Search Results (1,033)

The remarkable plasticity of plants is best exemplified by the capacity of their somatic cells to regenerate entire organs or the organism itself. The molecular and cellular events underlying this ability are complex and multifaceted. The initial phase leading to cell cycle reactivation is often called dedifferentiation. This process is triggered either by wounding or exogenous hormone application. In this opinion paper, I propose that the dedifferentiation of mature somatic cells is a two-step process. It involves a transition into a transient senescence-like state induced by stress and/or signals emanating from dying cells. This state entails the loss of genetic information required for cell differentiation, resulting in a critical cellular condition. In the absence of subsequent proliferative signals, dedifferentiating (senescing) cells become committed to programmed cell death. Exogenous and/or endogenous plant hormones, such as auxin and cytokinin, might override this pathway. This rescue step, in most cases, activates cell divisions to replace lost cells/tissues. If cell division is maintained, it may result in callus formation. A callus is not an undifferentiated, homogeneous mass of cells. It is an unorganised tissue with at least some cells having ground-tissue-like molecular identity and high developmental potential. A callus might also form from pre-existing competent cell populations, e.g., pericycle cells, with no senescence-like intermitting state. It is discussed whether this “one-step” callus-formation pathway can be considered dedifferentiation. Full article

Background/Objectives: Bovine respiratory disease complex (BRDC) is commonly treated empirically, as etiological diagnosis is often impractical under field conditions. Comparative evidence on antimicrobial efficacy in undifferentiated BRDC remains limited. This study aimed to compare the therapeutic efficacy of tulathromycin and ceftiofur for treating undifferentiated BRDC in dairy cattle and to describe hematological and biochemical responses following a tulathromycin metaphylaxis program implemented during the seasonal high-PM2.5 period in northern Thailand. Methods: Thirty-eight Holstein–Friesian cattle with clinical BRDC were randomly assigned to receive tulathromycin (2.5 mg/kg, single subcutaneous dose; n = 20) or ceftiofur (2.2 mg/kg, intramuscularly for three consecutive days; n = 18). The clinical parameters of the surviving cattle were monitored for 5 days, and hematological and biochemical profiles were assessed on Days 1 and 5 in the surviving cattle. In addition, 87 pregnant dairy heifers were enrolled in a metaphylaxis trial and allocated to no injection, one tulathromycin injection, or two injections administered one month apart. Results: Cure rates were comparable between the tulathromycin and ceftiofur groups (90.0% vs. 88.9%), with similar case fatality rates (10.0% vs. 11.1%). No significant between-group differences were observed for clinical, hematological, or biochemical parameters. Both treatments resulted in significant within-group clinical and hematological improvement. During the metaphylaxis trial, no animals developed clinical BRDC; however, significant differences were observed in selected hematological parameters among injection groups. Conclusions: Tulathromycin and ceftiofur demonstrated comparable efficacy for treating undifferentiated BRDC in dairy cattle under field conditions. In the metaphylaxis component, conducted during the seasonal high-PM2.5 period, the absence of clinical BRDC cases did not allow for evaluation of preventive efficacy. Nevertheless, differences in selected blood parameters were observed among injection groups and should be interpreted cautiously, warranting further investigation in studies incorporating low- and high-PM2.5 comparisons. Full article

Daoist female alchemy (nüdan 女丹) texts articulate a bodily paradigm in which humans and nature mutually enfold one another, and in which yin and yang interact in harmonious complementarity. Through an analysis of three key dimensions, the yin-yang cosmology embedded in these texts, the ways menstruation, desire, and the female breasts are reconceived in the course of cultivation, and the ideal of gestating an a priori (xiantian 先天) embryo, this article argues that nüdan writings present a gender-symmetrical, pre-sexual symbolic culture. This culture both acknowledges gender difference and ultimately transcends it, seeking a return to the undifferentiated, yin-yang combined condition of primordial Dao. These texts reveal that women and men possess complementary yin and yang attributes that must be reintegrated in order to return to the a priori state and attain infinite vitality. They likewise suggest that both women and men harbor active, originary desire, and that only through equivalent processes of bodily transformation, reverting the sexualized, adult bodies into the unsexualized bodies of the girl and boy, can practitioners acquire the power to gestate the inner elixir, symbolizing inexhaustible vitality. In this sense, nüdan writings develop a pre-sexual narrative centered on vitality, offering a resonant response to concerns within postmodern feminism regarding how to dismantle centralized, phallogocentric narratives while enriching non-gender-centralized symbolic cultures. They thus provide a special path to reconsider gender not by advancing forward, but by stepping back into a more primordial, integrated ideal. Full article

