The rate of W chromosome degeneration across multiple avian neo-sex chromosomes.

When sex chromosomes evolve recombination suppression, the sex-limited chromosome (Y/W) commonly degenerate by losing functional genes. The rate of Y/W degeneration is believed to slow down over time as the most essential genes are maintained by purifying selection, but supporting data are scarce especially for ZW systems. Here, we study W degeneration in Sylvioidea songbirds where multiple autosomal translocations to the sex chromosomes, and multiple recombination suppression events causing separate evolutionary strata, have occurred during the last ~ 28.1-4.5 million years (Myr). We show that the translocated regions have maintained 68.3-97.7% of their original gene content, compared to only 4.2% on the much older ancestral W chromosome. By mapping W gene losses onto a dated phylogeny, we estimate an average gene loss rate of 1.0% per Myr, with only moderate variation between four independent lineages. Consistent with previous studies, evolutionarily constrained and haploinsufficient genes were preferentially maintained on W. However, the gene loss rate did not show any consistent association with strata age or with the number of W genes at strata formation. Our study provides a unique account on the pace of W gene loss and reinforces the significance of purifying selection in maintaining essential genes on sex chromosomes.

Two-dimensional high-throughput on-cell screening of immunoglobulins against broad antigen repertoires.

Identifying high-affinity antibodies in human serum is challenging due to extremely low number of circulating B cells specific to the desired antigens. Delays caused by a lack of information on the immunogenic proteins of viral origin hamper the development of therapeutic antibodies. We propose an efficient approach allowing for enrichment of high-affinity antibodies against pathogen proteins with simultaneous epitope mapping, even in the absence of structural information about the pathogenic immunogens. To screen therapeutic antibodies from blood of recovered donors, only pathogen transcriptome is required to design an antigen polypeptide library, representing pathogen proteins, exposed on the bacteriophage surface. We developed a two-dimensional screening approach enriching lentiviral immunoglobulin libraries from the convalescent or vaccinated donors against bacteriophage library expressing the overlapping set of polypeptides covering the spike protein of SARS-CoV-2. This platform is suitable for pathogen-specific immunoglobulin enrichment and allows high-throughput selection of therapeutic human antibodies.

Longitudinal assessment of coronary plaque regression related to sodium-glucose cotransporter-2 inhibitor using coronary computed tomography angiography.

BACKGROUND: Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i) is a novel oral drug for treating type 2 diabetes mellitus (T2DM) with demonstrated cardiovascular benefits. Previous studies in apolipoprotein E knockout mice have shown that SGLT2i is associated with attenuated progression of atherosclerosis. However, whether this effect extends to T2DM patients with coronary atherosclerosis in real-world settings remains unknown. METHODS: In this longitudinal cohort study using coronary computed tomography angiography (CCTA), T2DM patients who underwent ≥ 2 CCTA examinations at our center between 2019 and 2022 were screened. Eligible patients had multiple study plaques, defined as non-obstructive stenosis at baseline and not intervened during serial CCTAs. Exclusion criteria included a CCTA time interval < 12 months, prior SGLT2i treatment, or initiation/discontinuation of SGLT2i during serial CCTAs. Plaque volume (PV) and percent atheroma volume (PAV) were measured for each study plaque using CCTA plaque analysis software. Patients and plaques were categorized based on SGLT2i therapy and compared using a 1:1 propensity score matching (PSM) analysis. RESULTS: The study included 236 patients (mean age 60.5 ± 9.5 years; 69.1% male) with 435 study plaques (diameter stenosis ≥ 50%, 31.7%). Following SGLT2i treatment for a median duration of 14.6 (interquartile range: 13.0, 20.0) months, overall, non-calcified, and low-attenuation PV and PAV were significantly decreased, while calcified PV and PAV were increased (all p < 0.001). Meanwhile, reductions in overall PV, non-calcified PV, overall PAV, and non-calcified PAV were significantly greater in SGLT2i-treated compared to non-SGLT2i-treated plaques (all p < 0.001). PSM analysis showed that SGLT2i treatment was associated with higher reductions in overall PV (- 11.77 mm3 vs. 4.33 mm3, p = 0.005), non-calcified PV (- 16.96 mm3 vs. - 1.81 mm3, p = 0.017), overall PAV (- 2.83% vs. 3.36%, p < 0.001), and non-calcified PAV (- 4.60% vs. 0.70%, p = 0.003). These findings remained consistent when assessing annual changes in overall and compositional PV and PAV. Multivariate regression models demonstrated that SGLT2i therapy was associated with attenuated progression of overall or non-calcified PV or PAV, even after adjusting for cardiovascular risk factors, medications, and baseline overall or non-calcified PV or PAV, respectively (all p < 0.05). The effect of SGLT2i on attenuating non-calcified plaque progression was consistent across subgroups (all p for interaction > 0.05). CONCLUSIONS: In this longitudinal CCTA cohort of T2DM patients, SGLT2i therapy markedly regressed coronary overall PV and PAV, mainly result from a significant reduction in non-calcified plaque.

