Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI.

Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.

The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model.

There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical models that recapitulate this comorbidity are lacking. We developed a polydrug model wherein male and female rats were allowed to self-administer intravenous heroin and oral alcohol (or saccharin control solution) over weeks of behavioral training, and then we conducted a series of progressive ratio tests to assess the animals' motivational state for heroin and alcohol. In this model, motivation for heroin is higher than alcohol, and DOI (0.4 mg/kg) administered prior to testing significantly reduced heroin motivation measured as the animals' break point, or maximum effort the animal is willing to expend to obtain a single infusion of heroin. The 5-HT2A receptor antagonist MDL 100,907 (0.3 mg/kg), but not the 5-HT2C receptor antagonist SB-242084 (0.5 mg/kg), blocked the therapeutic effect of DOI on heroin motivation. No significant effects on alcohol break points were observed, nor did MDL 100,907 or SB-242084 have any effect on break points on their own. These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD and comorbid alcohol use, by acting as a 5-HT2A receptor agonist.

Performance Comparison of DOI-Encoding PET Detectors Based on 1.1-mm Pitch BGO Arrays With Different Reflectors.

Bismuth germanate (BGO)-based positron emission tomography (PET) detectors are potential candidates for low-dose imaging PET scanners, owing to the high stopping power and low background radiation of BGO. In this paper, we compared the performance of two dual-ended readout PET detectors based on 15 × 15 BGO arrays. Both arrays had the same 1.1 mm pitch but utilized different reflectors - barium sulfate (BaSO4) and enhanced specular reflector film (ESR) - for high-resolution PET applications. The detectors were constructed with Hamamatsu 13361-2050-08 SiPM arrays. Each BGO element had dimensions of 1.02 × 1.02 × 20 mm3. The lateral surfaces of the BGO elements were unpolished (saw-cut), while the two ends were polished. Flood histograms showed that the detector based on the BGO array with BaSO4 reflector had much better crystal identification and depth-of-interaction (DOI) resolution. Specifically, the energy, DOI, and timing resolutions for the detector using the BGO array with BaSO4 reflector were 19.8 ± 1.5%, 4.13 ± 0.48 mm, and 2.80 ± 0.23 ns, respectively. In contrast, the values obtained using the BGO array with ESR reflector were 20.9 ± 2.1%, 7.69 ± 1.92 mm, and 2.93 ± 0.20 ns, respectively.

Biological sex modulates the efficacy of 2,5-dimethoxy-4-iodoamphetamine (DOI) to mitigate fentanyl demand.

BACKGROUND: Overdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. METHODS: Male and female Sprague-Dawley rats (n = 25-29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2µg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a » log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q0 and α. RESULTS: Male and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT2AR activation decreased Q0 in female rats but increased Q0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. CONCLUSION: DOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT2AR activation sex-dependently alters opioid reinforcement.

Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling.

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB2 receptor (CB2R) homodimerization by simultaneously binding both protomers of the CB2R-CB2R homodimer. Computational and pharmacological experiments showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This results in unique pharmacological properties, including increased potency in Gi-mediated signaling and enhanced recruitment of ß-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB2R activity, potentially leading to improved therapeutic outcomes.

Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis.

Psychedelics have emerged as promising therapeutics for several psychiatric disorders. Hypotheses around their mechanisms have revolved around their partial agonism at the serotonin 2 A receptor, leading to enhanced neuroplasticity and brain connectivity changes that underlie positive mindset shifts. However, these accounts fail to recognise that the gut microbiota, acting via the gut-brain axis, may also have a role in mediating the positive effects of psychedelics on behaviour. In this review, we present existing evidence that the composition of the gut microbiota may be responsive to psychedelic drugs, and in turn, that the effect of psychedelics could be modulated by microbial metabolism. We discuss various alternative mechanistic models and emphasize the importance of incorporating hypotheses that address the contributions of the microbiome in future research. Awareness of the microbial contribution to psychedelic action has the potential to significantly shape clinical practice, for example, by allowing personalised psychedelic therapies based on the heterogeneity of the gut microbiota.

