Search Results (426)

A newly emerging disease affecting Schizolobium parahyba (commonly known as pachaco), termed “decline and dieback,” has been reported in association with the fungal pathogens Fusarium sp. and Botryodiplodia sp. This study assessed the antagonistic potential of two Trichoderma sp. isolates (CEP-01 and CEP-02) against these phytopathogens under controlled laboratory conditions. The effects of three temperature regimes (5 ± 2 °C, 24 ± 2 °C, and 30 ± 2 °C) on the growth and inhibitory activity of two Trichoderma spp. isolates were evaluated using a completely randomized design. The first experiment included six treatments with five replicates, while the second comprised twelve treatments, also with five replicates. All assays were conducted on PDA medium. No fungal growth was observed at 5 ± 2 °C. However, at 24 ± 2 °C and 30 ± 2 °C, both isolates reached maximum growth within 72 h. At 24 ± 2 °C, both Trichoderma spp. isolates exhibited inhibitory activity against Fusarium sp. FE07 and FE08, with radial growth inhibition percentages (RGIP) ranging from 37.6% to 44.4% and 52,8% to 54.6%, respectively. When combined, the isolates achieved up to 60% inhibition against Fusarium sp., while Botryodiplodia sp. was inhibited by 40%. At 30 ± 2 °C, the antagonistic activity of Trichoderma sp. CEP-01 declined (25.6–32.4% RGIP), whereas Trichoderma sp. CEP-02 showed increased inhibition (60.3%–67.2%). The combination of isolates exhibited the highest inhibitory effect against Fusarium sp. FE07 and FE08 (68.4%–69.3%). Nonetheless, the inhibitory effect on Botryodiplodia sp. BIOT was reduced under elevated temperatures across all treatments. These findings reinforce the potential of Trichoderma spp. isolates as a viable and eco-friendly alternative for the biological control of pathogens affecting S. parahyba, contributing to more sustainable disease management practices. The observed inhibitory capacity of Trichoderma sp., especially under optimal temperature conditions, highlights its potential for application in integrated disease management programs, contributing to forest health and reducing reliance on chemical products. Full article

Nonspecific toxicity to normal and malignant cells restricts the clinical utility of many anticancer drugs. In particular, anemia in cancer patients develops due to drug-induced toxicity to red blood cells (RBCs). The anticancer alkaloid, cepharanthine (CEP), elicits distinct forms of cell death including apoptosis and autophagy, but its cytotoxicity to RBCs has not been investigated. Colorimetric and fluorometric techniques were used to assess eryptosis and hemolysis in control and CEP-treated RBCs. Cells were labeled with Fluo4/AM and annexin-V-FITC to measure Ca²⁺ and phosphatidylserine (PS) exposure, respectively. Forward scatter (FSC) was detected to estimate cell size, and extracellular hemoglobin along with lactate dehydrogenase and aspartate transaminase activities were assayed to quantify hemolysis. Physiological manipulation of the extracellular milieu and various signaling inhibitors were tested to dissect the underlying mechanisms of CEP-induced RBC death. CEP increased PS exposure and hemolysis indices and decreased FSC in a concentration-dependent manner with prominent membrane blebbing. Although no Ca²⁺ elevation was detected, chelation of intracellular Ca²⁺ by BAPTA-AM reduced hemolysis. Whereas SB203580, D4476, acetylsalicylic acid, necrosulfonamide, and melatonin inhibited both PS exposure and hemolysis, staurosporin, L-NAME, ascorbate, caffeine, adenine, and guanosine only prevented hemolysis. Interestingly, sucrose had a unique dual effect by exacerbating PS exposure and reversing hemolysis. Of note, blocking KCl efflux augmented PS exposure while aggravating hemolysis only under Ca²⁺-depleted conditions. CEP activates Ca²⁺-independent pathways to promote eryptosis and hemolysis. The complex cytotoxic profile of CEP can be mitigated by targeting the identified modulatory pathways to potentiate its anticancer efficacy. Full article

