded, placebo-controlled, clinical trial including patients with PMR/GCA receiving ongoing prednisolone ≤5 mg/day. Eligible patients undergo an adrenocorticotropic hormone (ACTH) test, and 250 patients with a stimulated cortisol<420 nmol/L (biochemical adrenal insufficiency) are randomised 1:1 to supplemental hydrocortisone or placebo during mild to moderate stress ('sick-days') for 6 months or until daily prednisolone is stopped. The goal is 200 patients completing ≥3 months intervention period. Patients continue prednisolone tapering according to PMR/GCA guidelines. In the event of severe stress (risk of adrenal crisis), patients receive open-label hydrocortisone treatment. 95 patients with stimulated cortisol ≥420 nmol/L serve as control group. The primary outcome is HRQoL measured as fatigue using ecological momentary assessments (EMA) of the General Fatigue scale from the Multidimensional Fatigue Inventory-20, five times daily in situations of stress ('sick-days'). EMA will be administered via a smartphone application 'EMA live'. Differences in mean fatigue scores during sick-days between hydrocortisone and placebo will be analysed using mixed models for repeated measures. Secondary outcomes include daily smartphone-based symptom reporting, additional HRQoL questionnaires, adrenal crises, adverse effects from glucocorticoid excess, serial ACTH tests and biomarkers of adrenal insufficiency. The study is approved by the Ethics Committee of the Capital Region of Denmark and the Danish Medicines Agency. Recruitment began June 2022. The last patient's last visit is expected in 2026. Results will be disseminated via peer-reviewed publication and conference presentations. EudraCT:2021-002528-18, CTIS:2024-518272-30-00, NCT05435781.
Large sternal resections jeopardize chest-wall rigidity and cardiopulmonary protection. Conventional reconstructions often trade anatomical conformity for convenience. Three-dimensional planning and patient-specific titanium (Ti-6Al-4 V) implants may reconcile oncologic goals with stable mechanics; however, detailed end-to-end workflows are seldom reported. We implemented a CT-to-implant workflow - segmentation, virtual resection, CAD with lateral rib-coupling flanges and soft-tissue eyelets, polymer prototype rehearsal, additive manufacturing, and single-stage implantation - for a 28-year-old man with a sternal giant cell tumor. Near-total sternectomy was followed by rigid prosthetic fixation to a manubrial sliver, xiphoid remnant, and medial rib stumps. Double-layer polypropylene mesh (deep barrier and superficial buttress) and preserved pectoral muscle coverage enabled flap-less soft-tissue reconstruction. Estimated blood loss was 300 ml. The patient was extubated on table, the subcutaneous drain was removed on postoperative day 2, the intercostal drain on postoperative day 5, and total hospital stay was 5 days. Recovery was uncomplicated with oral-analgesic pain control and satisfactory early function. The cost of the prosthesis was INR 180,000 (approximately US$1,950). Final histopathology confirmed giant cell tumor with negative margins (R0 resection). Preoperative spirometry showed a restrictive pattern; repeat spirometry at approximately 1 month showed an overall improvement of about 20% in major parameters, although the original postoperative printout was not retrievable. At 6-month follow-up, the patient had resumed work and reported only intermittent mild pain not requiring analgesics. We present a pragmatic operational blueprint for patient-specific sternal reconstruction that highlights anchorage strategy, rib coupling, and soft-tissue suspension. The case demonstrates feasibility in a specialized multidisciplinary setting, but longer-term oncologic, functional, and implant-durability data remain necessary.
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) aggregates that induce synaptic dysfunction and neuronal loss. Among the various Aβ species, soluble oligomers are considered the most neurotoxic forms and play a critical role in AD progression. Fukinolic acid (FA), a polyphenolic compound isolated from medicinal plants, has been reported to possess antioxidant and anti-inflammatory activities; however, its effects on Aβ aggregation have not been investigated. In the present study, we investigated whether FA modulates Aβ aggregation and synaptic dysfunction. Molecular docking analysis suggested that FA directly interacts with Aβ monomers at aggregation-prone regions. Consistent with this prediction, FA facilitated the formation of toxic Aβ oligomers and enhanced Aβ-induced neuronal cytotoxicity. The potentiation of Aβ toxicity by FA was abolished by an N-methyl-D-aspartate (NMDA) receptor antagonist, indicating the involvement of NMDA receptor-dependent signaling. Electrophysiological recordings showed that FA exacerbated Aβ-induced long-term potentiation (LTP) impairment in hippocampal slices without affecting basal synaptic transmission. In addition, FA administration increased Aβ deposition and reduced neuronal viability in the hippocampus of 5XFAD mice. FA treatment showed non-significant trends toward reduced hippocampal LTP and spontaneous alternation in the Y-maze test, indicating that further studies are required to determine whether FA affects synaptic and cognitive function in vivo. These findings suggest that FA promotes toxic Aβ oligomer formation and may aggravate Aβ-associated synaptic impairment through NMDA receptor-dependent mechanisms, highlighting the importance of evaluating the effects of natural compounds on Aβ pathology in AD.
Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by fibroblast growth factor 23 (FGF-23)-secreting tumors, typically of mesenchymal origin, leading to renal phosphate wasting and severe bone demineralization and fragility fractures. Diagnosing TIO remains a significant clinical challenge, particularly when coexisting mineral metabolism disorders, such as hypercalcemic hyperparathyroidism, are masking its clinical presentation. Case Presentation: A 74-year-old woman with fragility fractures, generalized bone pain, and nephrolithiasis was initially diagnosed with primary hyperparathyroidism due to concomitant hypercalcemia, hypophosphatemia, and elevated parathyroid hormone (PTH). Despite a successful parathyroidectomy, which normalized calcium levels, severe hypophosphatemia persisted due to renal phosphate wasting. High FGF-23 levels and subsequent functional imaging indicating a somatostatin receptor-positive lesion in the left popliteal fossa led to the diagnosis of TIO. Surgical resection immediately normalized FGF-23 levels, leading to a slower rise in phosphorus during follow-up. Histopathology revealed a tophaceous-like giant cell granulomatous reaction, recalling the earlier report by Prader. Conclusions: This case highlights that parathyroid disorders can coexist with TIO, and they may delay its diagnosis. In this circumstance, a high index of clinical suspicion is represented by the persistence of hypophosphatemia post-parathyroidectomy.
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Uterine lipoleiomyoma is a rare benign lipomatous variant of leiomyoma composed of mature adipose tissue and smooth muscle fibers. Fat-predominant variants are uncommon and may closely resemble pure uterine lipoma on imaging. We report the case of a 44-year-old woman presenting with progressive lower abdominal fullness. Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) demonstrated a large intramural fat-containing lesion arising from the uterine fundus with subtle internal soft tissue strands and no suspicious malignant features. Multiple smaller intramural fibroids were present peripherally. Based on imaging characteristics, a diagnosis of fat-predominant lipoleiomyoma was favored. Given the large size of the lesion and progressive abdominal fullness, the patient underwent a hysterectomy, and histopathological examination confirmed the diagnosis. This case highlights the characteristic imaging findings of uterine lipoleiomyoma and emphasizes the importance of recognizing benign fat-containing uterine lesions to improve diagnostic confidence and avoid unnecessary intervention.
Non-ossifying fibroma (NOF) is a common benign fibrous lesion seen in children and adolescents and is usually asymptomatic. It is often found incidentally and most commonly involves the metaphyseal region of long bones. However, when the lesion arises from the cortical bone and presents with pain, it may clinically and radiologically mimic osteoid osteoma, leading to diagnostic confusion. An 8-year-old boy presented with severe pain in the right leg for 3 weeks. Radiographs revealed a cortical lytic lesion in the proximal tibial diaphysis, and magnetic resonance imaging findings were suggestive of osteoid osteoma. Due to persistent symptoms and diagnostic uncertainty, surgical curettage and saucerization were performed. Histopathological examination revealed fibrocollagenous tissue composed of spindle-shaped cells arranged in a storiform pattern with scattered osteoclast-type multinucleated giant cells, confirming the diagnosis of NOF. Microbiological culture showed no growth. Painful cortical lesions in children can mimic osteoid osteoma both clinically and radiologically. Histopathological examination is essential for definitive diagnosis in atypical presentations. This case highlights the importance of considering NOF in the differential diagnosis of painful cortical lesions in children.
