Genetically engineered CD276-anchoring biomimetic nanovesicles target senescent escaped tumor cells to overcome chemoresistant and immunosuppressive breast cancer.

Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.

Gardenia jasminoides Ellis. Polysaccharides Alleviated Cholestatic Liver Injury by Increasing the Production of Butyric Acid and FXR Activation.

Gardenia jasminoides Ellis. polysaccharide (GPS) can protect against cholestatic liver injury (CLI) by regulating nuclear farnesoid X receptor (FXR).However, the mechanism via which GPS mediates the FXR pathway remains unclear. The aim of this study was to investigate the mechanism. Firstly, an alpha-naphthylisothiocyanate-induced cholestatic mouse model was administered with GPS to evaluate its hepatoprotective effects. The metabolic pathways influenced by GPS in cholestatic mice were detected by serum metabolomics. The effect of GPS on bile acid (BA) homeostasis, FXR expression, and liver inflammation were investigated. Second, the intestinal bacteria metabolites affected by GPS in vivo and in vitro were determined. The activation of FXR by sodium butyrate (NaB) was measured. Finally, the effects of NaB on cholestatic mice were demonstrated. The main pathways influenced by GPS involved BA biosynthesis. GPS upregulated hepatic FXR expression, improved BA homeostasis, reduced F4/80+ and Ly6G+ positive areas in the liver, and inhibited liver inflammation in cholestatic mice. Butyric acid was the most notable intestinal bacterial metabolite following GPS intervention. NaB activated the transcriptional activity of FXR in vitro, upregulated hepatic FXR and its downstream efflux transporter expression, and ameliorated disordered BA homeostasis in CLI mice. NaB inhibited the toll-like receptor 4/nuclear factor (TLR4/NF-κB) pathway and reduced inflammation and CLI in mice. An FXR antagonist suppressed the effects. In conclusion, GPS increased butyric acid production, which can activate hepatic FXR, reverse BA homeostasis disorder, and inhibit the TLR4/NF-κB inflammatory pathway, exerting protective effects against CLI.

Network disruption based on multi-modal EEG-MRI in α-synucleinopathies.

Background: Brain network dysfunction has been characterized by resting-state electroencephalography (EEG) and magnetic resonance imaging (MRI) in the prodromal stage. This study aimed to identify multi-modal electrophysiological and neuroimaging biomarkers for differential diagnosis in synucleinopathies and phenoconversion in isolated rapid eye movement sleep behavior disorder (iRBD). Methods: We enrolled 35 patients with multiple system atrophy (MSA), 32 with Parkinson's disease (PD), 30 with iRBD and 30 matched healthy controls (HC). Power spectral density (PSD) was calculated in different frequency bands. EEG functional connectivity (FC) was calculated using the weighted Phase Lag Index (wPLI) after source localization. Significant network disruptions were further confirmed by MRI FC analysis. Results: Quantitative EEG analysis demonstrated that delta and theta power spectral density significantly differed among MSA, PD and HC. The increased PSD was correlated with cognitive decline and olfactory dysfunction in PD. Band-specific FC profiles were observed in theta, alpha, and gamma bands. The hypoconnected alpha network significantly correlated with motor dysfunction, while the gamma FC distinguished PD from MSA. By integrating EEG and MRI network analyses, we found that FC between the olfactory cortex and dorsolateral prefrontal cortex was significantly different between MSA and PD. A multimodal discriminative model for MSA and PD, integrating spectral and FC attributes of EEG and MRI, yielded an area under the receiver operating characteristic curve of 0.900. Simultaneously, we found the FC abnormalities were more prominent than spectral features in iRBD indicating prodromal dysfunction. The decreased FC between the angular gyrus and striatum was identified in α-synucleinopathies. This hypoconnectivity was associated with dopaminergic degeneration in iRBD examined by dopamine transporter imaging. Discussion: Our study demonstrated EEG spectral and functional profiles in prodromal and clinical-defined synucleinopathies. Multimodal EEG and MRI provided a novel approach to discriminate MSA and PD, and monitor neurodegenerative progression in the preclinical phase.

Cdon is essential for organ left-right patterning by regulating dorsal forerunner cells clustering and Kupffer's vesicle morphogenesis.