Sperm flagellum defects are tightly associated with male infertility. Centriolar satellites are small multiprotein complexes that recruit satellite proteins to the centrosome and play an essential role in sperm flagellum biogenesis, but the precise mechanisms underlying this role remain unclear. Serologically defined colon cancer autoantigen protein 8 (SDCCAG8), which encodes a protein containing eight coiled-coil (CC) domains, has been associated with syndromic ciliopathies and male infertility. However, its exact role in male infertility remains undefined. Here, we used an Sdccag8 mutant mouse carrying a CC domains 5–8 truncated mutation (c.1351–1352insG p.E451GfsX467) that models the mutation causing Senior–Løken syndrome (c.1339–1340insG p.E447GfsX463) in humans. The homozygous Sdccag8 mutant mice exhibit male infertility characterized by multiple morphological abnormalities of the flagella (MMAF) and dysmorphic structures in the sperm manchette. A mechanistic study revealed that the SDCCAG8 protein is localized to the manchette and centrosomal region and interacts with PCM1, the scaffold protein of centriolar satellites, through its CC domains 5–7. The absence of the CC domains 5–7 in mutant spermatids destabilizes PCM1, which fails to recruit satellite components such as Bardet–Biedl syndrome 4 (BBS4) and centrosomal protein of 131 kDa (CEP131) to satellites, resulting in defective sperm flagellum biogenesis, as BBS4 and CEP131 are essential to flagellum biogenesis. In conclusion, this study reveals the central role of SDCCAG8 in maintaining centriolar satellite integrity during sperm flagellum biogenesis. Full article

Cellular senescence is a state of the durable cell cycle arrest of dysfunctional cells, which has been associated with the promotion of tumor cell reprogramming into a stem cell state. We previously reported that the mixed lineage kinase (MLK) inhibitor CEP-1347 promotes the differentiation of glioma stem cells (GSCs)—key contributors to glioblastoma recurrence and therapy resistance—into non-stem tumor cells. However, we also noted that CEP-1347–treated GSCs exhibited a morphological change suggestive of senescence. Therefore, we herein investigated whether CEP-1347 induces senescence in GSCs and, consequently, if senescent GSCs may be eliminated using senolytics. Cell death induced by CEP-1347 in combination with senolytic agents or with the knockdown of anti-apoptotic BCL2 family genes, as well as the effects of CEP-1347 on the expression of senescence markers and anti-apoptotic Bcl-2 family proteins, were examined. The results obtained showed that CEP-1347 induced senescence in GSCs accompanied by the increased expression of Bcl-xL. Among the panel of senolytic agents tested, navitoclax, a BH3 mimetic, efficiently induced cell death in GSCs when combined with CEP-1347 at concentrations clinically achievable in the brain. The knockdown of Bcl-xL resulted in more pronounced GSC death in combination with CEP-1347 than that of Bcl-2. These results suggest that combining CEP-1347 with the targeting of Bcl-xL, the expression of which increases with CEP-1347-induced senescence, is a rational approach to ensure the elimination of GSCs, thereby improving the outcomes of glioblastoma treatment. Full article

This study investigates the effects of transcutaneous electroacupuncture stimulation (TEAS) on eyeblink rate, EEG, and heart rate variability (HRV), emphasising whether eyeblink data—often dismissed as artefacts—can serve as useful physiological markers. Sixty-six participants underwent four TEAS sessions with different stimulation frequencies (2.5, 10, 80, and 160 pps, with 160 pps as a low-amplitude sham). EEG, ECG, PPG, and respiration data were recorded before, during, and after stimulation. Using non-parametric statistical analyses, including Friedman’s test, Wilcoxon, Conover–Iman, and bootstrapping, the study found significant changes across eyeblink, EEG, and HRV measures. Eyeblink laterality, particularly at 2.5 and 10 pps, showed strong frequency-specific effects. EEG power asymmetry and spectral centroids were associated with HRV indices, and 2.5 pps stimulation produced the strongest parasympathetic HRV response. Blink rate correlated with increased sympathetic and decreased parasympathetic activity. Baseline HRV measures, such as lower heart rate, predicted participant dropout. Eyeblinks were analysed using BLINKER software (v. 1.1.0), and additional complexity and entropy (‘CEPS-BLINKER’) metrics were derived. These measures were more predictive of adverse reactions than EEG-derived indices. Overall, TEAS modulates multiple physiological markers in a frequency-specific manner. Eyeblink characteristics, especially laterality, may offer valuable insights into autonomic function and TEAS efficacy in neuromodulation research. Full article

