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.

[Guidelines for construction of traditional Chinese medicine pharmacovigilance system in medical institutions].

The group standard Guidelines for construction of traditional Chinese medicine(TCM) pharmacovigilance system in medical institutions, managed by Chinese Association of Chinese Medicine and led by the Institute of Basic Research in Clinical Medicine,China Academy of Chinese Medical Sciences and Dongfang Hospital of Beijing University of Chinese Medicine, was announced on National Group Standard Information Platform on January 16, 2024, with the standard number T/CACM 1563. 2-2024. According to EU pharmacovigilance regulations and the second-level guidance principles of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH), the unique characteristics of TCM were fully considered, and the relevant systems and procedures for constructing TCM pharmacovigilance systems in medical institutions were clearly defined. This included establishing TCM pharmacovigilance information platforms, arranging staff, formulating various regulations, and monitoring adverse reactions of TCM(including TCM decoction pieces, granules, Chinese patent medicines, in-hospital preparations, and pre-marketed Chinese patent medicines). It aimed to develop a TCM pharmacovigilance system in medical institutions that was tailored to the characteristics of TCM. The system could be appropriately adjusted according to the scope of practice and actual circumstances of medical institutions at different levels. This will enhance the implementation of TCM pharmacovigilance work and safeguard medication safety. The group standard underwent multiple rounds of consultations with internal and external experts and has ultimately evolved into a guiding document applicable to medical institutions and related entities engaged in pharmacovigilance activities.

[Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines].

Oral Chinese patent medicine is the essence of effective prescriptions created and summarized by Chinese medical scientists through thousands of years of medical practice. It is portable and convenient, with an obvious curative effect and other characteristics. However, at present, oral Chinese patent medicine is rich in dosage forms, various in types, complex in mechanism of action, and broad in clinical positioning. In clinical application, there are often cases of drug use without reference to instructions,repeated drug use, and prolonged drug use, which highlights safety problems such as adverse reactions and hepatorenal toxicity. Oral Chinese patent medicine pharmacovigilance is facing challenges. World Health Organization(WHO) has issued the WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems, and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) has issued the ICH E2 pharmacovigilance guidelines. The United States has issued the Pharmacovigilance management standards and pharmacoepidemiological assessment guidelines, and the European Union has issued the Guidelines on good pharmacovigilance practices. Japan, South Korea, and other countries in the Asia Pacific region have established their own pharmacovigilance systems, but currently, there are no pharmacovigilance guidelines related to oral Chinese patent medicine in China. Therefore, experts from many disciplines and fields in China were invited to jointly develop the Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines, which aims to develop pharmacovigilance guidelines for clinical application that are consistent with China's national conditions and highlight the characteristics of oral Chinese patent medicine, and provide guidance for clinically safe and rational drug application in medical institutions.

[Pharmacovigilance guidelines for clinical application of traditional Chinese medicine injections].

In 2019, the newly revised Drug Administration Law of the People's Republic of China was issued and implemented,clearly proposing that China should establish a pharmacovigilance system. As a new traditional Chinese medicine(TCM) dosage form created in China, TCM injections have been widely used in clinic, and its pharmacovigilance has attracted much attention. In response to this situation, the project team convened a group of clinical, pharmaceutical and evidence-based medicine experts from all over the country to form an expert group, which formulated the Pharmacovigilance guidelines for clinical application of traditional Chinese medicine injections in strict accordance with the requirements of the group standards of the Chinese Association of Chinese Medicine.From the perspective of clinical application and considering the key elements of pharmacovigilance for clinical application of TCM injections, the guidelines put forward suggestions on the decision making of pharmacovigilance for clinical application of TCM injections from four key links, namely the monitoring and reporting, signal recognition, risk assessment and risk control, according to China's pharmacovigilance regulations and learning from foreign pharmacovigilance guidelines.

[Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use].