Cdon and boc are members of the cell adhesion molecule subfamily III Ig/fibronectin. Although they have been reported to be involved in muscle and neural development at late developmental stage, their early roles in embryonic development remain unknown. Here, we discovered that in zebrafish, cdon, but not boc, is expressed in dorsal forerunner cells (DFCs) and the epithelium of Kupffer's vesicle (KV), suggesting a potential role for cdon in organ left-right (LR) patterning. Further data showed that liver and heart LR patterning were disrupted in cdon morphants and cdon mutants. Mechanistically, we found that loss of cdon function led to defect in DFCs clustering, reduced KV lumen, and defective cilia, resulting in randomized Nodal/spaw signaling and subsequent organ LR patterning defects. Additionally, predominant distribution of a cdon morpholino (MO) in DFCs caused defects in DFC clustering, KV morphogenesis, cilia number/length, Nodal/spaw signaling, and organ LR asymmetry, similar to those observed in cdon morphants and cdon -/- embryos, indicating a cell-autonomous role for cdon in regulating KV formation during LR patterning. In conclusion, our data demonstrate that during gastrulation and early somitogenesis, cdon is essential for proper DFC clustering, KV formation, and normal cilia, thereby playing a critical role in establishing organ LR asymmetry.

Interaction between macrophages and ferroptosis: Metabolism, function, and diseases.

ABSTRACT: Ferroptosis, an iron-dependent programmed cell death process driven by reactive oxygen species-mediated lipid peroxidation, is regulated by several metabolic processes, including iron metabolism, lipid metabolism, and redox system. Macrophages are a group of innate immune cells that are widely distributed throughout the body, and play pivotal roles in maintaining metabolic balance by its phagocytic and efferocytotic effects. There is a profound association between the biological functions of macrophage and ferroptosis. Therefore, this review aims to elucidate three key aspects of the unique relationship between macrophages and ferroptosis, including macrophage metabolism and their regulation of cellular ferroptosis; ferroptotic stress that modulates functions of macrophage and promotion of inflammation; and the effects of macrophage ferroptosis and its role in diseases. Finally, we also summarize the possible mechanisms of macrophages in regulating the ferroptosis process at the global and local levels, as well as the role of ferroptosis in the macrophage-mediated inflammatory process, to provide new therapeutic insights for a variety of diseases.

Association between mode of delivery and early neurodevelopment: A prospective birth cohort study.

Previous research has assessed the effects of caesarean delivery (CD) on child neurodevelopment; however, whether the effects stem from the surgical procedure itself or its related medical conditions has not been conclusively determined. This study aimed to evaluate the associations among delivery mode, CD-related medical conditions and early childhood neurodevelopment. A total of 3829 maternal-infant pairs from a longitudinal birth cohort in Wuhan City, China, were included in the primary analysis. The neurodevelopment of the children was assessed by the Bayley Scales of Infant Development (BSID), the Conners Comprehensive Behaviour Rating Scale and the Chinese version of the Autism Behavior Checklist. Data on delivery mode and medical conditions were collected via medical records from the study hospital. Among the 3829 children for whom the BSID test was completed at two years of age, 50%, 27%, and 23% were delivered vaginally, by necessary CD, and by elective CD, respectively. Compared with vaginally delivered children, Necessary CD was associated with a 16.67% decrease in Mental Development Index (MDI) scores and a 13.37% decrease in Psychomotor Development Index (PDI) scores, while elective CD showed a 20.63% and 20.99% decrease after FDR correction, respectively. Similarly, among the 2448 children for whom the CBRS was completed, necessary CD was found to be associated with conduct disorders (adjusted ß: 0.06; 95% CI: 0.02, 0.09), hyperactivity (adjusted ß: 0.06; 95% CI: 0.02, 0.11), and hyperactivity index (adjusted ß: 0.07; 95% CI: 0.03, 0.11), while elective CD was significantly associated with hyperactivity problem scores (adjusted ß: 0.08, 95% CI: 0.03, 0.13). However, no significant association was found between CD and symptoms of autism in children, as assessed by the Autism Behavior Checklist (ABC). CONCLUSION: This study suggested that the adverse impact of CD on child neurodevelopment stems from the procedure itself rather than CD-related medical conditions. It is important to minimize the use of CD when there is no medical necessity. WHAT IS KNOWN: • Caesarean delivery (CD) may influence child neurodevelopment and other long-term outcomes. • In China, approximately one-quarter of CD are performed due to maternal request without medical indications. WHAT IS NEW: • The negative impact of CD on the neurodevelopmental outcomes of children may be primarily attributed to the procedure itself, as opposed to related medical conditions. • In the absence of medical indications, unnecessary CD may have adverse impacts on children's neurodevelopment.