Background: The growth of parcel volumes in urban areas, largely driven by e-commerce, has increased the complexity of pickup and delivery operations. To meet demands for cost efficiency, flexibility, and sustainability, CEP (Courier, Express, and Parcel) operators increasingly outsource segments of their last-mile networks. Methods: This study proposes a novel multidimensional cost model for outsourcing, integrating five key variables: transport unit type (parcel/pallet), service phase (pickup/delivery), vehicle category, powertrain type, and delivery point type. The model applies correction coefficients based on internal operational costs, further adjusted for location and service quality using a bonus/malus mechanism. Results: Each cost component is calculated independently, enabling full transparency and route-level cost tracking. A real-world case study was conducted using operational data from a CEP operator in Bosnia and Herzegovina. The model demonstrated improved accuracy and fairness in cost allocation, with measurable savings of up to 7% compared to existing fixed-price models. Conclusions: The proposed model supports data-driven outsourcing decisions, allows tailored cost structuring based on operational realities, and aligns with sustainable last-mile delivery strategies. It offers a scalable and adaptable tool for CEP operators seeking to enhance cost control and service efficiency in complex urban environments. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by a dense desmoplastic stroma and a highly immunosuppressive tumor microenvironment (TME). The focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is considered a critical regulator of various cellular processes involved in cancer development. FAK inhibitors (FAKi) have proven to be promising therapeutics for cancer treatment including for pancreatic cancer. As monotherapy, however, FAKi showed only a modest effect in clinical studies. In this study, we investigated the cytotoxicity of six FAKi (Defactinib, CEP-37440, VS-4718, VS-6062, Ifebemtinib and GSK2256098) used in clinical trials on five pancreatic tumor cell lines. We further examined whether their anti-tumor activity can be enhanced by combination with the oncolytic coxsackievirus B3 (CVB3) strain PD-H. IC₅₀ analyses identified Defactinib and CEP-37440 as the most potent inhibitors of tumor cell growth. VS-4718, VS-6062, and Ifebemtinib showed slightly lower activity, while GSK2256098 was largely ineffective. The combination of Defactinib, CEP-37440, VS-4718, and VS-6062 with PD-H resulted in varying effects on cytotoxicity, depending on the cell line and the specific FAKi, ranging from no enhancement to a pronounced increase. Using the Chou–Talalay method, we determined combination indices (CI), revealing synergistic, additive, but also antagonistic interactions between the respective FAKi and PD-H. Considering both oncolytic efficacy and the CI, the greatest enhancement in oncolytic activity was achieved when VS-4718 or CEP-37440 was combined with PD-H. These findings indicate that co-treatment with PD-H can potentiate the therapeutic activity of the selected FAKi and may represent a novel strategy to improve treatment outcomes in PDAC. Full article

