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Catastrophe mechanism and early warning indicators of seepage erosion-induced water inrush in karst cavities
Seepage-erosion-induced water inrush in karst cavities is a typical form of water-inrush disaster in karst tunnels. It is governed not only by the spatial distribution of karst cavities and hydraulic recharge conditions, but also by the particle-size gradation and composition of the cavity fill. During seepage erosion, fill particles are progressively transported by flowing water, which may trigger a sudden water-inrush catastrophe. To reveal the catastrophe mechanism and establish early-warning indicators, this study employs the Smoothed Particle Hydrodynamics (SPH) method to simulate the evolution of seepage-erosion-induced water inrush under different particle-size gradations, cavity confining stresses, and seepage velocities. The inflection point of the cumulative particle loss rate is used as an indicator of catastrophic transition. The relationships among particle-size gradation, confining stress, seepage velocity, and particle loss rate at the transition point are then analyzed to determine early-warning thresholds. The results show that fill-particle loss is positively correlated with both seepage velocity and confining stress. When the content of fine particles, such as rock cuttings and fine sand, exceeds 60%, the inflection point corresponds to a seepage velocity of 1.6 m/s and a confining stress of 2.6 MPa, with an early-warning particle-loss range of 8%−15%. When the content of coarse particles, such as coarse sand and gravel, exceeds 40%, the inflection point corresponds to a seepage velocity of 3.0 m/s and a confining stress of 4.5 MPa, with an early-warning particle-loss threshold of approximately 45%.
Pairing a Zn <sub>1</sub> O <sub>1</sub> Monomer With Oxide Supports via Dual Interfacial Metal–Oxygen Bonding for Stable Conversion of Syngas to Light Olefins
ABSTRACT Atomically dispersed metal oxides on oxide supports have garnered significant attention for their exceptional catalytic activity and selectivity, yet their practical application is often limited by poor stability. Here, we demonstrate that unlike isolated metal atoms on oxide supports, the stability of oxide monomers (e.g., Zn 1 O 1 , a prototype motif for a variety of (de)hydrogenation reactions) on oxide supports (M'O' x ) tightly relies on delicate pairing of two interfacial bonds: Zn–O' and O–M'. Supports with too low oxygen vacancy formation energy ( E v ) fail to firmly anchor the O anion in Zn 1 O 1 , whereas those with excessively high E v bind weakly to the cationic Zn. Tetragonal ZrO 2 (100), possessing a moderate E v , was theoretically screened to enable simultaneous optimization of the dual interfacial bonding and was experimentally verified through the anchoring of high‐density Zn 1 oxo monomers (1.5 Zn·nm −2 ) with exceptional resistance to aggregation and volatilization under harsh reductive conditions. When integrated with SAPO‐34 zeolite for syngas conversion, this bifunctional catalyst achieves an unprecedented light olefins production rate (25.6 mmol·g cat −1 ·h −1 ) and sustains remarkable stability for over 200 h at 400 °C, outperforming all previously reported catalysts. The interfacial pairing principle provides a foundational guideline for designing highly stable and active atomically dispersed metal oxo catalysts.
A computer vision-based approach for automatically extracting data from bar chart raster images to facilitate meta-analysis of biomedical literature
Although bar charts are widely used in scientific publications, their rasterized format within Portable Document Format (PDF) files complicates automated data extraction, hindering large-scale evidence synthesis and meta-analysis. To address this, we developed and evaluated an automated pipeline for extracting quantitative data from bar charts embedded in the biomedical literature. The four-stage pipeline comprises (1) image extraction and panel segmentation, (2) optical character recognition (OCR)-based text detection, (3) image disassembly to identify chart components, and (4) data reconstruction using numeric parsing and axis-based interpolation. The system combines edge detection, morphological operations, and convolutional neural network (CNN)-based figure classification using a transfer-learned Inception v3 model. Performance was validated on randomized controlled trials in age-related macular degeneration, with manually annotated values from a semi-automated labeling tool as the reference standard, and agreement was assessed using Bland–Altman analysis. Across 28 bar charts from ten publications, the pipeline correctly recognized 92.9% (95% confidence interval [CI], 77.4–98.0) of figure types, 96.0% (95% CI, 94.2–97.3) of text blocks, and 79.1% (95% CI, 74.7–83.0) of bars. For numerical reconstruction, 81.2% (95% CI, 76.3–85.2) of bar values fell within ±5% of the reference standard, 63.0% (95% CI, 57.3–68.3) within ±2%, and 48.6% (95% CI, 43.0–54.3) within ±1%. Bland–Altman analysis showed a small negative bias of −0.18 (95% CI, −0.34 to −0.02), with 94.9% of differences within the limits of agreement. Most outliers arose from OCR digit misclassification or ambiguous bar boundaries. This proof-of-concept study demonstrates the feasibility of automated data extraction from bar charts using a hybrid approach that combines image-processing heuristics with CNN-based classification. Although currently limited to bar charts and a single clinical domain, the pipeline represents a step toward scalable, end-to-end systems for automated evidence extraction to support meta-analyses across the biomedical literature.
