Inter-subject dynamic conditional correlation: A novel method to track the framewise network implication during naturalistic stimuli.

BACKGROUND: Naturalistic stimuli have become increasingly popular in modern cognitive neuroscience. These stimuli have high ecological validity due to their rich and multi-layered features. However, their complexity also presents methodological challenges for uncovering neural network reconfiguration. Dynamic functional connectivity using the sliding-window technique is commonly used but has several limitations. In this study, we introduce a new method called inter-subject dynamic conditional correlation (ISDCC). METHOD: ISDCC employs inter-subject analysis to remove intrinsic and non-neuronal signals, retaining only inter-subject-consistent stimuli-induced signals. It then applies dynamic conditional correlation (DCC) based on the generalized autoregressive conditional heteroskedasticity to calculate the framewise functional connectivity. To validate ISDCC, we analyzed simulation data with known network reconfiguration patterns and two publicly available narrative fMRI datasets. RESULTS: 1) ISDCC accurately unveiled the underlying network reconfiguration patterns in simulation data, demonstrating greater sensitivity than DCC; 2) ISDCC identified synchronized network reconfiguration patterns across listeners; 3) ISDCC effectively differentiated between stimulus types with varying temporal coherence; 4) network reconfigurations unveiled by ISDCC were significantly correlated with listener engagement during narrative comprehension. CONCLUSION: ISDCC is a precise and dynamic method for tracking network implications in response to naturalistic stimuli.

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.

Comprehensive analysis of the effects of the traditional stir-fry process on the dynamic changes of volatile metabolites in Hainan camellia oil.

The traditional stir-fry process before pressing is crucial to manufacture Hainan camellia oil. To assess the effects of the stir-fry process on Hainan camellia oil, six samples across different stir-fry stages were analyzed. The stir-fry process modified odors, volatile metabolite profiles, and human health-promoting functions of Hainan camellia oil. Totally, 350 volatile metabolites were detected, and heterocyclic compounds were revealed as the main contributors of strong aroma. Potential indicators for monitoring the stir-fry degree were established. Eight key aroma volatile metabolites were identified, including three new ones (1-octen-3-one, 2,3-butanedione, and vanillin). Lipids degradation and the Millard reaction are probably the main pathways for aroma generation. Over-stir-fry treatment diminished the contents of some important volatile metabolites but increased the risk of arising burnt odor. Our work offered insights into the effects of the stir-fry process and over-stir-fry treatment on Hainan camellia oil, which is meaningful for improving the hot-pressing technique.

Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke: a special outlook on mitochondrial delivery.

Ischemic stroke is a secondary cause of mortality worldwide, imposing considerable medical and economic burdens on society. Extracellular vesicles, serving as natural nano-carriers for drug delivery, exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke. However, the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency. By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles, their delivery efficacy may be greatly improved. Furthermore, previous studies have indicated that microvesicles, a subset of large-sized extracellular vesicles, can transport mitochondria to neighboring cells, thereby aiding in the restoration of mitochondrial function post-ischemic stroke. Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components, such as proteins or deoxyribonucleic acid, or their sub-components, for extracellular vesicle-based ischemic stroke therapy. In this review, we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies. Given the complex facets of treating ischemic stroke, we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process. Moreover, given the burgeoning interest in mitochondrial delivery, we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Transcriptomic and multi-cytokines profile analysis revealed new insights into the integrating mechanisms of cyanidin-3-O-glucoside on male reproductive damage amelioration.