Opposite Contractile Effects of Amphetamine-Related Hallucinogenic Drugs in the Isolated Human Atrium.

The present study examined three hallucinogenic amphetamine derivatives, namely, 2,5-dimethoxy-4-iodoamphetamine (DOI) as well as 2,5-dimethoxy-4-methylamphetamine (DOM) and 4-methylmethcathinone (mephedrone). The objective of this study was to test the hypothesis that DOI, DOM, and mephedrone would increase the contractile force in isolated human atrial preparations in a manner similar to amphetamine. To this end, we measured contractile force under isometric conditions in electrically stimulated (1 Hz) human atrial preparations obtained during open surgery. DOI and DOM alone or in the presence of isoprenaline reduced the contractile force concentration-dependently in human atrial preparations. These negative inotropic effects of DOM and DOI were not attenuated by 10 µM atropine. However, mephedrone increased the contractile force in human atrial preparations in a concentration- and time-dependent manner. Furthermore, these effects were attenuated by the subsequent addition of 10 µM propranolol or pretreatment with 10 µM cocaine in the organ bath. Therefore, it can be concluded that amphetamine derivatives may exert opposing effects on cardiac contractile force. The precise mechanism by which DOI and DOM exert their negative inotropic effects remains unknown at present. The cardiac effects of mephedrone are probably due to the release of cardiac noradrenaline.

Design and characterization of a hybrid PET detector with DOI capability.

BACKGROUND: Monolithic or semi-monolithic detectors are attractive for positron emission tomography (PET) scanners with depth-of-interaction (DOI) capability. However, they often require complicated calibrations to determine the interaction positions of gamma photons. PURPOSE: We introduce a novel hybrid detector design that combines pixelated and semi-monolithic elements to achieve DOI capability while simplifying the calibrations for positioning. METHODS: A prototype detector with eight hybrid lutetium-yttrium oxyorthosilicate (LYSO) layers having dimensions of 25.8 × 12.9 × 15 mm3 was constructed. The energy-weighted and energy-squared weighted averages were used for estimating the x- (pixelated direction) and y-positions (non-pixelated direction). Pseudo-pixels were defined as discrete areas on the flood image based on the crystal look-up table (LUT). The intrinsic spatial resolutions in the pixelated and non-pixelated directions were measured. The ratio of the maximum to the sum of the multipixel photon counter (MPPC) signals was used to estimate the DOI positions. The coincidence timing resolution (CTR) was measured using the average and energy-weighted average of the earliest n time stamps. Two energy windows of 250-700 and 400-600 keV were applied for the measurements. RESULTS: The pattern of the flood images showed discrete event clusters, demonstrating that simple calibrations for determining the x- and y-positions of events could be achieved. Under 400-600 keV energy window, the average intrinsic spatial resolutions were 1.15 and 1.34 mm for the pixelated and non-pixelated directions; the average DOI resolution of the second row of pseudo-pixels was 5.1 mm in full width at half maximum (FWHM); when using the energy-weighted average of the earliest four-time stamps, the best CTR of 350 ps was achieved. Applying a broader energy window of 250-700 keV only slightly degrades the DOI resolution while maintaining the intrinsic resolution; the best CTR degrades to 410 ps. CONCLUSIONS: The proposed hybrid detector concept was verified, and a prototype detector showed high performance for 3D positioning and timing resolution. The novel detector concept shows promise for preclinical and clinical PET scanners with DOI capability.

Proposal for a Global Classification and Nomenclature System for A/H9 Influenza Viruses.

Influenza A/H9 viruses circulate worldwide in wild and domestic avian species, continuing to evolve and posing a zoonotic risk. A substantial increase in human infections with A/H9N2 subtype avian influenza viruses (AIVs) and the emergence of novel reassortants carrying A/H9N2-origin internal genes has occurred in recent years. Different names have been used to describe the circulating and emerging A/H9 lineages. To address this issue, an international group of experts from animal and public health laboratories, endorsed by the WOAH/FAO Network of Expertise on Animal Influenza, has created a practical lineage classification and nomenclature system based on the analysis of 10,638 hemagglutinin sequences from A/H9 AIVs sampled worldwide. This system incorporates phylogenetic relationships and epidemiologic characteristics designed to trace emerging and circulating lineages and clades. To aid in lineage and clade assignment, an online tool has been created. This proposed classification enables rapid comprehension of the global spread and evolution of A/H9 AIVs.