Mining for QTL controlling maize low-phosphorus response genes combined with deep resequencing of RIL parental genomes and in silico GWAS analysis.

KEY MESSAGE: Extensive and comprehensive phenotypic data from a maize RIL population under both low- and normal-Pi treatments were used to conduct QTL mapping. Additionally, we integrated parental resequencing data from the RIL population, GWAS results, and transcriptome data to identify candidate genes associated with low-Pi stress in maize. Phosphorus (Pi) is one of the essential nutrients that greatly affect the maize yield. However, the genes underlying the QTL controlling maize low-Pi response remain largely unknown. In this study, a total of 38 traits at both seedling and maturity stages were evaluated under low- and normal-Pi conditions using a RIL population constructed from X178 (tolerant) and 9782 (sensitive), and most traits varied significantly between low- and normal-Pi treatments. Twenty-nine QTLs specific to low-Pi conditions were identified after excluding those with common intervals under both low- and normal-Pi conditions. Furthermore, 45 additional QTLs were identified based on the index value ((Trait_under_LowPi-Trait_under_NormalPi)/Trait_under_NormalPi) of each trait. These 74 QTLs collectively were classified as Pi-dependent QTLs. Additionally, 39 Pi-dependent QTLs were clustered in nine HotspotQTLs. The Pi-dependent QTL interval contained 19,613 unique genes, 6,999 of which exhibited sequence differences with non-synonymous mutation sites between X178 and 9782. Combined with in silico GWAS results, 277 consistent candidate genes were identified, with 124 genes located within the HotspotQTL intervals. The transcriptome analysis revealed that 21 genes, including the Pi transporter ZmPT7 and the strigolactones pathway-related gene ZmPDR1, exhibited consistent low-Pi stress response patterns across various maize inbred lines or tissues. It is noteworthy that ZmPDR1 in maize roots can be sharply up-regulated by low-Pi stress, suggesting its potential importance as a candidate gene for responding to low-Pi stress through the strigolactones pathway.

Male-biased recombination at chromosome ends in a songbird revealed by precisely mapping crossover positions.

Recombination plays a crucial role in evolution by generating novel haplotypes and disrupting linkage between genes, thereby enhancing the efficiency of selection. Here, we analyse the genomes of twelve great reed warblers (Acrocephalus arundinaceus) in a three-generation pedigree to identify precise crossover positions along the chromosomes. We located more than 200 crossovers and found that these were highly concentrated towards the telomeric ends of the chromosomes. Apart from this major pattern in the recombination landscape, we found significantly higher frequencies of crossovers in genic compared to intergenic regions, and in exons compared to introns. Moreover, while the number of recombination events was similar between the sexes, the crossovers were located significantly closer to the ends of paternal compared to maternal chromosomes. In conclusion, our study of the great reed warbler revealed substantial variation in crossover frequencies within chromosomes, with a distinct bias towards the sub-telomeric regions, particularly on the paternal side. These findings emphasise the importance of thoroughly screening the entire length of chromosomes to characterise the recombination landscape and uncover potential sex-biases in recombination.

How to update esophageal masses imaging using literature review (MRI and CT features).