Epidemiology, prognostic factors, and survival analysis in small cell esophageal carcinoma: A population-based study with external validation.

Small cell esophageal carcinoma (SCEC) is a poorly differentiated esophageal neuroendocrine neoplasm with a poor prognosis. This study aimed to explore the factors and treatment approaches influencing the prognosis of SCEC. In this retrospective study, we collected data from the 18 Surveillance, Epidemiology, and End Results (SEER) registries cohort between 2004 and 2019, as well as from a Chinese institutional registry covering the period from 2012 to 2022. We assessed the annual percentage change (APC) in incidence of SCEC. Kaplan-Meier and Cox regression analyses were conducted to evaluate survival outcomes. Additionally, nomograms were developed for overall survival (OS) and cancer-specific survival (CSS) in the SEER cohort for SCEC and validated in an independent Chinese cohort. This analysis included 299 SCEC patients from the SEER cohort and 66 cases from the Chinese cohort. During the period of 2004-2019, the incidence of SCEC reached a plateau, with an APC of -1.40 (95% confidence interval [CI]: -4.3 to 1.40, P > 0.05). Multivariable Cox regression analysis revealed that age, distant metastasis, and chemotherapy were independent factors for OS, while distant metastasis and chemotherapy were independent factors for CSS. The nomograms developed for OS and CSS in SCEC exhibited remarkable accuracy and reliable predictive capacity in estimating 1-year, 3-year, and 5-year OS and CSS. SCEC is a rare malignancy with aggressive behavior. Distant metastasis is significantly associated with worse OS and CSS in patients with SCEC. Currently, chemotherapy remains the primary treatment approach for SCEC.

Birthweight influences liver structure, function and disease risk: Evidence of a causal association.

AIM: Low birthweight is an issue during pregnancy associated with an increased risk of developing liver disease later in life. Previous Mendelian randomisation (MR) studies which explored this issue have not isolated the direct impact of the foetus on birthweight. In the present study, MR was used to assess whether direct foetal effects on birthweight were causally associated with liver structure, function and disease risk independent of intrauterine effects. MATERIALS AND METHODS: We extracted single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) about direct foetal-affected birthweight (321 223 cases) to conduct univariable and multivariable MR analyses to explore the relationships between birthweight and 4 liver structure measures, 9 liver function measures and 18 liver diseases. A two-step MR analysis was used to further assess and quantify the mediating effects of the mediators. RESULTS: When isolating direct foetal effects, genetically predicted lower birthweight was associated with a higher risk of non-alcoholic fatty liver disease (NAFLD) (odds ratios [OR], 95% confidence interval [CI]: 1.61, 1.29-2.02, p < 0.001), higher magnetic resonance imaging [MRI] proton density fat fraction (PDFF) and higher serum gamma glutamyltransferase (GGT). Two-step MR identified two candidate mediators that partially mediate the direct foetal effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.29%) and triglycerides (6.50%). CONCLUSIONS: Our MR analysis reveals a direct causal association between lower birthweight and liver MRI PDFF, as well as the development of NAFLD, which persisted even after accounting for the potential influence of maternal factors. In addition, we identified fasting insulin and triglycerides as mediators linking birthweight and hepatic outcomes, providing insights for early clinical interventions.

Prognostic value of transient ischemic dilatation by 13N-ammonia PET MPI for short-term outcomes in patients with non-obstructive CAD.