Pathogenic Surveillance of Foodborne Illness-Related Diarrhea - Beijing Municipality, China, 2013-2023.

What is already known about this topic?: Foodborne diseases present a significant public health concern, particularly in China, where they represent a significant food safety challenge. Currently, there is a need for a thorough and systematic analysis of the extended epidemiological patterns of foodborne diseases in Beijing Municipality. What is added by this report?: Monitoring results show that Norovirus and diarrheagenic Escherichia coli (DEC) are the most commonly identified foodborne diarrheal pathogens. Individuals aged 19-30 are at a higher risk of foodborne diarrhea in Beijing, with Salmonella infection being associated with fever symptoms. What are the implications for public health practice?: This study analyzes 11 years of consecutive monitoring data to enhance understanding of the epidemiological and clinical features of foodborne diarrhea in Beijing. It aims to identify high-risk populations, assist in clinical pathogen identification and treatment, and support the development of tailored preventive strategies.

Decoupling of cortical activity from behavioral state following administration of the classic psychedelic DOI.

Administration or consumption of classic psychedelics (CPs) leads to profound changes in experience which are often described as highly novel and meaningful. They have shown substantial promise in treating depressive symptoms and may be therapeutic in other situations. Although research suggests that the therapeutic response is correlated with the intensity of the experience, the neural circuit basis for the alterations in experience caused by CPs requires further study. The medial prefrontal cortex (mPFC), where CPs have been shown to induce rapid, 5-HT2A receptor-dependent structural and neurophysiological changes, is believed to be a key site of action. To investigate the acute neural circuit changes induced by CPs, we recorded single neurons and local field potentials in the mPFC of freely behaving male mice after administration of the 5-HT2A/2C receptor-selective CP, 2,5-Dimethoxy-4-iodoamphetamine (DOI). We segregated recordings into active and rest periods in order to examine cortical activity during desynchronized (active) and synchronized (rest) states. We found that DOI induced a robust decrease in low frequency power when animals were at rest, attenuating the usual synchronization that occurs during less active behavioral states. DOI also increased broadband gamma power and suppressed activity in fast-spiking neurons in both active and rest periods. Together, these results suggest that the CP DOI induces persistent desynchronization in mPFC, including during rest when mPFC typically exhibits more synchronized activity. This shift in cortical dynamics may in part underlie the longer-lasting effects of CPs on plasticity, and may be critical to their therapeutic properties.

Performance Characteristics of the NeuroEXPLORER, a Next-Generation Human Brain PET/CT Imager.

The collaboration of Yale, the University of California, Davis, and United Imaging Healthcare has successfully developed the NeuroEXPLORER, a dedicated human brain PET imager with high spatial resolution, high sensitivity, and a built-in 3-dimensional camera for markerless continuous motion tracking. It has high depth-of-interaction and time-of-flight resolutions, along with a 52.4-cm transverse field of view (FOV) and an extended axial FOV (49.5 cm) to enhance sensitivity. Here, we present the physical characterization, performance evaluation, and first human images of the NeuroEXPLORER. Methods: Measurements of spatial resolution, sensitivity, count rate performance, energy and timing resolution, and image quality were performed adhering to the National Electrical Manufacturers Association (NEMA) NU 2-2018 standard. The system's performance was demonstrated through imaging studies of the Hoffman 3-dimensional brain phantom and the mini-Derenzo phantom. Initial 18F-FDG images from a healthy volunteer are presented. Results: With filtered backprojection reconstruction, the radial and tangential spatial resolutions (full width at half maximum) averaged 1.64, 2.06, and 2.51 mm, with axial resolutions of 2.73, 2.89, and 2.93 mm for radial offsets of 1, 10, and 20 cm, respectively. The average time-of-flight resolution was 236 ps, and the energy resolution was 10.5%. NEMA sensitivities were 46.0 and 47.6 kcps/MBq at the center and 10-cm offset, respectively. A sensitivity of 11.8% was achieved at the FOV center. The peak noise-equivalent count rate was 1.31 Mcps at 58.0 kBq/mL, and the scatter fraction at 5.3 kBq/mL was 36.5%. The maximum count rate error at the peak noise-equivalent count rate was less than 5%. At 3 iterations, the NEMA image-quality contrast recovery coefficients varied from 74.5% (10-mm sphere) to 92.6% (37-mm sphere), and background variability ranged from 3.1% to 1.4% at a contrast of 4.0:1. An example human brain 18F-FDG image exhibited very high resolution, capturing intricate details in the cortex and subcortical structures. Conclusion: The NeuroEXPLORER offers high sensitivity and high spatial resolution. With its long axial length, it also enables high-quality spinal cord imaging and image-derived input functions from the carotid arteries. These performance enhancements will substantially broaden the range of human brain PET paradigms, protocols, and thereby clinical research applications.