Background: To improve the prognosis of patients with lung adenocarcinoma (LUAD), revolutionary treatments for metastatic lesions are essential. Methods: To identify genes closely involved in LUAD-cell-derived metastasis, we used RNA sequencing to generate microRNA (miRNA) expression signatures of brain metastatic lesions. Once tumor-suppressive miRNAs are identified, it will be possible to explore the numerous tumor-promoting genes that are regulated by miRNAs. Results: By comparison with a previously created LUAD signature, we identified several miRNAs whose expression was significantly suppressed in brain metastases. We focused on both strands of pre-miR-195 (miR-195-5p and miR-195-3p), which were significantly downregulated in brain metastatic tissues, and confirmed by ectopic expression assays that both strands of pre-miR-195 attenuated the aggressive phenotypes (cell proliferation, migration, and invasion) of LUAD cells. These data suggest that both strands of pre-miR-195 have tumor-suppressive functions in LUAD cells. Next, we explored the target molecules that each miRNA strand regulates in LUAD cells. We identified 159 target genes regulated by miR-195-5p and miR-195-3p, of which 12 genes (ANLN, CDC6, CDCA2, CDK1, CEP55, CHEK1, CLSPN, GINS1, KIF23, MAD2L1, OIP5, and TIMELESS) affect cell cycle/cell division and the prognosis of LUAD patients. Finally, we focused on two genes, ANLN (miR-195-5p target) and MAD2L1 (miR-195-3p target), and demonstrated their oncogenic functions and the molecular pathways they regulate in LUAD cells. Conclusions: The miRNA signature derived from lung cancer brain metastasis will be a landmark in the field, and analysis of this miRNA signature will accelerate the identification of genes involved in lung cancer brain metastasis. Full article

Pathological complete response (pCR) following neoadjuvant therapy for IBC has shown a strong correlation with event-free survival and overall survival. Over the past three decades, the five-year net survival rate for breast cancer has generally increased; however, several Eastern European countries exhibit lower survival rates. Data from Romania, specifically regarding Her2-positive breast cancer response to therapy, are notably limited. Background/Objectives: The aim of our study was to evaluate the response to NAT using chemotherapy and Her2-targeted therapy in a cohort of 167 patients diagnosed with invasive breast cancer in our institution. Methods: We retrospectively analyzed 167 consecutive cases diagnosed with IBC in our institution between January 2020 and September 2024 with Stages II and III Her2-positive IBC. The overall pCR rates and several factors cited in the literature as predictors of pCR were analyzed. Results: Overall, the pCR rate was 50.29%, with higher values in 3+ cases (62.28%) compared to 2+ cases/ISH amplified (24.53%). Higher pCR rates were observed in hormone-negative cases, Stage II cases, estrogen receptor-negative cases, and high Ki-67 values. Patient age, ISH group, Her2 copy number, Her2:CEP17 ratio, and clinical lymph node involvement did not seem to influence pCR rates in our study. Conclusions: The data presented in our study represent, to the best of our knowledge, the largest cohort of patients diagnosed with Her2-positive IBC from Romania. The presented results and the pCR predictive factors were comparable to those cited in other studies on Her2-positive IBC cases. Full article

The spacing between piles plays a crucial role in determining the load-bearing capacity of CEP group pile foundations equipped with a bearing platform. In this research, five sets of six-pile models with different pile spacings were created using ANSYS finite element analysis. To understand how damage impacts the system, this study examined displacement patterns and stress distribution within both the piles and the adjacent soil. Additionally, the force interaction between the piles and soil was explored to uncover the underlying failure mechanisms. The results shed light on how varying pile spacing affects the overall bearing capacity of the foundations. Based on our thorough analysis, we pinpoint the most effective pile spacing configuration. The findings reveal that, generally speaking, increasing the distance between piles tends to boost the load-bearing capacity of the entire group foundation. However, this relationship is not linear; once the spacing surpasses four times the cantilever’s diameter, further widening does not yield noticeable gains in performance. In real-world scenarios, it is advisable to keep the spacing between 3.5 to 4 times the cantilever diameter for optimal results. Moreover, the stability of the bearing platform and the plate plays a vital role in resisting sideways forces. Ensuring that the shear strength of the surrounding soil aligns with established standards is essential for maintaining the overall durability and safety of the group pile system. Full article

