Skinned Motion Retargeting with Preservation of Body Part Relationships.

Motion retargeting is an active research area in computer graphics and animation, allowing for the transfer of motion from one character to another, thereby creating diverse animated character data. While this technology has numerous applications in animation, games, and movies, current methods often produce unnatural or semantically inconsistent motion when applied to characters with different shapes or joint counts. This is primarily due to a lack of consideration for the geometric and spatial relationships between the body parts of the source and target characters. To tackle this challenge, we introduce a novel spatially-preserving Skinned Motion Retargeting Network (SMRNet) capable of handling motion retargeting for characters with varying shapes and skeletal structures while maintaining semantic consistency. By learning a hybrid representation of the character's skeleton and shape in a rest pose, SMRNet transfers the rotation and root joint position of the source character's motion to the target character through embedded rest pose feature alignment. Additionally, it incorporates a differentiable loss function to further preserve the spatial consistency of body parts between the source and target. Comprehensive quantitative and qualitative evaluations demonstrate the superiority of our approach over existing alternatives, particularly in preserving spatial relationships more effectively.

Comparative study on chemical constituents of different medicinal parts of Lonicera japonica Thunb. Based on LC-MS combined with multivariate statistical analysis.

Lonicerae japonicae flos (LJF), Lonicerae japonicae caulis (LJC), Lonicerae folium (LF) and Lonicerae fructus (LFR) are derived from Lonicera japonica Thunb., which are formed due to different medicinal parts. The efficacy of the 4 medicinal materials has similarities and differences. However, little attention has been paid to illustrate the differences in efficacy from the perspective of phytochemistry. In this study, ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap mass spectrometry (UPLC-Q-Exactive-Orbitrap-MS) was used to qualitatively analyze the ingredients in 4 herbs. A total of 86 compounds were plausibly or unambiguously identified, there were 54 common components among the 4 medicinal materials, and each kind of medicinal materials had its own unique components. On the basis of qualitative analysis, ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UPLC-QQQ-MS/MS) was used to quantitatively analyze 31 components contained in 4 medicinal materials, and principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and other multivariate statistical analysis were furtherly performed for comparing the component contents. The results showed that the samples from the same parts were clustered into one group, and the samples from different medicinal parts were significantly different. The analysis of variable importance projection (VIP) value of the OPLS-DA model showed that 10 components including chlorogenic acid, secologanic acid, isochlorogenic acid A, loganin, lonicerin, loganic acid, secoxyloganin, sweroside, luteolin and rhoifolin were the main difference components among the 4 medicinal materials. The study not only lays a solid foundation for the intrinsic quality control of 4 medicinal materials and the study of different effects of the 4 medicinal materials at the phytochemical level, but also provides a basis for more rational utilization of various parts of L. japonica and expansion of medicinal resources.

Unveiling the secrets of gastrointestinal mucous adenocarcinoma survival after surgery with artificial intelligence: A population-based study.

BACKGROUND: Research on gastrointestinal mucosal adenocarcinoma (GMA) is limited and controversial, and there is no reference tool for predicting postoperative survival. AIM: To investigate the prognosis of GMA and develop predictive model. METHODS: From the Surveillance, Epidemiology, and End Results database, we collected clinical information on patients with GMA. After random sampling, the patients were divided into the discovery (70% of the total, for model training), validation (20%, for model evaluation), and completely blind test cohorts (10%, for further model evaluation). The main assessment metric was the area under the receiver operating characteristic curve (AUC). All collected clinical features were used for Cox proportional hazard regression analysis to determine factors influencing GMA's prognosis. RESULTS: This model had an AUC of 0.7433 [95% confidence intervals (95%CI): 0.7424-0.7442] in the discovery cohort, 0.7244 (GMA: 0.7234-0.7254) in the validation cohort, and 0.7388 (95%CI: 0.7378-0.7398) in the test cohort. We packaged it into Windows software for doctors' use and uploaded it. Mucinous gastric adenocarcinoma had the worst prognosis, and these were protective factors of GMA: Regional nodes examined [hazard ratio (HR): 0.98, 95%CI: 0.97-0.98, P < 0.001)] and chemotherapy (HR: 0.62, 95%CI: 0.58-0.66, P < 0.001). CONCLUSION: The deep learning-based tool developed can accurately predict the overall survival of patients with GMA postoperatively. Combining surgery, chemotherapy, and adequate lymph node dissection during surgery can improve patient outcomes.

