Search Results (2,058)

Background/Objectives: High-grade serous carcinoma (HGSC) is the leading cause of ovarian cancer-related mortality. It usually arises from fallopian tube epithelium, with a smaller subset arising in non-tubal sites including the ovary or peritoneum. The origin of HGSCs without evidence of tubal involvement remains unclear. Moreover, in women with genetic predisposition to developing HGSC, the additional protection afforded by prophylactic removal of the ovaries in addition to the fallopian tubes has not yet been established. Methods: We used a well-characterized genetically engineered mouse model (GEMM) of oviductal HGSC based on conditional, somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 tumor suppressor genes (BPRN mice) to compare preventive effects for HGSC via bilateral salpingectomy versus bilateral salpingo-oophorectomy. We also explored the origins of non-tubal HGSCs in ectopic tubal-type epithelium (endosalpingiosis) present in the mouse ovaries and peritoneum. Results: While bilateral salpingectomy significantly reduced the incidence of HGSCs in the GEMM model, bilateral salpingo-oophorectomy completely prevented tumor development. We identified an example of HGSC with apparent origin in endosalpingiosis, implicating endosalpingiosis as a likely precursor for non-tubal HGSC. Conclusions: Our findings confirm the superiority of bilateral salpingo-oophorectomy over salpingectomy alone in reducing HGSC risk and affirm the rationale for surgical strategies to reduce HGSC risk in women carrying pathogenic variants of BRCA1/2 and other genes associated with homologous recombination deficiency. Our findings also illustrate how work with GEMMs can advance new insights into HGSC pathogenesis. Full article

Gastrodiae Rhizoma (tianma, TM), a traditional medicine that has food and medicine homology, faces controversy over retaining its epidermis (tianma pi, TP) during processing due to unclear phytochemical value. This study presents the first integrated approach combining GC–IMS, UHPLC–MS, and Caenorhabditis elegans (C. elegans) aging models to compare TP with the tuber core (tianma xin, TX). The results include the following: (1) A total of forty-seven volatile compounds were identified by GC–IMS, including 12 key aroma substances via relative odor activity value (ROAV ≥ 1), of which seven ((Z)-4-heptenal, β-citronellol, hexanal, 1-pentanol, 1-octen-3-one, 2-methylpropanol, and 2-butanone) were enriched in TP. (2) Non-targeted metabolomics revealed 1025 metabolites via UHPLC–MS, highlighting phenylpropanoid biosynthesis as the primary differential pathway (p < 0.05). Phenylpropanoids and polyketides exhibited predominant enrichment in TP (|log2FC| > 2, VIP > 1, p < 0.01). (3) In C. elegans models, TP outperformed TX in pharyngeal pumping (4.16%, p < 0.05), while both extended stress-resistant lifespan (p < 0.01). In conclusion, TP plays an essential role in establishing the characteristic odor profile of TM and retaining bioactive components, particularly phenylpropanoids. Preserving TP during processing optimally maintains the distinctive aroma profile and pharmacological value of TM, which provides valuable guidance for industrial utilization. Full article

Background: Haemophilus influenzae (Hi), a Gram-negative bacterium, is divided into two broad categories: encapsulated and non-capsulated isolates, also called non-typeable Hi isolates (NTHi). NTHi has become prevalent since the introduction of the vaccine against Hi of serotype b. Hi can cause local infections on respiratory mucosal surfaces and urogenital infections, which can lead to septic abortion in pregnant women. It can also cause invasive infections such as meningitis and septicemia. Moreover, NTHi isolates are becoming increasingly resistant to antibiotics. Vaccines targeting NTHi are not yet available. As these NTHi isolates are not encapsulated, vaccines should target proteins at the bacterial surface. However, vaccine development is hindered by the high variability of these proteins. We aimed to identify conserved outer membrane proteins (OMPs) for vaccines against NTHi. Methods: We analyzed core-genome multilocus sequence typing (cgMLST) of 1144 genomes of Hi collected between 2017 and 2022 and, of these, identified 514 conserved genes that encoded OMPs. We focused on two specific OMPs: Haem1295, encoding the protein P5 (P5), and Haem1040, encoding the protein 26 (P26). P5 is known to bind human complement regulatory protein factor H (FH), while both P5 and P26 are involved in enhancing immune responses. The genes encoding these proteins were cloned, overexpressed, purified, and tested in both active and passive protection models using systemic infection in mice. Results: P5 and P26 were found to be immunogenic during human infections. Vaccination with these proteins conferred protection against both homologous and heterologous NTHi isolates in mice, suggesting broad cross-protection. Conclusions: P5 and P26 are promising vaccine candidates showing cross-protection against NTHi and offering the additional benefit of targeting bacterial virulence factors, enhancing vaccine efficacy against NTHi isolates. Full article