OBJECTIVE: Transient ischaemic dilatation (TID) had incremental diagnostic and prognostic value in obstructive coronary artery disease (CAD), but its clinical significance in patients with non-obstructive CAD remains unknown. We aimed to explore the prognostic value of TID in patients with non-obstructive CAD by 13N-ammonia PET imaging. METHODS: We retrospectively studied 131 consecutive patients with non-obstructive CAD undergoing one-day rest-stress 13N-ammonia PET myocardial perfusion imaging (MPI). TID was automatically generated using CardIQ Physio software. The receiver operative characteristic (ROC) curve was used to determine the optimal threshold of TID. The follow-up outcome was major adverse cardiac events (MACE), a composite of re-hospitalization for heart failure or unstable angina, late revascularization, non-fatal myocardial infarction, and cardiac death. Cardiac event-free survivals for normal and abnormal TID were compared using Kaplan-Meier plots and log-rank tests. RESULTS: During a median follow-up of 42.08 ± 17.67 months, 22 (16.7%) patients occurred MACE. The optimal cut-off value of TID was 1.03 based on MACE. Our preliminary outcome analysis suggests that TID-abnormal subjects had a lower overall survival probability. Furthermore, our multivariate analysis reveals abnormal TID was the only independent predictor for MACE in non-obstructive CAD. In the subgroup analysis, an abnormal TID was an independent predictor for MACE in patients with abnormal perfusion patterns. CONCLUSION: Among patients with non-obstructive CAD, PET-derived TID ≥ 1.03 may identify those with a high risk of subsequent MACE independently. It was also an independent risk factor for poor prognosis in patients with abnormal perfusion.

Influence of Capsular Tension Rings on the IOL-Capsule Complex in Patients With Long Axial Length: A Clinical Observation Based on SS-OCT.

PURPOSE: To evaluate the influence of a capsular tension ring (CTR) on the intraocular lens (IOL)-capsule complex after cataract surgery in patients with long axial length. METHODS: This was a prospective study. Patients underwent phacoemulsification and IOL implantation, with or without CTR implantation. Swept-source optical coherence tomography was performed at 1 day, 1 week, 1 month, and 3 months postoperatively to determine the postoperative aqueous depth (PAD), capsular bend index (CBI), and IOL tilt and decentration. Spherical equivalent values were obtained through subjective refraction and autorefraction. Root mean square was adopted to evaluate the indices listed above. RESULTS: Forty-three patients (56 eyes) were included in the study. Generalized estimating equation analysis of PAD showed a statistical difference between groups (P = .031). The RMS of the change in PAD was smaller in the CTR group than in the non-CTR group during the 3 months after surgery (P = .015). CBI in the CTR group increased more from 1 to 3 months after surgery than that in the non-CTR group (P = .025). The RMS of the change in vertical decentration was smaller in the CTR group than in the non-CTR group during the 3-month follow-up (P = .009). CONCLUSIONS: CTR implantation can stabilize the axial position of the IOL within the capsular bag after cataract surgery in patients with long axial length without affecting the refractive stability. The formation of capsular bend may be slightly delayed in the early stage after CTR implantation, but it accelerates from 1 to 3 months after surgery. [J Refract Surg. 2024;40(9):e654-e661.].

CircRNAs expression profile and potential roles of circRERE-PMN in pre-metastatic lungs.

The successful pulmonary metastasis of malignant cancer cells depends on the survival of circulating tumor cells in a distant and hostile microenvironment. The formation of a pre-metastatic niche (PMN) creates a supportive environment for subsequent metastasis. Circular RNAs (circRNAs) are increasingly acknowledged as crucial elements in the mechanisms of metastasis due to their stable structures and functions, making them promising early metastasis detection markers. However, the specific expression patterns and roles of circRNAs in the lungs before metastasis remain largely unexplored. Our research aims to chart the circRNA expression profile and assess their impact on the lung PMN. We developed a lung PMN model and employed comprehensive RNA sequencing to analyze the differences in circRNA expression between normal and pre-metastatic lungs. We identified 38 significantly different circRNAs, primarily involved in metabolism, apoptosis, and inflammation pathways. We then focused on one specific circRNA, circ:chr4:150406196 - 150406664 (circRERE-PMN), which exhibited a significant change in expression and was prevalent in myeloid-derived suppressor cells (MDSCs), alveolar epithelial cells, and macrophages within the pre-metastatic lung environment. CircRERE-PMN was found to potentially regulate apoptosis and the expression of cytokines and chemokines through its interaction with the downstream target HUR in alveolar epithelial cells. Overall, our study highlights the crucial role of circRNAs in the formation of lung PMNs, supporting their potential as diagnostic or therapeutic targets for lung metastasis.

Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression.

