Type-I-interferon-responsive microglia shape cortical development and behavior.

Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.

A model-agnostic framework to enhance knowledge graph-based drug combination prediction with drug-drug interaction data and supervised contrastive learning.

Combination therapies have brought significant advancements to the treatment of various diseases in the medical field. However, searching for effective drug combinations remains a major challenge due to the vast number of possible combinations. Biomedical knowledge graph (KG)-based methods have shown potential in predicting effective combinations for wide spectrum of diseases, but the lack of credible negative samples has limited the prediction performance of machine learning models. To address this issue, we propose a novel model-agnostic framework that leverages existing drug-drug interaction (DDI) data as a reliable negative dataset and employs supervised contrastive learning (SCL) to transform drug embedding vectors to be more suitable for drug combination prediction. We conducted extensive experiments using various network embedding algorithms, including random walk and graph neural networks, on a biomedical KG. Our framework significantly improved performance metrics compared to the baseline framework. We also provide embedding space visualizations and case studies that demonstrate the effectiveness of our approach. This work highlights the potential of using DDI data and SCL in finding tighter decision boundaries for predicting effective drug combinations.

Integration of National Health Insurance claims data and animal models reveals fexofenadine as a promising repurposed drug for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common and costly progressive neurodegenerative disease of unclear etiology. A disease-modifying approach that can directly stop or slow its progression remains a major unmet need in the treatment of PD. A clinical pharmacology-based drug repositioning strategy is a useful approach for identifying new drugs for PD. METHODS: We analyzed claims data obtained from the National Health Insurance Service (NHIS), which covers a significant portion of the South Korean population, to investigate the association between antihistamines, a class of drugs commonly used to treat allergic symptoms by blocking H1 receptor, and PD in a real-world setting. Additionally, we validated this model using various animal models of PD such as the 6-hydroxydopmaine (6-OHDA), α-synuclein preformed fibrils (PFF) injection, and Caenorhabditis elegans (C. elegans) models. Finally, whole transcriptome data and Ingenuity Pathway Analysis (IPA) were used to elucidate drug mechanism pathways. RESULTS: We identified fexofenadine as the most promising candidate using National Health Insurance claims data in the real world. In several animal models, including the 6-OHDA, PFF injection, and C. elegans models, fexofenadine ameliorated PD-related pathologies. RNA-seq analysis and the subsequent experiments suggested that fexofenadine is effective in PD via inhibition of peripheral immune cell infiltration into the brain. CONCLUSION: Fexofenadine shows promise for the treatment of PD, identified through clinical data and validated in diverse animal models. This combined clinical and preclinical approach offers valuable insights for developing novel PD therapeutics.

Medial Patellar Plica Thickness as a Morphologic Predictor of the Medial Patellar Plica Syndrome.

OBJECTIVE: The aim of this study was to evaluate the association between medial patellar plica (MPP) syndrome and the morphological features of the MPP, including length, width, and thickness, on knee magnetic resonance imaging (MRI). MATERIALS AND METHODS: From 2018 to 2022, 167 patients diagnosed with isolated MPP syndrome based on both MRI and arthroscopic findings were included in the "study group" and 226 patients without knee pathology on both MRI and physical examination were included in the "control group." Finally, 393 patients (mean age, 38.9 ± 5.7 years) with 405 knee MRI examinations were included. Morphological MR features of MPP were assessed, including width, length, and thickness. Multivariate regression and receiver operating characteristic analyses were performed to identify the factors associated with MPP syndrome. RESULTS: The mean thickness of MPP was significantly higher in the study group than control group (2.3 ± 0.5 mm vs 1.0 ± 0.8 mm, P < 0.001). Moreover, on multivariate analysis, MPP thickness was the only significant factor associated with MPP syndrome (odds ratio, 6.452; 95% confidence interval, 0.816-15.073; P = 0.002). On receiver operating characteristic analysis, thickness ≥1.8 mm was estimated as the optimal cutoff for predicting MPP syndrome with sensitivity of 75.9%, specificity of 65.4%, and area under the curve of 0.727 (95% confidence interval, 0.667-0.788; P < 0.001). CONCLUSIONS: Measurement of MPP thickness on MRI could be a morphological predictor of MPP syndrome.

