Bacterial infection promotes tumorigenesis of colorectal cancer via regulating CDC42 acetylation.

Increasing evidence highlights the role of bacteria in promoting tumorigenesis. The underlying mechanisms may be diverse and remain poorly understood. Here, we report that Salmonella infection leads to extensive de/acetylation changes in host cell proteins. The acetylation of mammalian cell division cycle 42 (CDC42), a member of the Rho family of GTPases involved in many crucial signaling pathways in cancer cells, is drastically reduced after bacterial infection. CDC42 is deacetylated by SIRT2 and acetylated by p300/CBP. Non-acetylated CDC42 at lysine 153 shows an impaired binding of its downstream effector PAK4 and an attenuated phosphorylation of p38 and JNK, consequently reduces cell apoptosis. The reduction in K153 acetylation also enhances the migration and invasion ability of colon cancer cells. The low level of K153 acetylation in patients with colorectal cancer (CRC) predicts a poor prognosis. Taken together, our findings suggest a new mechanism of bacterial infection-induced promotion of colorectal tumorigenesis by modulation of the CDC42-PAK axis through manipulation of CDC42 acetylation.

Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia.

Frontotemporal dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioural variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA and 30 non-fluent variant PPA (nfvPPA) cases, and 110 healthy controls from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus healthy controls. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 healthy controls in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 healthy controls in Dataset 2) and symptom-specific networks [combined Datasets 1 and 2, apathy without depression versus non-apathy without depression (80:26), disinhibition versus non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks, respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions.

Global profiling of ribosomal protein acetylation reveals essentiality of acetylation homeostasis in maintaining ribosome assembly and function.

Acetylation is a global post-translational modification that regulates various cellular processes. Bacterial acetylomic studies have revealed extensive acetylation of ribosomal proteins. However, the role of acetylation in regulating ribosome function remains poorly understood. In this study, we systematically profiled ribosomal protein acetylation and identified a total of 289 acetylated lysine residues in 52 ribosomal proteins (r-proteins) from Salmonella Typhimurium. The majority of acetylated lysine residues of r-proteins were found to be regulated by both acetyltransferase Pat and metabolic intermediate acetyl phosphate. Our results show that acetylation plays a critical role in the assembly of the mature 70S ribosome complex by modulating r-proteins binding to rRNA. Moreover, appropriate acetylation is important for the interactions between elongation factors and polysomes, as well as regulating ribosome translation efficiency and fidelity. Dysregulation of acetylation could alter bacterial sensitivity to ribosome-targeting antibiotics. Collectively, our data suggest that the acetylation homeostasis of ribosomes is crucial for their assembly and function. Furthermore, this mechanism may represent a universal response to environmental signals across different cell types.

Early matrix softening contributes to vascular smooth muscle cell phenotype switching and aortic dissection through down-regulation of microRNA-143/145.

Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection.

Gut microbial metabolite trimethylamine N-oxide induces aortic dissection.

Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 µM vs. 1.85, IQR: 1.40 to 3.35 µM; p < 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or ß-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The in vitro experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The in vivo BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management.

Immunogenomic features of radiologically distinctive nodules in multiple primary lung cancer.

OBJECTIVES: To provide molecular and immunological attributes mechanistic insights for the management of radiologically distinctive multiple primary lung cancer (MPLC). METHODS: The Bulk RNA-seq data of MPLC were obtained from our center. The Bulk RNA-seq data and CT images of patients with single primary lung cancer (SPLC) were obtained from GSE103584. Immune infiltration algorithms were performed to investigate the disparities in the immunological microenvironment between the two groups. Single-cell gene analysis was used to explore immune cells composition and communication relationships between cells in MPLC. RESULTS: In MPLC, 11 pure ground-glass opacity nodules (pGGN) and 10 mixed GGN (mGGN) were identified, while in SPLC, the numbers were 18 pGGN and 22 mGGN, respectively. In MPLC, compared to pGGN, mGGN demonstrated a significantly elevated infiltration of CD8+ T cells. Single-cell gene analysis demonstrated that CD8+ T cells play a central role in the signaling among immune cells in MPLC. The transcription factors including MAFG, RUNX3, and TBX21 may play pivotal roles in regulation of CD8+ T cells. Notably, compared to SPLC nodules for both mGGN and pGGN, MPLC nodules demonstrated a significantly elevated degree of tumor-infiltrating immune cells, with this difference being particularly pronounced in mGGN. There was a positive correlation between the proportion of immune cells and consolidation/tumor ratio (CTR). CONCLUSIONS: Our findings provided a comprehensive description about the difference in the immune microenvironment between pGGN and mGGN in early-stage MPLC, as well as between MPLC and SPLC for both mGGN and pGGN. The findings may provide evidence for the design of immunotherapeutic strategies for MPLC.

