Experiments In Non-human Primates Research Articles

Use of Brain Death Recipients in Xenotransplantation: A Double-Edged Sword.

Organ transplants are used to treat many end-stage diseases, but a shortage of donors means many patients cannot be treated. Xenogeneic organs have become an important part of filling the donor gap. Many current studies of kidney, heart, and liver xenotransplantation have used gene-edited pig organs on brain-dead recipients. However, the endocrine system, immune system, and nervous system of brain-dead people are changed, which are different from that of real patients transplanted, and the current research results of brain death (BD) recipients are also different. So there are drawbacks to using brain-dead people for xenotransplantation. In addition, although the policy requires the use of non-human primate (NHP) experiments as the research standard for xenotransplantation, there are still differences between NHP and humans in terms of immunity. Therefore, to better study xenotransplantation, new models may be needed in addition to NHP and brain-dead individuals. Humanized animal models or organoids may be able to fill this gap.

Dynamic modulation of social gaze by sex and familiarity in marmoset dyads.

Social communication relies on the ability to perceive and interpret the direction of others' attention, and is commonly conveyed through head orientation and gaze direction in humans and nonhuman primates. However, traditional social gaze experiments in nonhuman primates require restraining head movements, significantly limiting their natural behavioral repertoire. Here, we developed a novel framework for accurately tracking facial features and three-dimensional head gaze orientations of multiple freely moving common marmosets (Callithrix jacchus). By combining deep learning-based computer vision tools with triangulation algorithms, we were able to track the facial features of marmoset dyads within an arena. This method effectively generates dynamic 3D geometrical facial frames while overcoming common challenges like occlusion. To detect the head gaze direction, we constructed a virtual cone, oriented perpendicular to the facial frame. Using this pipeline, we quantified different types of interactive social gaze events, including partner-directed gaze and joint gaze to a shared spatial location. We observed clear effects of sex and familiarity on both interpersonal distance and gaze dynamics in marmoset dyads. Unfamiliar pairs exhibited more stereotyped patterns of arena occupancy, more sustained levels of social gaze across social distance, and increased social gaze monitoring. On the other hand, familiar pairs exhibited higher levels of joint gazes. Moreover, males displayed significantly elevated levels of gazes toward females' faces and the surrounding regions, irrespective of familiarity. Our study reveals the importance of two key social factors in driving the gaze behaviors of a prosocial primate species and lays the groundwork for a rigorous quantification of primate behaviors in naturalistic settings.

Strain Response ofan Anatomically Accurate Nonhuman Primate Finite Element Brain Model Under Sagittal Loading.

Prevention and treatment of traumatic brain injuries is critical to preserving soldier brain health. Laboratory studies are commonly used to reproduce injuries, understand injury mechanisms, and develop tolerance limits; however, this approach has limitations for studying brain injury, which requires a physiological response. The nonhuman primate (NHP) has been used as an effective model for investigating brain injury for many years. Prior research using the NHP provides a valuable resource to leverage using modern analysis and modeling techniques to improve our understanding of brain injury. The objectives of the present study are to develop an anatomically accurate finite element model of the NHP and determine regional brain responses using previously collected NHP data. The finite element model was developed using a neuroimaging-based anatomical atlas of the rhesus macaque that includes both cortical and subcortical structures. Head kinematic data from 10 sagittal NHP experiments, four +Gx (rearward) and six -Gx (frontal), were used to test model stability and obtain brain strain responses from multiple severities and vectors. For +Gx tests, the whole-brain cumulative strain damage measure exceeding a strain threshold of 0.15 (CSDM15) ranged from 0.28 to 0.89, and 95th percentile of the whole-brain maximum principal strain (MPS95) ranged from 0.21 to 0.59. For -Gx tests, whole-brain CSDM15 ranged from 0.02 to 0.66, and whole-brain MPS95 ranged from 0.08 to 0.39. Recognizing that NHPs are the closest surrogate to humans combined with the limitations of conducting brain injury research in the laboratory, a detailed anatomically accurate finite element model of an NHP was developed and exercised using previously collected data from the Naval Biodynamics Laboratory. The presently developed model can be used to conduct additional analyses to act as pilot data for the design of newer experiments with statistical power because of the sensitivity and resources needed to conduct experiments with NHPs.

Evaluation of [18F]RoSMA-18-d6 as a CB2 PET Radioligand in Nonhuman Primates.

