Activated dormant stem cells recover spermatogenesis in chemoradiotherapy-induced infertility.

Male infertility is a recognized side effect of chemoradiotherapy. Extant spermatogonial stem cells (SSCs) may act as originators for any subsequent recovery. However, which type of SSCs, the mechanism by which they survive and resist toxicity, and how they act to restart spermatogenesis remain largely unknown. Here, we identify a small population of Set domain-containing protein 4 (Setd4)-expressing SSCs that occur in a relatively dormant state in the mouse seminiferous tubule. Extant beyond high-dose chemoradiotherapy, these cells then activate to recover spermatogenesis. Recovery fails when Setd4+ SSCs are deleted. Confirmed to be of fetal origin, these Setd4+ SSCs are shown to facilitate early testicular development and also contribute to steady-state spermatogenesis in adulthood. Upon activation, chromatin remodeling increases their genome-wide accessibility, enabling Notch1 and Aurora activation with corresponding silencing of p21 and p53. Here, Setd4+ SSCs are presented as the originators of both testicular development and spermatogenesis recovery in chemoradiotherapy-induced infertility.

Advances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion.

Acute myocardial infarction (AMI) is the leading cause of death worldwide, and reperfusion therapy is a critical therapeutic approach to reduce myocardial ischemic injury and minimize infarct size. However, ischemia/reperfusion (I/R) itself also causes myocardial injury, and inflammation is an essential mechanism by which it leads to myocardial injury, with macrophages as crucial immune cells in this process. Macrophages are innate immune cells that maintain tissue homeostasis, host defence during pathogen infection, and repair during tissue injury. During the acute phase of I/R, M1-type macrophages generate a pro-inflammatory milieu, clear necrotic myocardial tissue, and further recruit mononuclear (CCR2+) macrophages. Over time, the reparative (M2 type) macrophages gradually became dominant. In recent years, metabolic studies have shown a clear correlation between the metabolic profile of macrophages and their phenotype and function. M1-type macrophages are mainly characterized by glycolytic energy supply, and their tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS) processes are impaired. In contrast, M2 macrophages rely primarily on OXPHOS for energy. Changing the metabolic profile of macrophages can alter the macrophage phenotype. Altered energy pathways are also present in macrophages during I/R, and intervention in this process contributes to earlier and greater M2 macrophage infiltration, which may be a potential target for the treatment of myocardial I/R injury. Therefore, this paper mainly reviews the characteristics of macrophage energy metabolism alteration and phenotypic transition during I/R and its mechanism of mediating myocardial injury to provide a basis for further research in this field.

Evaluating the Accelerated BSN Program at the University of Washington and Its Potential for Implementation in China.

Nurses are the largest group in the health care system. The current care shortage remains a global challenge in the healthcare system.The accelerated second-degree nursing (ABSN) program was first proposed by the University of St.Louis in 1971 and then vigorously developed in the United States. Its purpose is to train more nursing talents to solve the medical needs of the poor in the United States. In the past few decades, this project has been carried out by many countries around the world to solve their domestic nursing problems.As a strategy to address severe care shortages, ABSN is continuing to increase rapidly.China as the world's second most populous country, coupled with aging year by year, the demand for nursing talents, and the ABSN project just gave China effective inspiration.Therefore, this article introduces the basic design of the bachelor's degree in nursing at the University of Washington, summarizes the characteristics of the training model, and draws on experience from the basic situation, training objectives, courses and evaluation methods. It is urgent to provide guidance and reference for the acceleration of nursing education in China.

Chiral Supramolecular Self-Assembly Catalysts with Enhanced Metal Ion Interaction for Higher Enantioselectivity.

