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.

A circuit from lateral septum neurotensin neurons to tuberal nucleus controls hedonic feeding.

Feeding behavior is regulated by both the homeostatic needs of the body and hedonic values of the food. Easy access to palatable energy-dense foods and the consequent obesity epidemic stress the urgent need for a better understanding of neural circuits that regulate hedonic feeding. Here, we report that neurotensin-positive neurons in the lateral septum (LSNts) play a crucial role in regulating hedonic feeding. Silencing LSNts specifically promotes feeding of palatable food, whereas activation of LSNts suppresses overall feeding. LSNts neurons project to the tuberal nucleus (TU) via GABA signaling to regulate hedonic feeding, while the neurotensin signal from LSNts→the supramammillary nucleus (SUM) is sufficient to suppress overall feeding. In vivo calcium imaging and optogenetic manipulation reveal two populations of LSNts neurons that are activated and inhibited during feeding, which contribute to food seeking and consumption, respectively. Chronic activation of LSNts or LSNts→TU is sufficient to reduce high-fat diet-induced obesity. Our findings suggest that LSNts→TU is a key pathway in regulating hedonic feeding.

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.

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.

Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory.

The ability to identify strange conspecifics in societies is supported by social memory, which is vital for gregarious animals and humans. The function of hippocampal principal neurons in social memory has been extensively investigated; however, the nonprincipal neuronal mechanism underlying social memory remains unclear. Here, we first observed parallel changes in the ability for social recognition and the number of parvalbumin interneurons (PVIs) in the ventral CA1 (vCA1) after social isolation. Then, using tetanus toxin-mediated neuronal lesion and optogenetic stimulation approaches, we revealed that vCA1-PVIs specifically engaged in the retrieval stage of social memory. Finally, through the in vivo Ca2+ imaging technique, we demonstrated that vCA1-PVIs exhibited higher activities when subjected mice approached a novel mouse than to a familiar one. These results highlight the crucial role of vCA1-PVIs for distinguishing novel conspecifics from other individuals and contribute to our understanding of the neuropathology of mental diseases with social memory deficits.

Establishment of evaluation criteria for the development of high quality ERα-targeted fluorescent probes.

ERα-targeted fluorescent probes are important tools for ERα study. In order to develop high quality ERα-targeted probes, a sound and complete evaluation system is essential but has not been established yet. Herein, we set up a series of evaluation criteria for ERα-targeted fluorescent probes including ERα binding affinity, fluorescence quantum yield, cytotoxicity, ERα tracking capacity, ERα selectivity and ERα labeling ability. To verify the practicability of the evaluation criteria, we designed and synthesized two ERα-targeted fluorescent probes and fully characterized their properties based on the proposed evaluation criteria. It showed that the probes exhibited better performance. Moreover, we applied the probes in MCF-7 cells to study the ERα motion characteristics for the first time. We hope that our evaluation criteria could be helpful for the establishment of a complete evaluation system for ERα-targeted fluorescent probes.

Transcriptional Regulation of T Cell Metabolism Reprograming.

T cell activation, differentiation, and function are tightly regulated by a complex network of transcription factors, epigenetic modifications, and signaling pathways of both TCR and cytokines. Over the past decade, it is increasingly clear that T cell immune responses are also regulated by their associated metabolic reprograming. Compared with relatively well-understood transcriptional regulation of T cell activation, differentiation, and function, less is known about the transcriptional regulation of T cell metabolic reprograming during T cell immune responses. In this review, we first describe how signaling pathways of TCR and cytokines regulate metabolic reprograming and then focus on transcription factors that control metabolic pathways and outcomes of T cell immune responses. A better understanding of T cell metabolic regulation will provide new strategies and targets for the treatment of T cell-related diseases.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.