-
Science Advances Jun 2024Seismic observations of impacts on Mars indicate a higher impact flux than previously measured. Using six confirmed seismic impact detections near the NASA InSight...
Seismic observations of impacts on Mars indicate a higher impact flux than previously measured. Using six confirmed seismic impact detections near the NASA InSight lander and two distant large impacts, we calculate appropriate scalings to compare these rates with lunar-based chronology models. We also update the impact rate from orbital observations using the most recent catalog of new craters on Mars. The snapshot of the current impact rate at Mars recorded seismically is higher than that found using orbital detections alone. The measured rates differ between a factor of 2 and 10, depending on the diameter, although the sample size of seismically detected impacts is small. The close timing of the two largest new impacts found on Mars in the past few decades indicates either a heightened impact rate or a low-probability temporal coincidence, perhaps representing recent fragmentation of a parent body. We conclude that seismic methods of detecting current impacts offer a more complete dataset than orbital imaging.
PubMed: 38941463
DOI: 10.1126/sciadv.adk7615 -
ELife Jun 2024Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we...
Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we examine the impact of mutations across the spectrum of viable amino acid sequences on the biophysical phenotypes of the highly expressed and multifunctional nucleocapsid protein. We find variation in the physicochemical parameters of its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also observe functional constraints that similarly occur in related coronaviruses. In biophysical experiments with several N-protein species carrying mutations associated with major variants, we find that point mutations in the IDRs can have nonlocal impact and modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, and liquid-liquid phase separation. In the Omicron variant, distant mutations in different IDRs have compensatory effects in shifting a delicate balance of interactions controlling protein assembly properties, and include the creation of a new protein-protein interaction interface in the N-terminal IDR through the defining P13L mutation. A picture emerges where genetic diversity is accompanied by significant variation in biophysical characteristics of functional N-protein species, in particular in the IDRs.
Topics: SARS-CoV-2; Coronavirus Nucleocapsid Proteins; Mutation; COVID-19; Humans; Intrinsically Disordered Proteins; Phosphoproteins; Nucleocapsid Proteins; Thermodynamics; Protein Stability
PubMed: 38941236
DOI: 10.7554/eLife.94836 -
Alternative Therapies in Health and... Jun 2024Colorectal cancer is a malignant tumor with high mortality, but is hard to detect at its early stage. Recent studies highlighted the crucial roles of Ezrin protein and...
OBJECTIVE
Colorectal cancer is a malignant tumor with high mortality, but is hard to detect at its early stage. Recent studies highlighted the crucial roles of Ezrin protein and MMP-9 in the development and malignancy of colorectal cancer, but Ezrin protein and MMP-9 in early diagnosis of colorectal cancer require further investigation. Therefore, we aimed to investigate their roles in the occurrence and metastasis of colorectal cancer, and to analyze their clinical significance in diagnosing and treating colorectal cancer.
METHOD
The diagnosis of collected colorectal cancer tissue and adjacent tissue samples from colorectal cancer patients confirmed by clinical symptoms was performed using Hematoxylin Eosin staining. The expression levels of Ezrin and MMP-9 in 50 colorectal cancer tissue and 50 cases adjacent colorectal cancer tissue were detected by the immuno-histochemical MaxVision method. The relationship between the positive expression rate of Ezrin and MMP-9 in colorectal cancer tissue and clinical pathological factors was analyzed, and the correlation between Ezrin and MMP-9 was examined.
RESULTS
The positive expression rate of Ezrin in colorectal cancer tissue (78%) was significantly higher compared to adjacent non-cancerous tissues (6.0%) (P < .05). There was no significant correlation of gender/age and Ezrin/MMP-9 expressions (P > .05). The expression level of Ezrin exhibited statistically significant differences in the pathological factors including tumor diameter, depth of invasion, degree of differentiation, presence or absence of lymph node metastasis, and distant metastasis (P < .05). Additionally, the positive expression rate of MMP-9 in colorectal cancer tissue (76%) was markedly elevated compared to adjacent tissues (8.0%) (P < .05). The expression level of MMP-9 showed statistically significant differences in the pathological factors including tumor diameter, depth of invasion, degree of differentiation, presence or absence of lymph node metastasis, and distant metastasis (P < .05). In addition, the expression of Ezrin and MMP-9 in colorectal cancer tissue showed a significant positive correlation (r=0.637, P < .01).