In silico analysis of the wheat BBX gene family and identification of candidate genes for seed dormancy and germination.

BACKGROUND: B-box (BBX) proteins are a type of zinc finger proteins containing one or two B-box domains. They play important roles in development and diverse stress responses of plants, yet their roles in wheat remain unclear. RESULTS: In this study, 96 BBX genes were identified in the wheat genome and classified into five subfamilies. Subcellular localization prediction results showed that 68 TaBBXs were localized in the nucleus. Protein interaction prediction analysis indicated that interaction was one way that these proteins exerted their functions. Promoter analysis indicated that TaBBXs may play important roles in light signal, hormone, and stress responses. qRT-PCR analysis revealed that 14 TaBBXs were highly expressed in seeds compared with other tissues. These were probably involved in seed dormancy and germination, and their expression patterns were investigated during dormancy acquisition and release in the seeds of wheat varieties Jing 411 and Hongmangchun 21, showing significant differences in seed dormancy and germination phenotypes. Subcellular localization analysis confirmed that the three candidates TaBBX2-2 A, TaBBX4-2 A, and TaBBX11-2D were nuclear proteins. Transcriptional self-activation experiments further demonstrated that TaBBX4-2A was transcriptionally active, but TaBBX2-2A and TaBBX11-2D were not. Protein interaction analysis revealed that TaBBX2-2A, TaBBX4-2A, and TaBBX11-2D had no interaction with each other, while TaBBX2-2A and TaBBX11-2D interacted with each other, indicating that TaBBX4-2A may regulate seed dormancy and germination by transcriptional regulation, and TaBBX2-2A and TaBBX11-2D may regulate seed dormancy and germination by forming a homologous complex. CONCLUSIONS: In this study, the wheat BBX gene family was identified and characterized at the genomic level by bioinformatics analysis. These observations provide a theoretical basis for future studies on the functions of BBXs in wheat and other species.

Functional analysis of a wheat class III peroxidase gene, TaPer12-3A, in seed dormancy and germination.

BACKGROUND: Class III peroxidases (PODs) perform crucial functions in various developmental processes and responses to biotic and abiotic stresses. However, their roles in wheat seed dormancy (SD) and germination remain elusive. RESULTS: Here, we identified a wheat class III POD gene, named TaPer12-3A, based on transcriptome data and expression analysis. TaPer12-3A showed decreasing and increasing expression trends with SD acquisition and release, respectively. It was highly expressed in wheat seeds and localized in the endoplasmic reticulum and cytoplasm. Germination tests were performed using the transgenic Arabidopsis and rice lines as well as wheat mutant mutagenized with ethyl methane sulfonate (EMS) in Jing 411 (J411) background. These results indicated that TaPer12-3A negatively regulated SD and positively mediated germination. Further studies showed that TaPer12-3A maintained H2O2 homeostasis by scavenging excess H2O2 and participated in the biosynthesis and catabolism pathways of gibberellic acid and abscisic acid to regulate SD and germination. CONCLUSION: These findings not only provide new insights for future functional analysis of TaPer12-3A in regulating wheat SD and germination but also provide a target gene for breeding wheat varieties with high pre-harvest sprouting resistance by gene editing technology.

Comprehensive genome-wide analysis of wheat xylanase inhibitor protein (XIP) genes: unveiling their role in Fusarium head blight resistance and plant immune mechanisms.