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [18F]RoSMA-18-d6, which proved to be highly suitable for in vitro and in vivo mapping of CB2 in rodents. The aim of this study was to assess the performance characteristics of [18F]RoSMA-18-d6 in nonhuman primates (NHPs) to pave the way for clinical translation. [18F]RoSMA-18-d6 was synthesized from the respective tosylate precursor according to previously reported procedures. In vitro autoradiograms with NHP spleen tissue sections revealed a high binding of [18F]RoSMA-18-d6 to the CB2-rich NHP spleen, which was significantly blocked by coincubation with the commercially available CB2 ligand, GW405833 (10 μM). In contrast, no specific binding was observed by in vitro autoradiography with NHP brain sections, which was in agreement with the notion of a CB2-deficient healthy mammalian brain. In vitro findings were corroborated by PET imaging experiments in NHPs, where [18F]RoSMA-18-d6 uptake in the spleen was dose-dependently attenuated with 1 and 5 mg/kg GW405833, while no specific brain signal was observed. Remarkably, we observed tracer uptake and retention in the NHP spinal cord, which was reduced by GW405833 blockade, pointing toward a potential utility of [18F]RoSMA-18-d6 in probing CB2-expressing cells in the bone marrow. If these observations are substantiated in NHP models of enhanced leukocyte proliferation in the bone marrow, [18F]RoSMA-18-d6 may serve as a valuable marker for hematopoietic activity in various pathologies. In conclusion, [18F]RoSMA-18-d6 proved to be a suitable PET radioligand for imaging CB2 in NHPs, supporting its translation to humans.

Expression of the excitatory opsin ChRERα can be traced longitudinally in rat and nonhuman primate brains with PET imaging.

Optogenetics is a widely used technology with potential for translational research. A critical component of such applications is the ability to track the location of the transduced opsin in vivo. To address this problem, we engineered an excitatory opsin, ChRERα (hChR2(134R)-V5-ERα-LBD), that could be visualized using positron emission tomography (PET) imaging in a noninvasive, longitudinal, and quantitative manner. ChRERα consists of the prototypical excitatory opsin channelrhodopsin-2 (ChR2) and the ligand-binding domain (LBD) of the human estrogen receptor α (ERα). ChRERα showed conserved ChR2 functionality and high affinity for [18F]16α-fluoroestradiol (FES), an FDA-approved PET radiopharmaceutical. Experiments in rats demonstrated that adeno-associated virus (AAV)-mediated expression of ChRERα enables neural circuit manipulation in vivo and that ChRERα expression could be monitored using FES-PET imaging. In vivo experiments in nonhuman primates (NHPs) confirmed that ChRERα expression could be monitored at the site of AAV injection in the primary motor cortex and in long-range neuronal terminals for up to 80 weeks. The anatomical connectivity map of the primary motor cortex identified by FES-PET imaging of ChRERα expression overlapped with a functional connectivity map identified using resting state fMRI in a separate cohort of NHPs. Overall, our results demonstrate that ChRERα expression can be mapped longitudinally in the mammalian brain using FES-PET imaging and can be used for neural circuit modulation in vivo.

Auxiliary liver xenotransplantation technique in a transgenic pig-to-non-human primate model: A surgical approach to prolong survival.

Xenotransplantation using pigs' liver offers a potentially alternative method to overcome worldwide donor shortage, or more importantly as a bridge to allotransplantation. However, it has been challenged by profound thrombocytopenia and fatal coagulopathy in non-human primate models. Here we suggest that a left auxiliary technique can be a useful method to achieve extended survival of the xenograft. Fifteen consecutive liver xenotransplants were carried out in a pig-to-cynomolgus model. Right auxiliary technique was implemented in two cases, orthotopic in eight cases, and left auxiliary in five cases. None of the right auxiliary recipients survived after surgery due to hemorrhage during complex dissection between the primate's right lobe and inferior vena cava. Orthotopic recipients survived less than 7days secondary to profound thrombocytopenia and coagulopathy. Two out of five left auxiliary xenotransplants survived more than 3weeks without uncontrolled thrombocytopenia or anemia, with one of them surviving 34days, the longest graft survival reported to date. Left auxiliary xenotransplant is a feasible approach in non-human primate experiments, and the feared risk of thrombocytopenia and coagulopathy can be minimized. This may allow for longer evaluation of the xenograft and help better understand histopathological and immunological changes that occur following liver xenotransplantation.

