Calcium-binding protein TgpCaBP regulates calcium storage of the zoonotic parasite Toxoplasma gondii.

Toxoplasma gondii, the causative parasite of toxoplasmosis, is an apicomplexan parasite that infects warm-blooded mammals. The ability of the calcium-binding proteins (CBPs) to transport large amounts of Ca2+ appears to be critical for the biological activity of T. gondii. However, the functions of some members of the CBP family have not yet been deciphered. Here, we characterized a putative CBP of T. gondii, TgpCaBP (TGME49_229480), which is composed of four EF-hand motifs with Ca2+-binding capability. TgpCaBP was localized in the cytosol and ER of T. gondii, and parasites lacking the TgpCaBP gene exhibited diminished abilities in cell invasion, intracellular growth, egress, and motility. These phenomena were due to the abnormalities in intracellular Ca2+ efflux and ER Ca2+ storage, and the reduction in motility was associated with a decrease in the discharge of secretory proteins. Therefore, we propose that TgpCaBP is a Ca2+ transporter and signaling molecule involved in Ca2+ regulation and parasitization in the hosts.IMPORTANCECa2+ signaling is essential in the development of T. gondii. In this study, we identified a calcium-binding protein in T. gondii, named TgpCaBP, which actively regulates intracellular Ca2+ levels in the parasite. Deletion of the gene coding for TgpCaBP caused serious deficits in the parasite's ability to maintain a stable intracellular calcium environment, which also impaired the secretory protein discharged from the parasite, and its capacity of gliding motility, cell invasion, intracellular growth, and egress from host cells. In summary, we have identified a novel calcium-binding protein, TgpCaBP, in the zoonotic parasite T. gondii, which is a potential therapeutic target for toxoplasmosis.

[Determination of individual components in finished motor gasoline by dual-channel three-column gas chromatography].

A method based on a dual-channel gas chromatograph equipped with three columns and three detectors was established for the determination of individual components in finished motor gasoline. The gasoline samples were separately introduced into the two injection ports of the chromatograph using two autosamplers. The components of the sample introduced into the first injection port (channel 1) were separated on a nonpolar PONA column (50 m×0.20 mm×0.5 µm) for gasoline analysis and detected by an flame ionization detector (FID). The components of the sample introduced into the second injection port (channel 2) were separated on another PONA column. Oxygenates (e.g., ethers and alcohols), other unconventional and prohibited additives that would co-elute with the hydrocarbons (e.g., methylal, dimethyl carbonate, sec-butyl acetate, and anilines), and some difficult-to-separate hydrocarbon pairs (e.g., 2,3,3-trimethylpentane and toluene) eluted from the PONA column and entered a DM-624 column (30 m×0.25 mm×1.4 µm) to achieve further separation according to the switch timetable using the Deans switch procedure and detected by an FID. The peak of 3-methylpentane, a common component in gasoline samples, also entered the DM-624 column by the Deans switch procedure for calculation purposes. The peak areas of target components on the PONA column in channel 1 were calculated using the peak areas on the DM-624 column as well as those of 3-methylpentane on both the DM-624 and PONA columns in channel 1 with a calibration factor between the two channels. The peak areas of co-eluted components were obtained by subtracting the calculated peak areas of the target components from those of the co-eluted peaks. The mass percentages of the individual components were calculated according to the normalization method using all peak areas on the PONA column in channel 1 with relative response factors. The mass percentages of the oxygenates, anilines, and individual hydrocarbons were determined, and the group-type distribution was calculated according to the carbon number. Separation and quantitation interferences between the additives and hydrocarbons were eliminated using this procedure. Twenty oxygenates and unconventional additives, each with a mass percentage of approximately 3%, were added to a real motor gasoline-92 sample and analyzed using the proposed method. The recoveries of the target components were between 90.1% and 118.2% with relative standard deviations (RSDs) between 0.2% and 5.1% (n=6). The analysis of a real ethanol-gasoline sample showed that the RSDs of contents of most components was less than 3% (n=6). Because the heart-cut of peaks using Deans switch technique requires the precise repeatability of retention times, the retention-time repeatability of components on the PONA column in channel 2 was investigated over an extended period of time after thousands of runs of real-sample analysis. The retention times of the same component in several randomly selected motor gasoline-92 samples varied from 0.01 to 0.03 min, indicating that the proper timetable for the Deans switch remained stable for two years. The precise repeatability of retention times was achieved owing to the high precision of the electric pneumatic control of the chromatograph and the stability of the column used. Real finished motor gasoline samples with different octane numbers (gasoline-92, gasoline-95, and ethanol gasoline-95) were analyzed using the developed method, and the results acquired were consistent with those of standard methods (GB/T 30519-2016, NB/SH/T 0663-2014, and SH/T 0693-2000). If some unconventional additives (such as methylal) were added to gasoline samples, the contents of these unconventional additives could also be detected, which means one run of the proposed method could provide results corresponding to three or four runs of different standard methods. The acquisition of information on the individual components of finished motor gasoline will assist in research on precise gasoline blending.

