Xanomeline treatment attenuates cocaine self-administration in rats and nonhuman primates.

The aim of this study was to characterize the novel LSD1-specific PET radiotracer [18F]MNI-1054 in rhesus monkeys and to utilize it to evaluate occupancy of TAK-418, a novel LSD1 inhibitor. To accomplish this, eleven 180-minute dynamic brain PET scans were performed in two rhesus monkeys (1 male/1 female), including baseline scans and a self-block with unlabeled MNI-1054 (3mg/kg) to assess total levels of specific binding. Displacement and blocking studies with TAK-418 were performed to confirm irreversible binding and to evaluate the dose-occupancy relationship of TAK-418. Scans were also acquired 24- and 48-hours post-TAK-418 dosing to assess LSD1 repopulation rates. Additional baseline and blocking studies with 3.0mg/kg TAK-418 were acquired in a male monkey to evaluate peripheral binding and occupancy in the testes, an organ with high LSD1 expression. Lastly, whole-body scans were obtained from two animals (1 male/1 female) to evaluate dosimetry. Across studies, [18F]MNI-1054 fraction in plasma was ~42% at 30min and ~14% at 180min after injection. Tracer kinetics were accurately modeled using an irreversible two-tissue compartment model, yielding Ki as the binding endpoint. The highest specific signal was found in the cerebellum, and the neuroanatomical signal profile was consistent with that of LSD1 expression. The specific signal was blocked in a dose-dependent fashion by the molecularly distinct LSD1 inhibitor TAK-418, with Omax = 95.6% and ED50 = 0.0224mg/kg in cerebellum. Scans at later time points yielded an LSD1 repopulation half-life estimate of 12.28h. Evidence of significant LSD1 expression and occupancy was found in testes with 3.0mg/kg TAK-418, however point occupancy levels could not be reliably estimated from Ki. The estimated whole-body effective dose was ~0.027 mSv/MBq, with the gallbladder wall being the limiting organ (0.18 mSv/MBq). [18F]MNI-1054 displayed acceptable brain penetrance, kinetics and LSD1 specificity as well as an acceptable dosimetry. Overall, these findings show its suitability as a viable PET probe to assess the binding profile of LSD1 inhibitors in the brain and support further evaluation in humans.

Bussuquara virus (BSQV), an orthoflavivirus discovered in Brazil in 1956, has been detected throughout the Americas in diverse mosquito and vertebrate species, including humans. Critical gaps in BSQV knowledge include its capacity for urban transmission and clinical pathogenesis outcomes, with insufficient historical experimentation to draw genomic or phenotypic comparisons to related orthoflavivirus species. The objective of this study was to conduct morphologic, genomic, phylogenetic, and in vitro viral fitness characterization of BSQV using the four available historical strains. We used next generation sequencing and rapid amplification of cDNA ends to construct consensus genomes, followed by phylogenetic analysis and genome annotation to evaluate orthoflavivirus evolutionary relationships and genome characteristics. Infected mosquito (C6/36) and non-human primate (Vero CCL81) cells were imaged with transmission electron microscopy. Viral replication kinetics were quantified across seventeen cell lines of mosquito, mammal, rodent, avian, non-human primate, and human origin. BSQV morphologic (virion diameter, cytopathic effect) and genomic (size, organization, architecture, sequence motifs) results were in line with canonical orthoflavivirus characteristics. One of the four strains (CoAr 41922) shared greater sequence homology to the Naranjal orthoflavivirus than other BSQV strains and was thus excluded from infection phenotype experiments. All three confirmed BSQV strains replicated robustly in most mosquito and all vertebrate cell lines, causing either minimal (mosquito) or moderate to extreme (vertebrate) cytopathic effects. We conclude that BSQV is a generalist orthoflavivirus with a broad range of susceptible vertebrate and mosquito vectors. Our data build a foundation for pathogenesis and vector competence studies to determine the potential of BSQV to emerge into epizootic and urban transmission cycles.