Retinoic Acid Treatment Mitigates PM2.5-Induced Type 2 Inflammation: Insights into Modulation of Innate Immune Responses.

Some studies have demonstrated the effects of particulate matter (PM) on chronic rhinosinusitis with nasal polyps (CRSwNP) development, as well as the therapeutic role of retinoic acid (RA) in nasal polypogenesis. However, the immunologic effect of PM in innate lymphoid cells (ILCs) and the exact mechanism of the therapeutic effect of RA remain unclear. Therefore, the present study investigated the effects of fine-dust-induced inflammation in CRSwNP and the mechanisms of the therapeutic effect of RA. PM2.5 exposure exacerbated pathological damage in the nasal mucosa of mice with nasal polyps (NP) via upregulation of type 2 inflammation. Additionally, PM2.5 exposure increased the expression of type 2 cytokines and epithelial-cell-derived cytokines (IL-33 and IL-25) significantly, as well as the ILC populations in human-NP-derived epithelial cells (HNECs). Moreover, RA supplementation significantly increased the expression of ILCreg in Lin-CD45+CD127+ cells, which in turn increased the levels of the anti-inflammatory cytokine IL-10. The findings suggest that PM2.5 exposures could aggravate the CRSwNP type 2 inflammation, and RA treatment may ameliorate fine-dust-induced inflammation by modulating the innate immune response.

RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter.

BACKGROUND: Megakaryocytes (MKs) are platelet precursors, which arise from hematopoietic stem cells (HSCs). While MK lineage commitment and differentiation are accompanied by changes in gene expression, many factors that modulate megakaryopoiesis remain to be uncovered. Replication initiation determinant protein (RepID) which has multiple histone-code reader including bromodomain, cryptic Tudor domain and WD40 domains and Cullin 4-RING E3 ubiquitin ligase complex (CRL4) recruited to chromatin mediated by RepID have potential roles in gene expression changes via epigenetic regulations. We aimed to investigate whether RepID-CRL4 participates in transcriptional changes required for MK differentiation. METHODS: The PCR array was performed using cDNAs derived from RepID-proficient or RepID-deficient K562 erythroleukemia cell lines. Correlation between RepID and DAB2 expression was examined in the Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal. The acceleration of MK differentiation in RepID-deficient K562 cells was determined by estimating cell sizes as well as counting multinucleated cells known as MK phenotypes, and by qRT-PCR analysis to validate transcripts of MK markers using phorbol 12-myristate 13-acetate (PMA)-mediated MK differentiation condition. Interaction between CRL4 and histone methylation modifying enzymes were investigated using BioGRID database, immunoprecipitation and proximity ligation assay. Alterations of expression and chromatin binding affinities of RepID, CRL4 and histone methylation modifying enzymes were investigated using subcellular fractionation followed by immunoblotting. RepID-CRL4-JARID1A-based epigenetic changes on DAB2 promoter were analyzed by chromatin-immunoprecipitation and qPCR analysis. RESULTS: RepID-deficient K562 cells highly expressing MK markers showed accelerated MKs differentiation exhibiting increases in cell size, lobulated nuclei together with reaching maximum levels of MK marker expression earlier than RepID-proficient K562 cells. Recovery of WD40 domain-containing RepID constructs in RepID-deficient background repressed DAB2 expression. CRL4A formed complex with histone H3K4 demethylase JARID1A in soluble nucleus and loaded to the DAB2 promoter in a RepID-dependent manner during proliferation condition. RepID, CRL4A, and JARID1A were dissociated from the chromatin during MK differentiation, leading to euchromatinization of the DAB2 promoter. CONCLUSION: This study uncovered a role for the RepID-CRL4A-JARID1A pathway in the regulation of gene expression for MK differentiation, which can form the basis for the new therapeutic approaches to induce platelet production. Video Abstract.

Robot-Assisted Transarterial Chemoembolization of Hepatocellular Carcinoma Using a Coaxial Microcatheter Driving Controller-Responder Robot System: Clinical Pilot Study.