Light and Acid‐Base Dual‐Regulated Atom Transfer Radical Polymerization With ppb Concentrations of Zwitterionic Photocatalysts
ABSTRACT Here, we introduce highly efficient, and acid/base‐responsive zwitterionic photocatalysts (PC) for photoinduced atom transfer radical polymerization (photoATRP). The electron‐withdrawing methylpyridinium substituent enhances the acidity of benzimidazole/naphthoimidazole, enabling the formation of potent electron‐donating benzimidazolate anion/naphthoimidazolate anion under weakly alkaline or even neutral conditions. The PCs exhibit visible light absorption and highly reducing excited states. Their fluorescence is quenched by the ATRP initiator with exceptional rate constants of k q > 10 9 M −1 s −1 , more than one order of magnitude higher than those of traditional PCs. At PC concentrations as low as 100 parts per billion (ppb), photoATRP of acrylates exhibits high initiation efficiency and excellent control over molecular weights and dispersity ( Đ < 1.1). Notably, the protonation of the PCs in acidic environments leads to the loss of photocatalytic activity and visible‐light absorption. Strict temporal control over polymer‐chain propagation is achieved through light on‐off switching combined with the weak base and acid stimuli. To our knowledge, this is the first demonstration of dual‐regulated polymerization using ppb‐level of PC concentrations.
Real-world regorafenib use among patients with advanced gastrointestinal stromal tumor in the United States
Background Gastrointestinal stromal tumors (GIST) are the most common gastrointestinal soft tissue sarcoma. Tyrosine kinase inhibitors are guideline-recommended therapy; however, resistance often occurs, requiring subsequent therapy. Regorafenib is a multikinase inhibitor approved for third-line therapy. Real-world data surrounding regorafenib’s use and place in therapy are limited. Objective To understand real-world regorafenib utilization and patient characteristics among US patients with advanced GIST. Methods This retrospective cohort claims analysis used data from Merative™ MarketScan ® research databases and included patients with ≥1 pharmacy claim for regorafenib during the identification period (10/2015–5/2023) and ≥1 GIST diagnoses any time prior to/on index date (first regorafenib prescription claim). Primary outcomes included duration of therapy (DOT) and time to next therapy (TTNT). Outcomes were stratified based on prior GIST treatment during the baseline period (BL) and initial regorafenib dose (i.e., low dose [LD] or regorafenib standard dose [RSD]) as of the index date. Results Nearly half (45.2%) of patients received imatinib and sunitinib prior to regorafenib initiation, and 73.5% received RSD. Patients who received prior imatinib or sunitinib alone before regorafenib had a numerically longer median DOT with regorafenib than those who received both in the BL before regorafenib (142.5 days [IQR: 87–257.5] vs 95 days [IQR: 53–192]). Patients receiving LD and RSD demonstrated similar median DOT (103.0 days [IQR: 41.5, 210.5] vs 94.5 days [IQR: (35.0, 171.0]) and TTNT (143 days [IQR: 70–293] vs 141 days [IQR: 77–191]). Conclusions Patients on LD and RSD had similar DOT and TTNT. Acknowledging the limitations from this real-world data, patients with prior imatinib or sunitinib alone appeared to have longer DOT on regorafenib than those who received both. Further research is warranted to explore the clinical benefits of these differences.