Understanding the interaction between metal ions as catalytic centers and supramolecular scaffolds as chiral substrates plays an important role in developing chiral supramolecular catalysts with high enantioselectivity. Herein, we found that compared with l-norleucine chiral amphiphile (l-NorC16), l-methionine chiral amphiphile (l-MetC16) with the only heteroatom of S site difference in the hydrophilic group can form a similar supramolecular chiral nanoribbon (NR) with the bilayer structure through the self-assembly approach; yet, the interaction between the Cu(II) ion catalytic centers and supramolecular scaffolds is reinforced, favoring the chirality transfer and therefore enhancing their catalytic enantioselectivity of Diels-Alder reaction from 23% [l-NorC16-NR-Cu(II)] to 78% [l-MetC16-NR-Cu(II)]. Our work demonstrates a new strategy from the perspective of strengthening the metal ion-supramolecular scaffold interaction for the preparation of chiral supramolecular catalysts with good catalytic enantioselectivity.

Presynaptic and Postsynaptic Mesolimbic Dopamine D3 Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice.

BACKGROUND: Past research has illuminated pivotal roles of dopamine D3 receptors (D3R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear. METHODS: We employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1 receptor (D1R)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D3R in cocaine and opioid actions. RESULTS: Our results revealed D3R expression in ∼25% of midbrain dopamine neurons and ∼70% of D1R-expressing neurons in the nucleus accumbens. While dopamine D2 receptors (D2R) were expressed in ∼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D3R from D1R-expressing neurons attenuated locomotor responses to D1-like and D2-like agonists. Strikingly, deletion of D3R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D3R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D3R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D1R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. CONCLUSIONS: We dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D3R are critically involved in the actions of opioids but not cocaine.

Involvement of dopamine D3 receptor in impulsive choice decision-making in male rats.

Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear. In this study, we used a food reward delay-discounting task (DDT) to identify low- and high-impulsive rats, in which low-impulsive rats exhibited preference for large delayed reward over small immediate rewards, while high-impulsive rats showed the opposite preference. We then examined D1, D2, and D3 receptor gene expression using RNAscope in situ hybridization assays. We found that high-impulsive male rats exhibited lower levels of D2 and D3, and particularly D3, receptor expression in the nucleus accumbens (NAc), with no significant changes in the insular, prelimbic, and infralimbic cortices. Based on these findings, we further explored the role of the D3 receptor in impulsive decision-making. Systemic administration of a selective D3 receptor agonist (FOB02-04) significantly reduced impulsive choices in high-impulsive rats but had no effects in low-impulsive rats. Conversely, a selective D3 receptor antagonist (VK4-116) produced increased both impulsive and omission choices in both groups of rats. These findings suggest that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, may hold therapeutic potentials for mitigating impulsivity in high-impulsive subjects.

Crystal Facet Controlled Metal-Support Interaction in Uricase Mimics for Highly Efficient Hyperuricemia Treatment.

The effect of strong metal-support interaction (SMSI) has never been systematically studied in the field of nanozyme-based catalysis before. Herein, by coupling two different Pd crystal facets with MnO2, i.e., (100) by Pd cube (Pdc) and (111) by Pd icosahedron (Pdi), we observed the reconstruction of Pd atomic structure within the Pd-MnO2 interface, with the reconstructed Pdc (100) facet more disordered than Pdi (111), verifying the existence of SMSI in such coupled system. The rearranged Pd atoms in the interface resulted in enhanced uricase-like catalytic activity, with Pdc@MnO2 demonstrating the best catalytic performance. Theoretical calculations suggested that a more disordered Pd interface led to stronger interactions with intermediates during the uricolytic process. In vitro cell experiments and in vivo therapy results demonstrated excellent biocompatibility, therapeutic effect, and biosafety for their potential hyperuricemia treatment. Our work provides a brand-new perspective for the design of highly efficient uricase-mimic catalysts.

Expression of chiral molecular and supramolecular structure on enantioselective catalytic activity.