CONCLUSION
Ezrin and MMP-9 may synergistically participate in the occurrence, invasion, and metastasis of colorectal cancer. The combined assessment of Ezrin and MMP-9 expression levels in colorectal cancer patients holds significant potential for clinical diagnosis and personalized therapeutic applications.
PubMed: 38940787
DOI: No ID Found -
Gynecologic Oncology Reports Aug 2024Endometrial large cell neuroendocrine carcinoma (LCNEC) is a highly malignant tumor that presents with neuroendocrine function. It is difficult to diagnose at an early...
Endometrial large cell neuroendocrine carcinoma (LCNEC) is a highly malignant tumor that presents with neuroendocrine function. It is difficult to diagnose at an early stage. Moreover, the diagnosis depends on the pathological and immunohistochemical findings. It is also prone to distant metastasis, but is difficult to treat and shows poor prognosis. Presently, there exists no unified treatment plan, and the prognosis of this disease is also poor. We reported here an analysis and literature review of a case of endometrial LCNEC to facilitate the comprehension of this disease and provide help toward clinical diagnosis and treatment.
PubMed: 38939507
DOI: 10.1016/j.gore.2024.101429 -
Polish Journal of Radiology 2024To evaluate the predictive capability of the apparent diffusion coefficient (ADC) at initial diagnosis in treatment-naive patients with laryngeal squamous cell carcinoma...
PURPOSE
To evaluate the predictive capability of the apparent diffusion coefficient (ADC) at initial diagnosis in treatment-naive patients with laryngeal squamous cell carcinoma (LSCC) for the development of future metastases.
MATERIAL AND METHODS
Magnetic resonance images of patients with pathologically proven non-metastatic, treatmentnaive LSCC were retrospectively evaluated. Follow-up positron emission tomography scans were assessed for the scanning of metastases.
RESULTS
A total of 37 patients (32 males and 5 females) with a mean age of 62.8 ± 8.9 years were enrolled. Mean tumour volume and ADC were 4.8 ± 62 cm and 0.72 ± 0.51 × 10 mm/s, respectively. Six local and 8 distant metastases were detected in a mean follow-up period of 17.5 ± 10.2 months. A significant association between ADC and the presence distant metastases ( = 0.046) and local metastases ( = 0.042) was found. The difference in mean ADC values between future metastatic and non-metastatic initial tumours was significant ( = 0.017).
CONCLUSIONS
Pre-treatment ADC values and volume of the initial tumour might provide early information about the development of future metastases in patients with LSCC in this series.
PubMed: 38938659
DOI: 10.5114/pjr/187675 -
Frontiers in Immunology 2024Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide, with human papillomavirus (HPV) infection contributing to cancer...
Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide, with human papillomavirus (HPV) infection contributing to cancer development. Conventional therapies achieve only limited efficiency, especially in recurrent or metastatic HNSCC. As the immune landscape decisively impacts the survival of patients and treatment efficacy, this study comprehensively investigated the immunological tumor microenvironment (TME) and its association with patient outcome, with special focus on several dendritic cell (DC) and T lymphocyte subpopulations. Therefore, formalin-fixed paraffin-embedded tumor samples of 56 HNSCC patients, who have undergone resection and adjuvant radiotherapy, were analyzed by multiplex immunohistochemistry focusing on the detailed phenotypic characterization and spatial distribution of DCs, CD8 T cells, and T-helper cell subsets in different tumor compartments. Immune cell densities and proportions were correlated with clinical characteristics of the whole HNSCC cohort and different HPV- or hypoxia-associated subcohorts. Tumor stroma was highly infiltrated by plasmacytoid DCs and T lymphocytes. Among the T-helper cells and CD8 T cells, stromal regulatory T cells and intraepithelial exhausted CD8 T cells expressing programmed cell death protein-1 (PD-1) and/or lymphocyte-activation gene-3 (LAG-3) were the predominant phenotypes, indicating an immunosuppressive TME. HPV-associated tumors showed significantly higher infiltration of type I and type II conventional DCs (cDC1, cDC2) as well as several CD8 T cell phenotypes including exhausted, activated, and proliferating T cells. On the contrary, tumors with hypoxia-associated gene signatures exhibited reduced infiltration for these immune cells. By multivariate Cox regression, immune-related prognostic factors were identified. Patient clusters defined by high infiltration of DCs and T lymphocytes combined with HPV positivity or low hypoxia showed significantly prolonged survival. Thereby, cDC1 and CD8 T cells emerged as independent prognostic factors for local and distant recurrence. These results might contribute to the implementation of an immune cell infiltration score predicting HNSCC patients' survival and such patient stratification might improve the design of future individualized radiochemo-(immuno)therapies.
Topics: Humans; Dendritic Cells; Squamous Cell Carcinoma of Head and Neck; Male; Female; CD8-Positive T-Lymphocytes; Middle Aged; Tumor Microenvironment; Head and Neck Neoplasms; Aged; Lymphocytes, Tumor-Infiltrating; Prognosis; Adult; Papillomavirus Infections
PubMed: 38938577
DOI: 10.3389/fimmu.2024.1414298 -
Frontiers in Genome Editing 2024With scientific progress and the development of new genomic techniques (NGTs), the spectrum of organisms modified for various purposes is rapidly expanding and includes...
Horizon scanning of potential environmental applications of terrestrial animals, fish, algae and microorganisms produced by genetic modification, including the use of new genomic techniques.
With scientific progress and the development of new genomic techniques (NGTs), the spectrum of organisms modified for various purposes is rapidly expanding and includes a wide range of taxonomic groups. An improved understanding of which newly developed products may be introduced into the market and released into the environment in the near and more distant future is of particular interest for policymakers, regulatory authorities, and risk assessors. To address this information need, we conducted a horizon scanning (HS) of potential environmental applications in four groups of organisms: terrestrial animals (excluding insects and applications with gene drives), fish, algae and microorganisms. We applied a formal scoping review methodology comprising a structured search of the scientific literature followed by eligibility screening, complemented by a survey of grey literature, and regulatory websites and databases. In all four groups of organisms we identified a broad range of potential applications in stages of basic as well as advanced research, and a limited number of applications which are on, or ready to be placed on, the market. Research on GM animals including fish is focused on farmed animals and primarily targets traits which increase performance, influence reproduction, or convey resistance against diseases. GM algae identified in the HS were all unicellular, with more than half of the articles concerning biofuel production. GM algae applications for use in the environment include biocontrol and bioremediation, which are also the main applications identified for GM microorganisms. From a risk assessor's perspective these potential applications entail a multitude of possible pathways to harm. The current limited level of experience and limited amount of available scientific information could constitute a significant challenge in the near future, for which risk assessors and competent authorities urgently need to prepare.
PubMed: 38938511
DOI: 10.3389/fgeed.2024.1376927 -
BMC Cancer Jun 2024Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the...
OBJECTIVE
Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function.
METHODS
In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis.
RESULTS
After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma.
CONCLUSIONS
Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.
Topics: Stomach Neoplasms; Humans; Ubiquitin Thiolesterase; Ubiquitination; Mice; Animals; Cell Line, Tumor; Cell Movement; Gene Expression Regulation, Neoplastic; Female; Male; Neoplasm Metastasis; Gene Expression Profiling; Epithelial-Mesenchymal Transition; Prognosis; Multiomics
PubMed: 38937694
DOI: 10.1186/s12885-024-12549-3 -
BMC Genomics Jun 2024The CBM13 family comprises carbohydrate-binding modules that occur mainly in enzymes and in several ricin-B lectins. The ricin-B lectin domain resembles the CBM13 module...
