Photoswitchable dynamics and RNAi synergist with tailored interface and controlled release reprogramming tumor immunosuppressive niche.

Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.

Emergency department clinical performance of ADVIA Centaur n-terminal prohormone of B-type natriuretic peptide assay.

BACKGROUND: Natriuretic peptide testing is guideline recommended as an aid to the diagnosis of heart failure (HF). We sought to evaluate the performance of the ADVIA Centaur (Siemens Healthcare Diagnostics, Tarrytown, NY) NT-proBNPII assay (PBNPII) in emergency department (ED) dyspneic patients. METHODS: Eligible patients presented to the ED with dyspnea, with their gold standard diagnosis determined by up to 3 cardiologists blinded to the PBNPII results. Patients were stratified into 3 groups based on PBNPII resultsa rule out group of NT-proBNP<300  pg/mL, an age-specific rule in group using cutoffs of 450, 900, and 1800 pg/mL, for <50, 50-75, and > 75 years respectively, and an intermediate cohort for results between the rule out and rule in groups. RESULTS: Of 3128 eligible patients, 1148 (36.7 %) were adjudicated as acute heart failure (AHF). The gold standard AHF diagnosis rate was 3.7, 24.3, and 67.2 % for patients with NTproBNPII in the negative, indeterminate, and positive groups, respectively. Overall likelihood ratios (LR) were 0.07 (95 % CI: 0.05,0.09), 0.55 (0.45,0.67), and 3.53 (3.26,3.83) for the same groups, respectively. Individual LR+for age dependent cutoffs were 5.01 (4.25,5.91), 3.71 (3.25,4.24), and 2.38 (2.10,2.69), respectively. NTproBNPII increased with increasing severity of HF when stratified by NYHA classification. CONCLUSIONS: The ADVIA Centaur PBNPII assay demonstrates acceptable clinical performance using the recommended single rule out and age dependent rule in cutoffs for an AHF diagnosis in dyspneic ED patients.

Regulatory mechanism of C4-dicarboxylates in cyclo (Phe-Pro) production.

Cyclo (Phe-Pro) (cFP), a cyclic dipeptide with notable antifungal, antibacterial, and antiviral properties, shows great promise for biological control of plant diseases. Produced as a byproduct by non-ribosomal peptide synthetases (NRPS), the regulatory mechanism of cFP biosynthesis remains unclear. In a screening test of 997 Tn5 mutants of Burkholderia seminalis strain R456, we identified eight mutants with enhanced antagonistic effects against Fusarium graminearum (Fg). Among these, mutant 88's culture filtrate contained cFP, confirmed through HPLC and LC-MS, which actively inhibited Fg. The gene disrupted in mutant 88 is part of the Dct transport system (Dct-A, -B, -D), responsible for C4-dicarboxylate transport. Knockout mutants of Dct genes exhibited higher cFP levels than the wild type, whereas complementary strains showed no significant difference. Additionally, the presence of exogenous C4-dicarboxylates reduced cFP production in wild type R456, indicating that these substrates negatively regulate cFP synthesis. Given that cFP synthesis is related to NRPS, we previously identified an NRPS cluster in R456, horizontally transferred from algae. Specifically, knocking out gene 2061 within this NRPS cluster significantly reduced cFP production. A Fur box binding site was predicted upstream of gene 2061, and yeast one-hybrid assays confirmed Fur protein binding, which increased with additional C4-dicarboxylates. Knockout of the Fur gene led to up-regulation of gene 2061 and increased cFP production, suggesting that C4-dicarboxylates suppress cFP synthesis by enhancing Fur-mediated repression of gene 2061.

The Development and Application of KinomePro-DL: A Deep Learning Based Online Small Molecule Kinome Selectivity Profiling Prediction Platform.