Amid accelerating climate change, understanding how wildlife adjusts to environmental constraints, particularly via habitat use, is essential. In high-altitude regions with extreme environmental conditions and strong ecological filtering effects, geomorphic and soil characteristics are critical factors influencing habitat utilization preferences. Previous studies of factors affecting wildlife habitat-use preferences have primarily focused on low-altitude areas. However, research remains scarce on the relationship between habitat utilization preferences of small mammals in plateau regions and geomorphic and soil characteristics. In this study, we selected 66 plots from 19 typical distribution areas of pikas in three counties of the Qinghai-Tibetan Plateau to assess the relationship between the pika's habitat-utilization preferences and geomorphic and soil characteristics at a large scale. The results revealed that the factors affecting the habitat use of pikas are potentially similar across regions. The resource selection index (Ei) showed a clear preference for specific geomorphic and soil characteristics. In addition, we found a significant correlation between PC1-PC4 and pika density, and both principal component analysis (PCA) and generalized additive models (GAM) indicated that all geomorphic and soil properties, except soil depth, affect the habitat use of pikas. Overall, pikas preferred flat terrain with a wide field of view ("beach") and sunny, south-facing slopes; including running water sources, with the distance between the preferred habitats to water resources related to the type of water resources. In addition, pikas preferred loam (Ei = 0.258), soil depths > 40 cm (Ei = 0.214) but < 60 cm (Ei = 0.241), soil organic matter between 5% and 15% (Ei = 0.359) and soil moisture between 10% and 20% (Ei = 0.290). Our results highlight that the habitat-utilization preferences of pikas are highly dependent on geomorphic and soil characteristics. Future analyses of factors affecting habitat utilization preferences for small mammals should take geomorphic and soil characteristics into consideration.
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In canonical developmental patterning, the embryo is exposed to gradients of signaling activators that elicit different cellular responses depending on the activator's concentration. Recent optogenetic studies of terminal ERK signaling downstream of Torso receptor tyrosine kinase in the early Drosophila embryo reveal that even a brief, 5-minute ERK stimulus is sufficient to rescue the development of larval "tail" structures. Here, we reveal components of the molecular network that defines this sensitive developmental fate response. We find that low ERK doses produce sustained Abdominal-B ( Abd-B ) expression comparable to that of wild-type embryos. Abd-B expression is adjacent to, but non-overlapping with, two other transcriptional repressors: the ERK effector Tailless (Tll) and the gap gene Giant (Gt). Analysis of gene expression patterns in response to optogenetic perturbations suggests that the Tll-dependent repression of gt constitutes the sensitive ERK-responsive step: even low tll expression leads to potent repression of gt in nearby regions, with Abd-B expression arising in a stripe between the tll and gt domains. Our work suggests that the spectrum of phenotypes produced through optogenetic manipulation can be used to define how robust patterning can arise from low doses of inductive signals. A very low dose of receptor tyrosine kinase signaling in the early embryo induces tail formation many hours later.Transient ERK activity results in stable Abd-B expression, beginning as a stripe in nuclear cycle 14.Optogenetic ERK inputs induce a spectrum of ectopic phenotypes that reveal mutually exclusive expression of Tailless, Giant, and Abd-B in the posterior. Tailless-dependent repression of giant is the sensitive ERK-responsive step.
Under field conditions, predator-prey interactions can be modulated by the diverse availability and suitability of food resources, which diet type may alter biological and behavioral parameters of predators. Amblyseius largoensis and Euseius concordis are phytoseiid predatory mites identified as potential biological control agents for the giant whitefly, Aleurodicus cocois, a major pest of cashew trees. In the present study, we investigated how exclusive and mixed diets composed of Ricinus communis pollen, A. cocois eggs, and Tetranychus urticae (used for comparison, as it is a standard prey in phytoseiid predation analysis) affect oviposition and predation by A. largoensis and E. concordis. In addition, we examined the effect of A. cocois egg age on consumption and feeding preference by these predators. Both species exhibited higher oviposition rates when fed exclusively on pollen, whereas diets composed solely of T. urticae resulted in the lowest values. The presence of pollen did not affect the predation rate of A. cocois eggs, indicating that the availability of this alternative resource does not compromise predatory efficiency. The age of A. cocois eggs offered as food did not affect predator oviposition; however, in both choice and no-choice tests, A. largoensis and E. concordis preferentially consumed older eggs (> 48 h). These results demonstrate that pollen availability increases reproductive potential without reducing predation capacity and that prey egg age influences consumption dynamics, providing ecologically relevant insights for management strategies that integrate the conservation of floral resources and the use of these phytoseiid mites in the biological control of A. cocois in cashew production systems.
