Knowledge-based machine learning for predicting and understanding the androgen receptor (AR)-mediated reproductive toxicity in zebrafish.

Traditional methods for identifying endocrine-disrupting chemicals (EDCs) that activate androgen receptors (AR) are costly, time-consuming, and low-throughput. This study developed a knowledge-based deep neural network model (AR-DNN) to predict AR-mediated adverse outcomes on female zebrafish fertility. This model started with chemical fingerprints as the input layer and was implemented through a five-layer virtual AR-induced adverse outcome pathway (AOP). Results indicated that the AR-DNN effectively and accurately screens new reproductive toxicants (AUC = 0.94, accuracy = 0.85), providing potential toxicity pathways. Furthermore, 1477 and 2448 chemicals that could lead to infertility were identified in the plastic additives list (PLASTICMAP, n = 7112) and the Inventory of Existing Chemical Substances in China (IECSC, n = 17741), respectively. Colourants containing steroid-like structures are the major active plastic additives that might lower female zebrafish fertility through AR binding, DNA binding, and transcriptional activation. While active IECSC chemicals primarily have the same fragments, such as benzonitrile, nitrobenzene, and quinolone. The predicted toxicity pathways were consistent with existing fish evidence, demonstrating the model's applicability. This knowledge-based approach offers a promising computational toxicology strategy for predicting and characterising the endocrine-disrupting effects and toxic mechanisms of organic chemicals, potentially leading to more efficient and cost-effective screening of EDCs.

Designing of Airspeed Measurement Method for UAVs Based on MEMS Pressure Sensors.

Airspeed measurement is crucial for UAV control. To achieve accurate airspeed measurements for UAVs, this paper calculates airspeed data by measuring changes in air pressure and temperature. Based on this, a data processing method based on mechanical filtering and the improved AR-SHAKF algorithm is proposed to indirectly measure airspeed with high precision. In particular, a mathematical model for an airspeed measurement system was established, and an installation method for the pressure sensor was designed to measure the total pressure, static pressure, and temperature. Secondly, the measurement principle of the sensor was analyzed, and a metal tube was installed to act as a mechanical filter, particularly in cases where the aircraft has a significant impact on the gas flow field. Furthermore, a time series model was used to establish the sensor state equation and the initial noise values. It also enhanced the Sage-Husa adaptive filter to analyze the unavoidable error impact of initial noise values. By constraining the range of measurement noise, it achieved adaptive noise estimation. To validate the superiority of the proposed method, a low-complexity airspeed measurement device based on MEMS pressure sensors was designed. The results demonstrate that the airspeed measurement device and the designed velocity measurement method can effectively calculate airspeed with high measurement accuracy and strong interference resistance.

Characterization of the Alkali and Hydrolysis Resistance of Polymer-Impregnated, Alkali-Resistant Glass Filaments.

The aim of this series of tests was to characterize the alkali and water resistance of alkali-resistant (durability) glass filaments, which were optimized with two non-vulcanized formulations based on co-polymerizing styrene-butadiene rubbers (CemFil-SBR1 and CemFil-SBR2). Furthermore, it was assessed which of the two polymer-impregnated multifilament yarns is the better alternative for use in cementitious binders. For this purpose, the impregnated multifilament yarns were chemically conditioned for up to twelve months at temperatures of 23 and 50 °C in 2.5 percent sodium hydroxide solution and 2.5 percent potassium hydroxide solution as well as in 3 percent salt and distilled water. The samples were then subjected to material science tests. The liquid absorption capacities and the changes in the mass of the composite materials were determined at different times during conditioning. The load-bearing capacity of the samples was also tested using uniaxial fiber strand tensile tests. The durability of the polymer-impregnated multifilament yarns was described in detail in conjunction with scanning electron microscopy images and nominal cross-section determinations. The test liquids caused a reduction in strength during the storage period, which was accelerated by increased temperatures. The reduction in strength is mainly due to glass corrosion of the filaments. Glass corrosion is delayed due to the good impregnation quality, which fundamentally improves the durability of the yarns. The results of the durability tests show that the polymer-impregnated multifilament yarns CemFil-SBR2 are probably more suitable for use in cementitious binders, as they have better alkali and hydrolysis resistance.