MRI offers new opportunities for detailed visualization of the different layers of the esophageal wall, as well as early detection and accurate characterization of esophageal lesions. Staging of esophageal tumors including extramural extent of disease, and status of the adjacent organ can also be performed by MRI with higher accuracy compared to other imaging modalities including CT and esophageal endoscopy. Although MDCT appears to be the primary imaging modality that is indicated for preoperative staging of esophageal cancer to assess tumor resectability, MDCT is considered less accurate in T staging. This review aims to update radiologists about emerging imaging techniques and the imaging features of various esophageal masses, emphasizing the imaging features that differentiate between esophageal masses, demonstrating the critical role of MRI in esophageal masses. CRITICAL RELEVANCE STATEMENT: MRI features may help differentiate mucosal high-grade neoplasia from early invasive squamous cell cancer of the esophagus, also esophageal GISTs from leiomyomas, and esophageal malignant melanoma has typical MR features. KEY POINTS: MRI can accurately visualize different layers of the esophagus potentially has a role in T staging. MR may accurately delineate esophageal fistulae, especially small mediastinal fistulae. MRI features of various esophageal masses are helpful in the differentiation.

CD22-targeted glyco-engineered natural killer cells offer a further treatment option for B-cell acute lymphoblastic leukemia.

Not available.

An oncolytic HSV-1 armed with Visfatin enhances antitumor effects by remodeling tumor microenvironment against murine pancreatic cancer.

Oncolytic viruses (OVs) have shown potential in converting a "cold" tumor into a "hot" one and exhibit effectiveness in various cancer types. However, only a subset of patients respond to oncolytic virotherapy. It is important to understand the resistance mechanisms to OV treatment in pancreatic ductal adenocarcinoma (PDAC) to engineer oncolytic viruses. In this study, we used transcriptome RNA sequencing (RNA-seq) to identify Visfatin, which was highly expressed in the responsive tumors following OV treatment. To explore the antitumor efficacy, we modified OV-mVisfatin, which effectively inhibited tumor growth. For the first time, we revealed that Visfatin promoted the antitumor efficacy of OV by remodeling the tumor microenvironment, which involved enhancing CD8+ T cell and DC cell infiltration and activation, repolarizing macrophages towards the M1-like phenotype, and decreasing Treg cells using single-cell RNA sequencing (scRNA-seq) and flow cytometry. Furthermore, PD-1 blockade significantly enhanced OV-mVisfatin antitumor efficacy, offering a promising new therapeutic strategy for PDAC.

Association of stress hyperglycemia ratio with left ventricular function and microvascular obstruction in patients with ST-segment elevation myocardial infarction: a 3.0 T cardiac magnetic resonance study.

BACKGROUND: Stress hyperglycemia, which is associated with poor prognosis in patients with acute myocardial infarction (AMI), can be determined using the stress hyperglycemia ratio (SHR). Impaired left ventricular function and microvascular obstruction (MVO) diagnosed using cardiac magnetic resonance (CMR) have also been proven to be linked to poor prognosis in patients with AMI and aid in risk stratification. However, there have been no studies on the correlation between fasting SHR and left ventricular function and MVO in patients with acute ST-segment elevation myocardial infarction (ASTEMI). Therefore, this study aimed to investigate the additive effect of fasting SHR on left ventricular function and global deformation in patients with ASTEMI and to explore the association between fasting SHR and MVO. METHODS: Consecutive patients who underwent CMR at index admission (3-7 days) after primary percutaneous coronary intervention (PPCI) were enrolled in this study. Basic clinical, biochemical, and CMR data were obtained and compared among all patients grouped by fasting SHR tertiles: SHR1: SHR < 0.85; SHR2: 0.85 ≤ SHR < 1.01; and SHR3: SHR ≥ 1.01. Spearman's rho (r) was used to assess the relationship between fasting SHR and left ventricular function, myocardial strain, and the extent of MVO. Multivariable linear regression analysis was performed to evaluate the determinants of left ventricular function and myocardial strain impairment in all patients with AMI. Univariable and multivariable regression analyses were performed to investigate the correlation between fasting SHR and the presence and extent of MVO in patients with AMI and those with AMI and diabetes mellitus (DM). RESULTS: A total of 357 patients with ASTEMI were enrolled in this study. Left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI) were significantly lower in SHR2 and SHR3 than in SHR1. Compared with SHR1 and SHR2 groups, left ventricular strain was lower in SHR3, as evidenced by global radial (GRS), global circumferential (GCS), and global longitudinal (GLS) strains. Fasting SHR were negatively correlated with LVEF, LVGFI, and GRS (r = - 0.252; r = - 0.261; and r = - 0.245; all P<0.001) and positively correlated with GCS (r = 0.221) and GLS (r = 0.249; all P <0.001). Multivariable linear regression analysis showed that fasting SHR was an independent determinant of impaired LVEF, LVGFI, GRS, and GLS. Furthermore, multivariable regression analysis after adjusting for covariates signified that fasting SHR was associated with the presence and extent of MVO in patients with AMI and those with AMI and DM. CONCLUSION: Fasting SHR in patients with ASTEMI successfully treated using PPCI is independently associated with impaired cardiac function and MVO. In patients with AMI and DM, fasting SHR is an independent determinant of the presence and extent of MVO.

Preparation of liquid yogurt in the presence of pectin and its formation mechanism.

We had previously observed that adding pectin into milk before fermentation inhibited gelation of yogurt but did not affect the pH. Thus, this work aimed to prepare such liquid yogurt and clarify its formation mechanism. It was found that liquid yogurt was obtained in the presence of 0.10%-0.20% pectin. However, at lower or higher pectin concentrations, yogurt was gelled. Confocal laser scanning microscopy analysis demonstrated that 0.10%-0.20% pectin induced milk protein aggregating into separated particles rather than a continuous network, which explained why liquid yogurt was formed. Moreover, adding 0.10%-0.20% pectin into the casein micelle suspension induced aggregation of casein micelles at pH 6.8. After pH decreased to 4.3, casein micelles showed more aggregation but they were still separated particles, which was the same in the corresponding yogurt samples. These results suggested that pectin changed the aggregation mode of casein micelles and induced formation of liquid yogurt.

Clinical efficacy of acupuncture therapy combined with core muscle exercises in treating patients with chronic nonspecific low back pain: a systematic review and meta-analysis of randomized controlled trials.

Introduction: This meta-analysis aimed to determine the clinical efficacy of acupuncture combined with core muscle exercises on pain and functional status in patients with chronic nonspecific low back pain. Methods: This study followed the Preferred Reporting Items for Systematic Reviews and meta-analysis criteria for systematic reviews and meta-analyses. Randomized controlled trials published till November 2023 were searched in PubMed, Web of Science, Cochrane, Embase, China National Knowledge Infrastructure, Chinese Biomedical Literature, and Wanfang databases. The search strategy was related to disease type, intervention, and control measures and was structured around the search terms "low back pain," "acupuncture therapy," and "exercise." Two reviewers applied inclusion and exclusion criteria. Sensitivity and fixed effects analyses were performed to determine the primary outcomes. Results: We included 11 randomized controlled trials (n = 727) on acupuncture combined with core muscle exercises in patients with chronic nonspecific low back pain. Compared with controls, clinical efficacy was significant, with improvements in pain scores (visual analog pain scale and numerical rating scale) and Oswestry Disability Index in the intervention group. Discussion: Acupuncture therapy combined with core muscle exercises improved pain and functional status in patients with chronic nonspecific low back pain, with favorable clinical outcomes compared with single-core muscle training. Multicenter large-sample trials are required to obtain more reliable conclusions.

Atrial lead perforation early after device implantation-a case report and literature review.

We report three patients with screw-in lead perforation in the right atrial free wall not long after device implantation. All the patients complained of intermittent stabbing chest pain associated with deep breathing during the implantation. The "dry" epicardial puncture was utilized to avoid hemopericardium during lead extraction in the first case. The atrial electrode was repositioned in all cases and replaced by a new passive fixation lead in two patients with resolution of the pneumothorax or pericardial effusion. A literature review of 50 reported cases of atrial lead perforation was added to the findings in our case report.

Surface defect detection of hot rolled steel based on multi-scale feature fusion and attention mechanism residual block.

To improve the precision of defect categorization and localization in images, this paper proposes an approach for detecting surface defects in hot-rolled steel strips. The approach uses an improved YOLOv5 network model to overcome the issues of inadequate feature extraction capacity and suboptimal feature integration when identifying surface defects on steel strips. The proposed method achieves higher detection accuracy and localization precision, making it more competitive and applicable in real production. Firstly, the multi-scale feature fusion (MSF) strategy is utilized to fuse shallow and deep features effectively and enrich detailed information relevant to target defects. Secondly, the CSPLayer Res2Attention block (CRA block) residual module is introduced to reduce the loss of defect information during hierarchical transmission, thereby enhancing the extraction of fine-grained features and improving the perception of details and global features. Finally, the experimental results indicate that the mAP on the NEU-DET and GC10-DET datasets approaches 78.5% and 67.3%, respectively, which is 4.9% and 2.1% higher than that of the baseline. Meanwhile, it has higher precision and more precise localization capabilities than other methods. Furthermore, it also achieves 59.2% mAP on the APDDD dataset, indicating its potential for growth in further domains.

Genetically engineered membrane-based nanoengagers for immunotherapy of pancreatic cancer.

Modulating macrophages presents a promising avenue in tumor immunotherapy. However, tumor cells have evolved mechanisms to evade macrophage activation and phagocytosis. Herein, we introduced a bispecific antibody-based nanoengager to facilitate the recognition and phagocytosis of tumor cells by macrophages. Specifically, we genetically engineered two single chain variable fragments (scFv) onto cell membrane: anti-CD40 scFv for engaging with macrophages and anti-Claudin18.2 (CLDN18.2) scFv for interacting with tumor cells. These nanoengagers were further constructed by coating scFv-anchored membrane into PLGA nanoparticle core. Our developed nanoengagers significantly boosted immune responses, including increased recognition and phagocytosis of tumor cells by macrophages, enhanced activation and antigen presentation, and elevated cytotoxic T lymphocyte activity. These combined benefits resulted in enhancing antitumor efficacy against highly aggressive "cold" pancreatic cancer. Overall, this study offers a versatile nanoengager design for immunotherapy, achieved through genetically engineering to incorporate antibody-anchored membrane.

Scoring model based on cardiac CT and clinical factors to predict early good mitral valve repair in rheumatic mitral disease.

OBJECTIVE: We aimed to evaluate the mitral valve calcification and mitral structure detected by cardiac computed tomography (cardiac CT) and establish a scoring model based on cardiac CT and clinical factors to predict early good mitral valve repair (EGMR) and guide surgical strategy in rheumatic mitral disease (RMD). MATERIALS AND METHODS: This is a retrospective bi-center cohort study. Based on cardiac CT, mitral valve calcification and mitral structure in RMD were quantified and evaluated. The primary outcome was EGMR. A logical regression algorithm was applied to the scoring model. RESULTS: A total of 579 patients were enrolled in our study from January 1, 2019, to August 31, 2022. Of these, 443 had baseline cardiac CT scans of adequate quality. The calcification quality score, calcification and thinnest part of the anterior leaflet clean zone, and papillary muscle symmetry were the independent CT factors of EGMR. Coronary artery disease and pulmonary artery pressure were the independent clinical factors of EGMR. Based on the above six factors, a scoring model was established. Sensitivity = 95% and specificity = 95% were presented with a cutoff value of 0.85 and 0.30 respectively. The area under the receiver operating characteristic of external validation set was 0.84 (95% confidence interval [CI] 0.73-0.93). CONCLUSIONS: Mitral valve repair is recommended when the scoring model value > 0.85 and mitral valve replacement is prior when the scoring model value < 0.30. This model could assist in guiding surgical strategies for RMD. CLINICAL RELEVANCE STATEMENT: The model established in this study can serve as a reference indicator for surgical repair in rheumatic mitral valve disease. KEY POINTS: • Cardiac CT can reflect the mitral structure in detail, especially for valve calcification. • A model based on cardiac CT and clinical factors for predicting early good mitral valve repair was established. • The developed model can help cardiac surgeons formulate appropriate surgical strategies.