Ulcerative colitis is a public health issue with a rising worldwide incidence. It has been found that current medications for treating UC may cause varying degrees of damage to male fertility. Our previous study demonstrated that cyanidin-3-O-glucoside (C3G) treatment could effectively restore reproductive damage in a mouse model of DSS induced colitis. However, the underlying mechanism of C3G alleviates UC induced male reproductive disorders remain scarce. The aim of this study is to discover the molecular mechanisms of C3G on the amelioration of UC stimulated reproductive disorders. The targeted genes toward UC-induced reproductive injury upon C3G treatments were explored by transcriptomic analysis. Hematological analysis, histopathological examination, and real time transcription-polymerase chain reaction (RT-PCR) analysis were applied for conjoined identification. Results showed that C3G may effectively target for reducing pro-inflammatory cytokine IL-6 in testis through cytokine-cytokine receptor interaction pathway. Transcriptome sequencing found that a series of genetic pathways involved in the protective effects of C3G on male reproduction were identified by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Further results presented that C3G could effectively restore mRNA expression levels of Ly6a and Col1a1, closely linked with UC induced male reproductive damage pathways. Sufficient results implied that Ly6a and Col1a1 may be treated as the promising therapeutic targets for the mechanism of C3G in treating UC induced reproductive impairment. C3G administration might be an effective dietary supplementation strategy for male reproduction improvement.

The effect of Ba Duan Jin exercise intervention on cardiovascular disease: a meta-analysis of randomized controlled trials.

Background: There is a growing interest in the use of complementary therapies for the prevention of disease and the maintenance of health. Furthermore, complementary therapies that incorporate exercise are becoming increasingly prevalent among the older adult, and thus may represent a crucial strategy for the primary and secondary prevention of cardiovascular disease (CVD). Exercise therapy, as a means to prevent and treat cardiovascular diseases, has been gradually applied in clinical practice. It has the advantages of reducing mortality, improving clinical symptoms, restoring physical function and improving quality of life. In recent years, traditional Chinese sports such as Ba Duan Jin and Qigong have developed rapidly. Therefore, a comprehensive systematic review is required to examine interventions involving Ba Duan Jin exercise in healthy adults or those at increased risk of CVD in order to determine the effectiveness of Ba Duan Jin exercise for the primary prevention of CVD. Objective: To investigate the effect of Ba Duan Jin exercise intervention for the primary prevention of cardiovascular diseases. Methods: Eight databases were systematically searched from inception to July, 2024 for randomized controlled trials (RCTs) to evaluated the impact of Ba Duan Jin exercise intervention on cardiovascular diseases. The search terms were "Cardiovascular diseases" "Ba Duan Jin" and "Randomized controlled." The Cochrane risk assessment tool was used to evaluate the study quality, and the meta-analysis was performed using Rev. Man 5.4 software. Results: Seventeen completed trials were conducted with 1,755 participants who were randomly assigned and met the inclusion criteria. All 17 studies were conducted in China. The meta-analysis indicates that Ba Duan Jin exercise therapy can provide long-term benefits (20-30 years) by reducing all-cause mortality (RR = 0.55, 95% CI: 0.44-0.68, p < 0.01) and stroke mortality (RR = 0.49, 95% CI: 0.36-0.66, p < 0.01) in hypertensive patients. Subgroup analyses reveal that Ba Duan Jin exercise therapy decreases SBP (MD = -4.05, 95% CI = -6.84 to -1.26, p < 0.01) and DBP (MD = -3.21, 95% CI = -5.22 to -1.20, p < 0.01) levels in patients with essential hypertension, significantly reduces serum TC (MD = -0.78, 95% CI = -1.06 to -0.50, p < 0.01), TG (MD = -0.78, 95% CI = -0.93 to -0.62, p < 0.01), and LDL-C (MD = -0.76, 95% CI = -0.92 to -0.60, p < 0.01) levels in patients with hyperlipidemia, increases HDL-C (MD = 0.32, 95% CI = 0.14-0.51, p < 0.01) levels, and produces beneficial effects on cardiovascular function. Additionally, it can alleviate anxiety (MD = -3.37, 95% CI = -3.84 to -2.89, p < 0.01) and improve sleep quality (MD = -2.68, 95% CI = -3.63to -1.73, p < 0.01). Conclusion: Ba Duan Jin exercise therapy can improve the physical and mental condition and quality of life of patients with cardiovascular diseases, and it is worthy of further promotion and application in clinical practice. Systematic review registration: PROSPERO, identifier: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024496934.

Multifunctional strain-activated liquid-metal composite films with electromechanical decoupling for stretchable electromagnetic shielding.