PET detectors with depth-of-interaction and time-of-flight capabilities.

In positron emission tomography (PET), measurements of depth-of-interaction (DOI) information and time-of-flight (TOF) information are important. DOI information reduces the parallax error, and TOF information reduces noise by measuring the arrival time difference of the annihilation photons. Historically, these have been studied independently, and there has been less implementation of both DOI and TOF capabilities because previous DOI detectors did not have good TOF resolution. However, recent improvements in PET detector performance have resulted in commercial PET scanners achieving a coincidence resolving time of around 200 ps, which result in an effect even for small objects. This means that TOF information can now be utilized even for a brain PET scanner, which also requires DOI information. Therefore, various methods have been proposed to obtain better DOI and TOF information. In addition, the cost of PET detectors is also an important factor to consider, since several hundred detectors are used per PET scanner. In this paper, we review the latest DOI-TOF detectors including the history of detector development. When put into practical use, these DOI-TOF detectors are expected to contribute to the improvement of imaging performance in brain PET scanners.

Virtual cylindrical PET for efficient DOI image reconstruction with sub-millimetre resolution.

Objective.Image reconstruction in high resolution, narrow bore PET scanners with depth of interaction (DOI) capability presents a substantial computational challenge due to the very high sampling in detector and image space. The aim of this study is to evaluate the use of a virtual cylinder in reducing the number of lines of response (LOR) for DOI-based reconstruction in high resolution PET systems while maintaining uniform sub-millimetre spatial resolution.Approach.Virtual geometry was investigated using the awake animal mousePET as a high resolution test case. Using GEANT4 Application for Tomographic Emission (GATE), we simulated the physical scanner and three virtual cylinder implementations with detector size 0.74 mm, 0.47 mm and 0.36 mm (vPET1, vPET2 and vPET3, respectively). The virtual cylinder condenses physical LORs stemming from various crystal pairs and DOI combinations, and which intersect a single virtual detector pair, into a single virtual LOR. Quantitative comparisons of the point spread function (PSF) at various positions within the field of view (FOV) were compared for reconstructions based on the vPET implementations and the physical scanner. We also assessed the impact of the anisotropic PSFs by reconstructing images of a micro Derenzo phantom.Main results.All virtual cylinder implementations achieved LOR data compression of at least 50% for DOI PET reconstruction. PSF anisotropy in radial and tangential profiles was chiefly influenced by DOI resolution and only marginally by virtual detector size. Spatial degradation introduced by virtual cylinders was most prominent in the axial profile. All virtual cylinders achieved sub-millimetre volumetric resolution across the FOV when 6-bin DOI reconstructions (3.3 mm DOI resolution) were performed. Using vPET2 with 6 DOI bins yielded nearly identical reconstructions to the non-virtual case in the transaxial plane, with an LOR compression factor of 86%. Resolution modelling significantly reduced the effects of the asymmetric PSF arising from the non-cylindrical geometry of mousePET.Significance.Narrow bore and high resolution PET scanners require detectors with DOI capability, leading to computationally demanding reconstructions due to the large number of LORs. In this study, we show that DOI PET reconstruction with 50%-86% LOR compression is possible using virtual cylinders while maintaining sub-millimetre spatial resolution throughout the FOV. The methodology and analysis can be extended to other scanners with DOI capability intended for high resolution PET imaging.