In this comprehensive genome-wide study, we identified and classified 83 Xylanase Inhibitor Protein (XIP) genes in wheat, grouped into five distinct categories, to enhance understanding of wheat's resistance to Fusarium head blight (FHB), a significant fungal threat to global wheat production. Our analysis reveals the unique distribution of XIP genes across wheat chromosomes, particularly at terminal regions, suggesting their role in the evolutionary expansion of the gene family. Several XIP genes lack signal peptides, indicating potential alternative secretion pathways that could be pivotal in plant defense against FHB. The study also uncovers the sequence homology between XIPs and chitinases, hinting at a functional diversification within the XIP gene family. Additionally, the research explores the association of XIP genes with plant immune mechanisms, particularly their linkage with plant hormone signaling pathways like abscisic acid and jasmonic acid. XIP-7A3, in particular, demonstrates a significant increase in expression upon FHB infection, highlighting its potential as a key candidate gene for enhancing wheat's resistance to this disease. This research not only enriches our understanding of the XIP gene family in wheat but also provides a foundation for future investigations into their role in developing FHB-resistant wheat cultivars. The findings offer significant implications for wheat genomics and breeding, contributing to the development of more resilient crops against fungal diseases.

Knowledge-Augmented Deep Learning for Segmenting and Detecting Cerebral Aneurysms With CT Angiography: A Multicenter Study.

Background Deep learning (DL) could improve the labor-intensive, challenging processes of diagnosing cerebral aneurysms but requires large multicenter data sets. Purpose To construct a DL model using a multicenter data set for accurate cerebral aneurysm segmentation and detection on CT angiography (CTA) images and to compare its performance with radiology reports. Materials and Methods Consecutive head or head and neck CTA images of suspected unruptured cerebral aneurysms were gathered retrospectively from eight hospitals between February 2018 and October 2021 for model development. An external test set with reference standard digital subtraction angiography (DSA) scans was obtained retrospectively from one of the eight hospitals between February 2022 and February 2023. Radiologists (reference standard) assessed aneurysm segmentation, while model performance was evaluated using the Dice similarity coefficient (DSC). The model's aneurysm detection performance was assessed by sensitivity and comparing areas under the receiver operating characteristic curves (AUCs) between the model and radiology reports in the DSA data set with use of the DeLong test. Results Images from 6060 patients (mean age, 56 years ± 12 [SD]; 3375 [55.7%] female) were included for model development (training: 4342; validation: 1086; and internal test set: 632). Another 118 patients (mean age, 59 years ± 14; 79 [66.9%] female) were included in an external test set to evaluate performance based on DSA. The model achieved a DSC of 0.87 for aneurysm segmentation performance in the internal test set. Using DSA, the model achieved 85.7% (108 of 126 aneurysms [95% CI: 78.1, 90.1]) sensitivity in detecting aneurysms on per-vessel analysis, with no evidence of a difference versus radiology reports (AUC, 0.93 [95% CI: 0.90, 0.95] vs 0.91 [95% CI: 0.87, 0.94]; P = .67). Model processing time from reconstruction to detection was 1.76 minutes ± 0.32 per scan. Conclusion The proposed DL model could accurately segment and detect cerebral aneurysms at CTA with no evidence of a significant difference in diagnostic performance compared with radiology reports. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Payabvash in this issue.

Myocardial bridging in obstructive hypertrophic cardiomyopathy: a risk factor for myocardial fibrosis.