Target-specific affinity separation of the bioactive compounds from herbal extract using the spin column packed with the immobilized protein microspheres prior to LC-MS analysis.

Excellent pretreatments before instrumental analysis are critical for separation and determination of target compounds for discovery of new drugs from herb medicines. We developed a rapid and highly-selective method to separate the bioactive compounds from herbal extract using protein affinity-selection spin column, which was packed with the new sorbent materials from integrating the recombinant ß2-adrenoceptor (ß2-AR) directly out of cell lysates onto the surface of microspheres. Protein affinity-selection spin column was placed in a centrifugal tube, where after the non-specific binders were released to the filtrate under the operational centrifugation, the specific binders on the spin column were cleaned with a washing solvent for LC-MS analysis. The known agonists of ß2-AR were retained/released on protein affinity-selection spin column but not on control column, demonstrating the method with good recovery (79.4∼95.7 %) and high repeatability (RSD < 3.5 %). The adsorption features of three ligands on the spin column were described best by Prism saturation binding model, and the high-affinity binding and the large binding capacity of the spin column make it feasible to trap the trace analytes effectively. It was applied in separating bioactive compounds from Alstoniae Scholaris extract, two of which were identified as picrinine and oleanolic acid in combination with LC-MS and verified as the potential agonists towards ß2-AR though molecular docking and cell experiments. Our study demonstrated that, the spin column with the immobilized protein sorbents in the centrifugal filter device represents a promising tool, enabling rapid and target-specific affinity separation of the bioactive compounds from herbal extract.

The use of virtual reality and augmented reality in ultrasound education, a narrative review of the literature.

Immersive virtual reality (IVR) and augmented reality (AR) are emerging technologies with significant potential in ultrasound education. IVR, utilizing head-mounted devices (HMDs), and AR, enhancing real-world views with digital overlays, have demonstrated their value in various educational and training scenarios. This narrative review examines the use of IVR and AR in ultrasound education, evaluating their effectiveness compared to traditional methods. Studies show that IVR and AR can match or surpass conventional training, offering benefits like standardized assessments and reduced costs. Despite some limitations, such as small sample sizes and potential conflicts of interest, the current data supports the viability of IVR and AR as tools for ultrasound education. Further research is needed to confirm these findings and explore broader applications.

Targeting the cancer cells and cancer-associated fibroblasts with next-generation FGFR inhibitors in prostate cancer co-culture models.

BACKGROUND: Inhibition of androgen receptor (AR) signaling is the main treatment strategy in advanced prostate cancer (PCa). A subset of castration resistant prostate cancer (CRPC) bypasses the AR blockade by increased fibroblast growth factor receptor (FGFR) signaling. The first- and second-generation, non-covalent FGFR inhibitors (FGFRis) have largely failed in the clinical trials against PCa. PURPOSE: In this study, we tested the drug sensitivity of LNCaP, VCaP, and CWR-R1PCa cell lines to second-generation, covalent FGFRis (FIIN1, FIIN2) and a novel FGFR downstream molecule inhibitor (FRS2αi). METHODS: 2D and 3D mono- and co-cultures of cancer cells, and cancer-associated fibroblasts (CAFs) were used to mimic tumor-stroma interactions in the extracellular matrix (ECM). The treatment responses of the FGFR signaling molecules, the viability and proliferation of cancer cells, and CAFs were determined through immunoblotting, migration assay, cell viability assay, and real-time imaging. Immunofluorescent and confocal microscopy images of control and treated cultures of cancer cells and CAFs, and their morphometric data were deduced. RESULTS: The FGFRis were more effective in mono-cultures of the cancer cells compared with co-cultures with CAFs. The FRS2αi was specifically effective in co-cultures with CAFs but was not cytotoxic to CAF mono-cultures as in the case of FIIN1 and FIIN2. At the molecular level, FRS2αi decreased p-FRS2α, p-ERK1/2, and activated apoptosis as monitored by cleaved caspase-3 activity in a concentration-dependent manner in the co-cultures. We observed no synergistic drug efficacy in the combination treatment of the FGFRi with ARi, enzalutamide, and darolutamide. The FRS2αi treatment led to a decrease in proliferation of cancer cell clusters in co-cultures as indicated by their reduced size and Ki67 expression. CONCLUSIONS: CAFs exert a protective effect on cancer cells and should be included in the in vitro models to make them physiologically more relevant in screening and testing of FGFRis. The FRS2αi was the most potent agent in reducing the viability and proliferation of the 3D organotypic co-cultures, mainly by disrupting the contact between CAFs and cancer cell clusters. The next-generation FGFRi, FRS2αi, may be a better alternative treatment option for overcoming ARi treatment resistance in advanced PCa.

Complement component 5a receptor 1 and leukotriene B4 receptor 1 regulate neutrophil extracellular trap (NET) formation through Rap1a/B-Raf/ERK signaling pathway and their deficiency in term low birth weight newborns leads to deficient NETosis.

BACKGROUND: Neutrophil extracellular traps (NETs) being one of the predominant activities of neutrophils has become its key defense mechanism owing to its extensive role in inflammation and infection. However, the mechanisms regulating NET formation or NETosis still remains to be better understood. Our earlier whole genome transcriptomic data revealed two G-protein couple receptors (GPCRs) - complement component 5a receptor 1 (C5aR1) and leukotriene B4 receptor 1 (LTB4R1) were downregulated in term low birth weight (tLBW) newborns with deficient NET formation abilities. Neutrophils employ C5aR1 and LTB4R1 for mediating their immune responses, inflammation and antimicrobial activity. Hence, this study was aimed to explore the role of two GPCRs, C5aR1 and LTB4R1 including their downstream signaling molecules in NETs induction and regulation. METHODS: The validation of the transcriptomic data for C5aR1 and LTB4R1 was done using quantitative real time PCR. Pharmacological inhibition of C5aR1 and LTB4R1 using W-54011 and LY223982 on neutrophils of adults and newborns' was done to study their impact on NETosis. Extracellular DNA release, Reactive oxygen species (ROS) generation, expression of NET proteins, and signaling molecules downstream to C5aR1 and LTB4R1 were quantified using plate reader based assay, immunofluorescence, and western blotting. Myeloperoxidase (MPO)-DNA quantified by flow cytometry. Knockdown studies using siRNA against C5aR1 and LTB4R1 were done in HL-60 cells derived surrogate neutrophils and expression of downstream molecules of the two GPCRs, C5aR1 and LTB4R1 signaling axis along with NET proteins was quantified by western blotting. RESULTS: The expression of C5aR1 and LTB4R1, extracellular DNA, ROS and NET associated proteins (NE, CitH3, PAD4 and MPO) was notably increased upon NET induction in healthy adults and normal birth weight (NBW) newborns' neutrophils. Pharmacological inhibition of these two GPCRs led to substantial reduction in NETosis, extracellular DNA, ROS generation, and expression of NET associated proteins like CitH3, NE, PAD4, MPO along with downstream signaling molecules Rap1a, B-Raf and pERK. Our observations suggest a precise role of C5aR1 and LTB4R1 on induction of NETs via Rap1a/B-Raf/ERK signaling axis. CONCLUSION: The C5aR1 and LTB4R1 signaling via Rap1a/B-Raf/ERK axis acts as a signal-relay mechanism to regulate NET formation in neutrophils. Further, C5aR1 and LTB4R1 signaling cascade along with NET-associated proteins are remarkably downregulated in tLBW newborns' neutrophils leading to impaired NETosis in them. Therefore, C5aR1 and LTB4R1 and their signaling molecules could provide an effective therapeutic target for compromised NETosis like tLBW newborns.

Treatment of Bullous Pemphigoid with Avdoralimab: Multicenter, Randomized, Open-Labeled Phase 2 Study.

RATIONALE: Experimental data support the role for C5a-C5aR1 axis activation in bullous pemphigoid. We assessed the efficacy and safety of avdoralimab, a specific anti-C5aR1 mAb, for treating bullous pemphigoid. METHODS: We conducted a phase 2 open-labeled randomized multicenter study. Patients with proven bullous pemphigoid were randomized (1:1) to receive superpotent topical steroids alone (group A) or with avdoralimab (group B). All patients received 0.05% clobetasol propionate cream until 15 days after the healing of lesions. Patients in group B additionally received 3 injections of avdoralimab every week for 12 weeks. The main criterion of evaluation was the proportion of patients with initial control of disease activity still in complete clinical remission at 3 months with no relapse during the study period. RESULTS: Fifteen patients were randomized: 7 to group A and 8 to group B. Two patients in group A and in group B achieved control of disease activity at week 4. Only 1 patient was still in complete clinical remission at week 12 in group B, and none was in group A. No adverse event related to the treatment was reported. CONCLUSIONS: This proof-of-concept pilot study did not show preliminary signal of additional avdoralimab efficiency compared with superpotent topical steroids alone.

Effect of prolonged wear and frame tightness of AR glasses on comfort.

The present study aimed to investigate the effect of frame tightness on the wearing comfort of augmented reality (AR) glasses during a prolonged video viewing task. A frame prototype of AR glasses with an adjustable frame width was adopted to accommodate variations in head size within the Chinese population, and two hundred participants were recruited to wear the glasses for an hour under five different tightness conditions. Local and overall discomfort ratings were obtained as outcome measures, and the ratings exhibited a significant increase with higher tightness levels. Furthermore, females and older people reported greater discomfort than other participants did, whereas previous spectacle use and body type had nonsignificant effects on wearing comfort. Consideration of approaches to alleviate frame tightness is crucial in the design of AR glasses targeting females and older people. These findings provide valuable ergonomic insights for AR glasses design and offer considerations applicable to the glasses-type wearable device industry.

3D virtual models and augmented reality for radical prostatectomy: a narrative review.

BACKGROUND AND OBJECTIVE: The increasing popularity of three-dimensional (3D) virtual reconstructions of two-dimensional (2D) imaging in urology has led to significant technological advancements, resulting in the creation of highly accurate 3D virtual models (3DVMs) that faithfully replicate individual anatomical details. This technology enhances surgical reality, providing surgeons with hyper-accurate insights into instantaneous subjective surgical anatomy and improving preoperative surgical planning. In the uro-oncologic field, the utility of 3D virtual reconstruction has been demonstrated in nephron-sparing surgery, impacting surgical strategy and postoperative outcomes in prostate cancer (PCa). The aim of this study is to offer a thorough narrative review of the current state and application of 3D reconstructions and augmented reality (AR) in radical prostatectomy (RP). METHODS: A non-systematic literature review was conducted using Medline, PubMed, the Cochrane Database, and Embase to gather information on clinical trials, randomized controlled trials, review articles, and prospective and retrospective studies related to 3DVMs and AR in RP. The search strategy followed the PICOS (Patients, Intervention, Comparison, Outcome, Study design) criteria and was performed in January 2024. KEY CONTENT AND FINDINGS: The adoption of 3D visualization has become widespread, with applications ranging from preoperative planning to intraoperative consultations. The urological community's interest in intraoperative surgical navigation using cognitive, virtual, mixed, and AR during RP is evident in a substantial body of literature, including 16 noteworthy investigations. These studies highlight the varied experiences and benefits of incorporating 3D reconstructions and AR into RP, showcasing improvements in preoperative planning, intraoperative navigation, and real-time decision-making. CONCLUSIONS: The integration of 3DVMs and AR technologies in urological oncology, particularly in the context of RP, has shown promising advancements. These technologies provide crucial support in preoperative planning, intraoperative navigation, and real-time decision-making, significantly improving the visualization of complex anatomical structures helping in the nerve sparing (NS) approach modulation and reducing positive surgical margin (PSM) rate. Despite positive outcomes, challenges such as small patient cohorts, lack of standardized methodologies, and concerns about costs and technology adoption persist.

Early Events in ß2AR Dimer Dynamics Mediated by Activation-Related Microswitches.

G-Protein-Coupled Receptors (GPCRs) make up around 3-4% of the human genome and are the targets of one-third of FDA-approved drugs. GPCRs typically exist as monomers but also aggregate to form higher-order oligomers, including dimers. ß2AR, a pharmacologically relevant GPCR, is known to be targeted for the treatment of asthma and cardiovascular diseases. The activation of ß2AR at the dimer level remains under-explored. In the current study, molecular dynamics (MD) simulations have been performed to understand activation-related structural changes in ß2AR at the dimer level. The transition from inactive to active and vice versa has been studied by starting the simulations in the apo, agonist-bound, and inverse agonist-bound ß2AR dimers for PDB ID: 2RH1 and PDB ID: 3P0G, respectively. A cumulative total of around 21-µs simulations were performed. Residue-based distances, RMSD, and PCA calculations suggested that either of the one monomer attained activation-related features for the apo and agonist-bound ß2AR dimers. The TM5 and TM6 helices within the two monomers were observed to be in significant variation in all the simulations. TM5 bulge and proximity of TM2 and TM7 helices may be contributing to one of the early events in activation. The dimeric interface between TM1 and helix 8 were observed to be well maintained in the apo and agonist-bound simulations. The presence of inverse agonists favored inactive features in both the monomers. These key features of activation known for monomers were observed to have an impact on ß2AR dimers, thereby providing an insight into the oligomerization mechanism of GPCRs.

Adapting Novel Augmented Reality Devices for Patient Simulations in Medical Education.

Extended reality (XR) simulations are becoming increasingly common in educational settings, particularly in medical education. Advancing XR devices to enhance these simulations is a booming field of research. This study seeks to understand the value of a novel, non-wearable mixed reality (MR) display during interactions with a simulated holographic patient, specifically in taking a medical history. Twenty-one first-year medical students at the University of North Carolina at Chapel Hill participated in the virtual patient (VP) simulations. On a five-point Likert scale, students overwhelmingly agreed with the statement that the simulations helped ensure they were progressing along learning objectives related to taking a patient history. However, they found that, at present, the simulations can only partially correct mistakes or provide clear feedback. This finding demonstrates that the novel hardware solution can help students engage in the activity, but the underlying software may need adjustment to attain sufficient pedagogical validity.

TRPS1, a sensitive marker for different histological and molecular types of breast cancer.

OBJECTIVES: We explored Trichorhinophalangeal syndrome type 1 (TRPS1) expression in special types of breast carcinoma, and analyzed the correlation between TRPS1 and androgen receptor (AR) expression in triple-negative breast cancer (TNBC). METHODS: TRPS1 expression was analyzed in 801 patients with special types of breast carcinoma. A total of 969 TNBC were used to analyze the correlation between the expression of TRPS1 and AR. TRPS1 expression was evaluated in 1975 cases of breast cancer with different molecular types. RESULTS: A total of 801 special types of breast cancers were stained with TRPS1.TRPS1 was positive in 100% (63/63) of mucinous carcinoma, 100% (7/7) adenoid cystic carcinomas (4 classic adenoid cystic carcinomas and 3 solid-basaloid adenoid cystic carcinomas), 100% (4/4) tubular carcinomas, 100% (2/2) secretory carcinomas, and 99.59% (243/244) invasive lobular carcinomas, 99.26% (267/269) invasive micropapillary carcinomas, 97.44% (38/39) ER-positive neuroendocrine tumors, 94.44% (34/36) metaplastic breast carcinomas (MBCs), 63.73% (65/102) apocrine carcinomas. TRPS1 was negative in all triple-negative neuroendocrine carcinomas (0/7).TRPS1 was positive in 92.86% (26/28) of metastatic special types of breast cancer. TRPS1 and AR expression were analyzed in 969 cases of TNBC. 90.40% were positive for TRPS1, and 42.41% were positive for AR. A significant inverse correlation between TRPS1 and AR expression was shown in TNBC (p < .001). TRPS1 showed a higher positive rate (93.13%) in TNBC compared to GATA binding protein 3 (GATA3), gross cystic disease fluid protein 15 (GCDFP-15) and forkhead box transcription Factor C 1 (FOXC1). CONCLUSIONS: In conclusion, our study demonstrated that TRPS1 is a highly sensitive marker for most special types of breast carcinoma. TRPS1 was positive in 63.73% of apocrine carcinomas. TRPS1 and AR expression was inversely correlated in TNBC.

Ultra-dense Green InGaN/GaN Nanoscale Pixels with High Luminescence Stability and Uniformity for Near-Eye Displays.

Ultra-dense (>4,000 pixels per inch) and highly stable full-color III-nitride nanoscale pixels are crucial for near-eye display technologies like virtual and augmented-reality glasses. In this context, InGaN-based long wavelength green microscale light-emitting diodes face major bottlenecks, such as low efficiency and inadequate wavelength stability. These challenges are associated with the presence of both nonradiative surface defects and the strain induced quantum-confined Stark effect. Herein, we report nanoscale pixelation of green InGaN/GaN LEDs incorporating strain-engineered ultra-dense nanowire (NW) arrays, corresponding to ∼36,000 pixels per inch. The NW pixel arrays exhibit a stable peak wavelength emission at ∼500 nm for over 3 orders of magnitude of injection current densities (from ∼4 A/cm2 to ∼1 kA/cm2). The observed wavelength stability enhancement (a reduced blue-shift of just ∼4 nm) directly results from the suppressed built-in electric field achieved by strain relaxation of the axial multi quantum wells in the NWs. Finite difference time domain simulations show that emission of the pixel array is significantly increased owing to the enhanced spontaneous emission rate (characterized by a high Purcell factor of ≈2) of the ultra-dense NWs. We have demonstrated top-down NWs, where each NW (diameter ranging down to 200 nm) shows excellent uniformity and light output characteristics in direct contrast to bottom-up grown NW heterostructures. The results of this study establish a viable route for realizing nanoscale pixels with high luminescence stability and wafer-scale uniformity with high (>20%) indium composition InGaN/GaN LED heterostructures, for next-generation near-eye displays.

PSD-95 Protein: A Promising Therapeutic Target in Chronic Pain.

Chronic pain, as a social public health problem, has a serious impact on the quality of patients' life. Currently, the main drugs used to treat chronic pain are opioids, antipyretic, and nonsteroidal anti-inflammatory drugs (NSAIDs). But the obvious side effects limit their use, so it is urgent to find new therapeutic targets. Postsynaptic density (PSD)-95 protein plays an important role in the occurrence and development of chronic pain. The over-expression of the PSD-95 protein and its interaction with other proteins are closely related to the chronic pain. Besides, the PSD-95-related drugs that inhibit the expression of PSD-95 as well as the interaction with other protein have been proved to treat chronic pain significantly. In conclusion, although more deep studies are needed in the future, these studies indicate that PSD-95 and the related proteins, such as NMDA receptor (NMDAR) subunit 2B (GluN2B), AMPA receptor (AMPAR), calmodulin-dependent protein kinase II (CaMKII), 5-hydroxytryptamine 2A receptor (5-HT2AR), and neuronal nitric oxide synthase (nNOS), are the promising therapeutic targets for chronic pain.

Analysis of IgE level influencing factors of common allergens for allergic rhinitis in northeastern China.

OBJECTIVES: This thesis aims to provide patients with a preventive and therapeutic basis by analyzing IgE level influencing factors of common allergens for Allergic Rhinitis (AR). METHOD: Multiple linear regression analysis is made upon questionnaires among 749 cases of AR patients that are divided into 5 age-based groups. Perform serum-specific IgE content testing on patients. RESULTS: Cockroach being an allergen, AR patients' IgE Level is influenced by allergic history, home-raised plants and animals. For AR patients with mugwort as an allergen, allergy and asthma history could increase IgE level, respectively, ß = 4.291 and ß = 4.364. If the allergen turns out to be peanut, allergic history would increase the IgE level (ß = 0.171), however, the level would be lower in female patients compared with male patients (ß = -0.078). For patients with egg as an allergen, allergic history, home-raised plants and animals (pets) would all affect the IgE level, respectively, ß = 0.182, ß = 0.118 and ß = -0.101. CONCLUSIONS: IgE level varies according to allergic history, home-raised plants & animals, gender, furniture renewal, asthma, and ages for patients with different allergens including cockroach, mold, mugwort, peanut, egg and crab. For each kind of allergen, the IgE levels react differently to different influencing factors, thus requiring a thorough analysis of each AR patient's allergen and allergenic factors.

Activation of ß3-AR by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue.

AIMS: ß3-AR (ß3-adrenergic receptor) is essential for cardiovascular homeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate ß3-AR activation-mediated PVAT function in AD/AA. METHODS AND RESULTS: Aortas from patients with thoracic aortic dissection (TAD) were collected to detect ß3-AR expression in PVAT. ApoE-/- and ß-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA, and subsequently received either placebo or mirabegron, a ß3-AR agonist. The results demonstrated an up-regulation of ß3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of ß3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor VEGF-C in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes (LNs) of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. CONCLUSIONS: Our findings illustrated the therapeutic potential of ß3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.

In Silico Analysis Predicts Mutational Consequences of CITED2, NUDT4, and Ar18B in Patients with Bipolar Disorder.

Bipolar disorder is a mood-related disorder, which can be portrayed as extreme shifts in energy, mood, and activity levels which can also be characterized by manic highs and depressive lows that can be often misdiagnosed as unipolar disorder due to primitive diagnostics techniques based on clinical assessments as well as diagnostic complexities arising due to its heterogeneous nature and overlapping symptoms with conditions like schizophrenia. leading to delays in treatment Strong evidence in support of genetic and epigenetic aspects of bipolar disorder, including mechanisms such as compromised hypothalamic-pituitary-adrenal axis, immune-inflammatory imbalances, oxidative stress, and mitochondrial dysfunction are found. Moreover, some previous research has already stated the role of genes like CITED2, NUDT4, and Arl8B in these processes. The primary goal of this study is to investigate the involvement of the genes in exploring and validating their potential as biomarkers for bipolar disorder. In silico tools like MutationTaster, PolyPhen2, SIFT, GTEx, PhenoScanner, and RegulomeDB were used to perform mutational and gene expression analyses. Results revealed potentially dangerous mutations caused in CITED2, NUDT4, and Arl8B, those which can have diverse outcomes. RegulomeDB, GTEx, and PhenoScanner reveal the involvement of these genes in various brain regions highlighting their relevance to bipolar disorder. This analysis suggests the potential utility of CITED2, NUDT4, and Arl8B as diagnostic markers hence shedding light on their roles to elaborate the molecular range of bipolar disorder. The study also contributes to providing valuable insights into the genetic and molecular basis of bipolar disorders.

Regulation of prostate-specific membrane antigen (PSMA) expression in prostate cancer cells after treatment with dutasteride and lovastatin.

PSMA expression gradually increases from benign prostatic hyperplasia to adenocarcinoma of the prostate and is therefore used for the development of improved diagnostic (PSMA)-based prostate cancer imaging tools. Pharmacological induction of PSMA is therefore eminent to further improve the detection rate of PSMA-based imaging. Our previous studies have demonstrated that lovastatin (Lova) and dutasteride (Duta) are able to induce PSMA expression. However, the mechanisms by which PSMA is regulated in prostate cancer remain poorly understood. Androgen receptor (AR) and homeobox B13 (HOXB13) are the best known regulators of PSMA, hence in the present study we aimed to explore the PSMA regulation by HOXB13 and AR signaling in LNCaP and VCaP cells following treatments with Lova and Duta. Furthermore, our previous research revealed a growth arrest in prostate cancer cells after Lova, but not after Duta treatment. To understand this discrepancy, we explored the influence of Lova and Duta on well known tumor growth promoters, such as AR, the mTOR/Akt signaling pathways and Cyclin D1. Our results showed that treatment with Lova leads to a significant inhibition of the investigated tumor promoters and results in growth regression of LNCaP and VCaP cells. In contrast, Duta does not show these effects. Furthermore, we confirm the cooperative effect of HOXB13 and AR in regulating PSMA in LNCaP cells, and extend the investigations to an additional prostate cancer cell line (VCaP).