Novel perspectives on autophagy-oxidative stress-inflammation axis in the orchestration of adipogenesis.

Adipose tissue, an indispensable organ, fulfils the pivotal role of energy storage and metabolism and is instrumental in maintaining the dynamic equilibrium of energy and health of the organism. Adipocyte hypertrophy and adipocyte hyperplasia (adipogenesis) are the two primary mechanisms of fat deposition. Mature adipocytes are obtained by differentiating mesenchymal stem cells into preadipocytes and redifferentiation. However, the mechanisms orchestrating adipogenesis remain unclear. Autophagy, an alternative cell death pathway that sustains intracellular energy homeostasis through the degradation of cellular components, is implicated in regulating adipogenesis. Furthermore, adipose tissue functions as an endocrine organ, producing various cytokines, and certain inflammatory factors, in turn, modulate autophagy and adipogenesis. Additionally, autophagy influences intracellular redox homeostasis by regulating reactive oxygen species, which play pivotal roles in adipogenesis. There is a growing interest in exploring the involvement of autophagy, inflammation, and oxidative stress in adipogenesis. The present manuscript reviews the impact of autophagy, oxidative stress, and inflammation on the regulation of adipogenesis and, for the first time, discusses their interactions during adipogenesis. An integrated analysis of the role of autophagy, inflammation and oxidative stress will contribute to elucidating the mechanisms of adipogenesis and expediting the exploration of molecular targets for treating obesity-related metabolic disorders.

A real-world pharmacovigilance study of polatuzumab vedotin based on the FDA adverse event reporting system (FAERS).

Background: Polatuzumab vedotin, the first FDA-approved antibody-drug conjugate (ADC) targeting CD79b, is utilized in the treatment of previously untreated diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), as well as relapsed or refractory (R/R) DLBCL. Despite its approval, concerns persist regarding the long-term safety profile of polatuzumab vedotin. This study aims to evaluate the adverse events (AEs) associated with polatuzumab vedotin since its approval in 2019, utilizing data mining strategies applied to the FDA Adverse Event Reporting System (FAERS). Methods: Signal detection employed four methodologies, including reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS), to evaluate and quantify the signals of polatuzumab vedotin-associated AEs. Additionally, subgroup analyses based on patients age, gender, and fatal cases were conducted to investigate AEs occurrences in specific subpopulations. Results: A total of 1,521 reports listing polatuzumab vedotin as a "principal suspect (PS)" drug were collected from the FAERS database. Through concurrent compliance with four algorithms, 19 significant Standardized MedDRA Query (SMQ) AEs and 92 significant Preferred Term (PT) AEs were detected. Subgroup analyses revealed a higher incidence of PTs in male patients compared to female patients, increased likelihood of polatuzumab vedotin-associated AEs in elder patients (>65 years), and AEs with a high risk of fatal cases include: blood lactate dehydrogenase increased, cytopenia, and hydronephrosis. The median time to AEs occurrence following polatuzumab vedotin initiation was 18.5 (5∼57.75) days, with 95% of AEs occurred within 162 days. Conclusion: This study identified various AEs associated with polatuzumab vedotin, offering critical insights for clinical monitoring and risk identification in patients receiving polatuzumab vedotin therapy.

Stockpiling turf alters microbial carbon and nitrogen use efficiency on the Tibetan Plateau.