PURPOSE: To evaluate the feasibility and safety of robot-assisted transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) using a new coaxial microcatheter driving controller-responder robot (CRR) system. MATERIALS AND METHODS: A single-center prospective pilot study approved by the institutional review board was conducted using this CRR developed after analyzing 20 cases of conventional TACE procedures from May to October 2021. The study included 10 patients with HCCs: 5 (median age, 72 years; range, 64-73 years) underwent robot-assisted TACE, and 5 (median age, 57 years; range, 44-76 years) underwent conventional TACE for comparison. The feasibility and safety of robot-assisted TACE were evaluated by assessing the technical success, procedure time, adverse event rate, radiation dose, and early tumor response. RESULTS: The entire TACE procedure was divided into 30 steps, of which 8 could be robotized. In robot-assisted TACE, technical success was achieved in 4 (80%) of 5 patients. No procedure-related adverse event was observed. The median procedure time was 56 minutes. At the 1-month follow-up, 3 of the 4 patients showed a complete or partial response after robot-assisted TACE. The median radiation doses for the operator and patients were 0.4 and 2,167.5 µSv in robot-assisted TACE and 53.2 and 2,989.7 µSv in conventional TACE, respectively. CONCLUSIONS: Robot-assisted TACE using a new CRR system was feasible and safe for the treatment of HCC and could remarkably decrease radiation exposure for the operators.

Structural basis for the dynamics of human methionyl-tRNA synthetase in multi-tRNA synthetase complexes.

In mammals, eight aminoacyl-tRNA synthetases (AARSs) and three AARS-interacting multifunctional proteins (AIMPs) form a multi-tRNA synthetase complex (MSC). MSC components possess extension peptides for MSC assembly and specific functions. Human cytosolic methionyl-tRNA synthetase (MRS) has appended peptides at both termini of the catalytic main body. The N-terminal extension includes a glutathione transferase (GST) domain responsible for interacting with AIMP3, and a long linker peptide between the GST and catalytic domains. Herein, we determined crystal structures of the human MRS catalytic main body, and the complex of the GST domain and AIMP3. The structures reveal human-specific structural details of the MRS, and provide a dynamic model for MRS at the level of domain orientation. A movement of zinc knuckles inserted in the catalytic domain is required for MRS catalytic activity. Depending on the position of the GST domain relative to the catalytic main body, MRS can either block or present its tRNA binding site. Since MRS is part of a huge MSC, we propose a dynamic switching between two possible MRS conformations; a closed conformation in which the catalytic domain is compactly attached to the MSC, and an open conformation with a free catalytic domain dissociated from other MSC components.

Mental health and governmental response policy evaluation on COVID-19 based on vaccination status in Republic of Korea.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has continued since the outbreak in December 2019. People experience depression and anxiety due to government policies and restrictions on physical activity due to the COVID-19 pandemic. This study aimed to compare and analyze people's experiences of COVID-19 blues, sports policy awareness, and participation intention according to their vaccination status. METHODS: This quantitative study used an online survey to collect demographic information, vaccination status, and variables. Data validity and reliability were verified through confirmatory factor analysis, and Cronbach's alpha coefficients were calculated using SPSS/AMOS 23.0. Finally, this comparative study was conducted using multivariate analysis of variance to investigate the differences in the dependent variables between the groups. RESULTS: The vaccinated group had higher scores for all factors related to COVID-19 blues (F = 19.147; p < .05; partial η2 = .046) and government policy (market responsiveness: F = 5.669, p < .05, partial η2 = .014; policy performance: F = 6.997, p < .05, partial η2 = .017; policy satisfaction: F = 7.647, p < .05, partial η2 = .019), apart from the intention to participate in sports (F = .014, p > .05, partial η2 = .000); these results demonstrate that people with COVID-19 blues and relatively high confidence in government quarantine policies were more likely to be vaccinated. In addition, all participants gave sports-participation intention the highest rating, regardless of their vaccination status; this reflects the current situation, in which individual activities are limited. CONCLUSIONS: This study analyzed the mental health of vaccinated and unvaccinated groups in Korean adult men, their perceptions of government policies, and their willingness to engage in physical activity. The findings are meaningful and highlight useful directions for future research. This study provides evidence which can help alleviate the mental damage caused by government quarantine policies and enable a better understanding of the COVID-19 pandemic. The results of this study provide important data for understanding the COVID-19 pandemic.