BACKGROUND: Myocardial bridging (MB) is common in patients with hypertrophic cardiomyopathy (HCM). There are sparse data on the impact of MB on myocardial fibrosis in HCM. This study was designed to evaluate the relationship between MB and myocardial fibrosis in patients with obstructive HCM. METHODS: In this cohort study, retrospective data were collected from a high-volume HCM center. Patients with obstructive HCM who underwent septal myectomy and preoperative cardiac magnetic resonance (CMR) were screened from 2011 to 2018. RESULTS: Finally, 492 patients were included in this study, with an average age of 45.7 years. Of these patients, 76 patients had MB. MB occurred mostly in the left anterior descending artery (73/76). The global extent of late gadolinium enhancement (LGE) was correlated with the degree of systolic compression (r = 0.33, p = 0.003). Multivariable linear regression analysis revealed that the degree of systolic compression was an independent risk factor for LGE (ß = 0.292, p = 0.007). The LGE fraction of basal and mid anteroseptal segments in patients with severe MB (compression ratio ≥ 80%) was significantly greater than that in patients with mild to moderate MB (compression ratio < 80%). During a median follow-up of 28 (IQR: 15-52) months, 15 patients died. Kaplan-Meier analysis did not identify differences in all-cause death (log-rank p = 0.63) or cardiovascular death (log-rank p = 0.72) between patients undergoing MB-related surgery and those without MB. CONCLUSIONS: MB with severe systolic compression was significantly associated with a high extent of fibrosis in patients with obstructive HCM. Concomitant myotomy or coronary artery bypass grafting might provide excellent survival similar to that of patients without MB. Identification of patients with severe MB and providing comprehensive management might help improve the prognosis of patients with HCM.

O-GlcNAcylation orchestrates porcine oocyte maturation through maintaining mitochondrial dynamics and function.

O-linked ß-N-acetylglucosamine (O-GlcNAc) modification exists widely in cells, playing a crucial role in the regulation of important biological processes such as transcription, translation, metabolism, and the cell cycle. O-GlcNAc modification is an inducible reversible dynamic protein post-translational modification, which regulates complex cellular activities through transient glycosylation and deglycosylation. O-GlcNAc glycosylation is specifically regulated by O-GlcNAc glycosyltransferase (O-GlcNAc transferase, OGT) and O-GlcNAc glycoside hydrolase (O-GlcNAcase). However, the mechanisms underlying the effects of O-GlcNAc modification on the female reproductive system, especially oocyte quality, remain unclear. Here, we found that after OGT was inhibited, porcine oocytes failed to extrude the first polar body and exhibited abnormal actin and microtubule assembly. Meanwhile, the mitochondrial dynamics and function were also disrupted after inhibition of OGT function, resulting in the occurrence of oxidative stress and autophagy. Collectively, these results inform our understanding of the importance of the glycosylation process for oocyte maturation, especially for the maturation quality of porcine oocytes, and the alteration of O-GlcNAc in oocytes to regulate cellular events deserves further investigation.

Root plasticity improves maize nitrogen use when nitrogen is limiting - an analysis using 3D plant modelling.

Plant phenotypic plasticity plays an important role in nitrogen (N) acquisition and use under nitrogen-limited conditions. However, this role has never been quantified as a function of N availability, leaving it unclear whether plastic responses should be considered as potential targets for selection. A combined modelling and experimentation approach was adopted to quantify the role of plasticity on N uptake and plant yield. Based on a greenhouse experiment we considered plasticity in two maize traits: root-to-leaf biomass allocation ratio and emergence rate of axial roots. In a simulation experiment we individually enabled or disabled both plastic responses for maize stands grown across six N levels. Both plastic responses contributed to maintaining a higher N uptake and plant productivity as N-availability declined, compared to stands in which plastic responses were disabled. We conclude that plastic responses quantified in this study may be a potential target trait in breeding programs for greater N uptake across N levels while it may only be important for the internal use of N under N-limited conditions in maize. Given the complexity of breeding for plastic responses, an a priori model analysis is useful to identify which plastic traits to target for enhanced plant performance.

Exploring the association of glioma tumor residuals from incongruent [18F]FET PET/MR imaging with tumor proliferation using a multiparametric MRI radiomics nomogram.