Comparative CNS Pharmacology of Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating MS (S46.007)

<h3>Objective:</h3> Compare three BTK inhibitors in Phase 3 development in multiple sclerosis (MS) according to relative potencies and CNS exposure. <h3>Background:</h3> Modulating CNS neuroinflammation represents a paradigm shift for treating MS. Tolebrutinib is a covalent BTK inhibitor designed and selected to optimize both potency and exposure to modulate BTK signaling within the CNS. <h3>Design/Methods:</h3> We used in vitro kinase assays, cellular activation assays, and pharmacokinetic (PK) sampling of cerebrospinal fluid (CSF) in the non-human primate (NHP) cynomolgus to compare tolebrutinib, evobrutinib, fenebrutinib under identical conditions. We then evaluated the CSF PK of tolebrutinib in healthy volunteers. <h3>Results:</h3> Kinase assays demonstrated that tolebrutinib reacted with BTK 65-times faster than evobrutinib (K_inact/K_i = 4.37 × 10⁻³ and 6.82 × 10⁻⁵ nM⁻¹*s⁻¹, respectively). Fenebrutinib, a reversible antagonist had a K_i value of 4.7 nM. Because of the slow off-rate (1.54 × 10⁻⁵ s⁻¹), the forward rate was also very slow (3.28 × 10³ M⁻¹ * s⁻¹). Estimated cellular potency (using B cell activation) was consistent with kinase data (IC50 = 0.7 nM, 34.5 nM, and 2.9 nM, respectively). In NHP, we observed similar levels of exposure in the CSF after oral doses of 10 mg/kg for each candidate. However, tolebrutinib CSF exposure (4.8 ng/mL) (kp, uu CSF=0.40) exceeded the IC90, while evobrutinib (3.2 ng/mL) (kp, uu CSF=0.13) and fenebrutinib (12.9 ng/mL) (kp, uu CSF=0.15) failed to reach the IC50. In healthy volunteers, a single oral dose of 60 or 120 mg resulted in bioactive CSF levels between 2 and 4 hrs. (0.51 and 1.03 ng/mL, respectively). <h3>Conclusions:</h3> Next-generation drug candidates in MS must achieve pharmacologically-relevant concentrations in the CNS to address the existing treatment gap. In these NHP experiments, tolebrutinib was the only BTK inhibitor to show bioactive CSF levels, adding to the evidence that tolebrutinib has potential to slow disability accumulation via modulating neuroinflammation. <b>Disclosure:</b> Timothy J. Turner has received personal compensation for serving as an employee of Sanofi. Timothy J. Turner has received stock or an ownership interest from Sanofi. Timothy J. Turner has received intellectual property interests from a discovery or technology relating to health care. Dr. NICOLAS has nothing to disclose. Mrs. Brun has nothing to disclose. Dimitry Ofengeim has received personal compensation for serving as an employee of Sanofi. Dimitry Ofengeim has received stock or an ownership interest from Sanofi. Dimitry Ofengeim has received personal compensation in the range of $500-$4,999 for serving as a Study Section Reveiwer with NIH.

A Proposed Human Structural Brain Connectivity Matrix in the Center for Morphometric Analysis Harvard-Oxford Atlas Framework: A Historical Perspective and Future Direction for Enhancing the Precision of Human Structural Connectivity with a Novel Neuroanatomical Typology