Insights into HIV-1 pathogenesis have come from studies of viral dynamics. However, there is little information on viral dynamics in lentiviral infections in which viral replication is naturally controlled in a subset of infected individuals. We evaluated the decay of simian immunodeficiency virus (SIV) RNA and cell-associated SIV genomes in a nonhuman primate (NHP) model in which replication of an engineered SIV variant is naturally controlled by cellular immune responses in most infected animals. This variant lacks a trafficking motif in the gp41 cytoplasmic tail. A trajectory of control was evident by 21 days after infection. In animals with natural control, we observed similar biphasic decay of intact proviruses in blood and lymph nodes, at rates close to those in animals that failed to control the virus and were put on antiretroviral therapy (ART). Both natural control and ART effectively blocked viral evolution, but not persistence. Thus, in this NHP model, natural control can be nearly as effective as ART in controlling viral replication.

The cerebral cortex provides the main input to the striatum, constituting the first step in cortico-basal ganglia loops. Decades of careful anatomical tract-tracing research have established the exquisite topography of each cortical region's projection to the striatum in nonhuman primates. In parallel, neuroimaging research has demonstrated the relationship between cortico-striatal resting-state functional connectivity and specific cognitive, behavioral, psychiatric, and neurological states in humans. However, still unclear is the extent to which functional connectivity recapitulates the specific topographies of cortico-striatal anatomical connectivity. Here, we combined datasets of cortico-striatal anatomical and functional connectivity in macaques to determine the degree of overlap between the two. Across multiple metrics of similarity, we found that anatomical and functional connectivity demonstrated higher correspondence in the frontal and primary somatosensory cortices, with lower correspondence in other brain regions. This suggests that there are many regions in the brain in which cortico-striatal functional connectivity may not be driven by direct anatomical connectivity.

Retrograde optogenetics reveals sensorimotor convergence within a corticotectal pathway of non-human primates.

Yellow fever (YF) is a highly lethal arboviral disease that is transmitted to humans by the bites of infected mosquitoes. However, the drivers of epidemic episodes are not well understood. In this ecological study, we analysed spatial and temporal patterns of the largest yellow fever outbreaks in the 21st century in Brazil. We describe the spatial and temporal patterns of 2178 human YF cases, 2911 non-human primate (NHP) cases and immunization coverage using the Global and Local Moran's Index, directional distribution and logistic regression models. Spatially distinct clusters were detected along heterogeneous forestland and ecological corridors. Human YF occurrence increased with a higher abundance and diverse genera of NHP YF cases along with seven other variables: lower vaccination coverage, lower elevation, moderate annual mean temperature, higher annual precipitation, increased vector abundance, low to moderate urbanization and forested land. Our results suggest that human YF epidemics are largely driven by vaccination coverage and environmental conditions that aid transmission in vectors and hosts. This sustains the local sylvatic cycle across administrative and political boundaries. These results reinforce the need to study YF spillover and dispersion dynamics at the human-animal-environment interface to improve disease control and devise multisectoral mitigation strategies.