BACKGROUND & AIMS: The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear. METHODS: Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilised to study fatty liver protection by T6BP. P-PTC, a peptide-proteolysis targeting chimaera, degrades PYK2 to block MASH progression. RESULTS: Since PYK2 activation is promoter signalling in steatohepatitis development, we find that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, pro-inflammatory factor release, and pro-fibrosis production by ubiquitin ligase CBL to degrade PYK2. Mechanistic evidence suggests that T6BP directly targets PYK2 and prevents its N-terminal FERM domain-triggered dimerization, disrupting downstream PYK2-JNK signalling hyperactivation. Additionally, T6BP favourably recruits CBL, a particular E3 ubiquitin ligase targeting PYK2, to form a complex and degrade PYK2. T6BP (F1), a core fragment of T6BP, directly blocks N-terminal FERM domain-associated dimerization of PYK2, followed by T6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specifically expressed using thyroxine binding globulin (TBG)-ground vectors. This inhibits the progression of MASH, metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC (MASH-HCC), and metabolic syndrome in dietary rodent models. First-ever peptide-proteolysis targeting chimaera (P-PTC) based on the core segment of T6BP as a ligand for targeted recruitment of CBL targeting metabolic disorders like MASH has been devised and validated in animal models. CONCLUSIONS: Our study revealed a previously unknown mechanism: identification of T6BP as a key eliminator of fatty liver strongly contributes to the development of promising therapeutic targets, and the discovery of crucial fragments of T6BP-based pharmacon that interrupt PYK2 dimerization are novel and viable treatments for fatty liver and its advanced symptoms and complications. IMPACT AND IMPLICATIONS: Excessive high-energy diet ingestion is critical in driving steatohepatitis via regulation of hepatocyte non-receptor tyrosine kinases. The mechanisms under lying the regulation of hepatocyte PYK2 in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear. Here, we found that T6BP as a critical fatty liver eliminator has a significant impact on the development of promising therapeutic targets. Additionally, vital T6BP-based pharmacon fragments that impede PYK2 dimerization have been found, offering new and effective treatments for advanced fatty liver symptoms and complications.

Fetal weight growth trajectories and childhood development: A population-based cohort study.

This study aimed to investigate whether fetal growth trajectories (FGTs) could predict early childhood development, indicate intrauterine metabolic changes, and explore potential optimal and suboptimal FGTs. FGTs were developed by using an unsupervised machine-learning approach. Children's neurodevelopment, anthropometry, and respiratory outcomes in the first 6 years of life were assessed at different ages. In a subgroup of participants, we conducted a metabolomics analysis of cord blood to reveal the metabolic features of FGTs. We identified 6 FGTs: early decelerating, early decelerating with late catch-up growth, early accelerating, early accelerating with late medium growth, late decelerating, and late accelerating. The early accelerating with late medium growth pattern might be the optimal FGT due to its associations with better psychomotor development, mental development, intelligence quotient, and lung function and a lower risk of behaviour and respiratory problems. Compared with the optimal FGT, early decelerating and late decelerating FGTs were associated with poor neurodevelopment and lung function, while early accelerating FGT was associated with more severe autistic symptoms, poor lung function, and increased risks of overweight/obesity. Metabolic alterations were enriched in amino acid metabolism for early decelerating and late decelerating FGTs, whereas altered metabolites were enriched in lipid metabolism for early accelerating FGT. These findings suggest that FGTs are predictors of early life development and may indicate intrauterine adaptive metabolism. The discovery of optimal and suboptimal FGTs provides potential clues for the early identification and intervention of fetal origin dysplasia or disease, but further research on related mechanisms is still needed.

RCDdb: A manually curated database and analysis platform for regulated cell death.

Regulated cell death is a pivotal regulatory mechanism governing the development and homeostasis of multicellular organisms. A comprehensive understanding of RCD's regulatory mechanisms is crucial for developing novel therapeutic strategies against diseases associated with cell death, such as cancer and neurodegenerative diseases. However, existing data repositories support limited types of cell death data and lack comprehensive annotation and analytical functionalities. Thus, establishing an extensive cell death database is an urgent imperative. To address this gap, we developed the Regulated Cell Death Database (RCDdb, chenyclab.com/RCDdb), the first comprehensively manually annotated database designed to support annotations and analytical capabilities across all RCD types. We compiled 3090 marker gene annotations associated with 15 RCD types from 2180 relevant articles. The RCDdb includes annotation data on these marker genes concerning diseases, drugs, pathways, proteins, and gene expressions. Furthermore, it provides 49 diverse visualization methods to present this information. More importantly, the RCDdb features three online analysis tools for identifying and analyzing RCD-related features within user-submitted data. Furthermore, the RCDdb offers a user-friendly interface for querying, browsing, analysis, and visualization of detailed information associated with each RCD category. This resource promises to significantly aid researchers in better understanding the mechanisms of cell death, thereby accelerating progress in research and therapeutic strategies aimed at combating RCD-related diseases.