A complete structural definition of the human nervous system must include delineation of its wiring diagram (e.g., Swanson LW. Brain architecture: understanding the basic plan, 2012). The complete formulation of the human brain circuit diagram (BCD [Front Neuroanat. 2020;14:18]) has been hampered by an inability to determine connections in their entirety (i.e., not only pathway stems but also origins and terminations). From a structural point of view, a neuroanatomic formulation of the BCD should include the origins and terminations of each fiber tract as well as the topographic course of the fiber tract in three dimensions. Classic neuroanatomical studies have provided trajectory information for pathway stems and their speculative origins and terminations [Dejerine J and Dejerine-Klumpke A. Anatomie des Centres Nerveux, 1901; Dejerine J and Dejerine-Klumpke A. Anatomie des Centres Nerveux: Méthodes générales d’étude-embryologie-histogénèse et histologie. Anatomie du cerveau, 1895; Ludwig E and Klingler J. Atlas cerebri humani, 1956; Makris N. Delineation of human association fiber pathways using histologic and magnetic resonance methodologies; 1999; Neuroimage. 1999 Jan;9(1):18–45]. We have summarized these studies previously [Neuroimage. 1999 Jan;9(1):18–45] and present them here in a macroscale-level human cerebral structural connectivity matrix. A matrix in the present context is an organizational construct that embodies anatomical knowledge about cortical areas and their connections. This is represented in relation to parcellation units according to the Harvard-Oxford Atlas neuroanatomical framework established by the Center for Morphometric Analysis at Massachusetts General Hospital in the early 2000s, which is based on the MRI volumetrics paradigm of Dr. Verne Caviness and colleagues [Brain Dev. 1999 Jul;21(5):289–95]. This is a classic connectional matrix based mainly on data predating the advent of DTI tractography, which we refer to as the “pre-DTI era” human structural connectivity matrix. In addition, we present representative examples that incorporate validated structural connectivity information from nonhuman primates and more recent information on human structural connectivity emerging from DTI tractography studies. We refer to this as the “DTI era” human structural connectivity matrix. This newer matrix represents a work in progress and is necessarily incomplete due to the lack of validated human connectivity findings on origins and terminations as well as pathway stems. Importantly, we use a neuroanatomical typology to characterize different types of connections in the human brain, which is critical for organizing the matrices and the prospective database. Although substantial in detail, the present matrices may be assumed to be only partially complete because the sources of data relating to human fiber system organization are limited largely to inferences from gross dissections of anatomic specimens or extrapolations of pathway tracing information from nonhuman primate experiments [Front Neuroanat. 2020;14:18, Front Neuroanat. 2022;16:1035420, and Brain Imaging Behav. 2021;15(3):1589–1621]. These matrices, which embody a systematic description of cerebral connectivity, can be used in cognitive and clinical studies in neuroscience and, importantly, to guide research efforts for further elucidating, validating, and completing the human BCD [Front Neuroanat. 2020;14:18].

Super-resolution in brain positron emission tomography using a real-time motion capture system

Super-resolution (SR) is a methodology that seeks to improve image resolution by exploiting the increased spatial sampling information obtained from multiple acquisitions of the same target with accurately known sub-resolution shifts. This work aims to develop and evaluate an SR estimation framework for brain positron emission tomography (PET), taking advantage of a high-resolution infra-red tracking camera to measure shifts precisely and continuously. Moving phantoms and non-human primate (NHP) experiments were performed on a GE Discovery MI PET/CT scanner (GE Healthcare) using an NDI Polaris Vega (Northern Digital Inc), an external optical motion tracking device. To enable SR, a robust temporal and spatial calibration of the two devices was developed as well as a list-mode Ordered Subset Expectation Maximization PET reconstruction algorithm, incorporating the high-resolution tracking data from the Polaris Vega to correct motion for measured line of responses on an event-by-event basis. For both phantoms and NHP studies, the SR reconstruction method yielded PET images with visibly increased spatial resolution compared to standard static acquisitions, allowing improved visualization of small structures. Quantitative analysis in terms of SSIM, CNR and line profiles were conducted and validated our observations. The results demonstrate that SR can be achieved in brain PET by measuring target motion in real-time using a high-resolution infrared tracking camera.

Opto-Array: an implantable array of LEDs built for behavioral optogenetic experiments in nonhuman primates

Opto-Array: an implantable array of LEDs built for behavioral optogenetic experiments in nonhuman primates

Generating patient-specific acoustic simulations for transcranial focused ultrasound procedures based on optical tracking information