PURPOSE: The study aimed to using multiparametric MRI radiomics to predict glioma tumor residuals (TRFET over MR) derived from incongruent [18F]fluoroethyl-L-tyrosine ([18F]FET) PET/MR imaging. METHODS: One hundred ten patients with gliomas who underwent [18F]FET PET/MR scanning were retrospectively analyzed. The TRFET over MR was identified by the discrepancy-PET that the extent of resection (EOR) based on MRI subtracted the biological tumor volume on PET images. The MRI parameters and radiomics features were extracted based on EOR and selected by the least absolute shrinkage and selection operator to construct radiomics score (Rad-score). The correlation network analysis of all features was analyzed by Spearman's correlation tests. The methods for evaluating the clinical usefulness consisted of the receiver operating characteristic curve, the calibration curve, and decision curve analysis. RESULTS: The Rad-score of the patients with the TRFET over MR was significantly higher than those with the non TRFET over MR (p < 0.001). The Rad-score was significantly correlated with the discrepancy-PET (r = 0.72, p < 0.001), Ki-67 level (r = 0.76, p < 0.001), and epidermal growth factor receptor (EGFR) of gliomas (r = 0.75, p < 0.001), respectively. Moreover, there was a difference of the correlation network analysis between the TRPET over MR group and non TRFET over MR group. The nomogram combing Rad-score and clinical features had the greatest performance in predicting TRFET over MR (AUC = 0.90/0.87, training/testing). There was a significant difference in prognosis (median OS, 17 m vs. 43 m) between patients with TRFET over MR and non TRFET over MR based on nomogram prediction (p < 0.001). CONCLUSION: The nomogram based on MRI radiomics would predict gliomas tumor residuals caused by the absence of 18F-PET PET examination and adjust EOR to improve prognosis.

Crowdsourced partner services among men who have sex with men living with HIV: A pilot randomized controlled trial in China.

BACKGROUND: This study aimed to assess the acceptability, feasibility, and preliminary effectiveness of a crowdsourced HIV partner services (PS) intervention among men who have sex with men living with HIV (MLWH) in China. METHODS: A pilot two-arm randomized controlled trial (RCT) was conducted in three HIV testing clinics in China. The control arm received conventional HIV PS while the intervention arm received a crowdsourced intervention, including HIV self-testing kits for secondary distribution (HIVST-SD), digital education materials, and assisted PS. The intervention was developed through two-phase crowdsourcing events including an open call and a Designathon. The primary outcomes were measured by the 3-month follow-up rate (i.e., the proportion of participants who completed the follow-up survey to report HIV PS outcomes three months after enrollment) and the frequency of using intervention components (feasibility), index evaluation of intervention components (acceptability), and the proportion of partners getting HIV testing (preliminary effectiveness). RESULTS: The study enrolled 121 newly diagnosed MLWH between July 2021 and May 2022. The 3-month follow-up rates were 93% (75/81) and 83% (33/40) in the intervention and control arms, respectively. Crowdsourced intervention components demonstrated feasibility, with all indexes utilizing digital educational materials, 23 successfully using HIVST-SD, and six employing provider-referral to notify nine sexual partners. Acceptability was high, with HIVST-SD and digital educational materials rated 4·4 and 4.1 out of 5. The proportion of partners receiving HIV testing was 11% higher in the intervention arm than in the control arm (marginal significance with 95% CI = [-2%, 24%], 38% vs. 27%). CONCLUSION: The crowdsourced HIV PS intervention was acceptable and feasible, suggesting the potential to facilitate partner HIV testing among Chinese MLWH. Further implementation research is recommended to expand HIV PS among key populations in low- and middle-income countries.Clinical trial registration ID: NCT04971967 (Protocol ID: 19-0496).

Striatal and Extrastriatal Monoaminergic Disruption in Progressive Supranuclear Palsy.

BACKGROUND: As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), 18F-9-fluoropropyldihydrotetrabenazine (18F-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP). OBJECTIVE: We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using 18F-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP. METHODS: We recruited 58 patients with PSP, 23 age- and duration-matched patients with PD, as well as 17 HCs. Patients were scanned using 18F-FP-DTBZ PET/computed tomography, and images were spatially normalized and analyzed based on the volume of interest. RESULTS: VMAT2 binding differed significantly in the striatum and substantia nigra among the groups (P < 0.001). A more severe disruption in the caudate was noted in the PSP group (P < 0.001) than in the PD group. However, no differences were found in the nucleus accumbens, hippocampus, amygdala, or raphe between the PD and PSP groups. Within the PSP group, striatal VMAT2 binding was significantly associated with the fall/postural stability subscore of the PSP Rating Scale, especially in the putamen. Furthermore, VMAT2 binding was correlated with Mini-Mental State Examination or Montreal Cognitive Assessment in the hippocampus. CONCLUSIONS: Caudate disruptions showed prominent differences among the groups. VAMT2 binding in the striatum and hippocampus reflects the severity of fall/postural stability and cognition, respectively. © 2024 International Parkinson and Movement Disorder Society.