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Polyploid giant cancer cells (PGCCs) are characterized by abnormal enlargement and considerable polyploidy. Though the presence of giant cancer cells has been documented for decades, they remain not fully understood, especially in clinical practice, due to diagnostic challenges, and confusion regarding synonyms for PGCCs still exists. Thus, understanding PGCCs may be a key clue to overcoming them. This review offers a comprehensive overview of PGCCs, integrating insights from basic research and clinical studies to enhance understanding of their complex biology and clinical implications. In basic research, PGCCs are known to emerge under various stressors, including chemotherapy exposure, radiation, viral infection, and hypoxic environments. These cells play crucial roles in tumor progression through multiple mechanisms: enhancing genetic diversity, and facilitating metastatic spread via asymmetrical cell division and genomic instability. In clinical studies, PGCC-containing tumors have been shown to exhibit marked treatment resistance and are associated with a poor prognosis across multiple solid tumor types, including prostate, lung, and pancreatic cancers. Despite these therapeutic challenges, taxane-based chemotherapy has shown promising results in PGCC-containing tumors, such as pleomorphic carcinoma and undifferentiated carcinoma. Furthermore, emerging targeted therapies directed at specific pathways in PGCCs, particularly those involving TP53, represent potential strategies to improve clinical outcomes of patients with PGCC-containing tumors.
Thrombus formation after successful left atrial appendage occlusion (LAAO) has been well described; however, the clinical course after aborted LAAO remains poorly characterized. An 84-year-old man with atrial fibrillation and a history of cardioembolic events underwent an attempted LAAO procedure that was aborted because of unfavorable appendage anatomy. A small thrombus suspected on transthoracic echocardiography the day after the procedure progressively enlarged over 3 months and ultimately required surgical thrombus removal and left atrial appendage resection. Thrombus formation after an aborted LAAO attempt is not routinely observed, particularly under therapeutic anticoagulation. In this case, temporary interruption of anticoagulation, local endothelial disruption, blood stasis, and a possible prothrombotic milieu may have contributed. Progressive native left atrial appendage thrombus may occur after aborted LAAO despite anticoagulation therapy. Careful postprocedural imaging surveillance should be considered in high-risk patients.
Thoracic aortic aneurysms (TAA) are predominantly degenerative. Non-infectious inflammatory aortitis, including giant cell arteritis (GCA), Takayasu arteritis and clinically isolated aortitis (CIA), represents a less understood aetiology with poorly characterised growth patterns. While GCA is linked to higher TAA risk, preoperative growth data for inflammatory TAA are scarce. This study compares growth rates in histologically proven inflammatory aortitis. We conducted a retrospective case-control study, including patients with histologically proven aortitis and matched controls with degenerative TAA. Cases and controls were matched for age, sex, surgical year and procedure type. Aneurysm growth rate (mm/month) was calculated from serial imaging. This study included 23 patients with histologically confirmed aortitis (13 GCA, 9 CIA) and 42 matched controls with degenerative TAA. The mean growth rate was significantly higher in the aortitis group (0.177±0.01 mm/month; 2.12 mm/year) compared with controls (0.039±0.02 mm/month; 0.47 mm/year), representing a 4.5-fold acceleration (p<0.001). Among inflammatory etiologies, CIA demonstrated faster growth (0.338±0.06 mm/month; 4.06 mm/year) than GCA (2.1 mm/year; p<0.01). Patients with CIA more frequently required Bentall procedures (33% vs 0%, p=0.047). No differences were observed in baseline demographics, cardiovascular risk factors or baseline aortic diameters between groups. Histologically, 70% of aortitis cases exhibited granulomatous inflammation. Inflammatory aortitis is associated with a 4.5-fold faster preoperative TAA growth rate compared with degenerative aneurysms, with CIA exhibiting two times the growth rate of GCA. Prospective studies are warranted to validate these results and optimise surveillance and management strategies for this high-risk population.
We present the case of a young man with no notable medical history and who was not on anticoagulant or antiplatelet therapy but presented with chest pain shortly and melena after eating nuts. He had a large 20-cm dissecting intramural hematoma in the esophagus. Despite providing proton pump inhibitors as conservative treatment for 2 days, his chest discomfort persisted and hemoglobin level declined substantially; thus, endoscopic hematoma fenestration was performed. Repeat esophagogastroduodenoscopy 1 week postoperatively revealed substantial improvement in esophageal hematoma, with notable mucosal regeneration.