During transcranial focused ultrasound (FUS) procedures, accurate targeting is important and neuronavigation with optically tracked tools is used to estimate the free-field focal location on pre-acquired images. Offline neuronavigation systems do not typically incorporate aberrating effects of the skull known to displace and distort the focus. Here, we developed a pipeline that integrated patient-specific acoustic simulations informed by transformations from optically tracked FUS procedures as a tool to evaluate transcranial pressure fields and demonstrated its use in three FUS scenarios: magnetic resonance imaging-guided (MR-guided) phantom experiments, MR-guided non-human primate (NHP) experiments, an offline behaving NHP experiments. Distance vectors between the estimated focus from optical tracking and peak intracranial location from simulations were less than 1 mm for all groups (Phantom: 0.6 ± 0.3 mm, NHP: 0.7 ± 0.3 mm, Behaving NHP: 0.5 ± 0.2 mm). Comparisons of the target registration error of MR measurements with the optically tracked focus (TRETracked) and simulated focus (TRESimulated) suggest that focal location errors are dominated by optical tracking errors rather than aberration through the skull in the NHP (Phantom: TRETracked: 3.3 ± 1.4 mm, Phantom TRESimulated: 3.3 ± 1.9 mm, NHP TRETracked: 3.9 ± 1.9 mm, NHP TRESimulated: 4.1 ± 1.6 mm). Our software pipeline provides patient-specific estimates of the acoustic field during transcranial FUS procedures.

Advances in Parkinson's disease induced by α-synuclein transmitted through the gut-brain axis

Parkinson's disease (PD) is the most common neurodegenerative disease. Along with the population aging of China, the increase of PD patients in China will result in serious economic and medical burdens. The typical pathological characteristics of PD are the death of dopaminergic neurons in the substantia nigra compacta and the pathological inclusion bodies formed by abnormally aggregated amyloid alpha-synuclein (α-Syn) in dopaminergic neurons, which is also named as Lewy body. Studies have found that the Lewy body exists not only in the central nervous system, but also in the peripheral nervous system. The abundant enteric nervous system in the gut is called the "second brain". The discovery of the gut-brain axis also proves that α-Syn can be transmitted bilaterally between the brain and the gut. The gut microbiota was shown to be involved in the formation and transmission of pathological α-Syn. Therefore, this article summarized the bilateral transmission relationship of α-Syn in the brain and the gut and illustrated the influence of gut microbiota on the abnormal aggregation of α-Syn. Combined with the current progresses on PD patients and animal models especially the non-human primate experiments, this article aimed to provide a reference for the screening and diagnosis of PD.

Identifying critical DO2 with compensatory reserve during simulated hemorrhage in humans.

Based on previous experiments in nonhuman primates, we hypothesized that DO2 crit in humans is 5-6ml O2 ·kg-1 min-1 . We measured the compensatory reserve (CRM) and calculated oxygen delivery (DO2 ) in 166 healthy, normotensive, nonsmoking subjects (97 males, 69 females) during progressive central hypovolemia induced by lower body negative pressure as a model of ongoing hemorrhage. Subjects were classified as having either high tolerance (HT; N=111) or low tolerance (LT; N=55) to central hypovolemia. HT and LT groups were matched for age, weight, BMI, and vital signs, DO2 and CRM at baseline. The CRM-DO2 relationship was best fitted to a logarithmic model in HT subjects (amalgamated R2 =0.971) and a second-order polynomial model in the LT group (amalgamated R2 =0.991). Average DO2 crit for the entire subject cohort was estimated at 5.3ml O2 ·kg-1 min-1 , but was ~14% lower in HT compared with LT subjects. The reduction in DO2 from 40% CRM to 20% CRM was 2-fold greater in the LT compared with the HT group. Average DO2 crit in humans is 5.3ml O2 ·kg-1 min-1 , but is ~14% lower in HT compared with LT subjects. The CRM-DO2 relationship is curvilinear in humans, and different when comparing HT and LT individuals. The threshold for an emergent monitoring signal should be recalibrated from 30% to 40% CRM given that the decline in DO2 from 40% CRM to 20% CRM for LT subjects is located on the steepest part of the CRM-DO2 relationship.

Identifying Critical DO2 with Compensatory Reserve during Simulated Hemorrhage in Humans