Microbial carbon use efficiency (CUE) and nitrogen use efficiency (NUE) are crucial parameters reflecting soil C and N sequestration. Concerns about how artificial activities disturb alpine meadow ecosystem are increasing, but the knowledge of variances in microbial CUE and NUE in response to turf storage remains scarce. Here, we conducted a turf storage experiment on the Tibetan Plateau with two common storage methods, laying turfs method (LT) and stacking turfs method (ST). Plant litter, aboveground and belowground biomass declined considerably in the LT and ST than those in natural meadow. Soil pH and available phosphorus were significantly lower, but soil organic carbon, total nitrogen, dissolved organic carbon, and available nitrogen were substantially higher in stored turfs (both ST and LT) than in natural meadow. These results led to a differentiation in nutrient status among treatments. Vetor model indicated a stronger C limitation (vector length > 0.61) in ST than that in the LT and a shift from N to P limitation (vector angle >55°) in all stored turfs. Microbial CUE was prominently higher in the LT than those in the ST, signifying that microbes allocated more exogenous C to self-growth in the LT. Microbial NUE declined considerably in stored turfs, indicating a great proportion of N used for catabolic process instead of anabolic process. Microbial CUE and NUE were tightly linked to nutrient content and availability, enzymatic stoichiometry, microbial traits and plant biomass. Our results suggest that variations in microbial CUE and NUE were indirectly regulated by soil physicochemical properties via mediating nutrient imbalance and enzymatic stoichiometry in stored turfs.

Targeting the transmembrane cytokine co-receptor neuropilin-1 in distal tubules improves renal injury and fibrosis.

Neuropilin-1 (NRP1), a co-receptor for various cytokines, including TGF-ß, has been identified as a potential therapeutic target for fibrosis. However, its role and mechanism in renal fibrosis remains elusive. Here, we show that NRP1 is upregulated in distal tubular (DT) cells of patients with transplant renal insufficiency and mice with renal ischemia-reperfusion (I-R) injury. Knockout of Nrp1 reduces multiple endpoints of renal injury and fibrosis. We find that Nrp1 facilitates the binding of TNF-α to its receptor in DT cells after renal injury. This signaling results in a downregulation of lysine crotonylation of the metabolic enzyme Cox4i1, decreases cellular energetics and exacerbation of renal injury. Furthermore, by single-cell RNA-sequencing we find that Nrp1-positive DT cells secrete collagen and communicate with myofibroblasts, exacerbating acute kidney injury (AKI)-induced renal fibrosis by activating Smad3. Dual genetic deletion of Nrp1 and Tgfbr1 in DT cells better improves renal injury and fibrosis than either single knockout. Together, these results reveal that targeting of NRP1 represents a promising strategy for the treatment of AKI and subsequent chronic kidney disease.

HiTE: a fast and accurate dynamic boundary adjustment approach for full-length transposable element detection and annotation.

Recent advancements in genome assembly have greatly improved the prospects for comprehensive annotation of Transposable Elements (TEs). However, existing methods for TE annotation using genome assemblies suffer from limited accuracy and robustness, requiring extensive manual editing. In addition, the currently available gold-standard TE databases are not comprehensive, even for extensively studied species, highlighting the critical need for an automated TE detection method to supplement existing repositories. In this study, we introduce HiTE, a fast and accurate dynamic boundary adjustment approach designed to detect full-length TEs. The experimental results demonstrate that HiTE outperforms RepeatModeler2, the state-of-the-art tool, across various species. Furthermore, HiTE has identified numerous novel transposons with well-defined structures containing protein-coding domains, some of which are directly inserted within crucial genes, leading to direct alterations in gene expression. A Nextflow version of HiTE is also available, with enhanced parallelism, reproducibility, and portability.

Picrasma quassioides leaves: Insights from chemical profiling and bioactivity comparison with stems.