Background/Objectives: Intergenerational care plays a significant role in shaping household dietary quality and human capital development in China. Influenced by the legacy of the one-child policy, the care provided in these families often prioritizes child-focused practices. This study examines how intergenerational care influences schoolchildren’s sugar-sweetened beverage (SSB) consumption. Methods: This study utilizes data from the 2014–2015 China Education Panel Survey (CEPS) to investigate the impact of intergenerational care on schoolchildren’s dietary behaviors, with a focus on sugar-sweetened beverage (SSB) consumption. We apply both ordinary least squares (OLS) regression and the ordered logit model to estimate the impacts, and we use the instrumental variables approach to address potential endogeneity. Results: Schoolchildren from only-child families report greater SSB consumption, while those from multi-child families consume less. Intergenerational care is linked to more digital media exposure, more pocket money, and less parental supervision. These findings withstand rigorous validation through multiple robustness checks, including sample restriction strategies and propensity score matching (PSM) analysis. The effect is especially pronounced among boys, schoolchildren from families with higher parental education levels, and schoolchildren attending schools without formal nutrition education programs. Conclusions: The result indicates that intergenerational care significantly increases SSB consumption among schoolchildren from only-child families. Community nutrition and school health education programs can reduce schoolchildren’s SSB consumption, thereby lowering risks of obesity and other public health concerns. Full article

Purpose: The acquirer’s corporate environmental performance (CEP) in mergers and acquisitions has been a subject of debate, yielding mixed results. This paper uses the US firm-level data of 1437 M&A deals from 2002–2019 to examine the impact of overall CEP, resource use, emissions, and innovation on the acquirers’ post-merger market value. Design/methodology/approach: This study employs multi-level fixed effects panel regression using Ordinary Least Squares (OLS) and the instrumental variable (IV) 2SLS method to estimate the models and compare the results with those from robust estimation. Absorbing the multiple levels of fixed effects (i.e., firm, industry, and year) offers a novel and robust algorithm for efficiently accounting for unobserved heterogeneity. The results from IV (2SLS) are more convincing, as the method overcomes the problem of endogeneity due to reverse causality and sample selection bias. Findings: The authors find that CEP has a significant impact on market value, particularly in the long term. While both resource use and emissions performance have positive effects, emissions performance has a stronger impact, presumably because external stakeholders and market participants are more concerned about emissions reduction. The performance of environmental innovation is relatively weak compared to other pillars. Descriptive analysis shows low average scores in environmental innovation compared to the resource use and emissions performance of the acquirers. However, large deals yield significant returns from investing in environmental innovation in both the short and long term compared to small deals. Practical implications: This paper offers several practical implications. First, environmental performance can help improve the acquirer’s long-term market value. Second, managers can focus on the strategic side of environmental performance, based on its pillars, and benchmark their relative position against peers. Third, environmental innovation can be considered a new potential, as the market as a whole in this area is still lagging. Given the growing pressure to improve environmental technology and innovation, prospective acquirers should confidently prioritise actions on green revenue, product innovation, and capital expenditure now rather than ticking these boxes later. Originality value: The key contribution is offering valuable insights into the impact of acquirers’ environmental performance on long-term value creation in mergers and acquisitions (M&A). These results fill the gap in the literature focusing mainly on the effect of environmental pillar and sub-pillar scores on acquirer’s firm value. The authors claim that analysing sub-pillar-level granularity is crucial for accurately measuring the effects on firm-level performance. Full article

PAN-gastrointestinal cancers (PAN-GI cancers), including the oral, esophageal, gastric, hepatocellular, pancreatic=, and colorectal cancers, are the leading cause of cancer-related mortality. Despite recent advances in identifying the molecular mechanisms driving these malignancies, the high incidence and recurrence of the PAN-gastrointestinal cancers and the low survival rates of patients indicate the need to introduce biomarkers for early diagnosis to improve diagnostic and therapeutic approaches. In the present study, using integrated transcriptomics, RNA-Seq and microarray data, from the TCGA and GEO databases, respectively, were combined to discover and validate a global biomarker panel for PAN-gastrointestinal cancers. In order to validate the bioinformatics data, the expression levels of genes in the molecular panel were evaluated using real-time quantitative polymerase chain reaction (qPCR) in tumor tissues of 21 patients with early diagnosis of gastric cancer and colorectal cancer (Stage I and II). By examining the transcriptomic profiles of six types of PAN-gastrointestinal cancers, a network of closely related hub genes (n = 167) with biomarker potential (p value < 0.05) was identified. Also, using ROC curve analysis and the Youden index, a molecular panel consisting of AURKA, CEP55, DTL, and TTK was presented (95% confidence interval and p value < 0.05), which showed exceptional sensitivity and specificity in differentiating malignant tissue from normal tissue (AUC > 80%). The diagnostic efficacy of these markers was confirmed by further validation using qPCR in colorectal and gastric tumor samples (p value < 0.05). In conclusion, a novel molecular signature panel including the AURKA, CEP55, DTL, and TTK genes could improve early cancer detection and diagnostic accuracy, and it may contribute to the treatment outcomes of PAN-gastrointestinal cancer patients. Full article