Nicotinamide benefited amino acid metabolism and rumen fermentation pattern to improve growth performance of growing lambs.

Objective: Nicotinamide (NAM) is easily degraded in the rumen, the rumen-protected NAM (RPN) supplementation might enable the use of NAM in ruminants. This study aimed to elucidate the effects of RPN supplementation on growth performance, rumen fermentation, antioxidant status and AA metabolism in growing lambs. Methods: A total of 128 healthy and similar lambs (21.3 ± 0.28 kg, 70 ± 6.3 days of age) were allotted to 1 of 4 groups. The treatments were 0, 0.5, 1 and 2 g/d RPN supplementation. The RPN products (50% bioavailability) were fed at 0700 h every day for 12 weeks. All lambs were fed the same pelleted total mixed rations to allow ad libitum consumption and had free access to water. Results: The RPN tended to increase the average daily gain and feed efficiency. The tendencies of RPN × Day interaction were found for dry matter intake during the entire study (P = 0.078 and 0.073, respectively). The proportions of acetic acid, isobutyric acid and isovaleric acid were decreased, whereas the proportions of propionic acid and valeric acid were increased (P < 0.05). The ratio of acetic acid to propionic acid was decreased (P < 0.05). Moreover, the antioxidative status was enhanced and the glucose concentration was increased by RPN (P < 0.05). In addition, 17 amino acids (AAs) were detected in plasma, of which 11 AAs were increased by RPN (P < 0.05). Plasma metabolomics analysis identified 1395 compounds belonging to 15 classes, among which 7 peptides were significantly changed after RPN supplementation. Conclusion: Overall, the results suggested that RPN supplementation favoured the rumen fermentation pattern to propionic acid-type with benefited glucose metabolism, enhanced antioxidant capacity, and changed the AA and small peptide metabolism. This study provides a new perspective for studying the relationship between vitamin and AA metabolism.

Microneedle-Delivered PDA@Exo for Multifaceted Osteoarthritis Treatment via PI3K-Akt-mTOR Pathway.

Osteoarthritis (OA) is marked by cartilage deterioration, subchondral bone changes, and an inflammatory microenvironment. The study introduces the Microneedle-Delivered Polydopamine-Exosome (PDA@Exo MN), a therapeutic that not only preserves cartilage and promotes bone regeneration but also improves localized drug delivery through enhanced penetration capabilities. PDA@Exo MN shows strong reactive oxygen species (ROS) scavenging abilities and high biocompatibility, fostering osteogenesis and balancing anabolic and catabolic processes in cartilage. It directs macrophage polarization from M0 to the anti-inflammatory M2 phenotype. RNA sequencing of treated chondrocytes demonstrates restored cellular function and activated antioxidant responses, with modulated inflammatory pathways. The PI3K-AKT-mTOR pathway's activation, essential for PDA@Exo's effects, is confirmed via bioinformatics and Western blot. In vivo assessments robustly validate that PDA@Exo MN prevents cartilage degradation and OA progression, supported by histological assessments and micro-CT analysis, highlighting its disease-modifying impact. The excellent biocompatibility of PDA@Exo MN, verified through histological (H&E) and blood tests showing no organ damage, underscores its safety and efficacy for OA therapy, making it a novel and multifunctional nanomedical approach in orthopedics, characterized by organ-friendliness and biosecurity.

Optimized path planning and scheduling strategies for connected and automated vehicles at single-lane roundabouts.

This paper focuses on the cooperative driving challenges of connected and automated vehicles (CAVs) at single-lane roundabouts. First, a geometric path planning method is proposed for CAVs navigating a single-lane roundabout. Based on this method, a vehicle roundabout model is established. Four potential traffic scenarios for CAVs are established, and the optimal arrival times at conflict points are analyzed. By correlating the optimal arrival times at conflict points with the optimal entry times into the roundabout, the multi-vehicle coordination problem in complex intersections is simplified to a speed control issue during entry. Utilizing the principles of optimal control and Pontryagin minimization, two speed optimization strategies are proposed. Finally, MATLAB is employed for simulation analysis. The results indicate that the control strategy proposed in this paper enables the system to clearly identify potential conflicts between vehicles and implement an optimal control strategy, ensuring that vehicles can navigate the roundabout efficiently in terms of time and fuel without collisions. Additionally, the minimum time interval is established at 0.2 seconds to completely prevent vehicle collisions. In this study, the fusion problem involving two vehicles at a single conflict point is further expanded to encompass multiple vehicles at multiple conflict points. Thus, the efficient scheduling of multiple vehicles in single-lane roundabouts is realized.

Associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan: A cross-sectional study in U.S. women.

Female reproductive timing and lifespan, with a close relation to long-term health outcomes, have been altered in U.S. women over the past decades. However, epidemiologic evidence of the potential causes was lacking. On the basis of 1981 naturally postmenopausal women from the National Health and Nutrition Examination Survey 1999-2020, this study aimed to investigate the associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan. Multivariate generalized linear regression and addictive models were used for single metal exposure analysis, and weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were employed for mixed exposures. In the fully adjusted model, higher urinary antimony concentration was associated with earlier age at menarche of 0.137 years, while higher concentrations of cadmium, cesium, lead, antimony, and thallium were associated with delayed age at menopause of 0.396-0.687 years. Additionally, urinary barium, cesium, lead, antimony, and thallium levels were associated with longer reproductive lifespan ranging between 0.277 and 0.713 years. Both WQS and BKMR models showed significantly positive associations of metal mixtures with age at menopause (ß: 0.667, 95 % CI: 0.120-1.213) and reproductive lifespan (ß: 0.686, 95 % CI: 0.092-1.280), with cadmium and lead identified as principal contributors. In conclusion, heavy metal exposures were associated with reproductive timing and lifespan of U.S. women, highlighting the need for further prevention and intervention strategies.

Plasmodium berghei TatD-like DNase hijacks host innate immunity by inhibiting the TLR9-NF-κB pathway.

Neutrophils and macrophages confine pathogens by entrapping them in extracellular traps (ETs) through activating TLR9 function. However, plasmodial parasites secreted TatD-like DNases (TatD) to counteract ETs-mediated immune clearance. We found that TLR9 mutant mice increased susceptibility to rodent malaria, suggesting TLR9 is a key protein for host defense. We found that the proportion of neutrophils and macrophages in response to plasmodial parasite infection in the TLR9 mutant mice was significantly reduced compared to that of the WT mice. Importantly, PbTatD can directly bind to the surface TLR9 (sTLR9) on macrophages, which blocking the phosphorylation of mitogen-activated protein kinase and nuclear factor-κB, negatively regulated the signaling of ETs formation by both macrophages and neutrophils. Such, P. berghei TatD is a parasite virulence factor that can inhibit the proliferation of macrophages and neutrophils through directly binding to TLR9 receptors on the cell surface, thereby blocking the activation of the downstream MyD88-NF-kB pathways.

Mucinous histology is a negative predictor of neoadjuvant chemoradiotherapy for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. RESULTS: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT. CONCLUSION: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.

Photothermal Catalytic Reduction and Bone Tissue Engineering Towards a Three-in-One Therapy Strategy for Osteosarcoma.

Osteosarcoma is one of the most dreadful bone neoplasms in young people, necessitating the development of innovative therapies that can effectively eliminate tumors while minimizing damage to limb function. An ideal therapeutic strategy should possess three essential capabilities: antitumor effects, tissue-protective properties, and the ability to enhance osteogenesis. In this study, self-assembled Ce-substituted molybdenum blue (CMB) nanowheel crystals are synthesized and loaded onto 3D-printed bioactive glass (CMB@BG) scaffolds to develop a unique three-in-one treatment approach for osteosarcoma. The CMB@BG scaffolds exhibit outstanding photothermally derived tumor ablation within the near-infrared-II window due to the surface plasmon resonance properties of the CMB nanowheel crystals. Furthermore, the photothermally synergistic catalytic effect of CMB promotes the rapid scavenging of reactive oxygen species caused by excessive heat, thereby suppressing inflammation and protecting surrounding tissues. The CMB@BG scaffolds possess pro-proliferation and pro-differentiation capabilities that efficiently accelerate bone regeneration within bone defects. Altogether, the CMB@BG scaffolds that combine highly efficient tumor ablation, tissue protection based on anti-inflammatory mechanisms, and enhanced osteogenic ability are likely to be a point-to-point solution for the comprehensive therapeutic needs of osteosarcoma.

Maternal mRNA deadenylation is defective in in vitro matured mouse and human oocytes.

Oocyte in vitro maturation is a technique in assisted reproductive technology. Thousands of genes show abnormally high expression in in vitro maturated metaphase II (MII) oocytes compared to those matured in vivo in bovines, mice, and humans. The mechanisms underlying this phenomenon are poorly understood. Here, we use poly(A) inclusive RNA isoform sequencing (PAIso-seq) for profiling the transcriptome-wide poly(A) tails in both in vivo and in vitro matured mouse and human oocytes. Our results demonstrate that the observed increase in maternal mRNA abundance is caused by impaired deadenylation in in vitro MII oocytes. Moreover, the cytoplasmic polyadenylation of dormant Btg4 and Cnot7 mRNAs, which encode key components of deadenylation machinery, is impaired in in vitro MII oocytes, contributing to reduced translation of these deadenylase machinery components and subsequently impaired global maternal mRNA deadenylation. Our findings highlight impaired maternal mRNA deadenylation as a distinct molecular defect in in vitro MII oocytes.

Prognostic impact of new-onset atrial fibrillation in myocardial infarction with and without improved ejection fraction.

AIMS: Improvement in left ventricular ejection fraction (impEF) often presents in contemporary acute myocardial infarction (AMI) patients. New-onset atrial fibrillation (NOAF) during AMI is an important predictor of subsequential heart failure (HF), while its impact on the trajectory of post-MI left ventricular ejection fraction (LVEF) and prognostic implication in patients with and without impEF remains undetermined. We aimed to investigate the prognostic impacts of NOAF in AMI patients with and without impEF. METHODS AND RESULTS: Consecutive AMI patients without a prior history of AF between February 2014 and March 2018 with baseline LVEF ≤ 40% and had ≥1 LVEF measurement after baseline were included. ImpEF was defined as a baseline LVEF ≤ 40% and a re-evaluation showed both LVEF > 40% and an absolute increase of LVEF ≥ 10%. Persistently reduced EF (prEF) was defined as the second measurement of LVEF either ≤40% or an absolute increase of LVEF < 10%. The primary endpoint was a major adverse cardiac event (MACE) that was composed of cardiovascular death and HF hospitalization. Cox regression analysis and competing risk analysis were performed to assess the association of post-MI NOAF with MACE. Among 293 patients (mean age: 66.6 ± 11.3 years, 79.2% of males), 145 (49.5%) had impEF and 67 (22.9%) developed NOAF. Higher heart rate (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.73-0.97; P = 0.015), prior MI (OR: 0.25, 95% CI: 0.09-0.69; P = 0.008), and STEMI (OR: 0.40, 95% CI: 0.21-0.77; P = 0.006) were independent predictors of post-MI impEF. Within up to 5 years of follow-up, there were 22 (15.2%) and 53 (35.8%) MACE in patients with impEF and prEF, respectively. NOAF was an independent predictor of MACE in patients with impEF (hazard ratio [HR]: 7.34, 95% CI: 2.49-21.59; P < 0.001) but not in those with prEF (HR: 0.78, 95% CI: 0.39-1.55; P = 0.483) after multivariable adjustment. Similar results were obtained when accounting for the competing risk of all-cause death (subdistribution HR and 95% CIs in impEF and prEF were 6.47 [2.32-18.09] and 0.79 [0.39-1.61], respectively). CONCLUSIONS: The NOAF was associated with an increased risk of cardiovascular outcomes in AMI patients with impEF.

Long-Term Remission with Novel Combined Immune-Targeted Treatment for Histiocytic Sarcoma Accompanied by Follicular Lymphoma: Case Report and Literature Review.