The increasing miniaturization and intelligence of flexible electronic devices pose a challenge to the facile and scalable fabrication of multifunctional stretchable electromagnetic interference (EMI) shielding films with strain-stable shielding effectiveness (SE). This paper presents a highly stretchable liquid metal/thermoplastic polyurethane (LM/TPU) composite film produced via a facile method of scraping and pre-stretching induced activation. The TPU matrix endows the activated LM/TPU (ALMT) film with excellent tensile properties (elongation at break >700%), and the stable and malleable three-dimensional conductive LM network enables the ALMT film to exhibit almost negligible resistance changes and strain-enhanced conductivity during stretching, resulting in excellent strain-insensitive far-field and near-field shielding capabilities. Moreover, the high EMI SE up to ∼60 dB in the tensile state (0-400%) and reduced thickness from ∼75 to ∼50 µm during stretching allow the SE/thickness values of the ALMT film to increase from ∼700 to ∼1200 dB mm-1, outperforming most of the reported LM/polymer composites. Furthermore, the stretchability of the ALMT film provides efficient Joule-heating performance even under substantial deformation, and it can also serve as a strain sensor for real-time monitoring of human motion. The strain-insensitive EMI shielding behavior as well as the outstanding Joule heating and sensing performance of the ALMT film renders it a promising candidate for next-generation flexible electronic devices.

Quantitative ternary network-oriented discovery of Q-markers from traditional Chinese medicine prescriptions: Bu-Zhong-Yi-Qi-Tang as a case study.

BACKGROUND: The proposal of Q-markers for traditional Chinese medicine (TCM) represents a novel avenue of research pertaining to the quality control of TCM prescriptions. However, prior exploratory studies on Q-markers with multiple properties consistently neglected the consideration of weights, hampering our ability to accurately gauge the significance of each property and potentially leading to a flawed comprehension of Q-markers. PURPOSE: In this study, a quantitative ternary network strategy was firstly proposed to visually discover the Q-markers from TCM prescriptions, and it has been successfully applied into the quality control study of Bu-Zhong-Yi-Qi-Tang (BZYQT), a classical TCM prescription. METHODS: Firstly, the contents of 34 components in BZYQT, along with the kinetic features of 17 candidate Q-markers in biosamples (plasma and small intestinal contents), were characterized by UPLC-QqQ-MS/MS, and their immunomodulatory activities in macrophages and splenic lymphocytes were also assessed. Next, the obtained data were integrated into three properties: testability, bioavailability, effectiveness, and their weights were calculated using the entropy weight method to further establish a ternary network for quantitatively screening Q-markers. Subsequently, the identified Q-markers of BZYQT were utilized for the holistic quality evaluation of 36 batches of the commercial BZYQT preparation, Bu-Zhong-Yi-Qi-Pill (BZYQP) produced by three manufacturers, through similarity evaluation of the Q-marker-based fingerprint. RESULTS: Nine compounds (hesperidin, astragaloside IV, ononin, 18ß-glycyrrhizic acid, narirutin, calycosin, cimigenoside, astragaloside II, and liquiritin) showing three core properties, including testability, bioavailability, and effectiveness, were screened out as Q-markers of BZYQT based on their rankings in terms of regression area of the ternary network. Employing Q-markers as common peaks, the similarity values of 36 batches BZYQP ranged 0.914-0.998 under HPLC-UVD mode, and 0.631-1.000 under HPLC-ELSD mode, which were less than the similarity values evaluated by the conventional common peaks (HPLC-UVD mode: 0.946-0.990; HPLC-ELSD mode: 0.957-0.997). This observation suggests that the identified Q-markers are more representative as common peaks in chromatographic fingerprints for the holistic quality evaluation of TCM-related products from different manufacturers. CONCLUSION: The quantitative discovery of Q-markers from BZYQT laid an important foundation for holistic quality assessment of its related commercially available products, and our work offering a new strategy for ensuring the consistency and efficacy of TCM prescriptions.

Precipitation contributes to alleviating pollution of rubber-derived chemicals in receiving watersheds: Combining confluent stormwater runoff from different functional areas.