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration and vision loss. While current management is largely supportive—relying on visual aids, orientation training, and nutritional supplementation—these interventions offer only symptomatic relief and do not halt disease progression. Advances in molecular genetics have led to the development of targeted treatments, including gene replacement therapy, RNA-based therapies, and CRISPR/Cas9 gene editing, offering promising strategies for disease modification. The approval of voretigene neparvovec for RPE65-associated RP marked a milestone in gene therapy, while ongoing trials targeting mutations in RPGR, USH2A, and CEP290 are expanding therapeutic options. Optogenetic therapy and stem cell transplantation represent additional strategies, particularly for patients with advanced disease. Challenges persist in delivery efficiency, immune responses, and treating large or dominant-negative mutations. Non-viral vectors, nanoparticle systems, and artificial intelligence-guided diagnostics are being explored to address these limitations and support personalized care. This review summarizes the current and emerging therapeutic landscape for RP, highlighting the shift toward precision medicine and the need for continued innovation to overcome genetic and phenotypic variability. Full article

Exploring the neurogenic potential of extraneural stem cells under the actions of proneurogenic biomolecules may enhance the success of autologous cell therapy for neurodegenerative diseases such as Parkinson’s. Neural stem and progenitor cells (NSPCs) from extraneural tissues have emerged as potential sources of functional dopaminergic (DA) neurons. Background/Objectives: This study aimed to generate DA neurons from ovarian cortical cells (OCC)-derived NSPCs to elucidate whether follicle-stimulating hormone (FSH) can enhance this process and to evaluate the electrophysiological functionality of differentiated neural cells using the patch-clamp technique. Methods: OCC-NSPCs were differentiated towards the DA pathway during the neurosphere (NS) assay after two culture periods for cell expansion (CEP-1, CEP-2) with one of these media: M1 (positive control with epidermal growth factor, EGF, and fibroblast growth factor2, FGF2), M2 (control), and M3 (M2 with FSH, 50 ng/mL). Image analysis, morphometric evaluation, cell proliferation assays, and gene expression analysis of NSPC-specific transcripts were performed. After CEP-2, NS cells were cultured for 30 days in a serum-free medium containing Sonic-Hedgehog, FGF2, FGF8, and brain-derived neurotrophic factor (BDNF) for differentiation. At the end of culture, expression, and immunolocalization of GFAP, Olig2, NeuN, and tyrosine hydroxylase (TH) were analyzed in cells, along with patch-clamp recordings in differentiated neurons. Results: Cell proliferation and NS development were larger in OCC-NSPCs from groups M1 and M3 than in M2. Expression of NSPC-related transcripts was higher in M2; however, M1 and M3 cultures showed greater expression of differentiation markers NeuN, GFAP, Olig2, and TH. NeuN, GFAP, and TH were immunolocalized in differentiated cells and NS that were generated during differentiation. TH was localized in neural precursor cells, some neurons, core cells of small-, medium-, and large-sized NS, and in cells close to the outer cell layer of large NS, with greatest immunolocalization percentages in NS primed with FSH during CEP-1/2 (M3). Electrophysiological recordings revealed a major incidence of plateau potentials and a significant proportion of complete action potentials, reflecting successful functional neuronal differentiation. Conclusions: DA precursors and functional neurons can be successfully obtained after OCC-NSPCs-directed differentiation. FSH priming during the expansion period enhances the neurogenic potential of these cells towards the DA pathway. Future research will explore the eventual therapeutic use of these findings for neurodegenerative diseases. Full article