Tailoring Photonic Transport in Cluster‐Assembled Crystals via Atomic‐Level Coordination Engineering
ABSTRACT The development of efficient optical waveguides requires precise control over photonic transport properties, yet linking atomic‐level structure to device performance remains challenging. This study demonstrates that atomic‐level coordination engineering of metal nanoclusters enables tailored photonic transport in cluster‐assembled crystals. Using bidentate phosphine ligands as molecular scalpels, we constructed a series of Pt 1 Ag x ( x = 18–37) nanoclusters with identical icosahedral kernels but systematically varied peripheral structures. The resulting crystals exhibit exceptionally low optical loss coefficient, with the Pt 1 Ag 18 SR 8 Cl 2 (DPPP) 4 (SR = 1‐adamantanethiol, DPPP = 1,3‐bis(diphenylphosphino)propane. Pt 1 Ag 18 ‐I for short.) crystal achieving a record‐low among cluster‐based active optical waveguides value of 6.4 × 10 −4 dB µm −1 . We establish quantitative positive correlations between waveguide performance and four key photophysical parameters: photoluminescence quantum yield, lifetime, refractive index, and polarization degree. This work provides a quantitative empirical structure–activity relationship (SAR) model for designing advanced photonic materials, bridging atomic‐scale precision with macroscopic optical device functionality for next‐generation integrated photonics.
Heat stress-induced photosynthetic impairment and autophagy modulation in Paris polyphylla var. yunnanensis: A physiological and molecular Perspective
High temperature is one of the major environmental stressors that severely affects plant growth. Paris polyphylla var. yunnanensis , a traditional Chinese herbal medicine, is sensitive to high temperature. However, the underlying mechanisms of its response to high temperature remain unclear. In this study, we investigated the physiological and proteomic change of P. polyphylla var. yunnanensis under different treatments (25°C, 30°C, 35°C, 40°C). Our results showed that high temperature directly impaired photosynthesis and disrupted metabolism, evidenced by reduced chlorophyll and photosynthetic rate, as well as accumulated proline and increased conductivity. A total of 893 differentially expressed proteins (DEPs) were identified, with significant changes in the expression levels of enzymes associated with protein processing and synthesis. Additionally, the expression levels of key proteins involved in the circadian pathway and the glutathione pathway were also notably upregulated. Dynamic changes in the endocytosis and autophagy-related proteins ATG3 and ATG8C were also observed, suggesting that these processes may play a significant protective role under high-temperature stress. Overall, this study provides an important starting point for improving the heat tolerance of P.polyphylla var. yunnanensis through genetic engineering.
In Situ Sonoafterglow Supramolecular Hydrogel From Natural Substrate for Post‐Surgical Glioblastoma Treatment
ABSTRACT Fluorescence imaging suffers from substantial background interference and a low signal‑to‑background ratio due to real‑time excitation. In contrast, afterglow luminophores enable prolonged emission after excitation ceases, effectively suppressing biological background noise and enhancing the imaging signal‑to‑background ratio. However, existing afterglow probes are largely limited to nanoparticles of semiconducting polymer or synthetic organic molecules, with no report of a natural‐product‐derived afterglow system in hydrogel form. This study pioneers the discovery that chlorogenic acid (CA), a natural antitumor agent, exhibits unique sonoafterglow properties. This finding prompted the design of a CA prodrug capable of self‑assembling in water into a CA‑based supramolecular hydrogel—representing the first example of a sonoafterglow hydrogel rather than conventional nanoparticle formulations. The VP@Pro‑CA gel formulation, which incorporates the sonosensitizer verteporfin (VP), allows post‑operative local injection for sonodynamic therapy (SDT) to prevent glioblastoma (GBM) recurrence. Crucially, the ONOO − ‑triggered afterglow emission enables real‑time therapeutic monitoring, demonstrating exceptional potential for GBM theranostics. Notably, CA constitutes a novel class of biosafe, small‑molecule sonoafterglow substrates with intrinsic pharmacological activity, offering unparalleled advantages for clinical translation in this emerging field.
Analysis of the work, health and well-being experience of immigrant personal support workers in minority language contexts in Canada: Scoping review protocol
Background The aging Canadian population has led to an increase in Canada’s use of home and community care services. In this context, the healthcare system relies heavily on personal support workers who work in various healthcare settings. A significant proportion of these workers are immigrants, and many live in linguistic minorities. Despite their pivotal role, the experiences and working conditions of these personal support workers are underrepresented in the scientific literature, specifically in intersectional analyses. This scoping review aims to examine the work experiences, health conditions, and well-being of immigrant personal support workers in Canada who work in a minority language setting. Eligibility criteria Studies addressing the work experiences, health conditions, and well-being of immigrant personal support workers in Canada who work in a minority language setting, and those published in English or French. There will have no restrictions on publication date. Method This review will follow the JBI recommendations for scoping reviews and incorporate the PRISMA-ScR checklist. We will develop an adapted search strategy for five relevant databases (Medline [Ovide], Web of Science, Embase, CINAHL, and Google Scholar). Two independent reviewers will select full-text articles based on pre-established inclusion criteria and extracted relevant data. The results will be presented in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews) guidelines. This scoping review contributes to expanding knowledge about the professional, health, and social realities of immigrant PSWs in Canada’s linguistic minority communities.