The function of pleckstrin homology (PH) domains is to recognize and bind to specific phosphoinositides in the membranes as part of diverse cellular signaling processes. The structure of some PH domains has been solved by X-ray crystallography, but structures of many PH domains remain to be elucidated. In green alga Chlamydomonas reinhardtii, none of the PH domains have been crystallized or characterized. The goal of our study was to model and characterize in detail the structures of all eleven of the PH domains identified in C. reinhardtii. Our computational strategy of integrating the information available on sequence, structure, and function with modeling and biophysical characterization has uncovered new biological predictions for these proteins. These predictions can be validated by future rationally designed experimental studies as an extension of this work. Our results suggest that nine of the eleven C. reinhardtii PH domains show the classical electrostatic polarization of PH domains with a positively charged binding pocket and negatively charged opposing end. Our docking results predict only two PH domains bind specifically to a particular phosphoinositide, while all the other nine PH domains may be able to bind various inositol phospholipids. The lack of preference for a specific phosphoinositide headgroup implies that the positive charge in the binding pocket of the PH domains may be crucial in driving the interaction with the negatively charged phosphoinositides in a non-specific or promiscuous manner. We identified putative homologs of Dynamin GTPase, calcium/calmodulin-dependent kinase, Arf GAP, Rhythm of Chloroplast 23 (ROC23), and oxysterol binding proteins in C. reinhardtii that contain PH domains. In addition, we identified two PH domain-containing proteins that may play a role in the mating process and others that may be important for signaling under phosphate deficiency. Full article

Canine distemper virus (CDV) is a multi-host morbillivirus whose evolution and host-switching capacity are largely determined by its hemagglutinin (H) gene. To reconsider the molecular evolution of this critical gene, we performed comprehensive phylogenetic, selection, and structural analyses on a curated dataset of 68 representative global H gene sequences. Our phylogenetic reconstruction confirmed the segregation of sequences into distinct, geographically associated lineages. To provide stronger evidence for viral adaptation, we performed a site-specific selection analysis, which identified 15 amino acid sites in the H protein undergoing significant episodic positive selection. Crucially, the majority of the known SLAM and Nectin-4 receptor-binding residues were found to be among these positively selected sites. We further contextualized these findings by mapping the sites onto a 3D homology model of the H protein, which confirmed their location on the exposed surfaces of the receptor-binding domain. This compilation provides quantitative evidence that the key functional regions of the H protein are direct targets for adaptive evolution, which has significant implications for understanding host tropism and the ongoing challenge of vaccine mismatch. Full article

Arginine vasotocin (AVT) is well known for its role in steroidogenesis and estradiol biosynthesis during early brain development in Epinephelus coioides. Despite its hormonal functions, the biological significance of AVT across different taxa remains poorly understood. Hence, the present study aims to unravel the evolutionary conservation and functional annotation of AVT in different taxa. Additionally, the antimicrobial properties of AVT were investigated across multiple conserved domains. From the sequence comparison results, AVT is highly conserved and a core motif across teleosts, mammals, plants, and bacteria, suggesting functional constraints under strong evolutionary selective pressure. Phylogenetic analyses highlighted AVT and its homologs evolved from a common ancestral gene. The functional enrichment analyses of the genes revealed different taxa that share an analogy with AVT genes. The major pathways for AVT and its homologs are identified in neuroendocrine, immune, and stress signaling. Importantly, a conserved AMP-like motif within the AVT sequence (GIRQCMSCGPGDRGR) was identified. The motif is predicted for its potential role in membrane permeabilization and antimicrobial defense. Physicochemical properties of this peptide showed cationic and amphipathic features, with cysteine residues conferring structural stability. Overall, the results underscore the pleiotropic role of AVT across different taxa, showing its evolutionary stability. AMP-like AVT motif was predicted as a promising candidate for synthetic peptide design. Experimental evaluation with peptides will determine their antimicrobial potential in infection models. Full article