BACKGROUND: In Chinese Pharmacopeia, Picrasma quassioides (PQ) stems and leaves are recorded as Kumu with antimicrobial, anti-cancer, anti-parasitic effects, etc. However, thick stems are predominantly utilized as medicine in many Asian countries, with leaves rarely used. By now, the phytochemistry and bioactivity of PQ leaves are not well investigated. METHODS: An Orbitrap Elite mass spectrometer was employed to comprehensively investigate PQ stems and leaves sourced from 7 different locations. Additionally, their bioactivities were evaluated against 5 fungi, 6 Gram-positive bacteria and 9 Gram-negative bacteria, a tumor cell line (A549), a non-tumor cell line (WI-26 VA4) and N2 wild-type Caenorhabditis elegans. RESULTS: Bioassay results demonstrated the efficacy of both leaves and stems against tumor cells, several bacteria and fungi, while only leaves exhibited anthelmintic activity against Caenorhabditis elegans. A total of 181 compounds were identified from PQ stems and leaves, including 43 ß-carbolines, 20 bis ß-carbolines, 8 canthinone alkaloids, 56 quassinoids, 12 triterpenoids, 13 terpenoid derivatives, 11 flavonoids, 7 coumarins, and 11 phenolic derivatives, from which 10 compounds were identified as indicator components for quality evaluation. Most alkaloids and triterpenoids were concentrated in PQ stems, while leaves exhibited higher levels of quassinoids and other carbohydrate (CHO) components. CONCLUSION: PQ leaves exhibit distinct chemical profiles and bioactivity with the stems, suggesting their suitability for medicinal purposes. So far, the antibacterial, antifungal, and anthelmintic activities of PQ leaves were first reported here, and considering PQ sustainability, the abundant leaves are recommended for increased utilization, particularly for their rich content of PQ quassinoids.

Comparison of the efficacy and safety of vertebroplasty with different pedicle approaches for osteoporotic vertebral.

OBJECTIVE: To compare the efficacy and safety of vertebroplasty through different pedicle approaches in the treatment of osteoporotic vertebral compression fracture osteoporotic vertebral compression fractures (OVCF) by network meta-analysis. METHODS: Pubmed, Embase, Cochrane Library, Web of Science. Database for literature retrieval, retrieval time from the establishment of the database to April 2023, the randomized controlled trials of unilateral vertebroplasty (UVP), bilateral vertebroplasty (BVP), unilateral kyphoplasty (UKP), bilateral kyphoplasty (BKP), curved vertebroplasty (CVP) and curved kyphoplasty (CKP) were screened, evaluated and the data were extracted and included in the analysis. STATA 15.0 and ReMan 5.3 were used for data analysis. This study was registered in the National Institute for Health Research (NIHR) with the registration number CRD42023405181. RESULTS: This study included 16 articles with a total of 1712 patients. The order of visual analogue scale (VAS) improvement from good to bad is CVP > BVP > UVP > CKP > BKP > UKP. The order of kyphotic angles improvement from good to bad is CKP > UKP > UKP > UVP > BVP > CVP. The order of bone cement injection from less to more is UVP > CVP > UKP > CKP > BVP > BKP. The order of bone cement leakage rate from less to more is CKP > CVP > UKP > BKP > UVP > BVP. The order of X-ray exposure time from less to more is CKP > CVP > UVP > BVP > UKP > BKP. The order of operation time from less to more is CVP > UVP > UKP > CKP > BVP > BKP. CONCLUSION: For patients with kyphotic angles, kyphoplasty has unique advantages in improving kyphotic angles. But generally speaking, curved approach can optimize the distribution of bone cement through unilateral approach to achieve the orthopedic effect of bilateral approach, which is a minimally invasive technique with better curative effect and higher safety in the treatment of OVCF.

Study on the treatment of dysphagia after stroke with electromyographic biofeedback intensive training.

BACKGROUND: Dysphagia, or swallowing disorder, is a common complication following stroke, significantly impacting patients' quality of life. Electromyographic biofeedback (EMGBF) therapy has emerged as a potential rehabilitation technique to improve swallowing function, but its efficacy in comparison with conventional treatments remains to be further explored. AIM: To investigate the effects of different treatment intensities of EMGBF on swallowing function and motor speed after stroke. METHODS: The participants were divided into three groups, all of which received routine neurological drug therapy and motor function rehabilitation training. On the basis of routine swallowing disorder training, the EMGBF group received additional EMGBF training, while the enhanced EMGBF group received two additional training sessions. Four weeks before and after treatment, the degree of swallowing disorder was evaluated using the degree of swallowing disorder score (VGF) and the Rosenbek penetration-aspiration scale (PAS). RESULTS: Initially, there was no significant difference in VGF and PAS scores among the groups (P > 0.05). After four weeks, all groups showed significant improvement in both VGF scores and PAS scores. Furthermore, the standardized swallowing assessment and videofluoroscopic dysphagia scale scores also improved significantly post-treatment, indicating enhanced swallowing function and motor function of the hyoid-bone laryngeal complex, particularly in the intensive EMGBF group. CONCLUSION: EMGBF training is more effective than traditional swallowing training in improving swallowing function and the movement rate of the hyoid laryngeal complex in patients with post-stroke dysphagia.