BackgroundHemorrhage is a leading cause of potentially‐survivable death in trauma. The basic principle for treatment of ongoing bleeding prior to hemorrhage control is that early detection and intervention will improve outcome. However, current monitoring technologies that rely on standard vital signs are unreliable in assessing the clinical status of trauma patients because of variability in the capacity of individuals to compensate for hypovolemia. A monitoring capability designed to measure changes in systemic oxygen delivery (DO2) would provide an earlier indicator of clinical status in patients with life‐threatening blood loss. Maintaining DO2 above the level associated with the onset of shock (i.e., DO2crit) until bleeding is controlled should be the aim of any hemorrhage intervention. But DO2crit has not been identified in humans. Over the past decade, measuring the physiological phenomenon of compensatory reserve (CRM) based on interrogation of arterial waveform morphology has provided a capability to assess the reduction in the capacity to compensate for ongoing progressive central hypovolemia. Based on non‐human primate hemorrhage experiments, we hypothesized that humans would demonstrate a linear relationship between CRM and DO2, allowing for the identification of a DO2crit in humans of ~5 to 6 ml O2·kg‐1·min‐1. We also hypothesized that individuals with high (HT) and low (LT) tolerance to hypovolemia (i.e., ‘good’ versus ‘poor’ compensators) would have similar CRM‐DO2 relationships and DO2crit.Study Design and MethodsCRM and calculated DO2 were measured in 166 healthy subjects (97 males, 69 females) with a mean ± SD age of 23 ± 4 years, height of 171 ± 11 cm, and weight of 69 ± 11 kg. All subjects underwent progressive central hypovolemia induced by lower body negative pressure as a model of ongoing hemorrhage to a physiological state of hemodynamic decompensation. Subjects were classified as having either high tolerance (HT; N = 111) or low tolerance (LT; N = 55) to central hypovolemia based on whether they completed 5 minutes at ‐60 mmHg LBNP.ResultsHT and LT groups were matched for age, weight, BMI, and vital signs, DO2 and CRM at baseline. The CRM‐DO2 relationship was best fitted to a logarithmic model in HT subjects (R2 = 0.971) and a polynomial model in the LT group (R2 = 0.991). Average DO2crit for the entire subject cohort was estimated at 5.3 ml O2·Kg‐1·min‐1, but was ~14% lower in HT compared to LT subjects. The reduction in DO2 from 40% CRM to 20% CRM was 2‐fold greater in the LT compared to the HT group.ConclusionsAverage DO2crit in humans is 5.3 ml O2·Kg‐1·min‐1, but is ~14% lower in HT compared to LT subjects. The CRM‐DO2 relationship is curvilinear in humans, and different when comparing HT and LT individuals. A threshold for an emergent monitoring signal should be set to 40% CRM given that the decline in DO2 from 40% CRM to 20% CRM for LT subjects is located on the steepest part of the CRM‐DO2 relationship.

Modelling behaviors relevant to brain disorders in the nonhuman primate: Are we there yet?

Recent years have seen a profound resurgence of activity with nonhuman primates (NHPs) to model human brain disorders. From marmosets to macaques, the study of NHP species offers a unique window into the function of primate-specific neural circuits that are impossible to examine in other models. Examining how these circuits manifest into the complex behaviors of primates, such as advanced cognitive and social functions, has provided enormous insights to date into the mechanisms underlying symptoms of numerous neurological and neuropsychiatric illnesses. With the recent optimization of modern techniques to manipulate and measure neural activity in vivo, such as optogenetics and calcium imaging, NHP research is more well-equipped than ever to probe the neural mechanisms underlying pathological behavior. However, methods for behavioral experimentation and analysis in NHPs have noticeably failed to keep pace with these advances. As behavior ultimately lies at the junction between preclinical findings and its translation to clinical outcomes for brain disorders, approaches to improve the integrity, reproducibility, and translatability of behavioral experiments in NHPs requires critical evaluation. In this review, we provide a unifying account of existing brain disorder models using NHPs, and provide insights into the present and emerging contributions of behavioral studies to the field.

Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy.

Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed—some animals exhibited large fluctuations in viral load after cART cessation—the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Challenge Experiments in Nonhuman Primates: An Ethical Perspective.

The COVID-19 pandemic has stimulated massive investment in biomedical research with the aims of understanding the disease and developing effective vaccine and therapeutic interventions. What role should animal research play in this scientific endeavor? Both the urgency to evaluate candidate interventions for human use and growing societal concern about ethical treatment of (nonhuman) animals put into question the justifiability of animal research as a precursor to clinical trials. Yet forgoing animal research in the rush to undertake human testing might expose human research participants to unacceptable risks. In this article, we apply a recently developed framework of principles for animal research ethics in exploring ethical questions raised by a SARS-CoV-2 infection challenge experiment involving rhesus macaques, which evaluated the protective efficacy of the mRNA-1273 vaccine that was recently approved for emergency use. Our aim is to illuminate the ethical issues while introducing, and illustrating the use of, the framework.