There are many kinds and dosage forms of Chinese patent medicines for external use on the market, which are widely used in clinical departments. The common adverse reactions of Chinese patent medicines for external use are skin reactions, and those for the rare severe diseases include palpitation, chest tightness, dyspnea, and anaphylactic shock. At present, World Health Organization(WHO), International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH),the United States, the European Union, and Asia-Pacific countries(such as Japan and South Korea) have not issued any pharmacovigilance guideline of Chinese patent medicines for external use. China has not issued any pharmacovigilance guideline for these medicines, only releasing the standard Evaluation of skin adverse reactions caused by Chinese patent medicines for external use(T/CACM 005-2017). To standardize the safe and reasonable use of Chinese patent medicines for external use, Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use was developed with the joint efforts of experts in diverse disciplines. The guideline provides guidance on the monitoring and reporting of adverse reactions/events, identification and assessment of risk signals, and risk control measures in the clinical application of Chinese patent medicines for external use to guide the rational use of these medicines in clinical practice. At the same time, the possible risks and risk control measures in clinical application of Chinese patent medicines for external use are listed for clinical reference. In addition, the guideline provides guidance for risk minimization plans and the standardization of activities related to pharmacovigilance of Chinese patent medicines for external use in China.

[Pharmacovigilance guidelines of Chinese patent medicines].

Drug administration law of the People's Republic of China(2019 revised edition), which came into effect on December 1, 2019, proposed that " the state shall establish a pharmacovigilance system". Pharmacovigilance work of Chinese patent medicines is more difficult, and it is necessary to carry out Pharmacovigilance activities that are in line with the characteristics of Chinese patent medicines. Pharmacovigilance guidelines of Chinese patent medicines(T/CACM 1563. 1-2024), based on the principles of Drug Administration Law of the People's Republic of China(2019 revised edition) and Pharmacovigilance quality management standards(No. 65 of 2021) of the National Medical Products Administration, draws on the EU Pharmacovigilance regulation and the secondary guidelines of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH), and it is drafted in accordance with the provisions of Guidelines for standardization work part 1: structure and drafting rules of standardization documents(GB/T1. 1-2020) based on the characteristics of Chinese patent medicines. It serves as a general document for a series of pharmacovigilance guidelines of Chinese patent medicines, such as Guidelines for construction of traditional Chinese medicine pharmacovigilance system in medical institutions(T/CACM 1563. 2-2024), Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines(T/CACM 1563. 3-2024), Pharmacovigilance guidelines for clinical application of traditional Chinese medicine injections(T/CACM 1563. 4-2024), Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use(T/CACM 1563. 5-2024), and Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration(T/CACM 1563. 6-2024), including four major elements of pharmacovigilance monitoring and reporting of Chinese patent medicines, signal identification, risk evaluation, and risk control, as well as pharmacovigilance activities for Chinese patent medicines, ensuring the safety of public drug use.

[Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration].

The group standard Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration was released on January 16, 2024, on the national group standards information platform by the Institute of Basic Research in Clinical Medicine of China Academy of Chinese Medical Sciences and School and Hospital of Stomatology of Peking University, under the centralized management by the China Association of Chinese Medicine. The standard number is T/CACM 1563.6-2024. It aims to propose key elements and specify technical methods for safety monitoring and reporting, signal identification, risk assessment, and risk control based on the Drug administration law of the People's Republic of China(revised in 2019), which establishes normative pharmacovigilance guideline of Chinese patent medicine for mucosal administration that is in line with the characteristics of traditional Chinese Medicine(TCM) based on the pharmacovigilance content for clinical application of Chinese patent medicine for mucosal administration. The group standard has been discussed by internal and external experts through multiple rounds of consultation. It serves as a guiding document for stakeholders involved in pharmacovigilance activities, including pharmaceutical license holders, drug manufacturers, medical institutions, research institutes, and pharmaceutical trading enterprises.

High internal phase emulsion stabilized by soy protein isolate-Rutin complex: Rheological properties, bioaccessibility and in vitro release kinetics.