Injectable Gelled Multiple Emulsion for Glucose-Responsive Insulin Delivery.

A glucose-responsive insulin delivery system that sustains blood glucose equilibrium for an extended duration can address the low therapeutic window of insulin in diabetes treatment. Herein, insulin is loaded in a water-in-oil-in-water (W1/O/W2) gelled multiple emulsion using poly (4-vinylphenylboronic acid) (PVPBA) homopolymer as an effective emulsifier. The gelled multiple emulsion exhibits a high encapsulation efficiency (99%), enhanced stability and remarkable shear-thinning behavior, making it easy to inject. Under hyperglycemic conditions, the gelled emulsion system instantly binds to glucose molecules and reduces the hydrogen bonds of the PVPBA homopolymer, resulting in insulin release. In a streptozotocin-induced type 1 diabetic mouse model, a single subcutaneous injection of the gelled emulsion rapidly responds to high blood glucose concentration (BGC) and release insulin in a glucose dependent manner, thus prolonging the antihyperglycemic effect compared with free insulin.

Utilizing bifurcated allogeneic vein grafts: a novel approach for preventing sinistral portal hypertension following Pancreaticoduodenectomy. a 10-year before and after study.

BACKGROUND: Sinistral portal hypertension (SPH) may occurs in patients with pancreatic carcinoma after pancreaticoduodenectomy (PD) with spleno-mesenterico-portal (S-M-P) cofluence resection. This study aimed to evaluate outcomes with the bifurcated allogeneic vein replacement in the prevention of SPH in pancreatic carcinoma patients. MATERIALS AND METHODS: A total of 81 patients were included. We retrospectively collected clinicopathological data from 66 patients underwent PD with S-M-P confluence resection in our hospital from Jan. 2011 to Dec. 2021, compared the correlation between different venous reconstruction methods using log-rank tests and clinical outcomes through univariate and multivariate analyses. Secondly, we prospectively collected clinical data and outcomes of 15 patients who underwent splenic vein reconstruction from Jan. 2021 to Jan. 2023. RESULTS: In the retrospective study, 43 cases received reconstruction by bifurcated allogeneic vein (Reconstruction group) and 23 cases received simply SV ligation (Ligation group). The preoperative platelet counts and spleen volume were similar between two groups (P>0.05). Nevertheless, at 1 month, 3 months and 6 months after operation, the related indexes of SPH such as platelet count, spleen volume, spleen volume ratio and esophagogastric varices (EGV) grade in Reconstruction group were better than those in Ligation group (P<0.05). 6 months after surgery, the incidence of SPH in Ligation group was significantly higher than in Reconstruction group (36.4% vs. 8.1%, respectively). In the prospective study, the incidence of SPH in patients undergoing SV reconstruction was 6.7% (1/15). CONCLUSION: Without compromising surgical outcomes, reconstruction of the S-M-P confluence by bifurcated allogeneic vein is a better method to avoid SPH in patients with advanced pancreatic carcinoma.

A transcriptional cascade involving BBX22 and HY5 finely regulates both plant height and fruit pigmentation in citrus.