Basic fibroblast growth factor (bFGF) and Transforming growth factor-beta (TGF-β) are key regulators of human pluripotent stem cell (hPSC) maintenance, supporting pluripotency and self-renewal. bFGF is particularly critical for sustaining the undifferentiated state and is commonly supplied through feeder-derived conditioned media. Similarly, TGF-β promotes hPSC expansion by modulating signaling pathways and contributing to a supportive stem cell niche. In this study, we investigated how the quality and variability of these growth factors influence hPSC culture performance. To address this, we developed and applied multiple physicochemical characterization methods—including size exclusion and reverse-phase chromatography—to assess growth factor purity and identify impurities across different material sources. Our findings show that certain post-translational modifications in TGF-β (e.g., oxidized variants) did not measurably affect hPSC culture. However, high temperature-dependent instability of bFGF preparations significantly altered hPSC morphology and growth. These findings underscore the need for improved quality control of growth factor components in culture media to ensure consistent hPSC maintenance, thus decreasing variability across experiments. This study highlights the value of correlating analytical physicochemical data with process performance, thereby advancing material understanding, enabling more efficient process development, and facilitating the identification of critical material attributes that affect the quality of cell therapy products. Full article

Background and Objectives: This study aimed to describe the clinical characteristics and survival outcomes of three representative complex karyotype soft tissue sarcoma (STS) subtypes—undifferentiated sarcoma (US, primarily undifferentiated pleomorphic sarcoma (UPS)), myxofibrosarcoma (MFS), and leiomyosarcoma of soft tissue (LMS-ST)—using data from a single-institution cohort. Materials and Methods: A retrospective review of 124 patients treated at a single tertiary referral center between 2002 and 2024 was conducted. Clinicopathologic characteristics and survival outcomes were analyzed. Kaplan–Meier methods were used to estimate overall survival (OS). Cox proportional hazards regression models were applied to identify independent prognostic factors for survival, incorporating variables such as age, sex, tumor stage, and treatment modality. Results: The cohort comprised 36 cases of US, 64 of MFS, and 24 of LMS-ST. OS and survival after cohort enrollment (S-NCC) were evaluated both by subtype and across the entire cohort to assess potential differences across tumor subgroups. In both univariable and multivariable analyses, US subtypes showed poorer survival than MFS and LMS-ST. FNCLCC grade 3 emerged as a significant adverse prognostic factor for survival across all three subtypes. For FNCLCC grade 3 patients, the presence of benign prostatic hyperplasia (BPH) was significantly associated with an increased risk of death. Conclusions: Among the three subtypes, US demonstrated the most aggressive clinical course, MFS was notable for frequent local recurrence but relatively favorable survival, and LMS-ST showed intermediate outcomes. These findings highlight the clinical heterogeneity of complex karyotype STS and provide a foundation for future studies integrating molecular and multi-omics data to refine risk stratification and therapeutic strategies. Full article