Ultrafine Iridium‐Oxide Solid Solutions for Efficient Acidic Water Oxidation
ABSTRACT The high cost and inadequate catalytic performance of IrO 2 are primary factors hindering the development of proton exchange membrane water electrolyzer (PEMWE). Herein, we propose dual criteria of cohesive energy ( ΔCE ) and atomic radius ( ΔR ) discrepancies between Ir and heteroatoms for guiding the synthesis of ultrafine IrO 2 ‐based solid solutions (M x Ir 1−x O 2 ). Elements of Mo and W with lowest ΔCE and ΔR exhibit the most facilitated alloying with Ir and minimized particle coarsening, enabling the fabrication of sub‐3 nm M x Ir 1−x O 2 (x = 33.3%−50%). The extensive Mo substitution in Mo 1/3 Ir 2/3 O 2 effectively modulates Ir─O covalency and generates abundant Brønsted acid sites as proton acceptors. These factors synergistically accelerate the deprotonation of *OH and *OOH and promote rapid proton transfer, thereby significantly reducing the energy barrier of oxygen evolution reaction (OER) and alleviating the proton accumulation‐induced site poisoning. Resultantly, Mo 1/3 Ir 2/3 O 2 delivers a low overpotential of 540 mV at 1 A cm −2 and an excellent stability of 700 h. PEMWE using Mo 1/3 Ir 2/3 O 2 achieves a high current density of 3 A cm −2 at 2.26 V and steadily operates at 1 A cm −2 for 625 h. This work transcends traditional hetero‐element doping paradigm for IrO 2 modification, offering a new perspective for developing high‐performance and low‐iridium OER catalysts.
Veterinarian–pharmacist collaboration in veterinary medicine: Roles, practices, and perceptions—A scoping review
Background Pharmacists are expanding their participation in veterinary healthcare teams and assuming roles beyond traditional dispensing duties. However, the scope of these collaborative practices and the degree of mutual recognition vary substantially across regions. Objectives This scoping review aimed to organize the existing literature on collaboration between veterinarians and pharmacists, clarifying current roles, practical applications, and professional perceptions within the veterinary field. Methods A scoping review was conducted to examine the roles, practices, and perceptions associated with veterinarian–pharmacist collaboration in veterinary medicine and related fields. Two researchers independently searched PubMed, Web of Science, the Cochrane Library, and Ichushi-Web, and additionally screened Google Scholar to identify gray literature (from database inception to August 2025, in English or Japanese). Records were independently screened at the title/abstract and full-text levels using predefined eligibility criteria, and relevant studies were identified. Results The search yielded 239 records, of which 16 studies published between 2007 and 2024 were included. Studies were conducted primarily in the United States (n = 7), New Zealand (n = 3), and Japan (n = 3); one study collected data from both Japan and Taiwan. Most studies employed cross-sectional survey designs. Pharmacist roles most frequently involved compounding and dispensing for animal patients (62.5%), followed by drug information (DI) and consultation (37.5%), inventory and supply management (25.0%), client education (18.8%), and safety and exposure control (12.5%). Conclusions This scoping review demonstrates that veterinarian–pharmacist collaboration is described within a limited and regionally variable evidence base, with pharmacists most often contributing through compounding/dispensing and drug information support. Sustained and scalable implementation will require improved mutual understanding of professional roles, strengthened veterinary-specific education for pharmacists, and more robust empirical research to inform collaborative practice models.