Dwarfing is a pivotal agronomic trait affecting both yield and quality. Citrus species exhibit substantial variation in plant height, among which internode length is a core element. However, the molecular mechanism governing internode elongation remains unclear. Here, we unveiled that the transcriptional cascade consisting of B-BOX DOMAIN PROTEIN 22 (BBX22) and ELONGATED HYPOCOTYL 5 (HY5) finely tunes plant height and internode elongation in citrus. Loss-of-function mutations of BBX22 in an early-flowering citrus (Citrus hindsii "SJG") promoted internode elongation and reduced pigment accumulation, whereas ectopic expression of BBX22 in SJG, sweet orange (C. sinensis), pomelo (C. maxima) or heterologous expression of BBX22 in tomato (Solanum lycopersicum) significantly decreased internode length. Furthermore, exogenous application of gibberellin A3 (GA3) rescued the shortened internode and dwarf phenotype caused by BBX22 overexpression. Additional experiments revealed that BBX22 played a dual role in regulation internode elongation and pigmentation in citrus. On the one hand, it directly bound to and activated the expression of HY5, GA metabolism gene (GA2 OXIDASE 8, GA2ox8), carotenoid biosynthesis gene (PHYTOENE SYNTHASE 1, PSY1) and anthocyanin regulatory gene (Ruby1, a MYB DOMAIN PROTEIN). On the other hand, it acted as a cofactor of HY5, enhancing the ability of HY5 to regulate target genes expression. Together, our results reveal the critical role of the transcriptional cascade consisting of BBX22 and HY5 in controlling internode elongation and pigment accumulation in citrus. Unraveling the crosstalk regulatory mechanism between internode elongation and fruit pigmentation provides key genes for breeding of novel types with both dwarf and health-beneficial fortification in citrus.

Resting-state dynamic functional connectivity in major depressive disorder: A systematic review.

As a novel measure, dynamic functional connectivity (dFC) provides insight into the dynamic nature of brain networks and their interactions in resting-state, surpassing traditional static functional connectivity in pathological conditions such as depression. Since a comprehensive review is still lacking, we then reviewed forty-five eligible papers to explore pathological mechanisms of major depressive disorder (MDD) from perspectives including abnormal brain regions and functional networks, brain state, topological properties, relevant recognition, along with longitudinal studies. Though inconsistencies could be found, common findings are: (1) From different perspectives based on dFC, default-mode network (DMN) with its subregions exhibited a close relation to the pathological mechanism of MDD. (2) With a corrupted integrity within large-scale functional networks and imbalance between them, longer fraction time in a relatively weakly-connected state may be a possible property of MDD concerning its relation with DMN. Abnormal transition frequencies between states were correlated to the severity of MDD. (3) Including dynamic properties in topological network metrics enhanced recognition effect. In all, this review summarized its use for clinical diagnosis and treatment, elucidating the non-stationary of MDD patients' aberrant brain activity in the absence of stimuli and bringing new views into its underlying neuro mechanism.

Prognostic Assessment in Patients With Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Using MRI-Based Radiomics.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) carries a poor prognosis. Radiomics may hold potential value in prognostic assessment. PURPOSE: To develop and validate an MRI-based radiomics model and combine it with clinical factors to assess progression-free survival (PFS) and overall survival (OS) of patients with PCNSL. STUDY TYPE: Retrospective and prospective. POPULATION: Three hundred seventy-nine patients (179 female, 53 ± 7 years) from 2014 to 2022. FIELD STRENGTH/SEQUENCE: T2/fluid-attenuated inversion recovery, contrast-enhanced T1WI and diffusion-weighted echo-planar imaging sequences on 3.0 T. ASSESSMENT: Radiomics features were extracted from enhanced tumor regions on preoperative multi-sequence MRI. Using a least absolute shrinkage and selection operator (LASSO) Cox regression model to select radiomic signatures in training cohort (N = 169). Cox proportional hazards models were constructed for clinical, radiomics, and combined models, with internal (N = 72) and external (N = 32) cohorts validating model performance. STATISTICAL TESTS: Chi-squared, Mann-Whitney, Kaplan-Meier, log-rank, LASSO, Cox, decision curve analysis, time-dependent Receiver Operating Characteristic, area under the curve (AUC), and likelihood ratio test. P-value <0.05 was considered significant. RESULTS: Follow-up duration was 28.79 ± 22.59 months (median: 25). High-risk patients, determined by the median radiomics score, showed significantly lower survival rates than low-risk patients. Compared with NCCN-IPI, conventional imaging and clinical models, the combined model achieved the highest C-index for both PFS (0.660 internal, 0.802 external) and OS (0.733 internal, 0.781 external) in validation. Net benefit was greater with radiomics than with clinical alone. The combined model exhibited performance with AUCs of 0.680, 0.752, and 0.830 for predicting 1-year, 3-year, and 5-year PFS, and 0.770, 0.789, and 0.863 for OS in internal validation, with PFS AUCs of 0.860 and 0.826 and OS AUCs of 0.859 and 0.748 for 1-year and 3-year survival in external validation. DATA CONCLUSION: Incorporating a multi-sequence MR-based radiomics model into clinical models enhances the assess accuracy for the prognosis of PCNSL. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Effect of Cyclic Ice Plug Deformation on Microstructure and Mechanical Behaviors of Nuclear-Grade Low-Carbon Tubular Steel.