High internal phase emulsions (HIPEs) are promising carrier materials for encapsulating and delivering hydrophobic bioactive compounds. By strategically adjusting the composition, particle size, or charge of HIPEs, it is possible to enhance both their stability and the bioaccessibility of hydrophobic polyphenols encapsulated within them. In this study, different soy protein isolate (SPI)-rutin (SPI-R) complexes (formed under various preheating temperatures) were used to stabilize HIPEs, while the particle size, and charge of HIPEs was further adjusted through different homogenization rates. The results demonstrated that an optimal preheating temperature of 70 °C for the complex and a homogenization rate of 15,000 rpm for HIPEs enhanced the stability of the entire emulsion system by producing more uniform and smaller droplet distribution with improved rheological properties. Furthermore, in vitro digestion experiments showed that HIPEs stabilized by the SPI-R complexes (HSR) at optimal homogenization rate had better loading efficiency (98.68 %) and bioaccessibility compared to other groups. Additionally, fitting results from release kinetics confirmed that rutin encapsulated by HSR could achieve sustained release effect. Overall, these findings suggest that HSR has great potential as an effective vehicle for delivering hydrophobic bioactive compounds like rutin within the food industry.

Research on microbial diversity and nutritional flavor formation of Xianju wheat paste.

BACKGROUND: Xianju wheat paste, a traditional condiment in Hubei Province, China, possesses nutritional value and a distinctive taste profile. Nevertheless, there remains a dearth of comprehensive comprehension regarding the intricate interplay between the microbial population and its nutritional profile in Xianju wheat paste. RESULTS: It was determined that Xianju wheat paste harbors predominant microbial genera such as Bacillus, Staphylococcus and Aspergillus. The findings from high-throughput sequencing analysis revealed the presence of 11 bacterial genera in Xianju wheat paste, with relative abundances exceeding 1%. These genera included Bacillus, Staphylococcus, Brevibacterium, Lactobacillus, Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Enterobacteriaceae, Pantoea, Brachybacterium, Klebsiella, Escherichia-Shigella and Ochrobactrum. Furthermore, six fungal genera were identified with relative abundances greater than 1%, specifically Aspergillus, Zygosaccharomyces, Cutaneotrichosporon, Candida, Millerozyma and Rhizopus. The correlation analysis indicated a significant impact of the microbial community and nutritional flavor on the second phase of fermentation in Xianju wheat paste. The predominant bacterium Bacillus in Xianju wheat paste facilitated the production of free amino acids, whereas Staphylococcus exhibited a negative correlation with free amino acid levels. The quantity of volatile compounds in Xianju wheat paste progressively increased during fermentation, with the presence of typical aroma compounds 4-vinyl-2-methoxyphenol significantly associated with Bacillus. This indicated Bacillus notably enhanced the production of aromatic substances. Furthermore, a strong correlation was observed between Staphylococcus and the 18 volatile organic compounds, highlighting their substantial contribution to these aroma compounds. CONCLUSION: This research indicates that the presence of microbial communities significantly contributes to the development of the nutritional flavor profile in Xianju wheat paste. © 2024 Society of Chemical Industry.

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.

Clinical characteristics and surgical strategy of sporadic cerebellar hemangioblastomas.

Hemangioblastoma is a rare benign vascular tumor that occurs mostly in the cerebellum. The aim of the present study was to analyze the clinical characteristics of sporadic cerebellar hemangioblastoma and its surgical strategy. A total of 76 cases of sporadic cerebellar hemangioblastoma (42 males and 34 females; age, 46.4±13.9 years; age range, 23-72 years) admitted to the Department of Neurosurgery of the General Hospital of Northern Theater Command (Shenyang, China) from July 2012 to April 2021 were retrospectively analyzed. All patients had only one isolated tumor and underwent surgical resection. Their basic characteristics, serial radiographic examinations, surgical records and follow-up were analyzed. A total of 57 patients with cystic hemangioblastoma and eight patients with cystic solid hemangioblastoma directly underwent resection treatment. Of 11 patients with solid hemangioblastoma, 8 underwent vascular embolization prior to surgical resection. Furthermore, 3 patients with solid hemangioblastoma who were not embolized prior to surgery had intraoperative hemorrhage and poor prognosis. In addition, 3 patients underwent partial resection of the tumor and all of them suffered recurrence after the surgery. A total of 71 patients achieved good neurologic improvement. However, 5 patients had a poor prognosis after the initial surgery. In conclusion, total microsurgical resection is essential to improve the health status of patients with sporadic cerebellar cystic hemangioblastoma. In addition, preoperative embolization of arteries supplying solid hemangioblastomas can reduce intraoperative bleeding and improve prognosis.