BACKGROUND
The CBM13 family comprises carbohydrate-binding modules that occur mainly in enzymes and in several ricin-B lectins. The ricin-B lectin domain resembles the CBM13 module to a large extent. Historically, ricin-B lectins and CBM13 proteins were considered completely distinct, despite their structural and functional similarities.
RESULTS
In this data mining study, we investigate structural and functional similarities of these intertwined protein groups. Because of the high structural and functional similarities, and differences in nomenclature usage in several databases, confusion can arise. First, we demonstrate how public protein databases use different nomenclature systems to describe CBM13 modules and putative ricin-B lectin domains. We suggest the introduction of a novel CBM13 domain identifier, as well as the extension of CAZy cross-references in UniProt to guard the distinction between CAZy and non-CAZy entries in public databases. Since similar problems may occur with other lectin families and CBM families, we suggest the introduction of novel CBM InterPro domain identifiers to all existing CBM families. Second, we investigated phylogenetic, nomenclatural and structural similarities between putative ricin-B lectin domains and CBM13 modules, making use of sequence similarity networks. We concluded that the ricin-B/CBM13 superfamily may be larger than initially thought and that several putative ricin-B lectin domains may display CAZyme functionalities, although biochemical proof remains to be delivered.
CONCLUSIONS
Ricin-B lectin domains and CBM13 modules are associated groups of proteins whose database semantics are currently biased towards ricin-B lectins. Revision of the CAZy cross-reference in UniProt and introduction of a dedicated CBM13 domain identifier in InterPro may resolve this issue. In addition, our analyses show that several proteins with putative ricin-B lectin domains show very strong structural similarity to CBM13 modules. Therefore ricin-B lectin domains and CBM13 modules could be considered distant members of a larger ricin-B/CBM13 superfamily.
Topics: Ricin; Phylogeny; Lectins; Protein Domains; Databases, Protein; Amino Acid Sequence; Sequence Homology, Amino Acid
PubMed: 38937673
DOI: 10.1186/s12864-024-10554-1 -
Scientific Data Jun 2024Bone metastasis is an essential factor affecting the prognosis of prostate cancer (PCa), and circulating tumor cells (CTCs) are closely related to distant tumor...
Bone metastasis is an essential factor affecting the prognosis of prostate cancer (PCa), and circulating tumor cells (CTCs) are closely related to distant tumor metastasis. Here, the protein-protein interaction (PPI) networks and Cytoscape application were used to identify diagnostic markers for metastatic events in PCa. We screened ten hub genes, eight of which had area under the ROC curve (AUC) values > 0.85. Subsequently, we aim to develop a bone metastasis-related model relying on differentially expressed genes in CTCs for accurate risk stratification. We developed an integrative program based on machine learning algorithm combinations to construct reliable bone metastasis-related genes prognostic index (BMGPI). On the basis of BMGPI, we carefully evaluated the prognostic outcomes, functional status, tumor immune microenvironment, somatic mutation, copy number variation (CNV), response to immunotherapy and drug sensitivity in different subgroups. BMGPI was an independent risk factor for disease-free survival in PCa. The high risk group demonstrated poor survival as well as higher immune scores, higher tumor mutation burden (TMB), more frequent co-occurrence mutation, and worse efficacy of immunotherapy. This study highlights a new prognostic signature, the BMGPI. BMGPI is an independent predictor of prognosis in PCa patients and is closely associated with the immune microenvironment and the efficacy of immunotherapy.
Topics: Humans; Algorithms; Biomarkers, Tumor; Bone Neoplasms; Machine Learning; Neoplastic Cells, Circulating; Prognosis; Prostatic Neoplasms; Protein Interaction Maps; Tumor Microenvironment
PubMed: 38937469
DOI: 10.1038/s41597-024-03551-2