Understanding the structure-function relationships encoded on chiral catalysts is important for investigating the fundamental principles of catalytic enantioselectivity. Herein, the synthesis and self-assembly of naphthalene substituted bis-l/d-histidine amphiphiles (bis-l/d-NapHis) in DMF/water solution mixture is reported. The resulting supramolecular assemblies featuring well-defined P/M nanoribbons (NRs). With combination of the (P/M)-NR and metal ion catalytic centers (Mn+ = Co2+, Cu2+, Fe3+), the (P)-NR-Mn+ as chiral supramolecular catalysts show catalytic preference to 3,4-dihydroxy-S-phenylalanine (S-DOPA) oxidation while the (M)-NR-Mn+ show enantioselective bias to R-DOPA oxidation. In contrast, their monomeric counterparts bis-l/d-NapHis-Mn+ display an inverse and dramatically lower catalytic selectivity in the R/S-DOPA oxidation. Among them, the Co2+-coordinated supramolecular nanostructures show the highest catalytic efficiency and enantioselectivity (select factor up to 2.70), while the Fe3+-coordinated monomeric ones show nearly racemic products. Analysis of the kinetic results suggests that the synergistic effect between metal ions and the chiral supramolecular NRs can significantly regulate the enantioselective catalytic activity, while the metal ion-mediated monomeric bis-l/d-NapHis were less active. The studies on association constants and activation energies reveal the difference in catalytic efficiency and enantioselectivity resulting from the different energy barriers and binding affinities existed between the chiral molecular/supramolecular structures and R/S-DOPA enantiomers. This work clarifies the correlation between chiral molecular/supramolecular structures and enantioselective catalytic activity, shedding new light on the rational design of chiral catalysts with outstanding enantioselectivity.

Phenylglycine amphiphile-metal ion chiral supramolecular nanozymes for enantioselective catalysis.

L/D-Phenylglycine amphiphiles and metal ions with peroxidase-like activity self-assembled into chiral nanoribbons, which act as efficient chiral supramolecular nanozymes for catalyzing the 3,4-dihydroxy-L/D-phenylalanine (L/D-DOPA) oxidation reactions. The catalytic efficiency and enantioselectivity are dominated by the chirality transfer and the synergistic effect between the metal ions and chiral nanoribbons.

ß-caryophyllene inhibits heroin self-administration, but does not alter opioid-induced antinociception in rodents.

A growing body of research indicates that ß-caryophyllene (BCP), a constituent present in a large number of plants, possesses significant therapeutic properties against CNS disorders, including alcohol and psychostimulant use disorders. However, it is unknown whether BCP has similar therapeutic potential for opioid use disorders. In this study, we found that systemic administration of BCP dose-dependently reduced heroin self-administration in rats under an FR2 schedule of reinforcement and partially blocked heroin-enhanced brain stimulation reward in DAT-cre mice, maintained by optical stimulation of midbrain dopamine neurons at high frequencies. Acute administration of BCP failed to block heroin conditioned place preference (CPP) in male mice, but attenuated heroin-induced CPP in females. Furthermore, repeated dosing with BCP for 5 days facilitated the extinction of CPP in female but not male mice. In the hot plate assay, pretreatment with the same doses of BCP failed to enhance or prolong opioid antinociception. Lastly, in a substitution test, BCP replacement for heroin failed to maintain intravenous BCP self-administration, suggesting that BCP itself has no reinforcing properties. These findings suggest that BCP may have certain therapeutic effects against opioid use disorders with fewer unwanted side-effects by itself.

AM6527, a neutral CB1 receptor antagonist, suppresses opioid taking and seeking, as well as cocaine seeking in rodents without aversive effects.