As benthic filter feeders, bivalve mollusks serve as ideal biological indicators. Bisphenol A (BPA) and its substitutes (BPS, BPF, and BPAF) are endocrine disruptors with reproductive toxicity, targeting estrogen receptors (ERs). However, their binding sites and affinity for shellfish ERs remain unclear. This study aims to identify ER binding sites of BPA and its substitutes, compare toxicity via molecular docking, and validate results through exposure experiments. The full-length cDNA of Corbicula fluminea ER was cloned using the RACE technique for the first time, the sequence length is 2138bp. Homologous models of LBD sequences from Danio rerio, C. fluminea, Azumapecten farreri, and Ruditapes philippinarum ERs were constructed via homology modeling and screened for optimal fit. Hydrogen bonds were observed during the docking process, with interaction sites including Glu-66, Arg-177, and other amino acid residues. Exposure experiments (1, 10, and 100 μg/L) showed an enhancement in ER mRNA expression. Based on the docking energies and results of the exposure experiments, it was concluded that the toxicity of BPA and BPS is similar and greater than that of BPF and BPAF. This study provides data for a reproductive risk assessment and aquatic toxicological monitoring of bisphenols. Full article

Phytopathogenic fungi secrete numerous effector proteins to disrupt plant defenses. At present, their sequence–structure–function relationships remain poorly understood owing to their diversity. Comprehensive understanding of conserved effectors is necessary to elucidate the molecular relationship between fungi and plants. To fill this research gap, we investigated the Colletotrichum higginsianum effector candidate (ChEC)-88 specifically expressed during infection. Notably, similar to the biotrophy-associated secreted protein 3 (BAS3) from Pyricularia oryzae, ChEC88 inhibited plant cell death caused by necrosis- and ethylene-inducing peptide 1-like protein (NLP1). Nuclear magnetic resonance analysis results revealed that ChEC88 adopted a novel pseudo two-fold symmetrical three-dimensional structure. Homology modeling suggested that BAS3 exhibited a ChEC88-like conformation despite sharing less than 50% sequence identity. Through PSI-BLAST searches, we found that ChEC88 homologs were conserved in various hemibiotrophic phytopathogenic fungi, including Colletotrichum, P. oryzae, and Fusarium species. Functional assays demonstrated that all of the representative homologs suppressed NLP1-induced plant cell death. Mutation experiments identified the residues critical for ChEC88 function. Overall, our findings suggest that hemibiotrophic phytopathogenic fungi share a conserved immune-suppression strategy mediated by ChEC88-like proteins and that such effectors possibly originated from a common ancestral lineage of phytopathogenic fungi. Full article

The intensive farming of aquaculture species such as red tilapia (Oreochromis spp.) across diverse production systems can lead to changes in genetic parameters and responses of economically important traits in this species. This study represents the first attempt to understand these changes in growth traits (body weight, total length), quality attributes (body colour), and survival rate in red tilapia. Data for these traits were collected from 75,950 individual fish, progeny of 970 full-sib families (comprising 970 dams and 486 sires); they were selected for high body weight and evaluated in two distinct culture environments: fresh- and saltwater ponds. A multi-trait mixed model was employed to estimate genetic parameters and selection responses. Genetic variance estimates for the quality and survival traits varied across the two environments. However, genetic correlations among the traits studied were similar between fresh and saline water. Furthermore, significant G × E interactions, particularly for the quality and survival traits, were evidenced by divergent genetic correlations (r_g = 0.57–0.83) between homologous traits across different environments. The findings emphasise the importance of incorporating G × E interactions into the selection program for red tilapia, particularly when the breeding objectives extend to include quality and survival traits. Selection strategies should consider the prevailing culture system—for instance, favouring genotypes suited to the freshwater pond environment over those adapted to the saltwater environment. Continual assessment of full-sib groups across these environments is recommended to refine our understanding of G × E interactions and optimise future breeding programs for red tilapia. This may involve selecting genotypes capable of consistent performance across environments or developing environment-specific breeding programs. Full article