Characterizing the kinome selectivity profiles of kinase inhibitors is essential in the early stages of novel small-molecule drug discovery. This characterization is critical for interpreting potential adverse events caused by off-target polypharmacology effects and provides unique pharmacological insights for drug repurposing development of existing kinase inhibitor drugs. However, experimental profiling of whole kinome selectivity is still time-consuming and resource-demanding. Here, we report a deep learning classification model using an in-house built data set of inhibitors against 191 well-representative kinases constructed based on a novel strategy by systematically cleaning and integrating six public data sets. This model, a multitask deep neural network, predicts the kinome selectivity profiles of compounds with novel structures. The model demonstrates excellent predictive performance, with auROC, prc-AUC, Accuracy, and Binary_cross_entropy of 0.95, 0.92, 0.90, and 0.37, respectively. It also performs well in a priori testing for inhibitors targeting different categories of proteins from internal compound collections, significantly improving over similar models on data sets from practical application scenarios. Integrated to subsequent machine learning-enhanced virtual screening workflow, novel CDK2 kinase inhibitors with potent kinase inhibitory activity and excellent kinome selectivity profiles are successfully identified. Additionally, we developed a free online web server, KinomePro-DL, to predict the kinome selectivity profiles and kinome-wide polypharmacology effects of small molecules (available on kinomepro-dl.pharmablock.com). Uniquely, our model allows users to quickly fine-tune it with their own training data sets, enhancing both prediction accuracy and robustness.

BAFF promotes follicular helper T cell development and germinal center formation through BR3 signal.

T follicular helper (Tfh) cells represent an important subset of CD4+ T cells that is crucial to the maturation and differentiation of B cells and the production of high-affinity antibodies. Since BAFF, a vital B cell survival factor, is also crucial to B cell maturation and differentiation, we assessed the effects of BAFF on Tfh cell development and function. We demonstrate that deficiency of BAFF, but not of APRIL, markedly inhibits Tfh cell development, germinal center (GC) formation, and antigen-specific antibody production. The promoting effect of BAFF on Tfh cell development is dependent on expression of BR3 on T cells, and its promoting effect on GC formation is dependent on expression of BR3 on both T cells and B cells. BAFF directly promotes expression of the Tfh cell-characteristic genes via NF-κB signaling. This effect does need BR3 expression. Thus, BAFF not only has direct effects on B cells, but it also has direct effects on Tfh cell differentiation via engagement of BR3 which collectively promote GC formation and production of high-affinity antibodies. This dual effect of BAFF on B cells and Tfh cells may help explain the clinical utility of BAFF antagonists in the management of certain autoimmune diseases.

Evidence and potential mechanism of action of indigo naturalis and its active components in the treatment of psoriasis.

BACKGROUND: Indigo naturalis is effective against psoriasis. Indigo, indirubin and tryptanthrin, the main active components of indigo naturalis, have anti-inflammatory properties. OBJECTIVE: To evaluate the efficacy and safety of indigo naturalis and its active components in the treatment of psoriasis. METHODS: Seven databases were searched for studies of indigo naturalis and its active components for the treatment of psoriasis. RESULTS: The findings demonstrated a higher response rate in the Chinese herbal medicine (CHM) formula groups than in the control group for Psoriasis Area and Severity Index 60 (PASI60) (Rate difference [RD] = 0.22, p < .0001). Among all adverse events, only the incidence of gastrointestinal adverse reactions was higher in the CHM formula group than in the control group (RD = 0.09, p < .0001). In preclinical in vivo studies, indirubin showed better performance in improving the phenotype of psoriasis-like mice compared to that in controls, including the PASI score (mean difference [MD] = -3.58, p < .0001), epidermal thickness (MD = -29.13, p < .0001), interleukin-(IL) 17 A mRNA expression (MD = -2.27, p = .0066) and IL-23 mRNA (MD = -5.36, p = .01). CONCLUSION: Indigo naturalis combined with conventional treatments is useful for treating psoriasis. Indigo naturalis display anti-proliferative, anti-inflammatory and anti-angiogenic effects by regulating the TAK1, JAK3/STAT3, Wnt/ß-catenin, Akt/PKB, FAK and AP-1/c-Jun pathway.

Indigo naturalis, a Chinese herb and its main active components, indigo, indirubin and tryptanthrin are effective in treating psoriasis.Indigo naturalis, indirubin, indigo and tryptanthrin have anti-proliferative, anti-inflammatory and anti-angiogenic effects via regulating the TAK1, JAK3/STAT3, Wnt/ß-catenin, Akt/PKB, FAK and AP-1/c-Jun pathways.

Photoinduction of Ferroptosis and cGAS-STING Activation by a H2S-Responsive Iridium(III) Complex for Cancer-Specific Therapy.