Addressing pain effectively remains a major global challenge for healthcare systems and public health initiatives. While this issue is pervasive worldwide, it is particularly pressing in the United States, where pain management using opioid analgesics has led to significant concerns due to widespread misuse, drug dependence, and overdose fatalities. A central dilemma for clinicians in pain management lies in balancing the delivery of sufficient pain relief while minimizing potential risks. Although preferential μ-opioid receptor (MOP) agonists, such as morphine and oxycodone, often remain a necessary therapeutic choice, particularly for individuals experiencing moderate to severe pain, their safety profiles present a clinical dilemma, as there are limited other options available to clinicians. A promising area of research focus is on the development of dual NOP/MOP receptor(NMR) agonists , compounds that co-activate the nociceptin/orphanin FQ (NOP) receptor and the MOP receptor. Despite sharing some structural homology with opioid receptors, the NOP receptor exhibits a distinct pharmacological profile. Activating the NOP receptor induces pain relief and, more importantly, counteracts important adverse effects associated with MOP activation including reduction in euphoria by inhibiting opioid-induced activation of dopaminergic neuron activity in the ventral tegmental area (VTA), which in turn reduces the likelihood of misuse. Preclinical data have shown a potential role of NOP activation in reducing the occurrence of opioid withdrawal symptoms and, perhaps most importantly, respiratory depression. Investigations in nonhuman primates support the NOP receptor's modulatory role, demonstrating that NOP agonism not only produced analgesia across various pain models (nociceptive, neuropathic, and inflammatory) but also lessened MOP-related negative outcomes, such as opioid reward-seeking behavior, the development of tolerance, and withdrawal symptoms. Preclinical studies using dual NMR agonists showed that administration of a NOP antagonist increased the side effects similar to those caused by a preferential MOP agonist, underscoring the role of NOP receptor activation in counteracting these adverse events. Altogether these findings suggest that dual NMR (NOP/MOP receptor) agonists represent a promising novel class of medications with the potential to achieve strong analgesia while lessening the side effects of opioid agonists.

Understanding the diversity of pathogenic microorganisms in wild primates is essential for assessing their health and zoonotic risks. In this study, metagenomic sequencing was applied to investigate the composition and seasonal dynamics of potential pathogenic microorganisms in the feces of François’ langurs. A total of 77 potential pathogenic taxa were identified, mainly belonging to Bacillota and Pseudomonadota. The most abundant genera were Streptococcus, Staphylococcus, Salmonella, Listeria, and Pseudomonas, while dominant species included Staphylococcus aureus, Streptococcus pneumoniae, Salmonella enterica, Listeria monocytogenes, and Escherichia coli. Significant seasonal differences were detected in both α- and β-diversity indices, with higher microbial diversity in spring and distinct community structures across seasons. Several genera and species, including Vibrio, Chlamydia, Mycobacteroides, Vibrio cholerae, Yersinia enterocolitica, Chlamydia trachomatis, and Mycobacteroides abscessus, showed marked seasonal fluctuations. The findings reveal that the pathogenic microbial community of François’ langurs is strongly shaped by seasonal environmental factors. The detection of multiple zoonotic pathogens suggests a potential risk of cross-species transmission, providing valuable baseline data for primate disease ecology and conservation health management.

Development of an AAV-delivered microRNA gene therapy for myotonic dystrophy type 1.

Metabolic dysfunction-associated fatty liver disease (MAFLD), a leading cause of hepatocellular carcinoma (HCC), poses a formidable therapeutic challenge because of the metabolic stress-induced aberrant immune microenvironment. However, no effective pharmacological therapies for the liver microenvironment remodeling in MAFLD are now available. Here, we developed a lipid nanoparticle (Def-LNP) that incorporates vitamin E-derived phosphatidylcholine (VEPC). Def-LNP effectively ameliorated the hepatic oxidative microenvironment to achieve sustained localized expression of target mRNA in hepatocytes in preclinical models, outperforming a commercially used LNP formulation. In vivo delivery efficiency, stability, and biosafety of Def-LNP were validated in various mammalian models, including mice, pigs, and nonhuman primates. Using clinical samples, we identified a pronounced correlation between T cell protein tyrosine phosphatase (TCPTP) and MAFLD pathogenesis. The administration of Def-LNP loaded with TCPTP-encoding mRNA (Def-LNP@mRNATCPTP) suppressed signal transducer and activator of transcription signaling in the hepatocytes of MAFLD mice, leading to hepatic metabolic reprogramming and immunological reconfiguration, a characteristic that is prominently lacking in conventional mRNA-based protein replacement therapy. In preclinical models, the administration of Def-LNP@mRNATCPTP successfully eliminated steatohepatitis, impeded hepatocarcinogenesis, and improved the therapeutic responsiveness of HCC to cancer vaccine and immune checkpoint blockade therapy. Def-LNP@mRNATCPTP represents a potential therapeutic strategy for MAFLD and MAFLD-related HCC, potentially offering treatment paradigms for immunotherapy for HCC and metabolic liver diseases.