Clinical value of deep vein thrombosis density on pre-contrast and post-contrast lower-extremity CT for prediction of pulmonary thromboembolism.

BACKGROUND: There was a lack of studies assessing the relationship between deep vein thrombosis (DVT) Hounsfield unit (HU) density and pulmonary thromboembolism (PTE). PURPOSE: To evaluate the clinical value of DVT density measured on pre- and post-contrast lower-extremity computed tomography (CT) for the prediction of PTE. MATERIAL AND METHODS: From 2017 to 2021, patients who underwent pulmonary CT angiography within one week after diagnosis of DVT on lower-extremity CT were included in this retrospective study. Then, the patients without PTE were included in "DVT group" and those with both DVT and PTE were included in the "DVT-PTE group." The DVT HU density was measured by drawing free-hand region of interests (ROIs) within the thrombus at the most proximal filling defect level. A receiver operating characteristic (ROC) analysis was used to evaluate the predictive value of DVT density for the risk of PTE. RESULTS: This study included a total of 94 patients (DVT group: n=56; DVT-PTE group: m=38). DVT density was significantly higher in the DVT-PTE group than the DVT group in both pre-contrast (53.5 ± 6.2 HU vs. 44.1 ± 7.9 HU; P < 0.001) and post-contrast CT (67.0 ± 8.6 HU vs. 57.1 ± 10.6 HU; P < 0.001). ROC analysis revealed that the area under curve, sensitivity, and specificity for predicting the risk of PTE were 0.739, 71.1%, and 64.2%, respectively, at a DVT density cutoff of 48.2 HU on pre-contrast CT and were 0.779, 73.7%, and 69.6% at a DVT density cutoff of 61.8 HU on post-contrast CT. CONCLUSION: The DVT density on both pre- and post-contrast CT could be a predictive factor of PTE.

Thrombus volume and Hounsfield unit density as a predictor of pulmonary embolism in patients with deep vein thrombosis.

BACKGROUND: There is a lack of studies evaluating the association between thrombus volume and density of deep vein thrombosis (DVT) and pulmonary embolism (PE). PURPOSE: To assess the clinical value of thrombus volume and density for prediction of PE in patients with DVT. MATERIAL AND METHODS: Among the patients with DVT, those without PE were classified as the "DVT-only group" and those with PE were classified as the "DVT-PE group." Thrombus volume and Hounsfield unit (HU) density of DVT was measured by drawing free-hand volume of interests within the thrombus. Multivariate regression and receiver operating characteristic (ROC) analysis was used to evaluate the predictive value of thrombus volume and density for PE. RESULTS: Of the included 145 patients (mean age=41.7 ± 10.3 years), there were 87 patients in the DVT-only group and 58 patients in the DVT-PE group. The DVT-PE group showed a significantly higher DVT density (67.4 ± 8.6 HU vs. 57.3 ± 10.4 HU; P < 0.001) and larger DVT volume (16.4 ± 13.9 cm3 vs. 12.8 ± 10.1 cm3; P = 0.016) than the DVT-only group. On multivariate analysis, thrombus density was the only associated factor for PE. ROC analysis showed that thrombus density ≥61.8 HU was the optimal cutoff for predicting PE with an area under the curve (AUC) of 0.774 and thrombus volume ≥14.0 cm3 was the cutoff with an AUC of 0.638. CONCLUSION: Though the results of our study should be considered within the limitations, DVT density could be a predictor for acute PE. Further studies are needed to clarify the clinical value of quantitative features of DVT including thrombus volume as an imaging biomarker for PE.

Prevalence and neglected rate of sacroiliitis on lumbar spine CT in patients with low back pain.