Pt Nanoplates Interfaced by Atomic CrO <sub>x</sub> Layer Enable High‐Power‐Density and Durable PEM Fuel Cells
ABSTRACT The dissolution of Pt‐based alloy catalysts remains a formidable challenge for oxygen reduction reaction (ORR) in proton exchange membrane fuel cells. Herein, we report a new stage‐dependent competitive adsorption synthetic strategy for making 2D Pt nanoplates interfaced by a stable, atomic‐layer CrO x (Pt–CrO x NPs). This strategy leverages strong Pt–CrO x electronic interactions to fundamentally suppress Pt dissolution and meantime greatly enhance ORR activity. The resulting Pt–CrO x NPs demonstrate exceptional electrochemical stability with a negligible 3.3% decline in mass activity after 30,000 cycles, significantly outperforming commercial Pt/C. Furthermore, the Pt–CrO x NPs‐based membrane electrode assembly in an H 2 ‐O 2 /air cell delivers an outstanding peak power density of 2.30/1.05 W cm −2 with a low cathode Pt loading of 0.1 mg Pt cm −2 , and 16 mV voltage loss at 0.8 A cm −2 after accelerated stability tests. Density functional theory (DFT) calculations further unveil that the Pt–CrO x interface weakens the binding of oxygenated intermediates to Pt and significantly increases the Pt vacancy formation energy, consequently suppressing Pt dissolution and contributing to superior fuel cells durability.
Counterion Dynamics in Chiral Supramolecular Polymerization
ABSTRACT Counterions have been studied in a broad range of chemical and biological systems, and their effects are typically evaluated by comparing different ionic species. However, the dynamic effects of a single counterion within a given system remain poorly understood. In this study, we demonstrate that counterion dynamics governs assembly pathways and chirality in supramolecular polymerization. To investigate this phenomenon, we designed dicationic tetrapyridyl Pd(II) complexes bearing two BF 4 − counterions, amide groups for hydrogen bonding, and either S ‐ or R ‐chiral side chains, and studied their supramolecular polymerization in nonpolar media. Under kinetic conditions, the S ‐chiral complex initially self‐assembles into nanoparticle‐like metastable aggregates (AggI) , which over time evolve into thermodynamically controlled supramolecular polymers (AggII) with inverted chiroptical signal through a competitive pathway. Spectroscopic, microscopic, and computational studies indicate that subtle changes in the position of the BF 4 − counterions modulate the packing of the π‐extended pyridine ligands and the hydrogen‐bonding arrangement, giving rise to distinct asymmetry amplification behavior and supramolecular chirality. These findings demonstrate that a single counterion can direct pathway‐dependent supramolecular polymerization into distinct helical states, highlighting the crucial role of charge desolvation and dynamics in governing supramolecular self‐assembly.
A Mechanical Planar Chiral Rotaxane Induces Single‐Handed Helicity in a Twisted Perylene Diimide
ABSTRACT The twisting of chromophores such as perylene diimides (PDIs) into helical structures affords chiroptical properties from discrete molecules, which are of significant value for chiral sensing, imaging and catalysis. Since most helical PDI derivatives are susceptible to racemisation, chiral induction provides a promising, yet underdeveloped, strategy for generating materials with persistent chiroptical properties. For the first time, we use a mechanically planar chiral rotaxane as a configurationally stable chirality source to induce single‐handed helicity in a molecular chromophore, yielding persistent circular dichroism and circularly polarised luminescence. The large π‐surface of the PDI also enables rotaxane self‐assembly, which is rare among mechanically interlocked molecules. While mechanical bonding is shown to influence the geometry of the resulting PDI dimers, mechanical planar chirality directs their handedness, thereby providing control at both the molecular and supramolecular levels.
Spontaneous Long‐Range Order and Alignment in Phase‐Separated Dynamic Covalent Networks Using Discrete Siloxanes
ABSTRACT For the first time, dynamic covalent networks are prepared that show spontaneous alignment and long‐range hexagonal columnar ordering. This is a consequence of the phase‐separation between the siloxane linkers and dynamic covalent acylsemicarbazide bonds that induce hydrogen bonding. The use of discrete siloxane linkers is crucial, as networks based on disperse siloxanes do not give ordered or aligned network structures. Optimization of the siloxane length is key in achieving the most pronounced effect. Interestingly, the optimized ordered networks are obtained through simple solvent evaporation, allowing to introduce near‐perfect homeotropic alignment as imaged with transmission electron microscopy and corroborated with grazing incidence small angle x‐ray scattering. The ordered network has improved (thermo)mechanical properties compared to the disordered networks. Additionally, order in the system slows down the network dynamics and improves creep resistance. We prepare actuators in a straightforward fashion by combining ordered and disordered networks, removing the need for any alignment step and simplifying the overall process significantly.