Background: Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare, high-grade, and aggressive tumor of the sinonasal tract. Due to the rarity of this malignancy, current treatment guidelines are based on small and often/mainly single-center retrospective datasets. In the absence of a universally accepted standard of care for SNUC, treatment approaches vary across countries and institutions, reflecting real-world clinical practice. The primary aim of this study was to describe real-world treatment and outcomes for patients with confirmed SNUC. Methods: This was an international, multi-center, retrospective, observational cohort study that pooled patients into the largest SNUC dataset to date. Fifteen centers were enrolled to contribute data, including seven from Europe, four from the United States, three from the United Kingdom, and one from Canada. In the absence of a universally accepted standard of care for SNUC, treatment approaches varied across countries and institutions, reflecting real-world clinical practice. Patients included were those with histologically confirmed SNUC who were treated between 1997 and 2021. Results: This study yielded 485 patients treated for SNUC. The median age at diagnosis was 55.6 years (IQR: 44.5–67.6), and 63.7% were male. Most cases presented at advanced stages, with 70.8% as T4a or T4b. Overall survival (OS) outcomes were available for 412 patients, with a median follow-up of 26.0 months. The 5- and 10-year OS were 47.2% (95% CI: 40.8–53.3%) and 39.6% (95% CI: 32.5–46.6%), respectively. Advanced age, dichotomized T-stage (T4a/b vs. T1–3), M-stage, and orbital involvement were significant poor prognostic factors on univariable analysis (p’s < 0.01). On multivariable analysis, orbital involvement (HR: 2.73, 95% CI: 1.42–5.27, p = 0.003) and distance metastasis stage (HR: 3.00, 95% CI: 1.25–7.21, p = 0.014) were both independently associated with worse OS. Conclusions: This observational study presents the largest multi-center cohort analysis of SNUC to date, providing new insights into prognostic factors for a rare cancer treated at global centers of excellence. Orbital involvement and the presence of metastases are candidate independent risk factors associated with poorer OS. Full article

In livestock farming, the reproductive function and breeding performance of Tan sheep are crucial for enhancing farming efficiency. Despite advances in research on sheep germ cells, studies on the identification of markers for spermatogonia, spermatocytes, and spermatozoa in Tan sheep remain limited and inadequate. In this study, Tan sheep were used as research subjects to investigate the morphological characteristics of testicular tissues, the developmental status of germ cells, and potential novel markers for spermatogonia, spermatocytes, and spermatozoa across different ages (0 days, 60 days, 180 days, and 365 days). Homology of the SMC3, G3BP1, and AKAP4 genes was analyzed via NCBI alignment. The localization and expression characteristics of these genes in the testis tissues of Tan sheep were investigated using HE staining, qPCR, and immunofluorescence double staining. The results showed that from 0 to 365 days of age, with increasing age, spermatogonia, spermatocytes, and spermatids exhibited an orderly distribution, and mature spermatozoa appeared in the tubular lumen, marking the initial establishment of the spermatogenic process. The homology of SMC3, G3BP1, and AKAP4 was 90%, 85%, and 81%. The mRNA levels of SMC3 and G3BP1 in the testes of 60-day-old Tan sheep were significantly increased, while AKAP4 expression showed a gradual increase with advancing age. SMC3 was co-localized with PLZF in undifferentiated spermatogonia, G3BP1 was co-expressed with SYCP2 in spermatocytes, and AKAP4 was co-expressed with PNA in spermatozoa. The findings of this study provide further supportive evidence for novel markers of spermatogonia, spermatocytes, and spermatozoa in Tan sheep. Full article

Colorectal cancer (CRC) progression and therapy resistance are driven in part by metabolic reprogramming and the persistence of cancer stem-like cells (CSCs). The seven in absentia homolog 2 (SIAH2)/with-no-lysine kinase 1 (WNK1) signaling axis has emerged as a potential regulator of these processes, yet its functional role in CRC metabolism and tumor–stroma crosstalk remains incompletely understood. Integrated analyses of The Cancer Genome Atlas–Colon Adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus (GEO, GSE17538) datasets revealed significant upregulation of SIAH2 and WNK1 in CRC tissues, with strong positive correlations to glycolysis- and hypoxia-associated genes, including PFKP, LDHA, BPGM, ADH1A, ADH1B, and HIF-1α. Single-cell and clinical profiling further demonstrated preferential enrichment of SIAH2 in undifferentiated, stem-like tumor cell populations. Functional studies across multiple CRC cell lines showed that SIAH2 silencing suppressed proliferation, clonogenic growth, tumor sphere formation, and cell-cycle progression, whereas SIAH2 overexpression exerted opposite effects. Seahorse extracellular flux analyses established that SIAH2 promotes glycolytic capacity and metabolic flexibility. At the protein level, SIAH2 regulated glycolytic enzymes and WNK1/hypoxia-inducible factor-1α (HIF-1α) signaling, effects that were amplified by cancer-associated fibroblast (CAF)-derived conditioned medium. CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target. Full article