Triggering ferroptosis represents a promising anticancer therapeutic strategy, but the development of a selective ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a H2S-responsive iridium(III) complex NA-Ir has been well-designed as a ferroptosis inducer. NA-Ir could selectively light up H2S-rich cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher anticancer activity under light irradiation. Mechanistic studies showed that NA-Ir-mediated PDT triggered lipid peroxidation and glutathione peroxidase 4 downregulation through ROS production and GSH depletion, resulting in ferroptosis through multiple pathways. Moreover, the intense mtDNA damage can activate the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway, leading to ferritinophagy and further ferroptosis. RNA-sequencing analysis showed that NA-Ir-mediated PDT mainly affects the expression of genes related to ferroptosis, autophagy, and cancer immunity. This study demonstrates the first cancer-specific example with ferroptosis and cGAS-STING activation, which provides a new strategy for multimodal synergistic therapy.

Ankrd1 regulates endogenous cardiac regeneration in mice by modulating cyclin D1.

Restoration of the expression of factors regulating neonatal heart regeneration in the adult heart can promote myocardial repair. Therefore, investigations of the regulatory factors that play key roles in neonatal heart regeneration are urgently needed for the development of cardiac regenerative therapies. In our previous study, we identified ankyrin repeat domain 1 (Ankrd1) through multiomics analysis in a neonatal mouse model of cardiac regeneration and hypothesized that Ankrd1 plays a regulatory role in neonatal heart regeneration. In the present study, we aimed to determine the role of Ankrd1 in neonatal heart regeneration and adult myocardial repair. Our findings confirmed that Ankrd1 could mediate cardiomyocyte proliferation and that Ankrd1 knockdown in cardiomyocytes inhibited myocardial regeneration after apical resection in neonatal mice. Furthermore, we found that cardiomyocyte-specific Ankrd1 overexpression promoted cardiac repair and cardiac function recovery after adult myocardial infarction (MI). Mechanistically, Ankrd1 could regulate the cell cycle of cardiomyocytes and significantly mediate cardiac regeneration, at least in part, through cyclin D1. Overall, our study demonstrates that Ankrd1 is an effective target for achieving cardiac repair after MI, providing new ideas for the treatment of ischemic heart disease in the future.

Unraveling the effects of prenatal anesthesia on neurodevelopment: A review of current evidence and future directions.

Human brain development is a complex, multi-stage, and sensitive process, especially during the fetal stage. Animal studies over the last two decades have highlighted the potential risks of anesthetics to the developing brain, impacting its structure and function. This has raised concerns regarding the safety of anesthesia during pregnancy and its influence on fetal brain development, garnering significant attention from the anesthesiology community. Although preclinical studies predominantly indicate the neurotoxic effects of prenatal anesthesia, these findings cannot be directly extrapolated to humans due to interspecies variations. Clinical research, constrained by ethical and technical hurdles in accessing human prenatal brain tissues, often yields conflicting results compared to preclinical data. The emergence of brain organoids as a cutting-edge research tool shows promise in modeling human brain development. When integrated with single-cell sequencing, these organoids offer insights into potential neurotoxic mechanisms triggered by prenatal anesthesia. Despite several retrospective and cohort studies exploring the clinical impact of anesthesia on brain development, many findings remain inconclusive. As such, this review synthesizes preclinical and clinical evidence on the effects of prenatal anesthesia on fetal brain development and suggests areas for future research advancement.

Shenqi Pill alleviates acetaminophen-induced liver injury: a comprehensive strategy of network pharmacology and spectrum-effect relationship reveals mechanisms and active components.