Manganese inhibits HBV transcription and promotes HBsAg degradation at non-toxic levels.

Chronic hepatitis B virus (HBV) infection continues to pose a significant global health challenge. However, therapeutic measures for a cure are lacking in clinical practice. Manganese, an essential trace element, has garnered attention due to its potential to activate innate immune pathways and its significant role in antiviral and antitumor immunity. Yet, the specific impact of manganese on chronic hepatitis B has been largely unexplored. Our research reveals that manganese substantially inhibits HBV replication in hepatocellular carcinoma cells at non-toxic levels. This suppression occurs independently of well-known anti-HBV innate immune pathways, such as the cGAS-STING pathway. Mechanistically, manganese decreases HBV transcription by diminishing the levels of liver-specific transcription factors. Furthermore, it activates the mTOR pathway, enhancing HBsAg ubiquitination through the upregulation of the ubiquitin ligase ß-TrCP and increasing proteasome activity via the augmentation of its subunits, leading to a ubiquitin-dependent degradation of HBsAg. Significantly, our study also uncovers a notable clinical correlation between manganese levels and chronic hepatitis B infection. These findings position manganese as a critical element in diminishing HBV replication, offering a new direction in the management of chronic hepatitis B.

IL-17A activates JAK/STAT signaling to affect drug metabolizing enzymes and transporters in HepaRG cells.

The founding family member, Interleukin (IL)-17A, is commonly known as IL-17 and has garnered increasingly attention for proinflammatory functions in autoimmune disorders. Although the effects of IL-17A on hepatic important drug-metabolizing enzymes and transporters (DMETs) expression still remain unclear, it is critical to ascertain owing to the well-established alterations of the drug disposition capacity of the liver occurring during immune imbalance. The present study was designed to explore the effects and mechanisms of IL-17A on DMETs mRNA and protein expression in HepaRG cells by real-time quantitative reverse transcription polymerase chain reaction and Western blot, respectively. It is discovered that IL-17A can inhibit most DMETs mRNA expression (drug-metabolizing enzymes of CYP1A2, CYP3A4, CYP2C9, CYP2C19, GSTA1 and UGT1A1 and transporters of NTCP, OCT1, OATP1B1, BCRP and MDR1) as well as the protein expression of CYP3A4 and CYP2C19, via the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. Thus, abnormal regulation of DMETs in IL-17A-mediated immune disorders such as psoriasis may cause alterations in pharmacokinetic processes and may occasionally result in unexpected drug-drug interactions (DDIs) in clinical practice.

Mesenchymal Stem/Stromal cells in solid tumor Microenvironment: Orchestrating NK cell remodeling and therapeutic insights.

Mesenchymal stem/stromal cells (MSCs), originating from normal tissues, possess the capacity to home to tumor sites and differentiate into tumor-associated MSCs (TA-MSCs), which are instrumental in shaping an immunosuppressive milieu within tumors. Natural killer (NK) cells, integral to the innate immune system, are endowed with the ability to eradicate target cells autonomously, serving as an immediate defense against neoplastic growths. Nonetheless, within the tumor microenvironment (TME), NK cells often exhibit a decline in both their numerical presence and functionality. TA-MSCs have been shown to exert profound inhibitory effects on the functions of tumor-infiltrating immune cells, notably NK cells. Understanding the mechanisms by which TA-MSCs contribute to NK cell dysfunction is critical for the advancement of immune surveillance and the enhancement of tumoricidal responses. This review summarizes existing literature on NK cell modulation by TA-MSCs within the TME and proposes innovative strategies to augment antitumor immunity.

Identifying optimal serum 1,3-ß-D-Glucan cut-off for diagnosing Pneumocystis Jirovecii Pneumonia in non-HIV patients in the intensive care unit.