Background: Nuclear protein in testis (NUT) carcinoma is a rare, aggressive, and poorly differentiated epithelial malignancy characterized by the rearrangement of NUTM1 (NUT midline carcinoma family member 1) on 15q14. It primarily originates along the midline structures, including the head, neck, thorax, and mediastinum. Although NUT carcinoma of the pelvic gynecological organs is exceedingly rare, reported cases have been limited to primary or metastatic ovarian tumors. Here, we present the first documented case of primary uterine NUT carcinoma. Case presentation: A 53-year-old postmenopausal woman presented with abnormal uterine bleeding and a uterine mass. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. The initial postoperative histopathological evaluation suggested undifferentiated endometrial sarcoma; however, subsequent immunohistochemical (IHC) analysis and fluorescence in situ hybridization revealed NUTM1 rearrangement, confirming the diagnosis of NUT carcinoma. The patient experienced tumor recurrence six months postoperatively and succumbed to the disease nine months later. Discussion: The pathological diagnosis was challenging; the presence of abrupt squamous differentiation prompted further IHC analysis, leading to the definitive diagnosis. Primary uterine NUT carcinoma may be misdiagnosed as other undifferentiated uterine tumors due to its rarity and histological overlap. Conclusions: Given the diagnostic challenges, NUT IHC staining and molecular testing for NUTM1 rearrangement should be considered in undifferentiated uterine tumors with ambiguous histopathological features. Full article

Background: Sarcomas are rare, aggressive malignancies with limited therapeutic options in advanced stages. This is the first real-world study in the MENA region evaluating the clinical utility of Next-Generation Sequencing (NGS) in guiding sarcoma treatment and improving outcomes. Methods: We retrospectively reviewed sarcoma patients who underwent NGS at a major referral center (2021–2024), comparing clinical and molecular outcomes between those who received NGS-based treatment adjustments (NBTA) and those who did not. Results: Seventy-eight patients were included (60% male; median age 44 years). Soft tissue sarcomas accounted for 70.5% of cases (n = 55), while bone sarcomas represented 29.5% (n = 23). Prior to NGS, 64.1% of patients had received a median of one line of systemic therapy. NGS was performed late in the disease course in 73% of cases. At least one mutation was detected in 87% (median 3 mutations). Targetable alterations were identified in 33% at the time of testing, rising to 42% with updated genomic knowledge and therapeutic advances. Overall, 20.5% received NBTA. Among non-NBTA patients, 67% had no actionable targets, 17% had no detectable mutations, and 16% were ineligible due to cost, limited access, or clinical deterioration. Tumor Mutational Burden was low in 79%, intermediate in 19%, and high in 2%, and all tumors were microsatellite stable. Patients receiving NBTA had a longer median Progression-Free Survival (9 vs. 2 months; p = 0.023). Median Overall Survival was longer in the NBTA group (74 vs. 48 months), though not statistically significant (p = 0.207). Genomic alterations were subtype-specific: EWSR1 rearrangements (Ewing and Desmoplastic small round cell tumors), CDK4 and MDM2 amplifications (Liposarcoma and Osteosarcoma), TP53 and RB1 mutations (Leiomyosarcoma), CDKN2A/B deletions (Undifferentiated Pleomorphic Sarcoma and Chondrosarcoma), and SS18 rearrangements (Synovial Sarcoma). Conclusions: Genomics-guided therapy in sarcoma is feasible and impactful. Expanding timely access to molecular profiling is essential for advancing precision oncology in the MENA region. Full article