Specific Alterations in Brain White Matter Networks and Their Impact on Clinical Function in Pediatric Patients With Thoracolumbar Spinal Cord Injury.

BACKGROUND: The alternation of brain white matter (WM) network has been studied in adult spinal cord injury (SCI) patients. However, the WM network alterations in pediatric SCI patients remain unclear. PURPOSE: To evaluate WM network changes and their functional impact in children with thoracolumbar SCI (TSCI). STUDY TYPE: Prospective. SUBJECTS: Thirty-five pediatric patients with TSCI (8.94 ± 1.86 years, 8/27 males/females) and 34 age- and gender-matched healthy controls (HCs) participated in this study. FIELD STRENGTH/SEQUENCE: 3.0 T/DTI imaging using spin-echo echo-planar and T1-weighted imaging using 3D T1-weighted magnetization-prepared rapid gradient-echo sequence. ASSESSMENT: Pediatric SCI patients were evaluated for motor and sensory scores, injury level, time since injury, and age at injury. The WM network was constructed using a continuous tracing method, resulting in a 90 × 90 matrix. The global and regional metrics were obtained to investigate the alterations of the WM structural network. topology. STATISTICAL TESTS: Two-sample independent t-tests, chi-squared test, Mann-Whitney U-test, and Spearman correlation. Statistical significance was set at P < 0.05. RESULTS: Compared with HCs, pediatric TSCI patients displayed decreased shortest path length (Lp = 1.080 ± 0.130) and normalized Lp (λ = 5.020 ± 0.363), and increased global efficiency (Eg = 0.200 ± 0.015). Notably, these patients also demonstrated heightened regional properties in the orbitofrontal cortex, limbic system, default mode network, and several audio-visual-related regions. Moreover, the λ and Lp values negatively correlated with sensory scores. Conversely, nodal efficiency values in the right calcarine fissure and surrounding cortex positively correlated with sensory scores. The age at injury positively correlated with node degree in the left parahippocampal gyrus and nodal efficiency in the right posterior cingulate gyrus. DATA CONCLUSION: Reorganization of the WM networks in pediatric SCI patients is indicated by increased global and nodal efficiency, which may provide promising neuroimaging biomarkers for functional assessment of pediatric SCI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 5.

Identification of genetic loci and candidate genes underlying freezing tolerance in wheat seedlings.

KEY MESSAGE: Ten stable loci for freezing tolerance (FT) in wheat were detected by genome-wide association analysis. The putative candidate gene TaRPM1-7BL underlying the major locus QFT.ahau-7B.2 was identified and validated. Frost damage restricts wheat growth, development, and geographical distribution. However, the genetic mechanism of freezing tolerance (FT) remains unclear. Here, we evaluated FT phenotypes of 245 wheat varieties and lines, and genotyped them using a Wheat 90 K array. The association analysis showed that ten stable loci were significantly associated with FT (P < 1 × 10-4), and explained 6.45-26.33% of the phenotypic variation. In particular, the major locus QFT.ahau-7B.2 was consistently related to all nine sets of FT phenotypic data. Based on five cleaved amplified polymorphic sequence (CAPS) markers closely linked to QFT.ahau-7B.2, we narrowed down the target region to the 570.67-571.16 Mb interval (0.49 Mb) on chromosome 7B, in which four candidate genes were annotated. Of these, only TaRPM1-7BL exhibited consistent differential expression after low temperature treatment between freezing-tolerant and freezing-sensitive varieties. The results of cloning and whole-exome capture sequencing indicated that there were two main haplotypes for TaRPM1-7BL, including freezing-tolerant Hap1 and freezing-sensitive Hap2. Based on the representative SNP (+1956, A/G), leading to an amino acid change in the NBS domain, a CAPS marker (CAPS-TaRPM1-7BL) was developed and validated in 431 wheat varieties (including the above 245 materials) and 318 F2 lines derived from the cross of 'Annong 9267' (freezing-tolerant) × 'Yumai 9' (freezing-sensitive). Subsequently, the TaRPM1-7BL gene was silenced in 'Yumai 9' by virus-induced gene silencing (VIGS), and these silenced wheat seedlings exhibited enhanced FT phenotypes, suggesting that TaRPM1-7BL negatively regulates FT. These findings are valuable for understanding the complex genetic basis of FT in wheat.