This study subjected nuclear-grade 20# pipeline steel to cyclic freeze-thaw ice plugging tests, simulating the plastic deformation experienced by pipes during ice plug removal procedures. Subsequently, the dislocation morphology and mechanical properties of the specimens post cyclic ice plugging were examined. The cyclic ice plugging process led to an increase in the dislocation density within the specimens. After 20 and 40 cycles of ice plugging, the internal dislocation structures evolved from individual dislocation lines and dislocation tangles to high-density dislocation walls and dislocation cells. These high-density dislocation walls and cells hindered dislocation motion, giving rise to strain hardening phenomena, thereby resulting in increased strength and hardness of the specimens with an increasing number of ice plugging cycles. In addition, a large stress field was generated around the dislocation buildup, which reduced the pipe material's plastic toughness. The findings elucidate the effects of cyclic ice plugging on the microstructure and properties of nuclear-grade 20# pipeline steel, aiming to provide a theoretical basis for the safe and stable application of ice plugging technology in nuclear piping systems.

Dams alter the control pattern of watershed land use to riverine nutrient distribution: Comparison of three major rivers under different hydropower development levels in Southwestern China.

Land use plays a critical role in managing water quality in a watershed, as it governs the import and distribution of nutrients. In addition to the land use, some rivers in Southwest China are encountering a new environmental stressor of damming, which is being driven by the national strategy of hydropower development. However, the coupling effect of land use and dams on nutrients remains poorly understood, challenging the effective management of riverine water quality. Therefore, this study examined the nutrients in the Nu, Yarlung Tsangpo (YT), and Lancang (LC) Rivers, which have no dam, 1 dam, and 11 dams, respectively, during different regulatory periods (spring and fall) to identify variations in nutrient control patterns influenced by land use and dams. The findings suggested that an increase in hydropower development contributed to a notable shift in nutrient patterns from land use regulation towards dam regulation and coupling effects. Land use dominated the nutrient variations of the Nu (27.4 %-32.8 %) and low hydropower development YT (25.2 %-30.9 %) Rivers during both seasons, but the primary contributors to the nutrient variations of the high hydropower development LC River were dams (17.9 %-41.6 %) and coupling effects (16.5 %-29.0 %). Dams transform nutrient levels and compositions through internal reservoir cycling, decoupling land use and nutrients. Partial least-squares structural equation model analysis further suggested that the coupling effects of the LC River were seasonal-specific, which was primarily attributed to hydrological variations that affected their interactions. During spring, the reservoir underwent a drainage mode characterized by high-level nutrients in the bottom water. Combined with the import of riverine nutrients, it exacerbated the increase of nutrients (synergistic effect). In contrast, the reservoir transitioned into a storage mode where it intercepted nutrients from the upstream and watershed during the fall, leading to a reduction in the previously observed increasing trend and an increase in nutrient variability (antagonism effect).

Revealing the Synergistic Effect of Cation and Anion Vacancies on Enhanced Fenton-Like Reaction: The Electron Density Modulation of O 2p-Co 3d Bands.