Identification of immune-related genes and small-molecule drugs in hypertension-induced left ventricular hypertrophy based on machine learning algorithms and molecular docking.

Background: Left ventricular hypertrophy (LVH) is a common consequence of hypertension and can lead to heart failure. The immune response plays an important role in hypertensive LVH; however, there is no comprehensive method to investigate the mechanistic relationships between immune response and hypertensive LVH or to find novel therapeutic targets. This study aimed to screen hub immune-related genes involved in hypertensive LVH as well as to explore immune target-based therapeutic drugs. Materials and methods: RNA-sequencing data from a mouse model generated by angiotensin II infusion were subjected to weighted gene co-expression network analysis (WGCNA) to identify core expression modules. Machine learning algorithms were applied to screen immune-related LVH characteristic genes. Heart structures were evaluated by echocardiography and cardiac magnetic resonance imaging (CMRI). Validation of hub genes was conducted by RT-qPCR and western blot. Using the Connectivity Map database and molecular docking, potential small-molecule drugs were explored. Results: A total of 1215 differentially expressed genes were obtained, most of which were significantly enriched in immunoregulation and collagen synthesis. WGCNA and multiple machine learning strategies uncovered six hub immune-related genes (Ankrd1, Birc5, Nuf2, C1qtnf6, Fcgr3, and Cdca3) that may accurately predict hypertensive LVH diagnosis. Immune analysis revealed that fibroblasts and macrophages were closely correlated with hypertensive LVH, and hub gene expression was significantly associated with these immune cells. A regulatory network of transcription factor-mRNA and a ceRNA network of miRNA-lncRNA was established. Notably, six hub immune-related genes were significantly increased in the hypertensive LVH model, which were positively linked to left ventricle wall thickness. Finally, 12 small-molecule compounds with the potential to reverse the high expression of hub genes were ruled out as potential therapeutic agents for hypertensive LVH. Conclusion: This study identified and validated six hub immune-related genes that may play essential roles in hypertensive LVH, providing new insights into the potential pathogenesis of cardiac remodeling and novel targets for medical interventions.

MIKC type MADS-box transcription factor LcSVP2 is involved in dormancy regulation of the terminal buds in evergreen perennial litchi (Litchi chinensis Sonn.).

SHORT VEGETATIVE PHASE (SVP), a member of the MADS-box transcription factor family, has been reported to regulate bud dormancy in deciduous perennial plants. Previously, three LcSVPs (LcSVP1, LcSVP2 and LcSVP3) were identified from litchi genome, and LcSVP2 was highly expressed in the terminal buds of litchi during growth cessation or dormancy stages and down-regulated during growth stages. In this study, the role of LcSVP2 in governing litchi bud dormancy was examined. LcSVP2 was highly expressed in the shoots, especially in the terminal buds at growth cessation stage, whereas low expression was showed in roots, female flowers and seeds. LcSVP2 was found to be located in the nucleus and have transcription inhibitory activity. Overexpression of LcSVP2 in Arabidopsis thaliana resulted in a later flowering phenotype compared to the wild-type control. Silencing LcSVP2 in growing litchi terminal buds delayed re-entry of dormancy, resulting in significantly lower dormancy rate. The treatment also significantly up-regulated litchi FLOWERING LOCUS T2 (LcFT2). Further study indicates that LcSVP2 interacts with an AP2-type transcription factor, SMALL ORGAN SIZE1 (LcSMOS1). Silencing LcSMOS1 promoted budbreak and delayed bud dormancy. Abscisic acid (200 mg/L), which enforced bud dormancy, induced a short-term increase in the expression of LcSVP2 and LcSMOS1. Our study reveals that LcSVP2 may play a crucial role, likely together with LcSMOS1, in dormancy onset of the terminal bud and may also serve as a flowering repressor in evergreen perennial litchi.

Production of the siderophore lysochelin in rich media through maltose-promoted high-density growth of Lysobacter sp. 3655.