Enhancement of Apple Stress Resistance via Proline Elevation by Sugar Substitutes.

Plants encounter numerous adversities during growth, necessitating the identification of common stress activators to bolster their resistance. However, the current understanding of these activators' mechanisms remains limited. This study identified three anti-stress activators applicable to apple trees, all of which elevate plant proline content to enhance resistance against various adversities. The results showed that the application of these sugar substitutes increased apple proline content by two to three times compared to the untreated group. Even at a lower concentration, these activators triggered plant stress resistance without compromising apple fruit quality. Therefore, these three sugar substitutes can be exogenously sprayed on apple trees to augment proline content and fortify stress resistance. Given their effectiveness and low production cost, these activators possess significant application value. Since they have been widely used in the food industry, they hold potential for broader application in plants, fostering apple industry development.

Aggression to Biomembranes by Hydrophobic Tail Chains under the Stimulus of Reductant.

Stimulus-responsive materials hold significant promise for antitumor applications due to their variable structures and physical properties. In this paper, a series of peptides with a responsive viologen derivative, Pep-CnV (n = 1, 2, 3) were designed and synthesized. The process and mechanism of the interaction were studied and discussed. An ultraviolet-visible (UV) spectrophotometer and fluorescence spectrophotometer were used to study their redox responsiveness. Additionally, their secondary structures were measured by Circular Dichroism (CD) in the presence or absence of the reductant, Na2SO3. DPPC and DPPG liposomes were prepared to mimic normal and tumor cell membranes. The interaction between Pep-CnV and biomembranes was investigated by the measurements of surface tension and cargo leakage. Results proved Pep-CnV was more likely to interact with the DPPG liposome and destroy its biomembrane under the stimulus of the reductant. And the destruction increased with the length of the hydrophobic tail chain. Pep-CnV showed its potential as an intelligent antitumor agent.

Endoscopic retrosigmoid trans-petrosal fissure approach for vestibular schwannomas: case series.

The management of vestibular schwannoma (VS) remains one of the most formidable challenges in neurosurgery owing to the eloquent nature of surrounding anatomy. Although endoscopy-assisted microsurgery has recently gained momentum in cerebellopontine angle region surgery, the feasibility of pure endoscopic technique has been rarely reported. Here we present the operative technique and preliminary outcomes of fully endoscopic retrosigmoid trans-petrosal fissure approach (ER-TPFA) for VS surgery. Clinical data of 36 consecutive cases of VS treated with the ER-TPFA from March 2021 to March 2023 were analyzed. The patients were placed in a modified lateral park-bench position, with the Dandy incision and suboccipital craniotomy performed. With the endoscopic holder, endoscopic procedures were performed using standard two-hand microsurgical techniques by one surgeon. Arachnoidal dissection of the petrosal fissure was performed for identifying the brainstem end of facial nerve and separating the tumor from the cerebellum, without brain retraction seen in traditional microsurgical technique. The tumors had an averaged size of 3.0 cm in diameter. According to the Hannover classification, nearly all the tumors were grade III-IV (97.3%). Using ER-TPFA, 33 patients (91.7%) achieved gross total resection. Anatomic preservation of the facial nerve was achieved in 35 cases, with 33 patients (91.7%) retaining a House-Brackmann score of 1-2 postoperatively. Four out of ten patients still had serviceable hearing 6 months after operation. Postoperatively, there was no post-craniotomy hematoma, cerebellar edema, and new-onset cerebellar ataxia. With a better visualization of the cerebellopontine angle region, ER-TPFA may help preserve facial nerve function and maintain high gross total resection rate while minimizing complications. We believe this retractorless technique can be a safe and effective alternative for the management of VS with satisfactory clinical results.

Fabrication, digestion behavior and ß-carotene bioaccessibility of emulsion-filled double-network gel: Effect of corn fiber gum/soy protein isolate ratio and surfactant types.

Emulsion fortified with ß-carotene was added to corn fiber gum (CFG)/soy protein isolate (SPI) double network gel matrix to obtain emulsion-filled gels (EFG) via dual induction of laccase and glucono-δ-lactone. Protein digestion was accompanied by the release of ß-carotene from gel matrix during in vitro digestion. The surfactant types and corn fiber gum/soy protein isolate ratio affected the ß-carotene bioaccessibility via changing oil-water interfacial composition and emulsion particle size during in vitro digestion. As compared with Tween-20 EFGs, emulsion droplets released from SPI EFGs was more susceptible to flocculation, followed with coalescence due to proteolysis of interfacial SPI during gastric digestion. The resulting oil droplets with large particle size exhibited lower lipase adsorption, thus reducing the free fatty acid content and ß-carotene bioaccessibility. The confocal laser scanning microscope (CLSM) observation confirmed that protein hydrolysate from gel matrix were adsorbed onto the oil-water interface competing with Tween-20 during intestinal digestion. For EFGs with higher CFG content, steric hindrance of CFG molecules and less emulsion release could inhibit droplet flocculation, thus enhancing ß-carotene bioaccessibility.

Untargeted metabolomics and physiological phenotypic analyses reveal the defense strategies of nitrite by Lactiplantibacillus plantarum PK25.

A comprehensive understanding of the defense strategies against nitrite by Lactiplantibacillus plantarum remains unknown. Herein, the effects of nitrite degradation process on metabolic profiling of L. plantarum PK25 were investigated by metabolomics and phenomenological measurement. A total of 633 metabolites were significantly different at 6, 12, and 24 incubation hours. Specifically, citrulline and lysine reduction facilitated strain survival by limiting cell growth. A significant reduction of unsaturated fatty acids was observed, which could induce reduced cell membrane fluidity to prevent nitrite entry. The accumulation of thymine and cytosine might be resulted from accelerated RNA expression to accelerate the repair of cells. Dopamine and ergothioneine could serve as antioxidants to prevent bacteria from oxidative stress. Furthermore, cell filamentation production, increased hydrophobicity, and altered antioxidant enzyme activity were favorable alterations made by strain. Our study demonstrated the metabolite profile alteration of L. plantarum during nitrite degradation, which provided a theoretical basis for targeting strain function.

Nucleoporin-associated steroid-resistant nephrotic syndrome.

Nucleoporins (Nups) are a class of proteins that assemble to form nuclear pore complexes, which are related to nucleocytoplasmic transport, gene expression, and the cell cycle. Pathogenic variants in six genes encoding Nups, NUP85, NUP93, NUP107, NUP133, NUP160, and NUP205, cause monogenic steroid-resistant nephrotic syndrome (SRNS), referred to as nucleoporin-associated SRNS. In this paper, we review the epidemiology, structure and function of Nups, pathogenesis, phenotypes and genotypes, and management of nucleoporin-associated SRNS as well as implications for genetic counseling. Affected individuals exhibit autosomal recessive isolated and syndromic SRNS, whose extrarenal manifestations include neurological disorders, growth and development disorders, cardiovascular disorders, and congenital malformations. The median ages at onset of NUP85-, NUP93-, NUP107-, NUP133-, NUP160-, and NUP205-associated SRNS are 7, 3, 4.1, 9, 7, and 2 years, respectively. Kidney biopsies reveal focal segmental glomerulosclerosis in 89% of patients. Most affected individuals are resistant to immunosuppressants. For the six subtypes of nucleoporin-associated SRNS, patients show progression to kidney failure at median ages of 8.5, 3.7, 6.9, 13, 15, and 7 years, respectively. Only two patients with NUP93-associated SRNS with nephrotic syndrome relapse post-transplant have been reported, and the recurrence rate is 12.5%. Next-generation sequencing using a targeted gene panel is recommended in cases of suspected nucleoporin-associated SRNS for genetic diagnosis. Renin-angiotensin-aldosterone system inhibitors are recommended for patients with nucleoporin-associated SRNS. Once genetic diagnosis is confirmed, immunosuppressant discontinuation should be considered, and kidney transplant is preferred when patients progress to kidney failure. Genetic counselling should be provided for asymptomatic siblings and future siblings of an affected individual. Further studies on the pathogenesis of nucleoporin-associated SRNS are needed to seek new therapeutic interventions.