Animal models serve as crucial research tools in human genetics research by combining scientific knowledge from laboratory findings and medicine. Biological study models while also providing the potential to create new treatments. Other species, such as rats, along with zebrafish and non-human primates, offer unique advantages when used in combination with mice in genetic studies, despite mice have been the conventional leaders due to their small size and ease of genetic modification. Rats offer better abilities in scientific studies due to their larger body size, which facilitates extensive experimental tests. These tests enable investigations of complex diseases, such as neurodegenerative disorders, cardiovascular diseases, and metabolic disorders. CRISPR-Cas9 gene editing tools have expanded the diversity of rat models, thereby enhancing their value as more accurate models for disease research. Using animals in human genetic research poses several challenges to be addressed. The three primary issues that the debate on the use of animals in scientific research is based on include the differences in biology with the various species and the ethical issues, and the expenditure of keeping the animals as models of research. The ethical factors applied in all the animal studies presented in this review have followed the established ethical principles, such as the 3Rs (Replacement, Reduction, and Refinement), to ensure humane treatment and scientific responsibility. The use of animal models, especially rats, remains significant in a holistic studies on human genetic disorders and the advancement of innovative treatment procedures. The particular aim of this review is to offer a comprehensive description of the nature, merits, and demerits of the regularly used animal models in human genetic studies to help researchers in choosing the best models to use in their studies.

Gene families are groups of evolutionarily related genes. One large gene family that has experienced rapid evolution lies within the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across the ∼60 million year history of the primates, some MHC genes have turned over completely, some have changed function, some have converged in function, and others have remained essentially unchanged. Past work has typically focused on identifying MHC alleles within particular species or comparing gene content, but more work is needed to understand the overall evolution of the gene family across species. Thus, despite the immunologic importance of the MHC and its peculiar evolutionary history, we lack a complete picture of MHC evolution in the primates. We readdress this question using sequences from dozens of MHC genes and pseudogenes spanning the entire primate order, building a comprehensive set of gene and allele trees with modern methods. Overall, we find that the Class I gene subfamily is evolving much more quickly than the Class II gene subfamily, with the exception of the Class II MHC-DRB genes. We also pay special attention to the often-ignored pseudogenes, which we use to reconstruct different events in the evolution of the Class I region. We find that despite the shared function of the MHC across species, different species employ different genes, haplotypes, and patterns of variation to achieve a successful immune response. Our trees and extensive literature review represent the most comprehensive look into primate MHC evolution to date.

The oncofetal antigen 5T4 is expressed in many solid tumors, making it an attractive antitumor target. XB010 is a novel, 5T4-targeted, antibody-drug conjugate developed using the SMARTag platform to optimize tolerability. We describe the development, design, and preclinical characterization of XB010. In vitro and in vivo efficacy of XB010 was assessed in cell-derived xenograft breast cancer cell lines (MCF-7 and MDA-MB-468) and in patient-derived xenograft tumor models (squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer). Additionally, the in vivo combinatorial efficacy of XB010 + anti-PD-1 antibody was assessed in an MC38-h5T4 syngeneic colon cancer xenograft model. The toxicity profile of XB010 was evaluated in both Sprague-Dawley rats and cynomolgus monkeys. XB010 demonstrated in vitro cytotoxic effects with sub-nanomolar potency in the MCF-7 and MDA-MB-468 breast cancer cell lines and in vivo tumor growth inhibition (80%-99%) compared with vehicle-treated animals in xenograft and patient-derived xenograft models at doses of 5 to 10 mg/kg XB010. In the syngeneic MC38-h5T4-expressing colon cancer xenograft model, XB010 + anti-PD-1 showed improved efficacy compared with either agent administered alone. XB010 safety assessments demonstrated tolerability of doses up to 60 mg/kg in rats and up to 25 mg/kg in nonhuman primates. XB010 is a novel anti-5T4 antibody-drug conjugate that exhibits potent antitumor activity, inhibiting cancer cell growth in vitro and tumor growth in various in vivo models, with an acceptable toxicity profile. These findings support the evaluation of XB010 in clinical studies.