Soil salinity severely impairs plant growth, and polyamines such as spermidine (Spd) are known to bolster stress tolerance by acting as osmoprotectants and signaling molecules. Using TiO₂ enrichment, iTRAQ quantification, and bioinformatics analysis, we identified 870 proteins and 157 differentially phosphorylated proteins. Functional annotation showed that salt stress activated key components of the Salt Overly Sensitive pathway, particularly serine threonine kinases (SOS2) and Ca²⁺ binding sensors (SOS3). Among thirty-six SOS-associated kinases detected, eight SOS2 isoforms, four MAPKs, and two SOS3 homologs were significantly upregulated by NaCl, and Spd further increased the phosphorylation of six SOS2 proteins and one SOS3 protein under salt stress, with no detectable effect on SOS1. qRT PCR revealed enhanced expression of MAPKs and calcium-dependent protein kinases, suggesting a phosphorylation-centered model in which Spd amplifies Ca²⁺-mediated SOS signaling and reinforces ion homeostasis through coordinated transcriptional priming and post-translational control. Additional, proteins involved in protein synthesis and turnover (ribosomal subunits, translation initiation factors, ubiquitin–proteasome components), DNA replication and transcription, and RNA processing showed differential expression under salt or Spd treatment. Central metabolic pathways were reprogrammed, involving glycolysis, the TCA cycle, the pentose phosphate pathway, as well as ammonium transporters and amino acid biosynthetic enzymes. These findings indicate that exogenous Spd regulated phosphorylation-mediated networks involving the SOS signaling pathway, protein homeostasis, and metabolism, thereby enhancing cucumber salt tolerance. Full article

Background/Objectives: Inteins are mobile genetic elements invading highly conserved genes across all domains of life and viruses. Five active intein insertion sites (MCM-a through e) had previously been identified and studied in the archaeal replicative helicase minichromosome maintenance (MCM) subunit gene mcm, making MCM an ideal system for dissecting the dynamics of multi-intein genes. However, work in this system thus far has been limited to particular archaeal groups. To better understand the dynamics and diversity of these inteins, MCM homologs spanning all archaeal groups were extracted from NCBI’s non-redundant protein sequence database, and the distribution and structural architectures of their inteins were characterized. Methods: The amino acid sequences of 4243 archaeal MCM homologs were retrieved from NCBI’s non-redundant protein sequence database. These sequences were systematically assessed for their intein content through within-group multiple sequence alignments. To characterize the inteins present at each site, extensive intein structure predictions and comparisons were performed. Phylogenetic analyses were used to investigate intein relatedness between and within sites, as well as the distribution of different MCM inteins in geographically overlapping populations of archaea. Results: In total, 11 active MCM intein insertion sites were identified, expanding on the previously known five. The insertion sites have varied invasion activity levels across archaeal groups, with Nanobdellati (DPANN) being the only group with all 11 sites active. In all but two (Methanonatronarchaeia and Hadarchaeota) of the archaeal groups studied where inteins were present, at least one MCM homolog was invaded by more than one intein. With respect to intein structure, within-intein insertions bearing semblance to DNA-binding domains were identified, with varied presence between inteins. Additionally, a study of archaeal MCM sequences of samples collected from the Atacama Desert in June 2013 revealed high MCM intein diversity levels. Conclusions: We identified six new active intein insertion sites in archaeal MCM, more than doubling the five previously known sites. All eleven intein insertion sites were either close to the ATP binding site, or the lined the channel through which the single-stranded DNA is pulled during the catalytic cycle of the helicase. Many of the analyzed inteins contained insertions bearing similarity to DNA-binding helix-turn-helix domains suggesting potential involvement in the intein homing process. Additionally, the high levels of MCM intein diversity observed in archaea from the Atacama Desert provide novel and strong support for a co-existence model of intein persistence. Full article