OBJECTIVE: The study aims to investigate the prevalence and neglected rate of sacroiliitis on lumbar spine computed tomography (CT) in patients with low back pain. MATERIALS AND METHODS: From January 2016 to December 2020, a total of 4827 patients (mean age: 35.4 ± 9.5 years) who underwent lumbar spine CT examinations were included in this retrospective study. The CT degree of sacroiliitis in all study population were retrospectively reviewed by two radiologists. The independent sample t-test was used to compare the continuous values and chi-squared or Fisher's exact test was used to compare the categorized values. RESULTS: Sacroiliitis was identified in 514 of 4827 patients (10.6%). Patients with sacroiliitis were significantly younger than those without sacroiliitis (32.1 ± 8.9 vs. 35.8 ± 9.5 years, p < 0.001). Moreover, significantly more patients with sacroiliitis had HLA-B27 (p < 0.001) positivity and inflammatory back pain syndrome (p = 0.003) than those without sacroiliitis. Among the 514 patients, sacroiliitis was recognized on primary reading in 386 patients (75.1%) but was neglected in the remaining 128 patients (24.9%). Of the 386 patients, 371 patients were followed up, and finally, 295 patients of them (79.5%) were diagnosed with axSpA. CONCLUSION: Radiologists should pay careful and more attention to sacroiliac joint on lumbar spine CT for early diagnosis of sacroiliitis in young patients with low back pain, which could result in early diagnosis and treatment of axSpA.

Differential dynamics of cullin deneddylation via COP9 signalosome subunit 5 interaction.

Cullin-RING E3 ubiquitin ligases (CRLs) spatiotemporally regulate the proteasomal degradation of numerous cellular proteins involved in cell cycle control, DNA replication, and maintenance of genome stability. Activation of CRLs is controlled via neddylation by NEDD8-activating, -conjugating, and -attaching enzymes to the C-terminus of scaffold cullins (CULs), whereas the COP9 signalosome (CSN) inactivates CRLs via deneddylation. Here, we show that the deneddylation rate of each CUL is differentially modulated. Dose- or time-dependent treatment with pevonedistat, a small molecule inhibitor of NEDD8-activating enzyme (NAE), rapidly inhibits neddylation in most CULs, including CUL1, CUL3, CUL4A/B, and CUL5, whereas the deneddylation of CUL2 is slowly increased. We revealed that the different deneddylation speeds of each CUL depend on its binding strength with CSN5, the catalytic core of the CSN complex. Immunoprecipitation analysis revealed that CUL2 has a lower binding affinity for CSN5 than other CULs. Consistently, released cells treated with CSN5 inhibitor showed that CUL2 was slowly converted to the deneddylated form compared to the rapid deneddylation of other CULs. These findings provide mechanistic insights into the different dynamics of CULs in neddylation-deneddylation conversion.

The differentially expressed gene signatures of the Cullin 3-RING ubiquitin ligases in neuroendocrine cancer.

Cullin-RING ubiquitin E3 ligase (CRLs) composed of four components including cullin scaffolds, adaptors, substrate receptors, and RING proteins mediates the ubiquitination of approximately 20% of cellular proteins that are involved in numerous biological processes. While CRLs deregulation contributes to the pathogenesis of many diseases, including cancer, how CRLs deregulation occurs is yet to be fully investigated. Here, we demonstrate that components of CRL3 and its transcriptional regulators are possible prognosis marker of neuroendocrine (NE) cancer. Analysis of Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal revealed that expression of CRL3 scaffold Cullin 3 (CUL3) highly correlates with NE signature, and CUL3 silencing inhibited NE cancer proliferation. Moreover, subset of 151 BTB (Bric-a-brac, Tramtrack, Broad complex) domain-containing proteins that have dual roles as substrate receptors and adaptor subunits in CRL3, as well as the expression of transcription factors (TFs) that control the transcription of BTB genes were upregulated in NE cancer. Analysis using published ChIP-sequencing data in small cell lung cancer (SCLC), including NE or non-NE SCLC verified that gene promoter of candidates which show high correlation with NE signature enriched H3K27Ac. These observations suggest that CRL3 is a master regulator of NE cancer and knowledge of specifically regulated CRL3 genes in NE cancer may accelerate new therapeutic approaches.