High estrogen during ovarian stimulation induced loss of maternal imprinted methylation that is essential for placental development via overexpression of TET2 in mouse oocytes.

BACKGROUND: Ovarian stimulation (OS) during assisted reproductive technology (ART) appears to be an independent factor influencing the risk of low birth weight (LBW). Previous studies identified the association between LBW and placenta deterioration, potentially resulting from disturbed genomic DNA methylation in oocytes caused by OS. However, the mechanisms by which OS leads to aberrant DNA methylation patterns in oocytes remains unclear. METHODS: Mouse oocytes and mouse parthenogenetic embryonic stem cells (pESCs) were used to investigate the roles of OS in oocyte DNA methylation. Global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels were evaluated using immunofluorescence or colorimetry. Genome-wide DNA methylation was quantified using an Agilent SureSelectXT mouse Methyl-Seq. The DNA methylation status of mesoderm-specific transcript homologue (Mest) promoter region was analyzed using bisulfite sequencing polymerase chain reaction (BSP). The regulatory network between estrogen receptor alpha (ERα, ESR1) and DNA methylation status of Mest promoter region was further detected following the knockdown of ERα or ten-eleven translocation 2 (Tet2). RESULTS: OS resulted in a significant decrease in global 5mC levels and an increase in global 5hmC levels in oocytes. Further investigation revealed that supraphysiological ß-estradiol (E2) during OS induced a notable decrease in DNA 5mC and an increase in 5hmC in both oocytes and pESCs of mice, whereas inhibition of estrogen signaling abolished such induction. Moreover, Tet2 may be a direct transcriptional target gene of ERα, and through the ERα-TET2 axis, supraphysiological E2 resulted in the reduced global levels of DNA 5mC. Furthermore, we identified that MEST, a maternal imprinted gene essential for placental development, lost its imprinted methylation in parthenogenetic placentas originating from OS, and ERα and TET2 combined together to form a protein complex that may promote Mest demethylation. CONCLUSIONS: In this study, a possible mechanism of loss of DNA methylation in oocyte caused by OS was revealed, which may help increase safety and reduce epigenetic abnormalities in ART procedures.

Synthesis and Evaluation of Novel 99mTc-Labeled FGFR2-Targeting Peptides.

To develop radiolabeled FGFR2-targeting probes for visualizing fibroblast growth factor receptor (FGFR) expression levels in the tumor microenvironment, four novel 99mTc-labeled FGFR2-targeting peptides ([99mTc]Tc-FGFR2-1, [99mTc]Tc-FGFR2-2, [99mTc]Tc-FGFR2-3, and [99mTc]Tc-FGFR2-4) with different amino acid linkers between the targeted peptide moiety and the 99mTc chelating group were designed and synthesized. The in vitro cellular inhibition, internalization, and efflux results demonstrated that the four 99mTc complexes exhibited FGFR2-specific binding and prolonged cellular retention in DU145 human prostate cancer cells, which indicated that modification from the glycine side (N-terminal) of CH02 was feasible. Among them, [99mTc]Tc-FGFR2-1 exhibited the highest in vitro cellular uptake and in vivo tumor uptake at 30 min postinjection, and tumor uptake could be significantly inhibited by the competitor CH02 (53% inhibited, p < 0.05), suggesting the tumor-specific targeting ability of [99mTc]Tc-FGFR2-1. The DU145-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 30 min postinjection of [99mTc]Tc-FGFR2-1, highlighting its potential as a SPECT imaging probe for tumor FGFR2 detection.