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by chronic inflammation, extracellular matrix degradation, and smooth muscle cell apoptosis. Porphyromonas gingivalis (P. gingivalis), a key periodontal pathogen, has been implicated in the progression of cardiovascular diseases, including AAA, but the underlying mechanisms remain unclear. In this study, we investigated the role of GroEL, a bacterial heat shock protein 60 homolog derived from P. gingivalis, in AAA development. We employed a CaCl₂-induced AAA mouse model to evaluate the in vivo effects of GroEL. Mice received periaortic CaCl₂ application followed by intravenous injections of recombinant GroEL. Histological analyses were performed to assess aneurysmal dilation, elastin degradation, and inflammatory cell infiltration. Flow cytometry and immunohistochemistry were used to determine macrophage phenotypes, while cytokine profiles were quantified via ELISA. In vitro, THP-1 monocytes were treated with GroEL to evaluate its impact on macrophage polarization and cytokine expression. Our results showed that GroEL administration significantly enhanced aortic diameter expansion and elastin breakdown, accompanied by increased infiltration of M1-like macrophages and elevated levels of pro-inflammatory cytokines such as TNF-α and IL-6. In vitro findings confirmed that GroEL promotes M1 polarization and inhibits M2 marker expression in THP-1-derived macrophages. These findings suggest that P. gingivalis-derived GroEL plays a pathogenic role in AAA by modulating macrophage polarization toward a pro-inflammatory phenotype. Targeting microbial components such as GroEL may offer new therapeutic strategies for AAA management. Full article

The structures of buildings employ elements with symmetrical cross sections (columns have two axes of symmetry, and connecting beams have at least one), leading to symmetrical states of stress and deformation under the action of mechanical and thermal loads. Thermal stresses, resulting from temperature variations and fires, must be taken into account during calculations. Thus, it is important to perform theoretical and experimental studies on the propagation of heat flux during fires. Experimental investigations on prototypes can be replaced by investigations into attached, reduced-scale models. With the help of the model law (ML), deduced by dimensional approaches, the results obtained by the model can be extrapolated to the prototype. In the present article, the Szirtes’ Modern Dimensional Analysis (MDA) method is proposed; this is a simple, reliable, and repeatable dimensional approach. By applying the MDA to both the structural elements and model of an entire industrial hall, in terms of thermal field propagation, the authors demonstrate the undeniable effectiveness of the method in these construction calculations. MDA enables the efficient and easy analysis of thermal states of the homologous points of the prototype, even for spatial structures. Full article

Objective: This study aimed to evaluate the mean age of eruption of permanent teeth and their clinical emergence sequence in a longitudinal sample of children from a multi-ethnic urban population. Methods: A total of 854 children (413 females and 441 males), aged between 4 and 13 years, were examined annually for a minimum of 4 consecutive years, as part of their annual dental screening appointment. The presence of permanent teeth was recorded at each examination. Mean and median ages, with standard deviations, of individual tooth eruption were calculated, in addition to the eruption sequence, and the analysis of the data was performed using the lognormal distribution model. Regarding the error of the method, two examiners reviewed all relevant dental screening forms, and any discrepancies were resolved through consultation with the senior author. Results: The sequence of permanent tooth eruption followed a consistent pattern across sexes, with distinct differences between the maxillary and mandibular arches. In the maxilla, eruption began with the first molar, while in the mandible, it started with the central incisor. Mandibular teeth generally erupted earlier than maxillary teeth, with girls experiencing earlier eruption than boys, with some exceptions, and prolonged eruption periods. No statistically significant differences were found in the timing of eruption between contralateral homologous teeth. Conclusions: Based on the present data, the observed sequence of tooth eruption in a multi-ethnic urban population showed similar patterns across sexes. Mandibular teeth generally erupt earlier than maxillary teeth, with girls experiencing earlier eruption than boys. Full article

Using the fly eye as a model system, we previously demonstrated that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration. Building upon this finding, we investigated whether the protective role of mask is conserved in mammals. To this end, we generated a transgenic mouse line carrying Cre-inducible ANKHD1, the human homolog of mask. Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we found that expressing ANKHD1 driven by CamK2a-Cre reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, ANKHD1 expression was associated with a trend toward reduced gliosis and preservation of the presynaptic marker Synaptophysin, suggesting a protective role of ANKHD1 against TauP301S-linked neuropathology. At 9 months of age, novel object recognition (NOR) testing revealed cognitive impairment in female, but not male, PS19 mice. Notably, co-expression of ANKHD1 restored cognitive performance in the affected female mice. Together, this study highlights the novel effect of ANKHD1 in counteracting the adverse effects induced by the mutant human Tau protein. This finding underscores ANKHD1’s potential as a unique therapeutic target for tauopathies. Full article