The release of rubber-derived chemicals (RDCs) in road surface runoff has received significant attention. Urban surface runoff is often the confluence of stormwater runoff from specific areas. However, the impact of precipitation on RDCs contamination in confluent stormwater runoff and receiving watersheds remains poorly understood. Herein, we investigated the profiles of RDCs and their transformation products in confluent stormwater runoff and receiving rivers affected by precipitation events. The results showed that 34 RDCs are ubiquitously present in confluent stormwater runoff and surface water, with mean concentrations of 1.03-2749 and 0.28-436 ng/L, respectively. The most dominant target compounds in each category were N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), 6PPD-quinone, 2-benzothiazolol, and 1,3-diphenylguanidine. Total RDCs concentrations in confluent stormwater runoff decreased spatially from industrial areas to business districts to college towns. A significant decrease in RDCs levels in surface water after rainfall was observed (P < 0.01), indicating that precipitation contributes to alleviating RDCs pollution in receiving watersheds. To our knowledge, this is the first report of N,N'-ditolyl-p-phenylenediamine quinone (DTPD-Q) levels in surface waters in China. The annual mass load of ∑RDCs reached 72,818 kg/y in confluent stormwater runoff, while 38,799 kg/y in surface water. The monitoring of confluent stormwater runoff is an efficient measure for predicting contamination loads from RDCs in rivers. Risk assessment suggested that most RDCs posed at least medium risks to aquatic organisms, especially 6PPD-quinone. The findings help to understand the environmental fate and risks of RDCs in the confluent stormwater runoff and receiving environments after precipitation events.

Genotypic and phenotypic characteristics of Acinetobacter baumannii isolates from the people's hospital of Qingyang City, Gansu province.

BACKGROUND: Acinetobacter baumannii (A. baumannii) is a common opportunistic pathogen in hospitals that causes nosocomial infection. In order to understand the phenotypic and genotypic characteristics of A. baumannii isolates, we sequenced and analyzed 62 A. baumannii isolates from a hospital in Gansu province. RESULTS: Non-repeated 62 A. baumannii isolates were collected from August 2015 to November 2021. Most isolates (56/62) were resistant to multiple drugs. All the 62 A. baumannii isolates were resistant to aztreonam and contained blaADC-25 gene which exists only on chromosome contigs. The 62 isolates in this study were not clustered in a single clade, but were dispersed among multiple clades in the common genome. Seven sequence types were identified by Multilocus sequence type (MLST) analysis and most isolates (52/62) belonged to ST2. The plasmids were grouped into 11 clusters by MOB-suite. CONCLUSIONS: This study furthers the understanding of A. baumannii antimicrobial-resistant genotypes, and may aid in prevention and control nosocomial infection caused by drug-resistant A. baumannii.

Modifying Parallel Excitations into One Framework for C(sp3)─H Bond Activation with Energy Combined More Than Two Photons.

Natural photosynthesis enzymes utilize energies of several photons for challenging oxidation of water, whereas artificial photo-catalysis typically involves only single-photon excitation. Herein, a multiphoton excitation strategy is reported that combines parallel photo-excitations with a photoinduced electron transfer process for the activation of C(sp3)─H bonds, including methane. The metal-organic framework Fe3-MOF is designed to consolidate 4,4',4″-nitrilotrisbenzoic units for the photoactivation of dioxygen and trinuclear iron clusters as the HAT precursor for photoactivating alkanes. Under visible light irradiation, the dyes and iron clusters absorbed parallel photons simultaneously to reach their excited states, respectively, generating 1O2 via energy transfer and chlorine radical via ligand-to-metal charge transfer. The further excitation of organic dyes leads to the reduction of 1O2 into O2 •- through a photoinduced electron transfer, guaranteeing an extra multiphoton oxygen activation manner. The chlorine radical abstracts a hydrogen atom from alkanes, generating the carbon radical for further oxidation transformation. Accordingly, the total oxidation conversion of alkane utilizing three photoexcitation processes combines the energies of more than two photons. This new platform synergistically combines a consecutive excited photoredox organic dye and a HAT catalyst to combine the energies of more than two photons, providing a promising multiphoton catalysis strategy under energy saving, and high efficiency.