Can Radiological Tumour Thickness Predict Pathological Prognostic Factors in Clinicoradiologically Node-Negative Oral Squamous Carcinoma? A Prospective Study.

Background: This research investigates potential connections between radiological tumour thickness determined by CT scans and various pathological prognostic factors. These factors include pathological tumour thickness (pTT), pathological depth of invasion (DOI), and positive cervical nodal metastasis. This analysis focuses on cases of clinicoradiologically node-negative squamous cell carcinoma of the buccal mucosa. Method: Sixty-one previously untreated clinicoradiologically node-negative squamous cell carcinoma of buccal mucosa were included in the study. The radiological tumour thickness in the preoperative CT scans is correlated with other prognostic factors like pathological tumour thickness, DOI and presence or absence of neck node. Result: Sixty-one patients were included in the study with a median age of 54 years (Range 27-84). Forty-two patients (68.9%) were male, and 19 were females (31.1%). There was no statistically significant difference in mean values of rTT among patients with positive or negative post-operative nodal metastases. However, a significant correlation could be established with rTT to other potential prognostic factors. Conclusion: Tumor thickness in preoperative CT scans can be used to predict post-operative prognostic factors in oral squamous cell carcinoma.

Prevalence of Reproductive Tract Infections and Association with Human Papillomavirus Infection Among Reproductive-Age Women - Six Tertiary Hospitals, China, June 2021-December 2022.

What is already known about this topic?: Previous studies have indicated a possible association between reproductive tract infections (RTIs) and high-risk human papillomavirus (HPV) infection, but the evidence is still inconclusive. What is added by this report?: This multicenter study found significantly higher positive rates of HPV, including general HPV, high-risk HPV, and HPV 16/18 infections, among women who tested positive for single or multiple RTIs compared to women who tested negative for RTIs in gynecological outpatient clinics. What are the implications for public health practice?: Infection with HPV, especially high-risk types, is linked to RTIs and imbalances in the vaginal microbiota. Implementing standardized protocols for identifying and treating RTIs could support the establishment of a healthy vaginal microenvironment. This, in turn, may offer a novel approach to preventing cervical cancer.

A multi-resolution TOF-DOI detector for human brain dedicated PET scanner.

Objective. We propose a single-ended readout, multi-resolution detector design that can achieve high spatial, depth-of-interaction (DOI), and time-of-flight (TOF) resolutions, as well as high sensitivity for human brain-dedicated positron emission tomography (PET) scanners.Approach. The detector comprised two layers of LYSO crystal arrays and a lightguide in between. The top (gamma ray entrance) layer consisted of a 16 × 16 array of 1.53 × 1.53 × 6 mm3LYSO crystals for providing high spatial resolution. The bottom layer consisted of an 8 × 8 array of 3.0 × 3.0 × 15 mm3LYSO crystals that were one-to-one coupled to an 8 × 8 multipixel photon counter (MPPC) array for providing high TOF resolution. The 2 mm thick lightguide introduces inter-crystal light sharing that causes variations of the light distribution patterns for high DOI resolution. The detector was read out by a PETsys TOFPET2 application-specific integrated circuit.Main result. The top and bottom layers were distinguished by a convolutional neural network with 97% accuracy. All crystals in the top and bottom layers were resolved. The inter-crystal scatter (ICS) events in the bottom layer were identified, and the measured average DOI resolution of the bottom layer was 4.1 mm. The coincidence time resolution (CTR) for the top-top, top-bottom, and bottom-bottom coincidences was 476 ps, 405 ps, and 298 ps, respectively. When ICS events were excluded from the bottom layer, the CTR of the bottom-bottom coincidence was 277 ps.Significance. The top layer of the proposed two-layer detector achieved a high spatial resolution and the bottom layer achieved a high TOF resolution. Together with its high DOI resolution and detection efficiency, the proposed detector is well suited for next-generation high-performance brain-dedicated PET scanners.