This study comprehensively characterizes the PEBP gene family in Cymbidium sinense, an orchid with a prolonged vegetative phase that limits its industrial production. Genome-wide analysis identified six CsPEBPs, classified into FT-like, TFL1-like, and MFT-like subfamilies. Evolutionary, gene structure, and collinearity analyses revealed both conservation and lineage-specific diversification of these genes. CsFTL3, a distinctive FT-like member, displayed notably high expression during the bud undifferentiated stage, followed by a sharp downregulation upon floral initiation. Functional studies identified CsFTL3 as a key floral repressor. Heterologous overexpression in Arabidopsis delayed flowering time from 32.0 days (wild-type) to 63.0–75.3 days (transgenic) and increased rosette leaf number from 12.6 to 33.0–34.5, while its knockdown via virus-induced gene silencing (VIGS) in C. sinense accelerated floral bud development and upregulated flowering-promoter genes. Phylogenetically, CsFTL3 falls within the flowering repressor FT-I clade, and multiple sequence alignment identified critical amino acid substitutions (Y134S, W138L, Q140E) that likely underpin its functional divergence from typical flowering promoters. Furthermore, promoter analysis revealed an enrichment of light-, hormone-, and stress-responsive cis-elements, and its expression was modulated by gibberellin (GA), abscisic acid (ABA), and low-temperature treatments. Predicted protein–protein interaction and transcriptional regulatory networks provide preliminary insights into its complex regulation. We conclude that CsFTL3 acts as a crucial floral inhibitor, integrating environmental and endogenous cues to repress flowering. These findings offer fundamental insights into the molecular mechanisms of flowering in orchids and provide a valuable genetic resource for molecular breeding programs aimed at achieving precise flowering time control. Full article

This review summarizes a growing collection of data on adult neurogenesis in various vertebrate species, with a focus on teleost fish and mammals. Teleost fish serve as exceptional models for studying the dynamics of the cell cycle and the functions of adult neural stem progenitor cells (aNSPCs) throughout the central nervous system (CNS). New information about the characteristics of cells in various areas of the telencephalon of non-model objects—juvenile masu salmon Oncorhynchus masou and chum salmon Oncorhynchus keta—during postembryonic ontogenesis and after traumatic injury expands the current understanding of the issue. The expression of molecular markers of adult-type glial precursors in the model zebrafish and non-model objects, juveniles O. masou and O. keta, was presented. Immunohistochemical (IHC) verification of BrdU and PCNA made it possible to identify a population of rapidly and slowly proliferating cells in the pallium of intact O. masou and after traumatic brain injury (TBI). In salmonids, unlike in mammals, progenitor cells are able to differentiate into neurons after injury. The expression of vimentin and GFAP in the aNSCPs has functional specificity. A comparative analysis of the expression of Pax transcription factors in various vertebrates and juveniles O. masou is presented. Pax genes maintain cells in an undifferentiated state and ensure the spatiotemporal formation of mature cell types in changing developing neurogenic niches. The functions of glutamine synthetase (GS) and H₂S in the brains of vertebrates and juvenile chum salmon under intact conditions and after TBI are characterized. In fish, unlike mammals, as a result of TBI, neuronal conduction is restored in the injury area, whereas in mammals the regenerative process is complicated by neuroinflammation and culminates in the formation of a glial scar. Full article