The ventral pathway of the human brain: A continuous association tract system

The brain hemispheres can be divided into an upper dorsal and a lower ventral system. Each system consists of distinct cortical regions connected via long association tracts. The tracts cross the central sulcus or the limen insulae to connect the frontal lobe with the posterior brain. The dorsal stream is associated with sensorimotor mapping. The ventral stream serves structural analysis and semantics in different domains, as visual, acoustic or space processing. How does the prefrontal cortex, regarded as the platform for the highest level of integration, incorporate information from these different domains? In the current view, the ventral pathway consists of several separate tracts, related to different modalities. Originally the assumption was that the ventral path is a continuum, covering all modalities. The latter would imply a very different anatomical basis for cognitive and clinical models of processing. To further define the ventral connections, we used cutting-edge in vivo global tractography on high-resolution diffusion tensor imaging (DTI) data from 100 normal subjects from the human connectome project and ex vivo preparation of fiber bundles in the extreme capsule of 8 humans using the Klingler technique. Our data showed that ventral stream tracts, traversing through the extreme capsule, form a continuous band of fibers that fan out anteriorly to the prefrontal cortex, and posteriorly to temporal, occipital and parietal cortical regions. Introduction of additional volumes of interest in temporal and occipital lobes differentiated between the inferior fronto-occipital fascicle (IFOF) and uncinate fascicle (UF). Unequivocally, in both experiments, in all subjects a connection between the inferior frontal and middle-to-posterior temporal cortical region, otherwise known as the temporo-frontal extreme capsule fascicle (ECF) from nonhuman primate brain-tracing experiments was identified. In the human brain, this tract connects the language domains of “Broca's area” and “Wernicke's area”. The differentiation in the three tracts, IFOF, UF and ECF seems arbitrary, all three pass through the extreme capsule. Our data show that the ventral pathway represents a continuum. The three tracts merge seamlessly and streamlines showed considerable overlap in their anterior and posterior course. Terminal maps identified prefrontal cortex in the frontal lobe and association cortex in temporal, occipital and parietal lobes as streamline endings. This anatomical substrate potentially facilitates the prefrontal cortex to integrate information across different domains and modalities.

The cingulate oculomotor cortex

Knowledge about the relevance and extent of human eye movement control in the cingulate cortex to date is very limited. Experiments in non-human primates brought about evidence for a potentially central role of the dorsal bank of the cingulate sulcus in saccadic eye movements. In humans, a putative cingulate eye field (CEF) in the same region has been proposed; however, its function and location still remain controversial. Another area in the posterior cingulate cortex, the cingulate sulcus visual area (CSv), has been shown to respond to visual motion cues and also ocular motor tasks. In this study we used multi-band neuroimaging (n = 46) to comprehensively characterize oculomotor responses along the entire cingulate cortex during the most common types of eye movements.We were able to robustly localize the CEF to the anterior portion of the midcingulate gyrus. The region gave responses during all oculomotor tasks and is embedded within the ventral attention network. Area CSv, which is located in the anterior portion of the posterior cingulate gyrus, on the other hand responded to smooth pursuit and optokinetic nystagmus only. It likewise represents a node within the ventral attention network but at the same time seems to be a distinctive part of the somatomotor network. Our findings support an executive role of the CEF, suggesting a cognitive control function in maintaining and adapting different kinds of eye movements. CSv on the other hand might be an interface for relaying oculomotor, visual motion and broad sensory signals related to self-motion.

Virus Vaccine Induced Immune Enhancement Mechanisms

In the present opinion, a go through current scientific literature have demonstrated that there are nine possible immune enhancement mechanisms [IE].IE following viral vaccine priming and exposure to live west nile, human immune-deficiency , dengue and corona virus challenges were documented. Five of which were antibody dependent[ADE ]and the other four were T cell dependent .A virus vaccine may expresses more than one of the five ADE mechanisms .Sars and Mers were mediating ADE. Sars cov-2 virus induce, TH17-Treg eosinophilic IE and in an ex-vivo cell culture study has shown to induce ADE mechanism both in covid -19 patients.Sars-cov-2 DNA vaccines have shown no IE in non-human primate experiments but covid-19 vaccines are expectable to induce ADE in human vaccinee, though this wait to be elucidated. Keywords: Antibody ,corona ,enhancement ,immune ,vaccine, virus. DOI: 10.7176/JHMN/86-05 Publication date: February 28 th 2021