BACKGROUND: Acetaminophen (APAP), commonly used for its antipyretic and analgesic properties, can cause severe liver injury or even acute liver failure when overdosed. However, the options for treating APAP-induced liver toxicity are limited. Shenqi Pill (SQP), a traditional Chinese herbal formula, has shown effectiveness in treating various liver ailments. SQP consists of cinnamon, aconite, rehmannia, cornus, peony bark, Chinese yam, poria, and alisma in a ratio of 1:1:8:4:3:4:3:3. However, the mechanisms and active components of SQP that counteract drug-induced liver injury (DILI) are not well understood. PURPOSE: This study aimed to explore the protective effects of SQP against APAP-induced liver injury in both laboratory and animal settings. It seeks to identify the active components and potential mechanisms by which SQP targets mitochondria to alleviate liver damage. METHODS: A mouse model with APAP-induced liver injury was established to assess SQP's therapeutic impact. This study then analyzed the components of SQP using UPLC-Q-TOF-MS in both in vivo and in vitro environments. Network pharmacology and the GEO database helped predict potential pathways and targets. Potential active components were identified through spectrum-effect relationship analysis and validated their efficacy using Seahorse assays and molecular docking. RESULTS: Treatment with SQP significantly reduced liver dysfunction, tissue damage, lipid metabolic disruptions, and inflammation caused by APAP in mice. In cellular tests, SQP-treated serum notably enhanced mitochondrial function, maintained membrane potential, decreased ROS levels, and prevented mitochondrial permeability transition pore opening. Biochemically, SQP reversed the suppression of p-AMPK, p-ACC, CPT1, and ACADM expression caused by APAP overdose. This study identified 97 in vitro and 24 in vivo components of SQP, with eight showing significant mitochondrial benefits. Molecular docking studies suggest that fuziline and paeoniflorin could activate AMPK. CONCLUSION: SQP effectively mitigates APAP-induced liver injury by enhancing mitochondrial function via the AMPK-ACC-CPT1-ACADM pathway. Moreover, this study introduces a novel strategy for analyzing the relationship between the chemical and pharmacological properties of drug-containing serum, successfully identifying compounds with mitochondrial activity. Fuziline and paeoniflorin, in particular, emerge as promising mitochondrial protectants and warrant further investigation. This research underpins the development of innovative treatments for DILI using SQP and its components.

Lonicera japonica Fermented by Lactobacillus plantarum Improve Multiple Patterns Driven Osteoporosis.

Osteoporosis (OP) represents a global health challenge. Certain functional food has the potential to mitigate OP. Honeysuckle (Lonicera japonica) solution has medicinal effects, such as anti-inflammatory and immune enhancement, and can be used in functional foods such as health drinks and functional snacks. The composition of honeysuckle changed significantly after fermentation, and 376 metabolites were enriched. In this study, we used dexamethasone to induce OP in the rat model. Research has confirmed the ability of FS (fermented Lonicera japonica solution) to enhance bone mineral density (BMD), repair bone microarchitectural damage, and increase blood calcium levels. Markers such as tartrate-resistant acid phosphatase-5b (TRACP-5b) and pro-inflammatory cytokines (TNF-α and IL-6) were notably decreased, whereas osteocalcin (OCN) levels increased after FS treatment. FS intervention in OP rats restored the abundance of 6 bacterial genera and the contents of 17 serum metabolites. The results of the Spearman correlation analysis showed that FS may alleviate OP by restoring the abundance of 6 bacterial genera and the contents of 17 serum metabolites, reducing osteoclast differentiation, promoting osteoblast differentiation, and reducing the inflammatory response. This study revealed that Lactobacillus plantarum-fermented honeysuckle alleviated OP through intestinal bacteria and serum metabolites and provided a theoretical basis for the development of related functional foods.

Genetically predicted the causal relationship between gut microbiota and the risk of polymyositis/dermatomyositis: a Mendelian randomization analysis.

Introduction: Observational studies suggest associations between gut microbiota and polymyositis (PM) and dermatomyositis (DM), but causal relationships are unclear. We investigate the causal effects of gut microbiota on PM and DM, providing insights hoping to provide insights for future treatment and prevention. Methods: Summary statistics of gut microbiota were obtained from a multi-ethnic Genome Wide Association Studies (GWAS) meta-analysis, including 119 taxa from 18,340 Europeans. PM/DM statistics were extracted from GWAS analyses. Mendelian randomization (MR) with IVW, MR-Egger, and weighted median methods was performed. Sensitivity analyses addressed heterogeneity and pleiotropy. Of the 119 bacterial genera studied, six showed causal links. Results: Alloprevotella (OR: 3.075, 95% CI: 1.127-8.386, p = 0.028), Ruminococcaceae UCG003 (OR: 4.219, 95% CI: 1.227-14.511, p = 0.022), Dialister (OR: 0.273, 95% CI: 0.077-0.974, p = 0.045) were associated with PM. Anaerotruncus (OR: 0.314, 95% CI: 0.112-0.882, p = 0.028), Ruminococcaceae UCG002 (OR: 2.439, 95% CI: 1.173-5.071, p = 0.017), Sutterella (OR: 3.392, 95% CI: 1.302-8.839, p = 0.012) were related to DM. Sensitivity analyses validated these associations. Discussion: We establish causal relationships between Ruminococcaceae, Sutterella, Anaerotruncus with DM, Alloprevotella, Ruminococcaceae UCG003, and Dialister with PM. Common microbiota, like Ruminococcaceae, have significant clinical implications. These findings open up greater possibilities for the gut microbiota to contribute to the development of PM/DM and for future monitoring of the gut microbiota in patients with PM/DM.