Aging humans and non-human primates both exhibit a similar pattern of cognitive decline beginning in middle age that is characterized by progressive impairments in rule learning, executive function, and working and recognition memory-functions often associated with dysfunction of prefrontal and medial temporal lobe regions. The heterogeneity and inter-subject variability in aging and age-related cognitive impairments present challenges for developing effective therapeutics and can be attributed to differing degrees of cortical white matter (WM) damage and alterations to local and long-range prefrontal and temporal networks. A promising therapeutic that has been shown to be efficacious in mitigating WM damage and improving cognitive function in rodent models is mesenchymal cell-derived extracellular vesicles (MSC-EVs). In the present study, late middle-aged rhesus monkeys were systemically administered monkey-derived MSC-EVs every 2 weeks for 18months. We demonstrate that MSC-EV treatment improves spatial working memory and decreases the frequency of perseverative responses with largely no effects on recognition memory. These cognitive improvements were associated with increases in MRI diffusion measures of WM structural integrity over time as well as preservation of inter-network functional connectivity as measured by resting-state functional MRI. These findings suggest that MSC-EV treatment can slow or reverse age-related cognitive decline while strengthening WM integrity and improving functional connectivity in late middle-agedrhesus monkeys.

Lamina cribrosa shape in non-human primates is different from that of humans.

Strategies to reduce the use of non-human primates in the development of oncology therapeutics: CD3-bispecifics.

Bussuquara virus (BSQV), an orthoflavivirus discovered in Brazil in 1956, has been detected throughout the Americas in diverse mosquito and vertebrate species, including humans. Critical gaps in BSQV knowledge include its capacity for urban transmission and clinical pathogenesis outcomes, with insufficient historical experimentation to draw genomic or phenotypic comparisons to related orthoflavivirus species. The objective of this study was to conduct morphologic, genomic, phylogenetic, and in vitro viral fitness characterization of BSQV using the four available historical strains. We used next generation sequencing and rapid amplification of cDNA ends to construct consensus genomes, followed by phylogenetic analysis and genome annotation to evaluate orthoflavivirus evolutionary relationships and genome characteristics. Infected mosquito (C6/36) and non-human primate (Vero CCL81) cells were imaged with transmission electron microscopy. Viral replication kinetics were quantified across seventeen cell lines of mosquito, mammal, rodent, avian, non-human primate, and human origin. BSQV morphologic (virion diameter, cytopathic effect) and genomic (size, organization, architecture, sequence motifs) results were in line with canonical orthoflavivirus characteristics. One of the four strains (CoAr 41922) shared greater sequence homology to the Naranjal orthoflavivirus than other BSQV strains and was thus excluded from infection phenotype experiments. All three confirmed BSQV strains replicated robustly in most mosquito and all vertebrate cell lines, causing either minimal (mosquito) or moderate to extreme (vertebrate) cytopathic effects. We conclude that BSQV is a generalist orthoflavivirus with a broad range of susceptible vertebrate and mosquito vectors. Our data build a foundation for pathogenesis and vector competence studies to determine the potential of BSQV to emerge into epizootic and urban transmission cycles.

Customizable artificial simulator for developing, planning, and training personnel on neurophysiology and surgical procedures in non-human primates.

Intrathalamic delivery of adeno-associated viral vector expressing progranulin as gene therapy for GRN-related frontotemporal dementia.