Siderophores are produced by bacteria in iron-restricted conditions. However, we found maltose could induce the biosynthesis of the siderophore lysochelin in Lysobacter sp. 3655 in rich media that are not compatible with siderophore production. Maltose markedly promoted cell growth, with over 300% increase in cell density (OD600) when LB medium was added with maltose (LBM). While lysochelin was not detectable when OD600 in LBM was below 5.0, the siderophore was clearly produced when OD600 reached 7.5 and dramatically increased when OD600 was 15.0. Coincidently, the transcription of lysochelin biosynthesis genes was remarkably enhanced following the increase of OD600. Conversely, the iron concentration in the cell culture dropped to 1.2 µM when OD600 reached 15.0, which was 6-fold lower than that in the starting medium. Moreover, mutants of the maltose-utilizing genes (orf2677 and orf2678) or quorum-sensing related gene orf644 significantly lowered the lysochelin yield. Transcriptomics analysis showed that the iron-utilizing/up-taking genes were up-regulated under high cell density. Accordingly, the transcription of lysochelin biosynthetic genes and the yield of lysochelin were stimulated when the iron-utilizing/up-taking genes were deleted. Finally, lysochelin biosynthesis was positively regulated by a TetR regulator (ORF3043). The lysochelin yield in orf3043 mutant decreased to 50% of that in the wild type and then restored in the complementary strain. Together, this study revealed a previously unrecognized mechanism for lysochelin biosynthetic regulation, by which the siderophore could still be massively produced in Lysobacter even grown in a rich culture medium. This finding could find new applications in large-scale production of siderophores in bacteria.

Prenatal diagnosis and family analysis of 17q12 microdeletion syndrome with fetal renal abnormalities.

Purpose: To analyze the prenatal diagnosis, parental verification, and pregnancy outcomes of three fetuses with 17ql2 microdeletion syndrome. Methods: We retrospectively reviewed 46 singleton pregnancies with anomalies in the urinary system who underwent amniocentesis from Feb 2022 to October 2023 in the Prenatal Diagnosis Center of Lianyungang Maternal and Child Health Hospital. These fetuses were subjected to chromosomal microarray analysis (CMA) and/or trio whole-exome sequencing (Trio-WES). We specifically evaluated these cases' prenatal renal ultrasound findings and clinical characteristics of the affected parents. Results: Three fetuses were diagnosed as 17q12 microdeletions, and the detection rate was 6.5% in fetuses with anomalies in the urinary system (3/46). The heterogeneous deletions range from 1.494 to 1.66 Mb encompassing the complete hepatocyte nuclear factor 1 homeobox B (HNF1B) gene. Fetuses with 17q12 deletion exhibited varied renal phenotypes. Moreover, the clinical phenotypes of the affected parents differed greatly in the two cases (case 2 and case 3) in which the deletion was inherited. For case 3, the mother manifested classic symptoms of 17q12 deletion syndrome as well as unreported characteristics, such as very high myopia. Conclusion: Our findings demonstrate the necessity and significance of offering prenatal genetic testing when various renal anomalies are detected. In addition, our study broadens the phenotypic spectrum of 17q12 deletions. Most importantly, our findings may allow timely supportive genetic counseling and guidance for pregnancy in affected families, e.g., with the help of preimplantation genetic testing (PGT).

FGL2 as a predictive biomarker for prognosis and immunotherapy in bladder cancer.

Background: Metastasis and immunosuppression result in unfavorable prognosis in bladder cancer (BLCA). FGL1 and FGL2 are two members of the fibrinogen-related proteins family, but their potential effects on BLCA remain elusive. Methods: The expression profile of FGL1 and FGL2 in BLCA was analyzed in multiple databases. Furthermore, the expression of FGL2 was validated in BLCA tissues. The predictive capability of FGL2 was evaluated by Kaplan-Meier analysis, univariate analysis, and multivariate Cox regression. A nomogram model was constructed based on FGL2 expression and clinicopathological parameters for clinical practice. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analyses (GSEA) were performed to investigate enrichment in the biological processes. In addition, the correlation between FGL2 and immunological characteristics in the BLCA tumor microenvironment (TME), including tumor-infiltrating immune cells (TICs), cancer-immunity cycles, immune checkpoint molecules (ICPs), immunophenoscores (IPS), and response to anti-PD-L1 immunotherapy was further analyzed. Results: FGL2 was found to be downregulated in BLCA due to hypermethylation of the FGL2 promoter region, which was associated with an unfavorable prognosis. Moreover, BLCA patients with high FGL2 expression exhibited better response to immunotherapy. Conclusions: Our research revealed that FGL2 was downregulated in BLCA and was negatively correlated with DNA methylation. High FGL2 expression was confirmed as an independent risk for prognosis. Moreover, FGL2 is a promising indicator for the response to immunotherapy in patients with BLCA.

