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Co-immunization with hemagglutinin stem immunogens elicits cross-group neutralizing antibodies and broad protection against influenza A viruses.

Current influenza vaccines predominantly induce immunity to the hypervariable hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, the immunosubdominant yet conserved HA stem harbors a supersite that is targeted by broadly neutralizing antibodies (bnAbs), representing a prime target for universal vaccines. Here, we showed that the co-immunization of two HA stem immunogens derived from group 1 and 2 influenza A viruses elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protecte…

Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggrega … es. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

A New Horizon in Reproductive Research with Pluripotent Stem Cells: Successful In Vitro Gametogenesis in Rodents, Its Application to Large Animals, and Future In Vitro Reconstitution of Reproductive Organs Such as "Uteroid" and "Oviductoid".

Recent success in derivation of functional gametes (oocytes and spermatozoa) from pluripotent stem cells (PSCs) of rodents has made it feasible for future application to large animals including endangered species and to ultimately humans. Here, we summarize backgrounds and recent studies on in vitro gametogenesis from rodent PSCs, and similar approaches using PSCs from large animals, including livestock, nonhuman primates (NHPs), and humans. We also describe additional developing approaches for in vitro reconstitution of reproductive organs, such as the ovary (ovarioid), testis (testisoid), an…

TRIM25 and ZAP target the Ebola virus ribonucleoprotein complex to mediate interferon-induced restriction.

Ebola virus (EBOV) causes highly pathogenic disease in primates. Through screening a library of human interferon-stimulated genes (ISGs), we identified TRIM25 as a potent inhibitor of EBOV transcription-and-replication-competent virus-like particle (trVLP) propagation. TRIM25 overexpression inhibited the accumulation of viral genomic and messenger RNAs independently of the RNA sensor RIG-I or secondary proinflammatory gene expression. Deletion of TRIM25 strongly attenuated the sensitivity of trVLPs to inhibition by type-I interferon. The antiviral activity of TRIM25 required ZAP and the effect…

Быстрое обнаружение биомаркера Эболы с оптическими микрорезонаторами.

Вирус Эболы (ЭБОВ) представляет собой высокоинфекционный патоген, при этом коэффициент смертности составляет 89%. Быстрое терапевтическое лечение и вспомогательные меры могут резко улучшить результаты лечения пациентов, однако симптомы заболевания ОВБ (ВЗБ) не отличаются спецификой от других эндемических заболеваний. С учетом высокой смертности и значительного дублирования симптомов существует острая потребность в чувствительной, быстрой диагностике ЭВД. По-прежнему трудно диагностировать ЭВД по лицу. Здесь мы описываем быструю и чувствительную диагностику ЭВД с помощью датчиков резонатора мик

Совпадение в аннотации оригинала
Ebola virus (EBOV) is a highly infectious pathogen, with a case mortality rate as high as 89%. Rapid therapeutic treatments and supportive m … Furthermore, we validated our assay with the detection of sGP in serum from EBOV-infected non-human primates. Our results demonstrate the utility of a high-sensitivity diagnostic platform for detection of sGP for diagnosis of EVD.

Development of a skin- and neuro-attenuated live vaccine for varicella.

Varicella caused by the primary infection of varicella-zoster virus (VZV) exerts a considerable disease burden globally. Current varicella v … in multiple small animal species. Finally, v7D is proven well-tolerated and immunogenic in nonhuman primates. Our preclinical data suggest that v7D is a promising candidate as a safer live varicella vaccine with reduced risk of vaccine-related complications, and could inform the design of other herpes virus vaccines.

Development of a Well-Characterized Cynomolgus Macaque Model of Marburg Virus Disease for Support of Vaccine and Therapy Development.

Marburg virus (MARV) is a filovirus that can infect humans and nonhuman primates (NHPs), causing severe disease and death. Of the filoviruses, Ebola virus (EBOV) has been the primary target for vaccine and therapeutic development. However, MARV has an average case fatality rate of approximately 50%, the infectious dose is low, and there are currently no approved vaccines or therapies targeted at infection with MARV. The purpose of this study was to characterize disease course in cynomolgus macaques intramuscularly exposed to MARV Angola variant. There were several biomarkers that reliably corr…

A molecular atlas of innate immunity to adjuvanted and live attenuated vaccines, in mice.

Adjuvants hold great potential in enhancing vaccine efficacy, making the understanding and improving of adjuvants critical goals in vaccinology. The TLR7/8 agonist, 3M-052, induces long-lived humoral immunity in non-human primates and is currently being evaluated in human clinical trials. However, the innate mechanisms of 3M-052 have not been fully characterized. Here, we perform flow cytometry, single cell RNA-seq and ATAC-seq to profile the kinetics, transcriptomics and epigenomics of innate immune cells in murine draining lymph nodes following 3M-052-Alum/Ovalbumin immunization. We find tha…

Generation of Adenovirus for In Vitro and In Vivo Studies of Hepatocytes.