Defect engineering is considered as a flexible and effective mean to improve the performance of Fenton-like reactions. Herein, a simple method is employed to synthesize Co3O4 catalysts with Co-O vacancy pairs (VP) for peroxymonosulfate (PMS) activation. Multi-scaled characterization, experimental, and simulation results jointly revealed that the cation vacancies-VCo contributed to enhanced conductivity and anion vacancies-VO provided a new active center for the 1O2 generation. Co3O4-VP can optimize the O 2p and Co 3d bands with the strong assistance of synergistic double vacancies to reduce the reaction energy barrier of the "PMS → Co(IV) = O → 1O2" pathway, ultimately triggering the stable transition of mechanism. Co3O4-VP catalysts with radical-nonradical collaborative mechanism achieve the synchronous improvement of activity and stability, and have good environmental robustness to favor water decontamination applications. This result highlights the possibility of utilizing anion and cation vacancy engineering strategies to rational design Co3O4-based materials widely used in catalytic reactions.

Disrupted dynamic brain functional connectivity in male cocaine use disorder: Hyperconnectivity, strongly-connected state tendency, and links to impulsivity and borderline traits.

Cocaine use is a major public health problem with serious negative consequences at both the individual and societal levels. Cocaine use disorder (CUD) is associated with cognitive and emotional impairments, often manifesting as alterations in brain functional connectivity (FC). This study employed resting-state functional magnetic resonance imaging (rs-fMRI) to examine dynamic FC in 38 male participants with CUD and 31 matched healthy controls. Using group spatial independent component analysis (group ICA) combined with sliding window approach, we identified two recurring distinct connectivity states: the strongly-connected state (state 1) and weakly-connected state (state 2). CUD patients exhibited significant increased mean dwell and fraction time in state 1, and increased transitions from state 2 to state 1, demonstrated significant strongly-connected state tendency. Our analysis revealed abnormal FC patterns that are state-dependent and state-shared in CUD patients. This study observed hyperconnectivity within the default mode network (DMN) and between DMN and other networks, which varied depending on the state. Furthermore, after adjustment for multiple comparisons, we found significant correlations between these altered dynamic FCs and clinical measures of impulsivity and borderline personality disorder. The disrupted FC and repetitive effects of precuneus and angular gyrus across correlations suggested that they might be the important hub of neural circuits related behaviorally and mentally in CUD. In summary, our study highlighted the potential of these disrupted FC as neuroimaging biomarkers and therapeutic targets, and provided new insights into the understanding of the neurophysiologic mechanisms of CUD.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Comparison of Aroma and Taste Profiles of Kiwi Wine Fermented with/without Peel by Combining Intelligent Sensory, Gas Chromatography-Mass Spectrometry, and Proton Nuclear Magnetic Resonance.

Kiwi wine (KW) is tipically made by fermenting juice from peeled kiwifruit, resulting in the disposal of peel and pomace as by-products. However, the peel contains various beneficial compounds, like phenols and flavonoids. Since the peel is edible and rich in these compounds, incorporating it into the fermentation process of KW presents a potential solution to minimize by-product waste. This study compared the aroma and taste profiles of KW from peeled (PKW) and unpeeled (UKW) kiwifruits by combining intelligent sensory technology, GC-MS, and 1H-NMR. Focusing on aroma profiles, 75 volatile organic compounds (VOCs) were identified in KW fermented with peel, and 73 VOCs in KW without peel, with 62 VOCs common to both. Among these compounds, rose oxide, D-citronellol, and bornylene were more abundant in UKW, while hexyl acetate, isoamyl acetate, and 2,4,5-trichlorobenzene were significantly higher in PKW. For taste profiles, E-tongue analysis revealed differences in the taste profiles of KW from the two sources. A total of 74 molecules were characterized using 1H-NMR. UKW exhibited significantly higher levels of tartrate, galactarate, N-acetylserotonin, 4-hydroxy-3-methoxymandelate, fumarate, and N-acetylglycine, along with a significantly lower level of oxypurinol compared to PKW. This study seeks to develop the theoretical understanding of the fermentation of kiwifruit with peel in sight of the utilization of the whole fruit for KW production, to increase the economic value of kiwifruit production.