Isotopic evidence for the dietary difference between Rhizostomeae Nemopilema nomurai and Semaeostomeae Cyanea nozakii.

Blooms of the Rhizostomeae Nemopilema nomurai and the Semaeostomeae Cyanea nozakii have become more prominent in the coastal waters of China since the end of the 20th century. However, the trophic ecology of these jellyfish species remain incompletely understood. In this study, the trophic characterizations of N. nomurai and C. nozakii populations were assessed using stable isotope analysis (SIA), with a focus on the important bloom area offshore of the Yangtze Estuary. Our results indicated obvious trophic differences between two scyphomedusae. The higher trophic position of the C. nozakii population in the coastal planktonic food web was reflected by its relatively large δ15N value compared to that of N. nomurai. The MixSIAR model indicated that small copepods (<1000 µm) and seston were important food sources for N. nomurai, and showed a stable dietary, irrespective of N. nomurai size. Conversely, C. nozakii exhibited a more diverse diet composition, and gelatinous organisms also were an important part of the diet of C. nozakii. Moreover, a pronounced ontogenetic shift in the diet of C. nozakii was observed, consisting of an increase in the proportion of zooplanktonic prey (excluding seston) in the C. nozakii diet with diameter. This study provides isotopic evidence of the substantial difference in trophic ecology between N. nomurai and C. nozakii, which resulted from the variations in SI values and diet compositions. Inconsistent size-based variation patterns were observed in trophic ontogenetic shifts within the N. nomurai and C. nozakii groups, highlighting a need for further investigation. These results will give insights into the characteristics of trophic ecology and functional roles of Rhizostomeae and Semaeostomeae, and indicate the need for a more careful consideration of the representations of Rhizostomeae and Semaeostomeae in coastal ecosystems, so as not to underestimate the knowledge of taxon-specific ecological effects on energy flow.

A Cellulose-Based Dual-Crosslinked Framework with Sensitive Shape and Color Changes in Acid/Alkaline Vapors.

Cellulose detectors, as green sensors, are some of the defensive mechanisms of plants which combat environmental stresses. However, extracted cellulose struggles to fulfil these functionalities due to its rigid physical/chemical properties. In this study, a novel cellulose dual-crosslinked framework (CDCF) is proposed. This comprises a denser temporary physical crosslinking bond (hydrogen bonding) and a looser covalent crosslinking bond (N,N-methylenebisacrylamide), which create deformable spaces between the two crosslinking sites. Abundant pH-sensitive carboxyl groups and ultralight, highly porous structures make CDCF response very sensitive in acid/alkaline vapor environments. Hence, a significant shrinkage of CDCF was observed following exposure to vapors. Moreover, a curcumin-incorporated CDCF exhibited dual shape and color changes when exposed to acid/alkaline vapors, demonstrating great potential for the multi-detection of acid/alkaline vapors.

Evolution of Chatbots in Nursing Education: Narrative Review.

Background: The integration of chatbots in nursing education is a rapidly evolving area with potential transformative impacts. This narrative review aims to synthesize and analyze the existing literature on chatbots in nursing education. Objective: This study aims to comprehensively examine the temporal trends, international distribution, study designs, and implications of chatbots in nursing education. Methods: A comprehensive search was conducted across 3 databases (PubMed, Web of Science, and Embase) following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram. Results: A total of 40 articles met the eligibility criteria, with a notable increase of publications in 2023 (n=28, 70%). Temporal analysis revealed a notable surge in publications from 2021 to 2023, emphasizing the growing scholarly interest. Geographically, Taiwan province made substantial contributions (n=8, 20%), followed by the United States (n=6, 15%) and South Korea (n=4, 10%). Study designs varied, with reviews (n=8, 20%) and editorials (n=7, 18%) being predominant, showcasing the richness of research in this domain. Conclusions: Integrating chatbots into nursing education presents a promising yet relatively unexplored avenue. This review highlights the urgent need for original research, emphasizing the importance of ethical considerations.

Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis.

AIMS: The widespread use of immune checkpoint inhibitors (ICIs) has demonstrated significant survival benefits for cancer patients and also carry the risk of immune-related adverse events (irAEs). ICIs-associated myocarditis is a rare and serious adverse event with a high mortality rate. Here, we explored the mechanism underlying ICIs-associated myocarditis. METHODS AND RESULTS: Using the peripheral blood of patients with ICIs therapy and ICIs treated mice with transplanted tumors, we dissect the immune cell subsets and inflammatory factors associated with myocarditis. Compared to the control group, patients with myocarditis after ICIs therapy showed an increase in NK cells and myeloid cells in peripheral blood, while T cells significantly decreased. Among T cells, there was an imbalance of CD4/CD8 ratio in the peripheral blood of myocarditis patients, with a significant decrease in central memory CD4+ T (CD4+ TCM) cells. RNA-Seq revealed that CD4+ TCM cells in myocarditis patients were an immunosuppressive cell subset, which highly express the immunosuppressive factor IL4I1. To elucidate the potential mechanism of the decrease in CD4+ TCM cells, protein array was performed and revealed that several inflammatory factors gradually increased with the severity of myocarditis in the myocarditis group, such as IL-1B/CXCL13/CXCL9, while the myocardial protective factor IL-15 decreased. Correlation analysis indicated a positive correlation between IL-15 and CD4+ TCM cells, with high expression of IL-15 receptor IL15RA. Furthermore, in vivo studies using an anti-PDL1 antibody in a mouse tumor model indicated a reduction in CD4+ TCM cells and an increase in CD8+ TEMRA cells, alongside evidence of cardiac fibrosis. Conversely, combining anti-PDL1 antibody treatment with IL-15 led to a resurgence of CD4+ TCM cells, a reduction in CD8+ TEMRA cells, and a mitigated risk of cardiac fibrosis. CONCLUSIONS: Our data highlight CD4+ TCM cells as a crucial role in cardiac protection during ICIs therapy. IL-15, IL4I1 and CD4+ TCM cells can serve as therapeutic targets to reduce ICIs-associated myocarditis in cancer patients.

Codelivery of Dual Gases with Metal-Organic Supramolecular Cage-Based Microenvironment-Responsive Nanomedicine for Atherosclerosis Therapy.

Atherosclerosis (AS) is a common cause of coronary heart disease and stroke. The delivery of exogenous H2S and in situ production of O2 within atherosclerotic plaques can help suppress inflammatory cell infiltration and alleviate disease progression. However, the uncontrolled release of gas donors hinders achieving effective drug concentrations and causes toxic effects. Herein, diallyl trisulfide (DATS)-loaded metal-organic cage (MOC)-68-doped MnO2 nanoparticles are developed as a microenvironment-responsive nanodrug with the capacity for the in situ co-delivery of H2S and O2 to inflammatory cells within plaques. This nanomedicine exhibited excellent monodispersity and stability and protected DATS from degradation in the circulation. In vitro studies showed that the nanomedicine reduced macrophage polarization toward an inflammatory phenotype and inhibited the formation of foam cells, while suppressing the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin-1ß. In a mouse model of ApoE-/- genotype, the nanomedicine reduces the plaque burden, inflammatory infiltration, and hypoxic conditions within the plaques. Furthermore, the treatment process and therapeutic effects can be monitored by magnetic resonance image (MRI), in real time upon Mn2+ release from the acidic- and H2O2- microenvironment-responsive MnO2 nanoparticles. The DATS-loaded MOC-68-doped MnO2-based nanodrug holds great promise as a novel theranostic platform for AS.

Management of chylothorax after retrocrural lymphadectomy in a patient with ovarian cancer: a case report.