Histiocytic sarcoma (HS) is an extremely rare but aggressive hematopoietic malignancy, and the prognosis has been reported to be rather unfavorable with a median overall survival of merely 6 months. We presented a 58-year-old female patient complaining of abdominal pain and fever, who was admitted to our institution in September 2021. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) scan showed enlargement of generalized multiple lymph nodes. Subsequently, laparoscopic retroperitoneal lesion biopsy and bone marrow aspiration were performed. The pathological findings indicated the diagnosis of HS concurrent with follicular lymphoma. The immunohistochemistry (IHC) staining of the tumor lesion revealed a high expression of CD38 and PD-L1 proteins. Furthermore, KRAS gene mutation was identified by means of next-generation sequencing. The patient exhibited poor treatment response to both first- and second-line cytotoxic chemotherapies. Therefore, she underwent six cycles of Daratumumab (anti-CD38 monoclonal antibody), Pazopanib (multi-target receptor tyrosine kinases inhibitor) combined with third-line chemotherapy, followed by involved-site radiotherapy and maintenance therapy with the PD-1 inhibitor Tislelizumab. Long-term partial remission was finally achieved after multi-modality treatment. Duration of remission and overall survival reached 22 and 32 months, respectively. Our case indicated that immuno-targeted treatment coupled with chemotherapy and radiotherapy might constitute a potential therapeutic option for HS.

Blocking CXCR4-CARM1-YAP axis overcomes osteosarcoma doxorubicin resistance by suppressing aerobic glycolysis.

Osteosarcoma, recognized for its aggressiveness and resistance to chemotherapy, notably doxorubicin, poses significant treatment challenges. This comprehensive study investigated the CXCR4-CARM1-YAP signaling axis and its pivotal function in controlling aerobic glycolysis, which plays a crucial role in doxorubicin resistance. Detailed analysis of Dox-resistant 143b/MG63-DoxR cells has uncovered the overexpression of CXCR4. Utilizing a combination of molecular biology techniques including gene silencing, aerobic glycolysis assays such as Seahorse experiments, RNA sequencing, and immunofluorescence staining. The study provides insight into the mechanistic pathways involved. Results demonstrated that disrupting CXCR4 expression sensitizes cells to doxorubicin-induced apoptosis and alters glycolytic activity. Further RNA sequencing revealed that CARM1 modulated this effect through its influence on glycolysis, with immunofluorescence of clinical samples confirming the overexpression of CXCR4 and CARM1 in drug-resistant tumors. Chromatin immunoprecipitation studies further highlighted the role of CARM1, showing it to be regulated by methylation at the H3R17 site, which in turn affected YAP expression. Crucially, in vivo experiments illustrated that CARM1 overexpression could counteract the tumor growth suppression that resulted from CXCR4 inhibition. These insights revealed the intricate mechanisms at play in osteosarcoma resistance to doxorubicin and pointed toward potential new therapeutic strategies that could target this metabolic and signaling network to overcome drug resistance and improve patient outcomes.

Development of ultra-short pulse reflectometry on the Experimental Advanced Superconducting Tokamak (EAST).

Microwave reflectometry is an invaluable diagnostic tool for measuring electron density profiles in large fusion devices. Density fluctuations near the plasma cutoff layer, particularly those that are time-varying on the timescale of the reflectometry measurement, can result in distortions in phase and/or amplitude of the reflected waveform, which present challenges to the accuracy of the reconstructed profile. The ultra-short pulse reflectometry (USPR) technique eliminates the time-varying issue in that reflectometry data are collected on a nanosecond timescale, essentially freezing the fluctuations in place. An X-mode dedicated 32-channel USPR system has been developed and installed on the EAST, covering the operation frequency range from 52 to 92 GHz. This system enables high-resolution density profile measurements in the plasma pedestal and scrape-off layer, with resolutions reaching 5 mm and 1 µs, respectively. Laboratory testing of the system performance has been conducted, demonstrating the potential of the USPR technique to provide accurate and high-temporal-resolution density profiles in challenging plasma environments.

Creating CoRu Dual Active Sites Codecorated Stable Porous Ceria Support for Enhanced Li-CO2 Batteries Cathodes.

Lithium-carbon dioxide (Li-CO2) battery represents a high-energy density energy storage with excellent real-time CO2 enrichment and conversion, but its practical utilization is hampered by the development of an excellent catalytic cathode. Here, the synergistic catalytic strategy of designing CoRu bimetallic active sites achieves the electrocatalytic conversion of CO2 and the efficient decomposition of the discharge products, which in turn realizes the smooth operation of the Li-CO2 battery. Moreover, obtained support based on metal-organic frameworks precursors facilitates the convenient diffusion and adsorption of CO2, resulting in higher reaction concentration and lower mass transfer resistance. Meanwhile, the optimization of the interfacial electronic structure and the effective transfer of electrons are achieved by virtue of the strong interaction of CoRu at the support interface. As a result, the Li-CO2 cell assembled based on bimetallic CoRu active sites achieved a discharge capacity of 19,111 mA h g-1 and a steady-state discharge voltage of 2.58 V as well as a cycle life of >175 cycles at a rate of 100 mA g-1. Further experiments combined with density-functional theory calculations achieve a deeply view of the connection between cathode and electrochemical performance and pave a way for the subsequent development of advanced Li-CO2 catalytic cathodes.