Preclinical research has demonstrated the efficacy of CB1 receptor (CB1R) antagonists in reducing drug-taking behavior. However, clinical trials with rimonabant, a CB1R antagonist with inverse agonist profile, failed due to severe adverse effects, such as depression and suicidality. As a result, efforts have shifted towards developing novel neutral CB1R antagonists without an inverse agonist profile for treating substance use disorders. Here, we assessed AM6527, a CB1R neutral antagonist, in addiction animal models. Our findings revealed that AM6527 did not affect cocaine self-administration under fixed-ratio reinforcement schedules but dose-dependently inhibited it under progressive-ratio reinforcement schedules. Additionally, AM6527 dose-dependently inhibited heroin self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and oral sucrose self-administration under a fixed-ratio reinforcement schedule, as well as cocaine- or heroin-triggered reinstatement of drug-seeking behavior in rats. However, chronic AM6527 administration for five consecutive days significantly inhibited heroin self-administration only during the initial two days, indicating tolerance development. Notably, AM6527 did not produce rewarding or aversive effects by itself in classical electrical intracranial self-stimulation and conditioned place preference tests. However, in optical intracranial self-stimulation (oICSS) maintained by optogenetic stimulation of midbrain dopamine neurons in DAT-cre mice, both AM6527 and rimonabant dose-dependently inhibited dopamine-dependent oICSS behavior. Together, these findings suggest that AM6527 effectively reduces drug-taking and seeking behaviors without rimonabant-like adverse effects. Thus, AM6527 warrants further investigation as a potential pharmacotherapy for opioid and cocaine use disorders.

The selective D3Receptor antagonist VK4-116 reverses loss of insight caused by self-administration of cocaine in rats.

Chronic psychostimulant use causes long-lasting changes to neural and cognitive function that persist after long periods of abstinence. As cocaine users transition from drug use to abstinence, a parallel transition from hyperactivity to hypoactivity has been found in orbitofrontal-striatal glucose metabolism and striatal D2/D3-receptor activity. Targeting these changes pharmacologically, using highly selective dopamine D3-receptor (D3R) antagonists and partial agonists, has shown promise in reducing drug-taking, and attenuating relapse in animal models of cocaine and opioid use disorder. However, much less attention has been paid to treating the loss of insight, operationalized as the inability to infer likely outcomes, associated with chronic psychostimulant use. Here we tested the selective D3R antagonist VK4-116 as a treatment for this loss in rats with a prior history of cocaine use. Male and female rats were first trained to self-administer cocaine or a sucrose liquid for 2 weeks. After 4 weeks of abstinence, performance was assessed using a sensory preconditioning (SPC) learning paradigm. Rats were given VK4-116 (15 mg/kg, i.p.) or vehicle 30 min prior to each SPC training session, thus creating four drug-treatment groups: sucrose-vehicle, sucrose-VK4-116, cocaine-vehicle, cocaine-VK4-116. The control groups (sucrose-vehicle, sucrose-VK4-116) showed normal sensory preconditioning, whereas cocaine use (cocaine-vehicle) selectively disrupted responding to the preconditioned cue, an effect that was reversed in the cocaine-VK4-116 group, which demonstrating responding to the preconditioned cue at levels comparable to controls. These preclinical findings demonstrate that highly selective dopamine D3R antagonists, particularly VK4-116, can reverse the long-term negative behavioral consequences of cocaine use.

Optical Intracranial Self-Stimulation (oICSS): A New Behavioral Model for Studying Drug Reward and Aversion in Rodents.

Brain-stimulation reward, also known as intracranial self-stimulation (ICSS), is a commonly used procedure for studying brain reward function and drug reward. In electrical ICSS (eICSS), an electrode is surgically implanted into the medial forebrain bundle (MFB) in the lateral hypothalamus or the ventral tegmental area (VTA) in the midbrain. Operant lever responding leads to the delivery of electrical pulse stimulation. The alteration in the stimulation frequency-lever response curve is used to evaluate the impact of pharmacological agents on brain reward function. If a test drug induces a leftward or upward shift in the eICSS response curve, it implies a reward-enhancing or abuse-like effect. Conversely, if a drug causes a rightward or downward shift in the functional response curve, it suggests a reward-attenuating or aversive effect. A significant drawback of eICSS is the lack of cellular selectivity in understanding the neural substrates underlying this behavior. Excitingly, recent advancements in optical ICSS (oICSS) have facilitated the development of at least three cell type-specific oICSS models-dopamine-, glutamate-, and GABA-dependent oICSS. In these new models, a comparable stimulation frequency-lever response curve has been established and employed to study the substrate-specific mechanisms underlying brain reward function and a drug's rewarding versus aversive effects. In this review article, we summarize recent progress in this exciting research area. The findings in oICSS have not only increased our understanding of the neural mechanisms underlying drug reward and addiction but have also introduced a novel behavioral model in preclinical medication development for treating substance use disorders.