Optical switch with an ultralow DC drift based on thin-film lithium tantalate.

We present an electro-optic (EO) switch with ultralow DC drift on a thin-film lithium tantalate (TFLT) platform, even with SiO2 cladding and without post-annealing processes. The flat Vπ and EO responses have been measured across various driving frequencies, input optical powers, and temperatures. Stable optical switching is achievable in the low-frequency range. The experiment also demonstrated superior long-term stability (up to 2 h) compared to thin-film lithium niobate optical switches under similar on-chip optical power conditions (around -8 dBm).

Weakly-supervised Depth Estimation and Image Deblurring via Dual-Pixel Sensors.

Dual-pixel (DP) imaging sensors are getting more popularly adopted by modern cameras. A DP camera captures a pair of images in a single snapshot by splitting each pixel in half. Several previous studies show how to recover depth information by treating the DP pair as an approximate stereo pair. However, dual-pixel disparity occurs only in image regions with defocus blur which is unlike classic stereo disparity. Heavy defocus blur in DP pairs affects the performance of depth estimation approaches based on matching. Therefore, we treat the blur removal and the depth estimation as a joint problem. We investigate the formation of the DP pair, which links the blur and depth information, rather than blindly removing the blur effect. We propose a mathematical DP model that can improve depth estimation by the blur. This exploration motivated us to propose our previous work, an end-to-end DDDNet (DP-based Depth and Deblur Network), which jointly estimates depth and restores the image in a supervised fashion. However, collecting the ground-truth (GT) depth map for the DP pair is challenging and limits the depth estimation potential of the DP sensor. Therefore, we propose an extension of the DDDNet, called WDDNet (Weakly-supervised Depth and Deblur Network), which includes an efficient reblur solver that does not require GT depth maps for training. To achieve this, we convert all-in-focus images into supervisory signals for unsupervised depth estimation in our WDDNet. We jointly estimate an all-in-focus image and a disparity map, then use a Reblur and Fstack module to regularize the disparity estimation and image restoration. We conducted extensive experiments on synthetic and real data to demonstrate the competitive performance of our method when compared to state-of-the-art (SOTA) supervised approaches. Index Terms-Dual-pixel Sensor, Weakly-supervised, Depth Estimation, Deblur and Reblu.

Effect of different growth hormone pretreatment times in assisted reproductive therapy for patients with diminished ovarian reserve: A retrospective pilot cohort study.

This study aimed to evaluate the effect of different growth hormone (GH) pretreatment times in assisted reproductive therapy in patients with diminished ovarian reserve (DOR). A retrospective pilot cohort analysis was performed on patients with DOR receiving GH pretreatment in the Assisted Reproduction Unit of Sir Run Run Shaw Hospital. A total of 1459 patients met the criteria and were divided into four groups according to GH pretreatment time as follows: 53 were in the 2-month pretreatment group (GH1), 400 were in the 1-month pretreatment group (GH2), 414 were in the ovulation induction period pretreatment group (GH3), and 592 were in the non-GH pretreatment group (control group). In addition, GH1, GH2, and GH3 were combined in the GH pretreatment group. Baseline characteristics and treatment outcomes were compared between the groups. The number of oocytes retrieved in the GH pretreatment, GH1, GH2, and GH3 groups was significantly higher than that in the control group (all P < .01). The numbers of oocytes retrieved in the GH1 and GH2 groups were similar but were nominally higher than those in the GH3 group. Estradiol concentrations in the GH pretreatment, GH2, and GH3 groups were significantly higher than those in the control group on the day of human chorionic gonadotropin injection (all P < .01). In the GH1 group, 22 patients had >1 assisted reproductive therapy cycle (non-GH pretreatment) before GH pretreatment, and the number of oocytes retrieved in the GH pretreatment cycle was higher than that in the non-GH pretreatment cycle, but this was not significant. These findings suggest that the GH pretreatment time was appropriately prolonged, and the number of oocytes retrieved nominally increased. In patients with DOR, GH pretreatment improved treatment outcomes. More than 1 month of GH pretreatment did not increase the number of oocytes retrieved.