Reprogramming macrophage by targeting VEGF and CD40 potentiates OX40 immunotherapy.

The low clinical response rate of checkpoint blockades, such as PD-1 and CTLA-4, highlighted the requirements of agonistic antibodies to boost optimal T cell responses. OX40, a co-stimulatory receptor on the T cells, plays a crucial role in promoting T cell survival and differentiation. However, the clinical efficacy of anti-OX40 agonistic antibodies was unimpressive. To explore the mechanism underlying the action of anti-OX40 agonists to improve the anti-tumor efficacy, we analyzed the dynamic changes of tumor-infiltrating immune cells at different days post-treatments using single-cell RNA-sequencing (scRNA-seq). In this study, we found that tumor-infiltrating regulatory T (Treg) cells were reduced after two rounds of anti-OX40 treatment, but the increase of infiltration and activation of CD8+ effector T cells, as well as M1 polarization in the tumor were only observed after three rounds of treatments. Moreover, our group first analyzed the antitumor effect of anti-OX40 treatments on regulating the macrophages and discovered the dynamic changes of vascular endothelial growth factor (VEGF) and CD40 signaling pathways on macrophages, indicating their possibility to being potential combination targets to improve the anti-OX40 agonists efficacy. The combination of VEGFR inhibitors or anti-CD40 agonist antibody with anti-OX40 agonists exhibited more remarkable inhibition of tumor growth. Therefore, the mechanism-driven combination of anti-OX40 agonists with VEGFR inhibitors or anti-CD40 agonists represented promising strategies.

The MRI radiomics signature can predict the pathologic response to neoadjuvant chemotherapy in locally advanced esophageal squamous cell carcinoma.

OBJECTIVES: To investigate the MRI radiomics signatures in predicting pathologic response among patients with locally advanced esophageal squamous cell carcinoma (ESCC), who received neoadjuvant chemotherapy (NACT). METHODS: Patients who underwent NACT from March 2015 to October 2019 were prospectively included. Each patient underwent esophageal MR scanning within one week before NACT and within 2-3 weeks after completion of NACT, prior to surgery. Radiomics features extracted from T2-TSE-BLADE were randomly split into the training and validation sets at a ratio of 7:3. According to the progressive tumor regression grade (TRG), patients were stratified into two groups: good responders (GR, TRG 0 + 1) and poor responders (non-GR, TRG 2 + 3). We constructed the Pre/Post-NACT model (Pre/Post-model) and the Delta-NACT model (Delta-model). Kruskal-Wallis was used to select features, logistic regression was used to develop the final model. RESULTS: A total of 108 ESCC patients were included, and 3/2/4 out of 107 radiomics features were selected for constructing the Pre/Post/Delta-model, respectively. The selected radiomics features were statistically different between GR and non-GR groups. The highest area under the curve (AUC) was for the Delta-model, which reached 0.851 in the training set and 0.831 in the validation set. Among the three models, Pre-model showed the poorest performance in the training and validation sets (AUC, 0.466 and 0.596), and the Post-model showed better performance than the Pre-model in the training and validation sets (AUC, 0.753 and 0.781). CONCLUSIONS: MRI-based radiomics models can predict the pathological response after NACT in ESCC patients, with the Delta-model exhibiting optimal predictive efficacy. CLINICAL RELEVANCE STATEMENT: MRI radiomics features could be used as a useful tool for predicting the efficacy of neoadjuvant chemotherapy in esophageal carcinoma patients, especially in selecting responders among those patients who may be candidates to benefit from neoadjuvant chemotherapy. KEY POINTS: • The MRI radiomics features based on T2WI-TSE-BLADE could potentially predict the pathologic response to NACT among ESCC patients. • The Delta-model exhibited the best predictive ability for pathologic response, followed by the Post-model, which similarly had better predictive ability, while the Pre-model performed less well in predicting TRG.