Introduction and importance: With the widespread use of positron emission tomography and computed tomography (PET/CT), a significantly greater proportion of patients with advanced ovarian cancer (OC) are now diagnosed with superior renal-vein lymph node metastases involving retrocrural and mediastinal nodes. To the authors' knowledge, retrocrural lymphadenectomy has not yet been reported in patients with OC. The authors performed retrocrural lymph node resection in a patient with ovarian cancer. Case presentation: A 64-year-old woman with ovarian cancer who had not undergone surgery upon initial diagnosis was admitted to the authors' hospital because tumour markers increased during bevacizumab maintenance therapy. PET/CT imaging revealed adnexal masses and multiple metastases in pelvic, para-aortic, retrocrural, and mediastinal lymph nodes. Reduction surgery was performed, and retrocrural lymph nodes were excised. However, the patient's postoperative course was complicated by a chylothorax. Because of the failure of conservative treatment, interventional embolization was performed, but failed to obstruct lymphatic vessels. The patient underwent reoperation. A fistula was located where Hem-o-lock clips penetrated the pleura, clearly indicating the injury site, which was then sutured and embedded in the surrounding diaphragmatic tissue and filled with gel sponge. The patient recovered from chylous leakage postoperatively. She later underwent chemotherapy and targeted maintenance therapy. Clinical discussion: The authors may have injured the communicating branch of the thoracic duct posterior to the diaphragm during the first operation and did not ligate it. The accumulated chylous fluid finally penetrated through the weak point on the pleura and led to chylothorax 3 days later. If conservative treatment or interventional embolization are unsuccessful, surgical treatment should be selected in time. Conclusion: The location of the retrocrural lymph node at the anastomosis of the chylous cistern and the thoracic duct may pose a significant risk of chylous leakage as a complication of lymphadenectomy. Full exposure of the surgical field and thorough ligation of the lymphatic vessels may lead to successful superior renal-vein lymphadenectomy.

The Application of Pneumatic Arm in Neuroendoscopic Transsphenoidal Pituitary Adenoma Resection.

OBJECTIVE: To summarize the application experience of the pneumatic arm in transnasal sphenoidal pituitary adenoma resection under neuroendoscope. METHODS: A retrospective analysis was conducted on the clinical data of 52 patients with pituitary adenoma who underwent endoscopic transsphenoidal surgery with pneumatic arm fixation in the Neurosurgery Department of the First Affiliated Hospital of Anhui Medical University from July 2021 to March 2024. Among them, there were 5 cases of pituitary microadenoma, 35 cases of macroadenoma, and 12 cases of giant adenoma. Head CT and a full set of hormones were re-examined within 24 hours after surgery to evaluate the surgical effect. Follow-up was conducted by the outpatient department after surgery to assess the clinical symptoms, hormone level, and imaging of all patients. RESULTS: Among 52 patients, gross total resection was achieved in 48 cases (92.3%), subtotal resection in 3 cases (5.8%), and partial resection in 1 case (1.9%). Preoperatively, 43 patients had diminished vision, with 40 showing improvement postoperatively, 1 worsening, and 2 having no significant improvement. Thirty-eight patients had headaches preoperatively, and all showed varying degrees of improvement postoperatively. Routine hormone examination within 24 hours after surgery showed that all 20 prolactinoma patients had restored normal hormone levels, 10 of 12 growth hormone-secreting adenoma patients normalized, and 4 of 6 cases of adrenocorticotropic hormone-secreting adenoma immediately relieved after surgery. Postoperative complications included intracranial hematoma in 1 case, cerebrospinal fluid leakage in 2 cases, transient diabetes insipidus in 6 cases, intracranial infection in 1 case, and no death cases. The median follow-up time of 52 patients was 18.6 months (range: 1-32 mo). During the follow-up period, the initial clinical symptoms of all patients improved to varying degrees, and they were able to work and live normally. At the last follow-up, 1 patient had recurrent tumor and 1 patient had progression. CONCLUSION: Transnasal sphenoidal resection of pituitary adenoma using a pneumatic arm-fixed neuroendoscope allows the operator to perform the surgery with both hands, resulting in satisfactory overall tumor resection and fewer surgical complications. This technique has good clinical value for promotion.

Two novel compound heterozygous loss-of-function mutations cause fetal IRAK-4 deficiency presenting with Pseudomonas Aeruginosa sepsis.

PURPOSE: To report a case of a five-month-old Chinese infant who died of interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency presenting with rapid and progressive Pseudomonas aeruginosa sepsis. METHODS: The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay. RESULTS: Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, IRAK-4 (NM_016123.3): c.942-1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity. CONCLUSIONS: Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.

Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC.