GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice.

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor-positive (GLP-1R-positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.

Zona incerta mediates early life isoflurane-induced fear memory deficits.

The potential long-term effects of anesthesia on cognitive development, especially in neonates and infants, have raised concerns. However, our understanding of its underlying mechanisms and effective treatments is still limited. In this study, we found that early exposure to isoflurane (ISO) impaired fear memory retrieval, which was reversed by dexmedetomidine (DEX) pre-treatment. Measurement of c-fos expression revealed that ISO exposure significantly increased neuronal activation in the zona incerta (ZI). Fiber photometry recording showed that ZI neurons from ISO mice displayed enhanced calcium activity during retrieval of fear memory compared to the control group, while DEX treatment reduced this enhanced calcium activity. Chemogenetic inhibition of ZI neurons effectively rescued the impairments caused by ISO exposure. These findings suggest that the ZI may play a pivotal role in mediating the cognitive effects of anesthetics, offering a potential therapeutic target for preventing anesthesia-related cognitive impairments.

Cellular and circuit architecture of the lateral septum for reward processing.

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.

Discovery of Novel ERα and Aromatase Dual-Targeting PROTAC Degraders to Overcome Endocrine-Resistant Breast Cancer.

Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.

Probing nanoscale structural response of collagen fibril in human Achilles tendon during loading using in situ SAXS.

The specific viscoelastic mechanical properties of the human Achilles tendon are strongly dependent on the structural characteristics of collagen. Although research on the deformation mechanisms of the Achilles tendon in various animals is extensive, understanding of these mechanisms in the human Achilles tendon remains largely empirical and macroscopic. In this work, the evolution of D-space, orientation, and average length of voids between fibers are investigated during the stretching using SAXS techniques. Initially, the void length increases marginally, while the misorientation breadth decreased rapidly as the D-space steadily increased. In the second region, D-space and the void length increase sharply under rising stress, even though misorientation width decreased. During the third region, the increases in void length and D-space decelerate, but the misorientation width widens, suggesting the onset of irreversible microscopic fibril failure in the Achilles tendon. In the final region, the fibers undergo macroscopic failure, with D-space and void length returning to their initial states. The macroscopic alterations are elucidated by the nanoscale structural responses, providing a fundamental understanding of the mechanisms driving the complex biomechanics, tissue structural organization, and Achilles tendon regeneration.

Fluorescence theranostic PROTACs for real-time visualization of ERα degradation.

Proteolysis targeting chimera (PROTAC) technology, a groundbreaking strategy for degradation of pathogenic proteins by hijacking of the ubiquitin-proteasome-system has become a promising strategy in drug design. However, the real-time monitoring and visualization of protein degradation processes have been long-standing challenges in the realm of drug development. In this research, we sought to amalgamate the highly efficient protein-degrading capabilities of PROTAC technology with the visualization attributes of fluorescent probes, with the potential to pave the path for the design and development of a novel class of visual PROTACs. These novel PROTACs uniquely possess both fluorescence imaging and therapeutic characteristics, all with the goal of enabling real-time observations of protein degradation processes. Our approach involved the utilization of a high ER-targeting fluorescent probe, previously reported in our laboratory, which served as a warhead that specifically binds to the protein of interest (POI). Additionally, a VHL ligand for recruiting E3 ligase and linkers of various lengths were incorporated to synthesize a series of novel ER-inherent fluorescence PROTACs. Among them, compound A3 demonstrated remarkable efficiency in degrading ERα proteins (DC50 = 0.12 µM) and displaying exceptional anti-proliferative activity against MCF-7 cells (IC50 = 0.051 µM). Furthermore, it exhibited impressive fluorescence imaging performance, boasting an emission wavelength of up to 582 nm, a Stokes shift of 116 nm, and consistent optical properties. These attributes make it especially suitable for the real-time, in situ tracking of ERα protein degradation processes, thus may serve as a privileged visual theranostic PROTAC for ERα+ breast cancer. This study not only broadens the application spectrum of PROTAC technology but also introduces a novel approach for real-time visualization of protein degradation processes, ultimately enhancing the diagnostic and treatment efficacy of PROTACs.

Novel estrogen receptor ß/histone deacetylase dual-targeted near-infrared fluorescent probes as theranostic agents for imaging and treatment of prostate cancer.

Estrogen receptor (ER) ß and histone deacetylases (HDACs), when overexpressed, are associated closely with the occurrence and development of prostate cancer and are, therefore, considered important targets and biomarkers used in the clinical treatment of prostate cancer. The present study involved the design and synthesis of the first ERß and HDAC dual-target near-infrared fluorescent probe with both imaging capacity and antitumor activity for prostate cancer. Both P1 and P2 probes exhibited excellent ERß selectivity, with P1 being almost exclusively selective for ERß compared to ERα. In addition, P1 exhibited good optical properties, such as strong near-infrared emission, large Stokes shift, and better anti-interference ability, along with excellent imaging ability for living cells. P1 also exhibited potent inhibitory activity against HDAC6 and DU-145 cells, with IC50 values of 52 nM and 0.96 µM, respectively. Further, P1 was applied successfully for the in vivo imaging of prostate cancer in a mouse model, and significant in vivo antitumor efficacy was achieved. The developed dual-target NIR fluorescent probe is expected to serve as an effective tool in the research on prostate cancer, leading to novel insights for the theranostic study of diseases related to ERß and HDACs.

From Lidar Measurement to Rotor Effective Wind Speed Prediction: Empirical Mode Decomposition and Gated Recurrent Unit Solution.

Conventional wind speed sensors face difficulties in measuring wind speeds at multiple points, and related research on predicting rotor effective wind speed (REWS) is lacking. The utilization of a lidar device allows accurate REWS prediction, enabling advanced control technologies for wind turbines. With the lidar measurements, a data-driven prediction framework based on empirical mode decomposition (EMD) and gated recurrent unit (GRU) is proposed to predict the REWS. Thereby, the time series of lidar measurements are separated by the EMD, and the intrinsic mode functions (IMF) are obtained. The IMF sequences are categorized into high-, medium-, and low-frequency and residual groups, pass through the delay processing, and are respectively used to train four GRU networks. On this basis, the outputs of the four GRU networks are lumped via weighting factors that are optimized by an equilibrium optimizer (EO), obtaining the predicted REWS. Taking advantages of the measurement information and mechanism modeling knowledge, three EMD-GRU prediction schemes with different input combinations are presented. Finally, the proposed prediction schemes are verified and compared by detailed simulations on the BLADED model with four-beam lidar. The experimental results indicate that compared to the mechanism model, the mean absolute error corresponding to the EMD-GRU model is reduced by 49.18%, 53.43%, 52.10%, 65.95%, 48.18%, and 60.33% under six datasets, respectively. The proposed method could provide accurate REWS prediction in advanced prediction control for wind turbines.

Identification of Novel Dual-Target Estrogen Receptor α Degraders with Tubulin Inhibitory Activity for the Treatment of Endocrine-Resistant Breast Cancer.

Endocrine resistance remains a significant problem in the clinical treatment of estrogen receptor α-positive (ERα+) breast cancer (BC). In this study, we developed a series of novel dual-functional ERα degraders based on a bridged bicyclic scaffold with selenocyano (SeCN) side chains. These compounds displayed potent ERα degradation and tubulin depolymerization activity. Among them, compounds 35s and 35t exhibited the most promising antiproliferative and ERα degradation activity in multiple ERα+ BC cell lines bearing either wild-type or mutant ERα. Meanwhile, compounds 35s and 35t disrupted the microtubule network by restraining tubulin polymerization, evidenced by 35t inducing cell cycle arrest in the G2/M phase. In MCF-7 and LCC2 xenograft models, compounds 35s and 35t remarkably suppressed tumor growth without noticeable poisonousness. Finally, this study provided guidance for developing new dual-target antitumor drug candidates for the ERα+ BC therapy, especially for the resistant variant.

Exosomes: Potential key players towards novel therapeutic options in diabetic wounds.

Diabetic wounds are usually difficult to heal, and wounds in foot in particular are often aggravated by infection, trauma, diabetic neuropathy, peripheral vascular disease and other factors, resulting in serious foot ulcers. The pathogenesis and clinical manifestations of diabetic wounds are complicated, and there is still a lack of objective and in-depth laboratory diagnosis and classification standards. Exosomes are nanoscale vesicles containing DNA, mRNA, microRNA, cyclic RNA, metabolites, lipids, cytoplasm and cell surface proteins, etc., which are involved in intercellular communication and play a crucial role in vascular regeneration, tissue repair and inflammation regulation in the process of diabetic wound healing. Here, we discussed exosomes of different cellular origins, such as diabetic wound-related fibroblasts (DWAF), adipose stem cells (ASCs), mesenchymal stem cells (MSCs), immune cells, platelets, human amniotic epithelial cells (hAECs), epidermal stem cells (ESCs), and their various molecular components. They exhibit multiple therapeutic effects during diabetic wound healing, including promoting cell proliferation and migration associated with wound healing, regulating macrophage polarization to inhibit inflammatory responses, promoting nerve repair, and promoting vascular renewal and accelerating wound vascularization. In addition, exosomes can be designed to deliver different therapeutic loads and have the ability to deliver them to the desired target. Therefore, exosomes may become an innovative target for precision therapeutics in diabetic wounds. In this review, we summarize the latest research on the role of exosomes in the healing of diabetic wound by regulating the pathogenesis of diabetic wounds, and discuss their potential applications in the precision treatment of diabetic wounds.

ABVS-Based Radiomics for Early Predicting the Efficacy of Neoadjuvant Chemotherapy in Patients with Breast Cancers.

Background: Neoadjuvant chemotherapy (NAC) plays a significant role in breast cancer (BC) management; however, its efficacy varies among patients. Current evaluation methods may lead to delayed treatment alterations, and traditional imaging modalities often yield inaccurate results. Radiomics, an emerging field in medical imaging, offers potential for improved tumor characterization and personalized medicine. Nevertheless, its application in early and accurately predicting NAC response remains underinvestigated. Objective: This study aims to develop an automated breast volume scanner (ABVS)-based radiomics model to facilitate early detection of suboptimal NAC response, ultimately promoting personalized therapeutic approaches for BC patients. Methods: This retrospective study involved 248 BC patients receiving NAC. Standard guidelines were followed, and patients were classified as responders or non-responders based on treatment outcomes. ABVS images were obtained before and during NAC, and radiomics features were extracted using the PyRadiomics toolkit. Inter-observer consistency and hierarchical feature selection were assessed. Three machine learning classifiers, logistic regression, support vector machine, and random forest, were trained and validated using a five-fold cross-validation with three repetitions. Model performance was comprehensively evaluated based on discrimination, calibration, and clinical utility. Results: Of the 248 BC patients, 157 (63.3%) were responders, and 91 (36.7%) were non-responders. Radiomics feature selection revealed 7 pre-NAC and 6 post-NAC ABVS features, with higher weights for post-NAC features (min >0.05) than pre-NAC (max <0.03). The three post-NAC classifiers demonstrated AUCs of approximately 0.9, indicating excellent discrimination. DCA curves revealed a substantial net benefit when the threshold probability exceeded 40%. Conversely, the three pre-NAC classifiers had AUCs between 0.7 and 0.8, suggesting moderate discrimination and limited clinical utility based on their DCA curves. Conclusion: The ABVS-based radiomics model effectively predicted suboptimal NAC responses in BC patients, with early post-NAC classifiers outperforming pre-NAC classifiers in discrimination and clinical utility. It could enhance personalized treatment and improve patient outcomes in BC management.

Structure-guided identification of novel dual-targeting estrogen receptor α degraders with aromatase inhibitory activity for the treatment of endocrine-resistant breast cancer.

Drug resistance is a major challenge in conventional endocrine therapy for estrogen receptor (ER) positive breast cancer (BC). BC is a multifactorial disease, in which simultaneous aromatase (ARO) inhibition and ERα degradation may effectively inhibit the signal transduction of both proteins, thus potentially overcoming drug resistance caused by overexpression or mutation of target proteins. In this study, guided by the X-ray structure of a hit compound 30a in complex with ER-Y537S, a structure-based optimization was performed to get a series of multiacting inhibitors targeting both ERα and ARO, and finally a novel class of potent selective estrogen receptor degraders (SERDs) based on a three-dimensional oxabicycloheptene sulfonamide (OBHSA) scaffold equipped with aromatase inhibitor (AI) activity were identified. Of these dual-targeting SERD-AI hybrids, compound 31q incorporating a 1H-1,2,4-triazole moiety showed excellent ERα degradation activity, ARO inhibitory activity and remarkable antiproliferative activity against BC resistant cells. Furthermore, 31q manifested efficient tumor suppression in MCF-7 tumor xenograft models. Taken together, our study reported for the first time the highly efficient dual-targeting SERD-AI hybrid compounds, which may lay the foundation of translational research for improved treatment of endocrine-resistant BC.

Huo Xiang Zheng Qi Oral Liquid Combined with 5-HT3 Receptor Antagonists and Dexamethasone Can Prevent Chemotherapy-Induced Nausea and Vomiting for Patients Receiving Multiday Cisplatin-Based Regimen: A Multicenter Trial.

Background: Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects associated with deterioration in the quality of life. This study aimed to assess the clinical value of Huoxiang Zhengqi (HXZQ) oral liquid, a Chinese patent medicine, in combination with 5-HT3 receptor antagonists (RAs) and dexamethasone, in preventing CINV in patients receiving multiday cisplatin-based chemotherapy. Methods: In this multicenter, exploratory randomized clinical trial, the authors compared the efficacy of HXZQ oral liquid against a control group receiving a placebo, in combination with 5-HT3 RAs and dexamethasone, in preventing CINV in chemotherapy-naive patients receiving a multiday cisplatin-based regimen between January 2021 and September 2021. The primary endpoint was the complete response (CR) rate. The secondary endpoints included days with no CINV, the incidence of CINV, and life function. Results: Sixty patients were randomized into two groups and included in the study. The CR rate was significantly improved by HXZQ oral liquid in acute CINV (63.33% vs. 33.33%, p = 0.020) and CINV beyond the risk phase (96.67% vs. 46.67%, p = 0.000). The number of days with no CINV was significantly more in the HXZQ group compared with the control group in the overall phase (18.10 ± 3.64 vs. 12.13 ± 7.63, p = 0.002). Significantly higher Functional Living Index-Emesis total and domain scores were observed in the HXZQ group. Conclusions: HXZQ oral liquid combined with 5-HT3 RAs and dexamethasone is a feasible and safe approach to prevent CINV in patients receiving multiday cisplatin-based chemotherapy who cannot use neurokinin 1 RAs. Clinical Trial Registration: ChiCTR2000040123.

Diagnosis of primary biliary melanoma with distinct imaging features: a case report and literature review.

Primary biliary melanoma arises from proliferating melanocytes in the mucosal surface of the bile duct and is extremely rare. Since the vast majority of biliary melanomas represent metastases of cutaneous origin, accurate preoperative diagnosis of melanoma and exclusion of other primary sources are vital in cases involving primary lesions. Although melanomas with pigmented cells have typical signal characteristics, obtaining a non-invasive pre-treatment diagnosis remains difficult, due to their low incidence. Here, the case of a 61-year-old male Asian patient who presented with upper quadrant abdominal pain, swelling and jaundice for 2 weeks, and who was diagnosed with primary biliary melanoma following extensive preoperative blood analyses, computed tomography (CT) and magnetic resonance imaging (MRI), is described. Post-resection immunohistochemistry confirmed the diagnosis and the patient received six chemotherapy cycles of temozolomide and cisplatin, however, progression of multiple liver metastases was observed at the 18-month follow-up CT. The patient continued with pembrolizumab and died 17 months later. The present case of primary biliary melanoma is the first reported diagnosis based on typical MRI features and the exhaustive exclusion of a separate primary origin.

Development of Highly Efficient Estrogen Receptor ß-Targeted Near-Infrared Fluorescence Probes Triggered by Endogenous Hydrogen Peroxide for Diagnostic Imaging of Prostate Cancer.

Hydrogen peroxide is one of the most important reactive oxygen species, which plays a vital role in many physiological and pathological processes. A dramatic increase in H2O2 levels is a prominent feature of cancer. Therefore, rapid and sensitive detection of H2O2 in vivo is quite conducive to an early cancer diagnosis. On the other hand, the therapeutic potential of estrogen receptor beta (ERß) has been implicated in many diseases including prostate cancer, and this target has attracted intensive attention recently. In this work, we report the development of the first H2O2-triggered ERß-targeted near-infrared fluorescence (NIR) probe and its application in imaging of prostate cancer both in vitro and in vivo. The probe showed good ERß selective binding affinity, excellent H2O2 responsiveness and near infrared imaging potential. Moreover, in vivo and ex vivo imaging studies indicated that the probe could selectively bind to DU-145 prostate cancer cells and rapidly visualizes H2O2 in DU-145 xenograft tumors. Mechanistic studies such as high-resolution mass spectrometry (HRMS) and density functional theory (DFT) calculations indicated that the borate ester group is vital for the H2O2 response turn-on fluorescence of the probe. Therefore, this probe might be a promising imaging tool for monitoring the H2O2 levels and early diagnosis studies in prostate cancer research.

Opioid Receptors Modulate Firing and Synaptic Transmission in the Paraventricular Nucleus of the Thalamus.

The paraventricular nucleus of the thalamus (PVT) is involved in drug addiction-related behaviors, and morphine is a widely used opioid for the relief of severe pain. Morphine acts via opioid receptors, but the function of opioid receptors in the PVT has not been fully elucidated. Here, we used in vitro electrophysiology to study neuronal activity and synaptic transmission in the PVT of male and female mice. Activation of opioid receptors suppresses the firing and inhibitory synaptic transmission of PVT neurons in brain slices. On the other hand, the involvement of opioid modulation is reduced after chronic morphine exposure, probably because of desensitization and internalization of opioid receptors in the PVT. Overall, the opioid system is essential for the modulation of PVT activities.SIGNIFICANCE STATEMENT Opioid receptors modulate the activities and synaptic transmission in the PVT by suppressing the firing rate and inhibitory synaptic inputs. These modulations were largely diminished after chronic morphine exposure.

Glioma grade discrimination with dynamic contrast-enhanced MRI: An accurate analysis based on MRI guided stereotactic biopsy.

PURPOSE: To evaluate the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) metrics for glioma grading on a point-to-point basis. METHODS: Forty patients with treatment-naïve glioma underwent DCE-MR examination and stereotactic biopsy. DCE-derived parameters including endothelial transfer constant (Ktrans), volume of extravascular-extracellular space (ve), fractional plasma volume (fpv), and reflux transfer rate (kep) were measured within ROIs on DCE maps accurately matched with biopsies used for histologic grades diagnosis. Differences in parameters between grades were evaluated by Kruskal-Wallis tests. Diagnostic accuracy of each parameter and their combination was assessed using receiver operating characteristic curve. RESULTS: Eighty-four independent biopsy samples from 40 patients were analyzed in our study. Significant statistical differences in Ktrans and ve were observed between grades except ve between grade 2 and 3. Ktrans showed good to excellent accuracy in discriminating grade 2 from 3, 3 from 4, and 2 from 4 (area under the curve = 0.802, 0.801 and 0.971, respectively). Ve indicated good accuracy in discriminating grade 3 from 4 and 2 from 4 (AUC = 0.874 and 0.899, respectively). The combined parameter demonstrated fair to excellent accuracy in discriminating grade 2 from 3, 3 from 4, and 2 from 4 (AUC = 0.794, 0.899 and 0.982, respectively). CONCLUSION: Our study had identified Ktrans, ve and the combination of parameters to be an accurate predictor for grading glioma.

Wounds under diabetic milieu: The role of immune cellar components and signaling pathways.

A major challenge in the field of diabetic wound healing is to confirm the body's intrinsic mechanism that could sense the immune system damage promptly and protect the wound from non-healing. Accumulating literature indicates that macrophage, a contributor to prolonged inflammation occurring at the wound site, might play such a role in hindering wound healing. Likewise, other immune cell dysfunctions, such as persistent neutrophils and T cell infection, may also lead to persistent oxidative stress and inflammatory reaction during diabetic wound healing. In this article, we discuss recent advances in the immune cellular components in wounds under the diabetic milieu, and the role of key signaling mechanisms that compromise the function of immune cells leading to persistent wound non-healing.

Self-supervised multi-modal fusion network for multi-modal thyroid ultrasound image diagnosis.

Ultrasound is a typical non-invasive diagnostic method often used to detect thyroid cancer lesions. However, due to the limitations of the information provided by ultrasound images, shear wave elastography (SWE) and color doppler ultrasound (CDUS) are also used clinically to assist in diagnosis, which makes the diagnosis time-consuming, labor-intensive, and highly subjective process. Therefore, automatic diagnosis of benign and malignant thyroid nodules is beneficial for the clinical diagnosis of the thyroid. To this end, based on three modalities of gray-scale ultrasound images(US), SWE, and CDUS, we propose a deep learning-based multi-modal feature fusion network for the automatic diagnosis of thyroid disease based on the ultrasound images. First, three ResNet18s initialized by self-supervised learning are used as branches to extract the image information of each modality, respectively. Then, a multi-modal multi-head attention branch is used to remove the common information of three modalities, and the knowledge of each modal is combined for thyroid diagnosis. At the same time, to better integrate the features between modalities, a multi-modal feature guidance module is also proposed to guide the feature extraction of each branch and reduce the difference between each-modal feature. We verify the multi-modal thyroid ultrasound image diagnosis method on the self-collected dataset, and the results prove that this method could provide fast and accurate assistance for sonographers in diagnosing thyroid nodules.