Single-stage resection of uterine fibroids and intravascular leiomyomatosis: a case report.

BACKGROUND: Uterine Fibroids (UFs) are common benign tumors in the female reproductive tract, but their progression to intravascular leiomyomatosis (IVL) is rare. Presently, there are few reports on single-stage resection of UFs and IVL. CASE PRESENTATION: A 47-year-old woman, G2P2, had been diagnosed multiple UFs four years ago and now developed heart failure. Imaging examinations revealed that UFs had invaded the right iliac vein and extended into the right atrium through the inferior vena cava. Through multidisciplinary collaboration and a single-stage resection, the patient has survived for over 24 months post-surgery, and her heart function has significantly improved compared to preoperative levels, with no recurrence of UFs observed. CONCLUSIONS: Single-stage resection of IVL and UF is feasible and advantageous for this case, and selecting the appropriate surgical approach is crucial.

Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform.

COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, CFP-1, that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5. By using this platform, we identified 2-aminothiazole-4-carboxylic acids as new CSN5 inhibitors, which inhibited CSN5 but slightly downregulated PD-L1 in cancer cells. Furthermore, through the integration of deep learning-enabled virtual screening, we discovered that shikonins are nanomolar CSN5 inhibitors, which can upregulate PD-L1 in HCT116 cells. The binding modes of these structurally distinct inhibitors with CSN5 were explored by using microsecond-scale molecular dynamics simulations and tryptophan quenching assays.

FLI1 in PBMCs contributes to elevated inflammation in combat-related posttraumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with significant public health implications that arise following exposure to traumatic events. Recent studies highlight the involvement of immune dysregulation in PTSD, characterized by elevated inflammatory markers. However, the precise mechanisms underlying this immune imbalance remain unclear. Previous research has implicated friend leukemia virus integration 1 (FLI1), an erythroblast transformation-specific (ETS) transcription factor, in inflammatory responses in sepsis and Alzheimer's disease. Elevated FLI1 levels in peripheral blood mononuclear cells (PBMCs) have been linked to lupus severity. Yet, FLI1's role in PTSD-related inflammation remains unexplored. In our study, PBMCs were collected from Veterans with and without PTSD. We found significantly increased FLI1 expression in PBMCs from PTSD-afflicted Veterans, particularly in CD4+ T cells, with no notable changes in CD8+ T cells. Stimulation with LPS led to heightened FLI1 expression and elevated levels of inflammatory cytokines IL-6 and IFNγ in PTSD PBMCs compared to controls. Knockdown of FLI1 using Gapmers in PTSD PBMCs resulted in a marked reduction in inflammatory cytokine levels, restoring them to control group levels. Additionally, co-culturing PBMCs from both control and PTSD Veterans with the human brain microglia cell line HMC3 revealed increased inflammatory mediator levels in HMC3. Remarkably, HMC3 cells co-cultured with PTSD PBMCs treated with FLI1 Gapmers exhibited significantly lower inflammatory mediator levels compared to control Gapmer-treated PTSD PBMCs. These findings suggest that suppressing FLI1 may rebalance immune activity in PBMCs and mitigate microglial activation in the brain. Such insights could provide novel therapeutic strategies for PTSD.

(Phosphino)(stannyl)carbene.

The synthesis of a (phosphino)(stannyl)carbene is documented. The combination of phosphino and stannyl substituents imparts a highly ambiphilic nature to this carbene, enabling reactions with cyanide, isocyanide, and carbon monoxide. This leads to rare stannylketenimines and a stannylketene.