Speckle-Tracking Echocardiography in Right Ventricular Function of Clinically Well Patients with Heart Transplantation.

Heart transplantation (HT) is the mainstream therapy for end-stage heart disease. However, the cardiac graft function can be affected by several factors. It is important to monitor HT patients for signs of graft dysfunction. Transthoracic echocardiography is a simple, first-line, and non-invasive method for the assessment of cardiac function. The emerging speckle-tracking echocardiography (STE) could quickly and easily provide additive information over traditional echocardiography. STE longitudinal deformation parameters are markers of early impairment of ventricular function. Although once called the "forgotten ventricle", right ventricular (RV) assessment has gained attention in recent years. This review highlights the potentially favorable role of STE in assessing RV systolic function in clinically well HT patients.

SOD3 suppresses early cellular immune responses to parasite infection.

Host immune responses are tightly controlled by various immune factors during infection, and protozoan parasites also manipulate the immune system to evade surveillance, leading to an evolutionary arms race in host‒pathogen interactions; however, the underlying mechanisms are not fully understood. We observed that the level of superoxide dismutase 3 (SOD3) was significantly elevated in both Plasmodium falciparum malaria patients and mice infected with four parasite species. SOD3-deficient mice had a substantially longer survival time and lower parasitemia than control mice after infection, whereas SOD3-overexpressing mice were much more vulnerable to parasite infection. We revealed that SOD3, secreted from activated neutrophils, bound to T cells, suppressed the interleukin-2 expression and concomitant interferon-gamma responses crucial for parasite clearance. Overall, our findings expose active fronts in the arms race between the parasites and host immune system and provide insights into the roles of SOD3 in shaping host innate immune responses to parasite infection.

Assessment of left ventricular ejection fraction in artificial intelligence based on left ventricular opacification.

Background: Left ventricular opacification (LVO) improves the accuracy of left ventricular ejection fraction (LVEF) by enhancing the visualization of the endocardium. Manual delineation of the endocardium by sonographers has observer variability. Artificial intelligence (AI) has the potential to improve the reproducibility of LVO to assess LVEF. Objectives: The aim was to develop an AI model and evaluate the feasibility and reproducibility of LVO in the assessment of LVEF. Methods: This retrospective study included 1305 echocardiography of 797 patients who had LVO at the Department of Ultrasound Medicine, Union Hospital, Huazhong University of Science and Technology from 2013 to 2021. The AI model was developed by 5-fold cross validation. The validation datasets included 50 patients prospectively collected in our center and 42 patients retrospectively collected in the external institution. To evaluate the differences between LV function determined by AI and sonographers, the median absolute error (MAE), spearman correlation coefficient, and intraclass correlation coefficient (ICC) were calculated. Results: In LVO, the MAE of LVEF between AI and manual measurements was 2.6% in the development cohort, 2.5% in the internal validation cohort, and 2.7% in the external validation cohort. Compared with two-dimensional echocardiography (2DE), the left ventricular (LV) volumes and LVEF of LVO measured by AI correlated significantly with manual measurements. AI model provided excellent reliability for the LV parameters of LVO (ICC > 0.95). Conclusions: AI-assisted LVO enables more accurate identification of the LV endocardium and reduces observer variability, providing a more reliable way for assessing LV function.

Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

Heterotopic pregnancy: a case report of intrauterine hydatidiform mole with tubal pregnancy.

We herein report a rare case of simultaneous intrauterine molar pregnancy and tubal pregnancy. A woman of childbearing age who had never been pregnant underwent an ultrasound examination 70 days after the onset of menopause. She had a history of ovulation induction. The ultrasound findings suggested a partial hydatidiform mole. She was then pathologically confirmed to have a complete hydatidiform mole after uterine suction dilation and curettage. On postoperative day 4, an ultrasound examination before discharge showed an inhomogeneous mass in the left adnexal region with mild lower abdominal pain. On postoperative day 17, the blood human chorionic gonadotropin level did not drop as expected, and a follow-up examination still indicated a mass in the left adnexal region. We were unable to rule out an ectopic hydatidiform mole. Hysteroscopy with laparoscopic exploration of the left adnexal mass and salpingotomy suggested a diagnosis of intrauterine hydatidiform mole combined with left tubal pregnancy.