Background: Dendritic cells (DCs) are heterogeneous antigen-presenting cells that bridge innate and adaptive immunity. Recent classifications of hematolymphoid neoplasms highlight the complex origins of DC-related neoplasms. DCs have also been associated with the progression of multiple myeloma (MM). This report presents the case of a patient with MM in whom bone marrow analysis revealed an unusual additional clonal population of immature cells, in addition to plasmacytoid DCs, that later evolved into plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia (pDC-AML). Methods: The bone marrow of a 69-year-old man with neutropenia and thrombocytopenia was examined by morphology, immunohistochemistry, flow cytometry, cytogenetics, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). Serial assessments were performed before and during treatment with bortezomib and dexamethasone for MM, and later with daunorubicin/cytarabine for AML. Results: Initial bone marrow analysis revealed coexisting clonal plasma cells with t(11;14) and a population of CD34+/CD123+/CD45RA+ cells lacking lineage markers, in addition to pDCs, suggestive of precursor DCs rather than acute undifferentiated leukemia. Cytogenetic analysis identified a small clone with isolated del(20q), which corresponded in size to the clone of undifferentiated cells and to the clone with pathogenic variants detected by NGS in the BCOR, RUNX1, and SRSF2 genes. Myeloma therapy decreased both MM and undifferentiated cells; however, within four months, pDC-AML evolved with del(20q) and higher variant allele frequencies of the previously detected gene variants. Remission was achieved with standard AML chemotherapy. Conclusions: This case supports evidence that MM-associated immune dysfunction and bone marrow niche alterations may promote secondary myeloid malignancies independently of cytotoxic therapy. It demonstrates the earliest events in pDC-AML evolution. Furthermore, the immature immunophenotype raises the question of appropriate treatment, since a diagnosis of acute undifferentiated leukemia can be established. Full article

Neuroblastoma (NB), a pediatric cancer of sympatho-adrenal (SA) lineage, is marked by disrupted differentiation and cellular heterogeneity. INSM1, a zinc-finger transcription factor, is highly expressed in NB and developing SA tissues, where it regulates neuroendocrine differentiation, especially in chromaffin cells. We investigated INSM1’s role in maintaining an undifferentiated, progenitor-like state in NB and its regulation via metabolic and epigenetic mechanisms. Transcriptomic profiling, promoter assays, and metabolic flux analysis revealed that INSM1 expression correlates with methionine cycle activity, particularly the S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio. Disruption of SAM/SAH balance altered INSM1 promoter activity and histone methylation, implicating epigenetic control in NB cell fate. Retinoic acid-induced differentiation downregulated INSM1 and N-Myc, linking INSM1 to tumor cell immaturity. INSM1 overexpression in SH-SY-5Y cells upregulated neuroendocrine and thyroid hormone-related genes (CHGA, CHGB, DDC, NCAM1, DIO3, TH), while suppressing genes involved in cell cycle (RRM, CDC25A), methionine metabolism (AHCY, MAT2A), transcriptional regulation (MYBL2, EZH2), and oncogenic signaling (ALK, LINC011667). These findings suggest that INSM1 promotes NB aggressiveness by sustaining a neuroendocrine progenitor-like phenotype through metabolic-epigenetic coupling. Full article

The close spatial and genetic coexistence of Skarn-type and Hydrothermal Vein-type Pb-Zn deposits in the Shanghulin area, Inner Mongolia, poses a significant challenge to conventional “ undifferentiated” prediction models. This study aims to decouple these distinct metallogenic patterns using a data-driven, “type-specific modeling” strategy, establishing separate prediction models for Skarn-type and Hydrothermal Vein-type mineralization. Our workflow first employs Lasso–RFECV for rigorous pre-screening of over 60 geoscience features to identify the optimal predictive subset. Subsequently, an XGBoost model is trained on these selected features, and the SHAP framework is applied to interpret the geological significance of its decision logic. The results confirm two distinct indicator systems. (1) The Skarn-type model is controlled by spatial proximity to a heat source, heavily relying on Distance_to_Volcano and high-temperature indicators (CLR_Mo, CLR_W, CLR_Mn). (2) The Hydrothermal Vein-type model is “chemical fingerprint-driven”, prioritizing CLR_Y and identifying a complex “leaching-enrichment” pattern: mineralization requires simultaneous wall-rock leaching (low CLR_Al₂O₃, low CLR_Y) and specific metal enrichment (high CLR_Co, high CLR_Zn). This study confirms the controlling factors: Skarn-type deposits are governed by magmatic proximity, whereas Hydrothermal Vein-type deposits are defined by specific alteration geochemical signatures. The proposed “Lasso–RFECV → XGBoost → SHAP” workflow successfully decouples these independent, geologically meaningful prospectivity models from complex data, offering a new paradigm for precise exploration. Full article