A review of the biological activities of lactoferrin: mechanisms and potential applications.

Lactoferrin, a multifunctional iron-binding protein found in milk and other body fluids, possesses numerous biological activities. The functional activity of lactoferrin lies not only in its iron-binding capacity but also in the molecular mechanisms by which it can affect important chemical components in the host. However, the molecular mechanisms underlying these activities remain unelucidated. In this paper, we review the structure, properties, and contents of different lactoferrin milk sources. The different biological activities, namely antibacterial, antiviral, immunomodulatory, anti-inflammatory, bone regeneration, and improved metabolic disorder bioactivities, and the associated potential mechanisms of lactoferrin are summarized with the aim of providing a reference for the development of lactoferrin-related products.

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review.

Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V2/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V2/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V2/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

Deep decarbonization potential and implementation path under provincial differences in China's fleet electrification.

Fleet electrification is considered to be an important measure for reducing carbon emissions in the road transport industry. Considering the heterogeneity of the NEV market penetration and the vehicle types in different provinces, how to design targeted and time-sequenced road transport decarbonisation reduction strategies has become a key issue that needs to be discussed urgently. In this study, the NEVs ownership in China's 31 provinces is used as an intermediate variable. Considering the process of energy transition and changes in vehicle structure, a two-layer scenario framework that combines Shared Socioeconomic Pathways scenarios and model structure was developed to predict carbon emissions. This study firstly analyzes the electrification process and carbon emission reduction potential of provincial road transport industry by region, vehicle type and stage. The potential for reducing carbon emissions was determined under benchmark, transition, and electrification scenarios. The results indicate that the Pearson Correlation Coefficient-Discrete Wavelet Transform-Bidirectional Long Short-term Memory prediction model has an mean absolute percentage error of 8.583 and an R-squared of 0.975. China's road transportation industry total carbon emissions will reach its peak as early as 2027, due to the rapid implementation of renewable energy and fleet electrification. Shanghai, Jiangsu, Shandong, Henan, and Guangdong have set carbon peak targets that can be achieved faster with the transition plan for new energy vehicles to replace fossil fuel vehicles. This paper proposes a timing-responsive deep decarbonization path and policy recommendations for China's road transport industry in sub provincial and time-series settings.

Peptidome profiling of human, bovine, and donkey colostrum through label-free quantitative analysis reveals proteolysis of milk proteins.

Proteins and peptides play vital roles in different biological processes in vivo. As a dynamic hydrolysis system, milk is rich in proteins and proteases and provides a constant supply of endogenous bioactive peptides to newborn mammals. Previous studies have primarily focused on researching bioactive peptides by adding exogenous enzymes to milk samples. However, such an approach overlooks the significance of endogenous peptides and parent proteins that naturally exist in milk. Herein, we analyzed and compared parent proteins and their releasing peptides in human colostrum (HC), bovine colostrum (BC), and donkey colostrum (DC). The predominant proteins and hydrolyzed peptides in the three types of milk were identified. Among them, peptides were found to possess common bioactivities, including ACE inhibitory, antioxidant, antibacterial and immunomodulatory properties in HC, BC, and DC. Furthermore, the biological functions of these parent proteins were clarified using bioinformatics. These insights offer a novel perspective on natural bioactive peptides and the potential utilization of specific parent proteins and peptides to develop infant formulae derived from diverse milk sources.

Ameliorating and refining islet organoids to illuminate treatment and pathogenesis of diabetes mellitus.

Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D) culture model, closely mimics tissues or organs in vivo. Insulin-secreting islet organoid, derived from stem cells induced in vitro with 3D structures, has emerged as a potential alternative for islet transplantation and as a possible disease model that mirrors the human body's in vivo environment, eliminating species difference. This technology has gained considerable attention for its potential in diabetes treatment. Despite advances, the process of stem cell differentiation into islet organoid and its cultivation demonstrates deficiencies, prompting ongoing efforts to develop more efficient differentiation protocols and 3D biomimetic materials. At present, the constructed islet organoid exhibit limitations in their composition, structure, and functionality when compared to natural islets. Consequently, further research is imperative to achieve a multi-tissue system composition and improved insulin secretion functionality in islet organoid, while addressing transplantation-related safety concerns, such as tumorigenicity, immune rejection, infection, and thrombosis. This review delves into the methodologies and strategies for constructing the islet organoid, its application in diabetes treatment, and the pivotal scientific challenges within organoid research, offering fresh perspectives for a deeper understanding of diabetes pathogenesis and the development of therapeutic interventions.

A bispecific antibody exhibits broad neutralization against SARS-CoV-2 Omicron variants XBB.1.16, BQ.1.1 and sarbecoviruses.

The Omicron subvariants BQ.1.1, XBB.1.5, and XBB.1.16 of SARS-CoV-2 are known for their adeptness at evading immune responses. Here, we isolate a neutralizing antibody, 7F3, with the capacity to neutralize all tested SARS-CoV-2 variants, including BQ.1.1, XBB.1.5, and XBB.1.16. 7F3 targets the receptor-binding motif (RBM) region and exhibits broad binding to a panel of 37 RBD mutant proteins. We develop the IgG-like bispecific antibody G7-Fc using 7F3 and the cross-neutralizing antibody GW01. G7-Fc demonstrates robust neutralizing activity against all 28 tested SARS-CoV-2 variants and sarbecoviruses, providing potent prophylaxis and therapeutic efficacy against XBB.1 infection in both K18-ACE and BALB/c female mice. Cryo-EM structure analysis of the G7-Fc in complex with the Omicron XBB spike (S) trimer reveals a trimer-dimer conformation, with G7-Fc synergistically targeting two distinct RBD epitopes and blocking ACE2 binding. Comparative analysis of 7F3 and LY-CoV1404 epitopes highlights a distinct and highly conserved epitope in the RBM region bound by 7F3, facilitating neutralization of the immune-evasive Omicron variant XBB.1.16. G7-Fc holds promise as a potential prophylactic countermeasure against SARS-CoV-2, particularly against circulating and emerging variants.

Protein phosphatase SCP4 regulates cartilage development and endochondral osteogenesis via FoxO3a dephosphorylation.

The regulatory mechanisms involved in embryonic development are complex and yet remain unclear. SCP4 represents a novel nucleus-resident phosphatase identified in our previous study. The primary aim of this study was to elucidate the function of SCP4 in the progress of cartilage development and endochondral osteogenesis. SCP4-/- and SCP4Col2ER mice were constructed to assess differences in bone formation using whole skeleton staining. ABH/OG staining was used to compare chondrocyte differentiation and cartilage development. Relevant biological functions were analysed using RNA-sequencing and GO enrichment, further validated by immunohistochemical staining, Co-IP and Western Blot. Global SCP4 knockout led to abnormal embryonic development in SCP4-/- mice, along with delayed endochondral osteogenesis. In parallel, chondrocyte-specific removal of SCP4 yielded more severe embryonic deformities in SCP4Col2ER mice, including limb shortening, reduced chondrocyte number in the growth plate, disorganisation and cell enlargement. Moreover, RNA-sequencing analysis showed an association between SCP4 and chondrocyte apoptosis. Notably, Tunnel-positive cells were indeed increased in the growth plates of SCP4Col2ER mice. The deficiency of SCP4 up-regulated the expression levels of pro-apoptotic proteins both in vivo and in vitro. Additionally, phosphorylation of FoxO3a (pFoxO3a), a substrate of SCP4, was heightened in chondrocytes of SCP4Col2ER mice growth plate, and the direct interaction between SCP4 and pFoxO3a was further validated in chondrocytes. Our findings underscore the critical role of SCP4 in regulating cartilage development and endochondral osteogenesis during embryonic development partially via inhibition of chondrocytes apoptosis regulated by FoxO3a dephosphorylation.

Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy.

Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.