Spatially Coupled Cl <sub>2</sub> Confinement and Activation at Curved Ni Single‐Atom Sites for Highly Reversible Li–Cl <sub>2</sub> Batteries
ABSTRACT Leveraging the high‐potential Cl 2 /LiCl redox couple (∼3.6 V), rechargeable Li‐Cl 2 batteries hold compelling promise for next‐generation energy storage. However, their practical viability is severely impeded by poor Cl 2 retention and sluggish conversion kinetics, particularly under deep‐cycling and high‐rate regimes. Here, we present a spatially coupled Cl 2 ‐management cathode that integrates Cl 2 confinement and short‐range transport within a micropore‐rich matrix with spontaneous activation at dense pore wall‐anchored, curved Ni single‐atom sites. Via this closed‐loop pathway from Cl 2 storage to LiCl deposition, the Li‐Cl 2 battery achieves a remarkable 1.21 V polarization reduction at 1500 mAh g −1 cut‐off capacity at 2000 mA g −1 . Consequently, an ultrahigh cumulative capacity exceeding 1.0 million mAh g −1 , which doubles the lifespan of state‐of‐the‐art Li‐Cl 2 systems, is achieved through the integrated approach incorporating this pathway, the robust, partially graphitized support, and an optimized discharge‐cutoff protocol. Furthermore, the exceptional all‐climate robustness (–40°C to +70°C), coupled with a high reversible areal capacity of 7.65 mAh cm −2 in pouch cells, establishes a new paradigm for practical, high‐energy storage systems.
Impact of AI Agents on the Thinking Process of Students in the Indian Education System
Artificial Intelligence (AI) agents are rapidly transforming the educational environment by influencing the way students learn, think, and solve problems. This paper examines the impact of AI agents on the thinking process of students in the Indian education system. The study discusses the growing use of AI tools such as ChatGPT, Gemini, and coding assistants for academic writing, learning support, research, and problem-solving. It highlights both the positive and negative effects of AI on students. AI agents improve access to information, personalized learning, productivity, and digital skills, while excessive dependence on these tools may reduce critical thinking, creativity, independent learning, and problem-solving abilities. The paper also examines ethical concerns such as plagiarism, misinformation, privacy risks, and academic dishonesty. The study concludes that balanced and responsible integration of AI in education is necessary to ensure that technology supports rather than replaces human thinking and intellectual development.
An Explainable Hybrid Artificial Intelligence Approach for Robust Image Forgery Detection and Authentication Using Cognitive Image Authenticity Intelligence Engine
An image manipulation develop rapidly and AI-based tools become popular among image editors allowing manipulations of high complexity and posing risks to digital forensics, journalism investigation, medicine and cyber security, the problem of image forgery detection becomes increasingly important. At present, the algorithms used in the field of image forgery detection and authentication sufferfrom the following shortcomings.It was designed to detect particular type of image manipulations, have poor generalizability to heterogeneous data sets, require significant computing resources and do not provide for explain ability of decisions made. To achieve, this research proposes to apply the concept of Cognitive Image Authenticity Intelligence Engine (CIAIE) an explainable hybrid artificial intelligence algorithm designed for the image forgery detection and authentication. The proposed algorithm utilizes such technologies as Principal Component Analysis (PCA), Conventional Neural Network (CNN), Vision Transformer (ViT), U-Net, Extreme Gradient Boosting (XGBoost), and Explainable AI (XAI) for dimensionality reduction, feature extraction, forgery localization, authenticity classification and decision making. The experimental evaluation carried out in Python showed the superior performance of the proposed approach with the accuracy of 94.68%. The proposed method was capable of achieving accurate, interpretable, and computationally efficient real-time image authentication, making it appropriate for many digital forensic and cyber security purposes.