Effect of Airborne Particulate Matter on the Immunologic Characteristics of Chronic Rhinosinusitis with Nasal Polyps.

The inflammatory mechanisms of environmental pollutants in chronic rhinosinusitis (CRS) have recently been proposed. However, the mechanisms underlying the inflammatory effects of particulate matter (PM) on nasal polyp (NP) tissues remain unknown. Here we investigated the mechanism underlying the inflammatory effects of PM10 on human nasal polyp-derived fibroblasts (NPDFs). We isolated NPDFs from human NP tissues obtained from patients with CRS with NPs (CRSwNP). The NPDFs were exposed to PM10 in vitro. Immunologic characteristics were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, Western blot, and flow cytometry. Additionally, we investigated the effect of NPDF-conditioned media (CM) on the expression of CD4+ T cell inflammatory mediators. PM10-treated NPDFs significantly upregulated interleukin (IL)-6, IL-4, and IL-33 expression and CXCL1 protein levels than PM10-treated normal tissues. MAP kinase, AP-1, and NF-kB were the primary cell signaling proteins. Immune cells in NPDF-CM had elevated IL-13, IL-17A, and IL-10 expression, but no significant difference in IFN-γ, TNF-α, and IL-4 expression. Moreover, under a Th2 inducing condition, NPDF-CM-treated CD4+ T cells had increased expression of IL-13, IL-10, and IL-17, which was reversed on ST2 inhibitor addition. Our study suggests that PM10 exposure could significantly increase the Th2 inflammatory pathway in NP tissues, specifically the IL-33/ST2 pathway-mediated immune response.

Multi-scale causality analysis between COVID-19 cases and mobility level using ensemble empirical mode decomposition and causal decomposition.

The global spread of the coronavirus disease 2019 (COVID-19) pandemic has affected the world in many ways. Due to the communicable nature of the disease, it is difficult to investigate the causal reason for the epidemic's spread sufficiently. This study comprehensively investigates the causal relationship between the spread of COVID-19 and mobility level on a multi time-scale and its influencing factors, by using ensemble empirical mode decomposition (EEMD) and the causal decomposition approach. Linear regression analysis investigates the significance and importance of the influential factors on the intrastate and interstate causal strength. The results of an EEMD analysis indicate that the mid-term and long-term domain portrays the macroscopic component of the states' mobility level and COVID-19 cases, which represents overall intrinsic characteristics. In particular, the mobility level is highly associated with the long-term variations of COVID-19 cases rather than short-term variations. Intrastate causality analysis identifies the significant effects of median age and political orientation on the causal strength at a specific time-scale, and some of them cannot be identified from the existing method. Interstate causality results show a negative association with the interstate distance and the positive one with the airline traffic in the long-term domain. Clustering analysis confirms that the states with the higher the gross domestic product and the more politically democratic tend to more adhere to social distancing. The findings of this study can provide practical implications to the policymakers that whether the social distancing policies are effectively working or not should be monitored by long-term trends of COVID-19 cases rather than short-term.

Comparison of the Characteristics of Recycled Carbon Fibers/Polymer Composites by Different Recycling Techniques.

In this study, three recycling methods, namely, mechanical grinding, steam pyrolysis, and the supercritical solvent process, which are used to acquire recycled carbon fibers (RCFs), were compared for their application in synthesizing polymer-matrix composites. RCF-reinforced polyethylene (PE) composites were prepared to compare the mechanical properties of the composites generated using the three recycling methods. The PE/RCF composites exhibited 1.5 times higher mechanical strength than the RCF-reinforced PE composites, probably because of the surface oxidation effects during the recycling processes that consequently enhanced interfacial forces between the RCF and the matrix. Further, the steam pyrolysis process showed the highest energy efficiency and can thus be applied on a large production scale in domestic recycled CF markets.

Molecular double clips within RepID WD40 domain control chromatin binding and CRL4-substrate assembly.