Polyvinylpyrrolidone-Coated Cubic Hollow Nanocages of PdPt3 and PdIr3 as Highly Efficient Self-Cascade Uricase/Peroxidase Mimics.

Uricase-catalyzed uric acid (UA) degradation has been applied for hyperuricemia therapy, but this medication is limited by H2O2 accumulation, which can cause oxidative stress of cells, resulting in many other health issues. Herein, we report a robust cubic hollow nanocage (HNC) system based on polyvinylpyrrolidone-coated PdPt3 and PdIr3 to serve as highly efficient self-cascade uricase/peroxidase mimics to achieve the desired dual catalysis for both UA degradation and H2O2 elimination. These HNCs have hollow cubic shape with average wall thickness of 1.5 nm, providing desired synergy to enhance catalyst's activity and stability. Density functional theory calculations suggest the PdIr3 HNC surface tend to promote OH*/O* desorption for better peroxidase-like catalysis, while the PdPt3 HNC surface accelerates the UA oxidation by facilitating O2-to-H2O2 conversion. The dual catalysis power demonstrated by these HNCs in cell studies suggests their great potential as a new type of nanozyme for treating hyperuricemia.

GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice.

G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆9-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.

Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

Ultrahigh-Q and angle-robust chiroptical resonances beyond BIC splitting.

Chiroptical resonances inspired by bound states in the continuum (BICs) open a new, to the best of our knowledge, avenue to enhance chiral light-matter interaction. Symmetry breaking is the widely employed way, wherein the circularly polarized states (CPSs) arise from BIC splitting. Here, we utilize a far-field interference mechanism to create ultrahigh-Q (typically, 2.36 × 106) chiroptical resonance beyond BIC splitting, in which CPSs coexist with BICs in the momentum space. Accordingly, the spin-selective absorption with ultranarrow linewidth is achieved at the CPS points, which can be regulated by monolayer transition metal dichalcogenides (TMDCs). In addition, the chiral response of our scheme exhibits the incident-direction robustness and flexible tunability. Our findings may facilitate potential applications in light manipulation, spin-valley interaction, and chiral sensing.

Self-Assembled Metal-Coordination Nanohelices as Efficient and Robust Chiral Supramolecular Catalysts for Enantioselective Reactions.

The development of chiral nanostructures-based supramolecular catalysts with satisfied enantioselectivity remains a significantly more challenging task. Herein, the synthesis and self-assembly of various amino acid amphiphiles as chiral supramolecular catalysts after metal ion coordination is reported and systematically investigate their enantioselectivity in asymmetric Diels-Alder reactions. In particular, the self-assembly of l/d-phenylglycine-based amphiphiles (l/d-PhgC16) and Cu(II) into chiral supramolecular catalysts in the methanol/water solution mixture is described, which features the interesting M/P nanohelices (diameter ≈8 nm) and mostly well-aligned M/P nanoribbons (NRs). The M/P supramolecular catalysts show both high but inverse enantioselectivity (>90% ee) in Diels-Alder reactions, while their monomeric counterparts display nearly racemic products. Analysis of the catalytic results suggests the outstanding enantioselectivities are closely related to the specific stereochemical microenvironment provided by the arrangement of the amphiphiles in the supramolecular assembly. Based on the experimental evidence of chirality transfer from supramolecular nanohelices to coordinated Cu(II) and substrate aza-chalcone and the molecular dynamics simulations, the enantioselective catalytic mechanisms are proposed. Moreover, the relationships between molecular structures of amino acid amphiphiles (the hydrophilic head group and hydrophobic alkyl chain length) in supramolecular catalysts and enantioselectivity in Diels-Alder reactions are elaborated.