GIRK Channels Regulate Circadian Rhythms of Excitability in Prokineticin 2 Neurons of the Suprachiasmatic Nucleus and Modulate Behavioral Circadian Rhythms
The suprachiasmatic nucleus (SCN), the central circadian clock in mammals, generates robust yet adaptable circadian rhythms through electrically mediated coordination among heterogeneous peptidergic neuronal populations with presumed cell type-specific roles. Previous studies have proposed that circadian changes in membrane excitability of individual SCN neurons arise from time-of-day-dependent shifts in the relative balance of subthreshold Na⁺ and K⁺ conductances. Although multiple channels have been implicated in these processes, how nocturnally dominant K⁺ conductances are implemented in a cell type-specific manner remains poorly understood. Prokineticin 2 (Prok2) has been identified as a SCN signaling peptide essential for behavioral circadian regulation; however, the electrophysiological properties of Prok2-expressing neurons and the mechanisms underlying their diurnal rhythmicity remain largely unexplored. Here, using electrophysiological approaches in mice of either sex, we show that Prok2 neurons exhibit diurnal variations in electrical properties, with higher excitability during the day and reduced excitability at night, and that G protein-coupled inwardly rectifying potassium (GIRK) channel-mediated basal current contributes to nighttime hyperpolarization. Immunofluorescence and single-cell RT-PCR analyses revealed that GIRK1 and GIRK3 are the predominant GIRK subunits expressed in Prok2 neurons. Moreover, Prok2 neuron-specific deletion of GIRK3 using in vivo genome editing resulted in significant nocturnal depolarization and induced abnormalities in behavioral rhythms, including delayed activity onset and circadian period lengthening, with altered SCN network activity. Together, these findings suggest that tonic, G protein-dependent regulation of GIRK channels provides a night-specific inhibitory mechanism that contributes to intrinsic diurnal neuronal excitability in Prok2 neurons and supports the regulation of behavioral circadian rhythms. Significance Statement In the mammalian suprachiasmatic nucleus, neuronal populations expressing distinct peptides interact through coordinated electrical activity to generate circadian rhythms. However, the ion channel mechanisms underlying diurnal rhythmicity of electrical activity in functionally distinct cell types remain incompletely understood. Here, using a comprehensive approach, we identify G protein-coupled inwardly rectifying potassium (GIRK) channels as a key determinant of nocturnal hyperpolarization in prokineticin 2 (Prok2)-expressing neurons, regulatory nodes involved in behavioral circadian rhythms. We further demonstrate that Prok2 neuron-specific loss of the GIRK3 subunit alters behavioral rhythms. These findings suggest that G protein-dependent regulation of GIRK channels is a key mechanism underlying diurnally patterned intrinsic electrical activity in Prok2 neurons and contributes to behavioral circadian rhythms.
Unpacking Ventral Pallidum GABA Neuron Contributions to Opioid Drug Reward in Rats
Addiction is a heterogeneous disorder, and the specific psychological processes and neural mechanisms involved are hard to parse in humans. Animal models are useful in this regard, as biological substrates of addiction-relevant behaviors can be examined one at a time. Ventral pallidum GABAergic neurons (VP GABA ), are key players in circuits underlying natural and drug reward, but the exact behavioral processes to which they contribute are still not precisely defined. Here we systematically examined the necessity of VP GABA neurons for opioid and food reward seeking and taking behaviors, using reversible chemogenetic inhibition in GAD1:Cre, predominately female, rats. We found that VP GABA inhibition revealed their preferential roles in highly-motivated pursuit and choice of heroin, but lesser involvement in unconditioned heroin effects, or in similarly motivated pursuit and choice of another rewarding opioid drug, remifentanil. Specifically, inhibiting VP GABA decreased cued- but not heroin-primed reinstatement of heroin seeking, decreased progressive ratio heroin pursuit, and increased selection of heroin over food when rats were forced to choose. In contrast, VP GABA inhibition did not alter remifentanil progressive ratio or choice of remifentanil over food, nor did it affect locomotion or food intake after heroin, or general arousal or anxiety-like states. These findings reveal a previously underappreciated specificity in the functions of VP GABA neurons, and show they may play distinct roles in overtly similar behaviors rewarded by different classes of opioid drugs. Results also highlight the usefulness, when investigating the biological substrates of addiction, of parsing heterogeneities not just in neural circuits, but also in the specific behavioral processes they mediate. Significance Statement Opioid addiction is a heterogeneous disorder, which makes it difficult to pinpoint the neural processes underlying its various components. Here we show that VP GABA neurons play surprisingly specific roles in behaviors relevant to opioid use disorder. VP GABA inhibition selectively reduced choice of heroin over food, highly-motivated heroin progressive ratio self-administration, and cue-triggered reinstatement, yet spared other heroin-induced behaviors. In contrast, closely matched behaviors motivated by the similarly-reinforcing fentanyl derivative remifentanil including choice of remifentanil over food, were spared. These results reveal unexpected reward- and process-specific functions of VP GABA neurons, highlighting the importance of comprehensive behavioral profiling in such experiments for identifying how neural mechanisms depend upon particular drugs and behavioral models—an essential step toward developing effective addiction interventions.