Although non-alcoholic steatohepatitis (NASH) can progress to liver cancer and liver failure, no FDA-approved drugs exist to treat NASH. Dec … virus is a promising treatment method in preclinical animal models, including rodents and non-human primates, and is used in many clinical trials. Here, we describe a step-by-step protocol to generate adenovirus for basic medical research. We discuss critical steps during virus propagation and purification and provide notes about how to avoid common pitfal …

Heterologous immunization with adenovirus vectored and inactivated vaccines effectively protects against SARS-CoV-2 variants in mice and macaques.

To cope with the decline in COVID-19 vaccine-induced immunity caused by emerging SARS-CoV-2 variants, a heterologous immunization regimen using chimpanzee adenovirus vectored vaccine expressing SARS-CoV-2 spike (ChAd-S) and an inactivated vaccine (IV) was tested in mice and non-human primates (NHPs). Heterologous regimen successfully enhanced or at least maintained antibody and T cell responses and effectively protected against SARS-CoV-2 variants in mice and NHPs. An additional heterologous booster in mice further improved and prolonged the spike-specific antibody response and conferred effec…

Common fronto-temporal effective connectivity in humans and monkeys.

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, … nsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.

Single-trial decoding of movement intentions using functional ultrasound neuroimaging.

New technologies are key to understanding the dynamic activity of neural circuits and systems in the brain. Here, we show that a minimally invasive approach based on ultrasound can be used to detect the neural correlates of movement planning, including directions and effectors. While non-human primates (NHPs) performed memory-guided movements, we used functional ultrasound (fUS) neuroimaging to record changes in cerebral blood volume with 100 μm resolution. We recorded from outside the dura above the posterior parietal cortex, a brain area important for spatial perception, multisensory integra…

Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage.

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-…

Topography of Visual Features in the Human Ventral Visual Pathway.

Visual object recognition in humans and nonhuman primates is achieved by the ventral visual pathway (ventral occipital-temporal cortex, VOTC), which shows a well-documented object domain structure. An on-going question is what type of information is processed in the higher-order VOTC that underlies such observations, with recent evidence suggesting effects of certain visual features. Combining computational vision models, fMRI experiment using a parametric-modulation approach, and natural image statistics of common objects, we depicted the neural distribution of a comprehensive set of visual f…

Early life stress is associated with earlier emergence of permanent molars.

Exposure to adversity can accelerate biological aging. However, existing biomarkers of early aging are either costly and difficult to collect, like epigenetic signatures, or cannot be detected until late childhood, like pubertal onset. We evaluated the hypothesis that early adversity is associated with earlier molar eruption, an easily assessed measure that has been used to track the length of childhood across primates. In a preregistered analysis (n = 117, ages 4 to 7 y), we demonstrate that lower family income and exposure to adverse childhood experiences (ACEs) are significantly associated …

Fusion peptide priming reduces immune responses to HIV-1 envelope trimer base.

Soluble "SOSIP"-stabilized envelope (Env) trimers are promising HIV-vaccine immunogens. However, they induce high-titer responses against the glycan-free trimer base, which is occluded on native virions. To delineate the effect on base responses of priming with immunogens targeting the fusion peptide (FP) site of vulnerability, here, we quantify the prevalence of trimer-base antibody responses in 49 non-human primates immunized with various SOSIP-stabilized Env trimers and FP-carrier conjugates. Trimer-base responses account for ∼90% of the overall trimer response in animals immunized with tri…

The Roles of the Cortical Motor Areas in Sequential Movements.

The ability to learn and perform a sequence of movements is a key component of voluntary motor behavior. During the learning of sequential m … together into a meaningful action has been a topic of much interest. Studies in human and non-human primates have shown that a brain-wide distributed network is active during the learning and performance of skilled sequential movements. The current challenge is to identify a unique contribution of each area to the complex process of learning and maintenanc …

Antibody-drug conjugate MORAb-202 exhibits long-lasting antitumor efficacy in TNBC PDx models.

The antibody-drug conjugate (ADC) MORAb-202, consisting of farletuzumab paired with a cathepsin B-cleavable linker and eribulin, targets fol … bited durable efficacy proportional to tumor FRA expression. Toxicology studies (Q3Wx2) in nonhuman primates suggested that the major observed toxicity of MORAb-202 is hematologic toxicity. Overall, these findings support the concept that MORAb-202 represents a promising investigational ADC for the treatment of TNBC patients.

A modular approach toward producing nanotherapeutics targeting the innate immune system.

Immunotherapies controlling the adaptive immune system are firmly established, but regulating the innate immune system remains much less exp … vival in a heart transplantation mouse model. Last, we studied mTORi-NB biodistribution in nonhuman primates by PET/MR imaging and evaluated its safety, paving the way for clinical translation.

Incomplete antiviral treatment may induce longer durations of viral shedding during SARS-CoV-2 infection.

The duration of viral shedding is determined by a balance between de novo infection and removal of infected cells. That is, if infection is … r rate. Using a simple mathematical model, we quantified SARS-CoV-2 infection dynamics in non-human primates and characterized the kinetics of viral shedding. We counterintuitively found that treatments initiated early, such as 0.5 d after virus inoculation, with intermediate to relatively high efficacy (30-70% inhibition of virus replication) yield a prol …