Associations between depression symptom burden and delirium risk: a prospective cohort study.

BACKGROUND AND OBJECTIVES: Delirium and depression are increasingly common in aging. There is considerable clinical overlap, including shared symptoms and comorbid conditions, including Alzheimer's disease (AD), functional decline, and mortality. Despite this, the long-term relationship between depression and delirium remains unclear. This study assessed the associations of depression symptom burden and its trajectory with delirium risk in a 12-year prospective study of older individuals during hospitalization. RESEARCH DESIGN AND METHODS: 319,141 UK biobank participants between 2006-2010 (mean 58y [range 37-74, SD=8], 54% female) reported frequency (0-3) of four depressive symptoms (mood, disinterest, tenseness, or lethargy) in the preceding 2 weeks, and aggregated into a depressive symptom burden score (0-12). New-onset delirium was obtained from hospitalization records during 12y median follow-up. 40,451 (mean age 57±8; range 40-74y) had repeat assessment on average 8y after their first. Cox proportional hazard models examined whether depression symptom burden and trajectory predicted incident delirium during hospitalization. RESULTS: 5,753 (15 per 1000) newly developed delirium during follow-up. Increased risk for delirium was seen for mild (aggregated scores 1-2, hazards ratio, HR=1.16, [95% confidence interval 1.08-1.25], p<0.001), modest (scores 3-5, 1.30 [1.19-1.43], p<0.001) and severe (scores ≥ 5, 1.38 [1.24-1.55], p<0.001) depressive symptoms, versus none in the fully adjusted model. These findings were independent of the number of hospitalizations and consistent across hospitalization settings (e.g., surgical, medical, or critical care) and specialty (e.g., neuropsychiatric, cardiorespiratory or other). Worsening depression symptoms (≥1 point increase), compared to no change/improved score, were associated with an additional 39% increased risk (1.39 [1.03-1.88], p=0.03) independent of baseline depression burden. The association was strongest in those over 65y at baseline (p for interaction <0.001). DISCUSSION AND IMPLICATIONS: Depression symptom burden and worsening trajectory predicted delirium risk during hospitalization. Increased awareness of subclinical depression symptoms may be warranted for delirium prevention.

GPR55 is expressed in glutamate neurons and functionally modulates nicotine taking and seeking in rats and mice.

Cannabis legalization continues to progress in the USA for medical and recreational purposes. G protein-coupled receptor 55 (GPR55) is a putative "CB3" receptor. However, its functional role in cannabinoid action and drug abuse is not explored. Here we report that GPR55 is mainly expressed in cortical and subcortical glutamate neurons and its activation attenuates nicotine taking and seeking in rats and mice. RNAscope in situ hybridization detected GPR55 mRNA in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons in wildtype, but not GPR55-knockout, mice. GPR55 mRNA was not detected in midbrain dopamine (DA) neurons in either genotype. Immunohistochemistry assays detected GPR55-like staining, but the signal is not GPR55-specific as the immunostaining was still detectable in GPR55-knockout mice. We then used a fluorescent CB1-GPR55 ligand (T1117) and detected GPR55 binding in cortical and subcortical glutamate neurons, but not in midbrain DA neurons, in CB1-knockout mice. Systemic administration of O-1602, a GPR55 agonist, dose-dependently increased extracellular glutamate, not DA, in the nucleus accumbens. Pretreatment with O-1602 failed to alter Δ9-tetrahydrocannabinol (D9-THC)-induced triad effects or intravenous cocaine self-administration, but it dose-dependently inhibited nicotine self-administration under fixed-ratio and progressive-ratio reinforcement schedules in rats and wildtype mice, not in GPR55-knockout mice. O-1602 itself is not rewarding or aversive as assessed by optical intracranial self-stimulation (oICSS) in DAT-Cre mice. These findings suggest that GPR55 is functionally involved in nicotine reward process possibly by a glutamate-dependent mechanism, and therefore, GPR55 deserves further research as a new therapeutic target for treating nicotine use disorder.