The cell cycle is modulated by ubiquitin ligases, including CRL4, which facilitate degradation of the chromatin-bound substrates involved in DNA replication and chromosome segregation. One of the members of the CRL4 complex, RepID (DCAF14/PHIP), recognizes kinetochore-localizing BUB3, known as the CRL4 substrate, and recruits CRL4 to the chromatin/chromosome using the WD40 domain. Here, we show that the RepID WD40 domain provides different platforms to CRL4 and BUB3. Deletion of the H-box or exon 8 located in the RepID WD40 domain compromises the interaction between RepID and CRL4, whereas BUB3 interacts with the exon 1-2 region. Moreover, deletion mutants of other exons in the WD40 domain lost chromatin binding affinity. Structure prediction revealed that the RepID WD40 domain has two beta-propeller folds, linked by loops, which are possibly crucial for chromatin binding. These findings provide mechanistic insights into the space occupancy of the RepID WD40 domain to form a complex with CRL4, BUB3, or chromatin.

Glans inflation morphology and female cloaca copulatory interactions of the male American alligator phallus†.

The phallic glans of the American alligator (Alligator mississippiensis) is the distal termination of the semen-conducting sulcus spermaticus and during copulation has the closest, most intimate mechanical interactions with the female urodeum, the middle cloacal chamber that contains the opening to the vaginal passages and oviducts. However, the details of this interface leading to insemination and gamete uptake are unclear. Here, we: (1) histologically characterize the underlying tissue types and morphologically quantify the shape changes associated with glans inflation into the copulatory conformation, (2) digitally reconstruct from MRI the 3D shape of functional tissue compartments, and (3) diffusible iodine-based contrast-enhanced computed tomography image the copulatory fit between male phallus and female cloaca. We discuss these results in relation to tissue type material properties, the transfer on intromittent forces, establishing potential copulatory lock, inflated glans volume scaling with body mass/length, the mechanics of semen targeting and insemination, and potential female cryptic choice impacting multiple clutch paternity. In part, this study further clarifies the phallic morphological variation observed among crocodylians and begins to investigate the role(s) these divergent male forms play during copulation interacting with female cloacal forms to increase reproductive success.

Radiomics analysis of contrast-enhanced CT for classification of hepatic focal lesions in colorectal cancer patients: its limitations compared to radiologists.

OBJECTIVE: To evaluate diagnostic performance of a radiomics model for classifying hepatic cyst, hemangioma, and metastasis in patients with colorectal cancer (CRC) from portal-phase abdominopelvic CT images. METHODS: This retrospective study included 502 CRC patients who underwent contrast-enhanced CT and contrast-enhanced liver MRI between January 2005 and December 2010. Portal-phase CT images of training (n = 386) and validation (n = 116) cohorts were used to develop a radiomics model for differentiating three classes of liver lesions. Among multiple handcrafted features, the feature selection was performed using ReliefF method, and random forest classifiers were used to train the selected features. Diagnostic performance of the developed model was compared with that of four radiologists. A subgroup analysis was conducted based on lesion size. RESULTS: The radiomics model demonstrated significantly lower overall and hemangioma- and metastasis-specific polytomous discrimination index (PDI) (overall, 0.8037; hemangioma-specific, 0.6653; metastasis-specific, 0.8027) than the radiologists (overall, 0.9622-0.9680; hemangioma-specific, 0.9452-0.9630; metastasis-specific, 0.9511-0.9869). For subgroup analysis, the PDI of the radiomics model was different according to the lesion size (< 10 mm, 0.6486; ≥ 10 mm, 0.8264) while that of the radiologists was relatively maintained. For classifying metastasis from benign lesions, the radiomics model showed excellent diagnostic performance, with an accuracy of 84.36% and an AUC of 0.9426. CONCLUSION: Albeit inferior to the radiologists, the radiomics model achieved substantial diagnostic performance when differentiating hepatic lesions from portal-phase CT images of CRC patients. This model was limited particularly to classifying hemangiomas and subcentimeter lesions. KEY POINTS: • Albeit inferior to the radiologists, the radiomics model could differentiate cyst, hemangioma, and metastasis with substantial diagnostic performance using portal-phase CT images of colorectal cancer patients. • The radiomics model demonstrated limitations especially in classifying hemangiomas and subcentimeter liver lesions.