BACKGROUND: Serum (1,3)-ß-D-glucan (BDG) detection for diagnosis of Pneumocystis jirovecii pneumonia (PJP) in non-human immunodeficiency virus (HIV) immunocompromised patients lacks intensive care unit (ICU)-specific data. We aimed to assess its performance and determine the optimal cutoff for PJP in ICU population. METHODS: This retrospective study included critically ill non-HIV immunocompromised patients admitted to a medical ICU with suspected pneumonia, undergoing simultaneous microbiological testing for P. jirovecii on lower respiratory tract specimens and serum BDG. Confounders affecting BDG positivity were explored by multivariable logistic regression. Optimal cut-offs were derived from Youden's index for the entire cohort and subgroups stratified by confounders. Diagnostic performance of serum BDG was estimated at different cutoffs. RESULTS: Of 400 patients included, 42% were diagnosed with PJP and 58.3% had positive serum BDG. Serum BDG's area under the receiver operating characteristic curve was 0.90 (0.87-0.93). At manufacturer's 150 pg/ml cut-off, serum BDG had high sensitivity and negative predictive value (94%), but low specificity and positive predictive value (67%). Confounders associated with a positive serum BDG in PJP diagnosis included IVIG infusion within 3 days (odds ratio [OR] 9.24; 95% confidence interval [CI] 4.09-20.88, p < 0.001), other invasive fungal infections (OR 4.46; 95% CI 2.10-9.49, p < 0.001) and gram-negative bacteremia (OR 29.02; 95% CI 9.03-93.23, p < 0.001). The application of optimal BDG cut-off values determined by Youden's index (252 pg/ml, 390 pg/ml, and 202 pg/ml) specific for all patients and subgroups with or without confounders improved the specificity (79%, 74%, and 88%) and corresponding PPV (75%, 65%, and 85%), while maintaining reasonable sensitivity and NPV. CONCLUSIONS: Tailoring serum BDG cutoff specific to PJP and incorporating consideration of confounders could enhance serum BDG's diagnostic performance in the ICU settings.

New record of Miniopterusmagnater (Chiroptera, Miniopteridae) from south-western China and a comparative study of three species of Miniopterus in China.

Background: This research documents a new record of Miniopterusmagnater in the south-western region of China, a significant discovery given the limited diversity of the Miniopterus genus within the country. Only three species of Miniopterus occur in China: Miniopterusmagnater, Miniopterusfuliginosus and Miniopteruspusillus. These species share a high degree of morphological similarity, particularly in their external characteristics. This underscores the necessity for the identification of additional distinguishing traits that can aid in the taxonomic differentiation of these closely-related species. New information: During the 2023 field expedition to various nature reserves in Yunnan Province, China, we encountered specimens of the genus Miniopterus. Utilising a combination of morphological assessments and phylogenetic analyses, we identified six individuals as Miniopterusmagnater. A review of the existing geographical distribution data revealed that this species is primarily found in central and southern regions of China, with no previous records from the south-western part of the country. Based on our findings, we present a novel record of Miniopterusmagnater's distribution in the south-western region of China.

Prospective Study on the Association Between Blood Heavy Metal Levels and Pulmonary Function in University Students from a Medical College in Shandong Province, China.

Background: This study aimed to examine the blood concentrations of selected heavy metals, their corresponding pulmonary functions, and their interrelationship with university students. Methods: This prospective study, conducted from September 2019 to September 2020, encompassed 593 university students. Participants completed self-administered questionnaires regarding demographic factors and underwent lung function testing and blood mercury analysis at two distinct intervals: an initial assessment and a follow-up examination. Pulmonary function was assessed using Forced Vital Capacity, Forced Expiratory Volume in one second, and Peak Expiratory Flow. The blood concentrations of various heavy metals were determined through inductively coupled plasma mass spectrometry. Results: Notable disparities in pulmonary function emerged among university students when categorized by gender, Body Mass Index, physical activity, and seafood consumption frequency, all showing statistical significance (p<0.05). Blood levels of Pb, Mn, Co, and Ni exhibited diverse patterns and extents of correlation with pulmonary function (p<0.05 in each instance). Specifically, a positive correlation was observed with blood Pb levels, while Mn, Co, and Ni levels were inversely correlated with pulmonary function (p<0.01 for both observations). Conclusion: This study uncovered significant and complex relationships between the blood concentrations of individual heavy metals and pulmonary function in university students. These findings highlight the need for further research to elucidate these associations in greater detail.

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.

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.