Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine.

BACKGROUND: MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated approximately 50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting that efforts to improve this vaccine design might yield a vaccine suitable for licensure. METHODS: A messenger RNA (mRNA)-based vaccine candidate encoding HCMV gB and pentameric complex (PC), mRNA-1647, is currently in late-stage efficacy trials. However, its immunogenicity has not been compared to the partially effective gB/MF59 vaccine. We assessed neutralizing and Fc-mediated immunoglobulin G (IgG) effector antibody responses induced by mRNA-1647 in both HCMV-seropositive and -seronegative vaccinees from a first-in-human clinical trial through 1 year following third vaccination using a systems serology approach. Furthermore, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative gB/MF59 vaccine recipients. RESULTS: mRNA-1647 vaccination elicited and boosted HCMV-specific IgG responses in seronegative and seropositive vaccinees, respectively, including neutralizing and Fc-mediated effector antibody responses. gB-specific IgG responses were lower than PC-specific IgG responses. gB-specific IgG and antibody-dependent cellular phagocytosis responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited higher neutralization and antibody-dependent cellular cytotoxicity (ADCC) responses. CONCLUSIONS: Overall, mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses, with lower gB-specific IgG responses but higher neutralization and ADCC responses compared to the gB/MF59 vaccine. CLINICAL TRIALS REGISTRATION: NCT03382405 (mRNA-1647) and NCT00133497 (gB/MF59).

Arousal modulates the amygdala-insula reciprocal connectivity during naturalistic emotional movie watching.

Emotional arousal is a complex state recruiting distributed cortical and subcortical structures, in which the amygdala and insula play an important role. Although previous neuroimaging studies have showed that the amygdala and insula manifest reciprocal connectivity, the effective connectivities and modulatory patterns on the amygdala-insula interactions underpinning arousal are still largely unknown. One of the reasons may be attributed to static and discrete laboratory brain imaging paradigms used in most existing studies. In this study, by integrating naturalistic-paradigm (i.e., movie watching) functional magnetic resonance imaging (fMRI) with a computational affective model that predicts dynamic arousal for the movie stimuli, we investigated the effective amygdala-insula interactions and the modulatory effect of the input arousal on the effective connections. Specifically, the predicted dynamic arousal of the movie served as regressors in general linear model (GLM) analysis and brain activations were identified accordingly. The regions of interest (i.e., the bilateral amygdala and insula) were localized according to the GLM activation map. The effective connectivity and modulatory effect were then inferred by using dynamic causal modeling (DCM). Our experimental results demonstrated that amygdala was the site of driving arousal input and arousal had a modulatory effect on the reciprocal connections between amygdala and insula. Our study provides novel evidence to the underlying neural mechanisms of arousal in a dynamical naturalistic setting.

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques.

The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized Wuhan-Hu-1 SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The antibodies recognized and potently neutralized a panel of different Spike variants including Alpha, Delta, Epsilon, Eta and A.23.1, but to a lesser extent Beta and Gamma. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.

Test-retest reliability of dynamic functional connectivity in naturalistic paradigm functional magnetic resonance imaging.

Dynamic functional connectivity (dFC) has been increasingly used to characterize the brain transient temporal functional patterns and their alterations in diseased brains. Meanwhile, naturalistic neuroimaging paradigms have been an emerging approach for cognitive neuroscience with high ecological validity. However, the test-retest reliability of dFC in naturalistic paradigm neuroimaging is largely unknown. To address this issue, we examined the test-retest reliability of dFC in functional magnetic resonance imaging (fMRI) under natural viewing condition. The intraclass correlation coefficients (ICC) of four dFC statistics including standard deviation (Std), coefficient of variation (COV), amplitude of low frequency fluctuation (ALFF), and excursion (Excursion) were used to measure the test-retest reliability. The test-retest reliability of dFC in naturalistic viewing condition was then compared with that under resting state. Our experimental results showed that: (a) Global test-retest reliability of dFC was much lower than that of static functional connectivity (sFC) in both resting-state and naturalistic viewing conditions; (b) Both global and local (including visual, limbic and default mode networks) test-retest reliability of dFC could be significantly improved in naturalistic viewing condition compared to that in resting state; (c) There existed strong negative correlation between sFC and dFC, weak negative correlation between dFC and dFC-ICC (i.e., ICC of dFC), as well as weak positive correlation between dFC-ICC and sFC-ICC (i.e., ICC of sFC). The present study provides novel evidence for the promotion of naturalistic paradigm fMRI in functional brain network studies.

Marmoset Brain ISH Data Revealed Molecular Difference Between Cortical Folding Patterns.

Literature studies have demonstrated the structural, connectional, and functional differences between cortical folding patterns in mammalian brains, such as convex and concave patterns. However, the molecular underpinning of such convex/concave differences remains largely unknown. Thanks to public access to a recently released set of marmoset whole-brain in situ hybridization data by RIKEN, Japan; this data's accessibility empowers us to improve our understanding of the organization, regulation, and function of genes and their relation to macroscale metrics of brains. In this work, magnetic resonance imaging and diffusion tensor imaging macroscale neuroimaging data in this dataset were used to delineate convex/concave patterns in marmoset and to examine their structural features. Machine learning and visualization tools were employed to investigate the possible transcriptome difference between cortical convex and concave patterns. Experimental results demonstrated that a collection of genes is differentially expressed in convex and concave patterns, and their expression profiles can robustly characterize and differentiate the two folding patterns. More importantly, neuroscientific interpretations of these differentially expressed genes, as well as axonal guidance pathway analysis and gene enrichment analysis, offer novel understanding of structural and functional differences between cortical folding patterns in different regions from a molecular perspective.

The Cerebral Cortex is Bisectionally Segregated into Two Fundamentally Different Functional Units of Gyri and Sulci.

The human cerebral cortex is highly folded into diverse gyri and sulci. Accumulating evidences suggest that gyri and sulci exhibit anatomical, morphological, and connectional differences. Inspired by these evidences, we performed a series of experiments to explore the frequency-specific differences between gyral and sulcal neural activities from resting-state and task-based functional magnetic resonance imaging (fMRI) data. Specifically, we designed a convolutional neural network (CNN) based classifier, which can differentiate gyral and sulcal fMRI signals with reasonable accuracies. Further investigations of learned CNN models imply that sulcal fMRI signals are more diverse and more high frequency than gyral signals, suggesting that gyri and sulci truly play different functional roles. These differences are significantly associated with axonal fiber wiring and cortical thickness patterns, suggesting that these differences might be deeply rooted in their structural and cellular underpinnings. Further wavelet entropy analyses demonstrated the validity of CNN-based findings. In general, our collective observations support a new concept that the cerebral cortex is bisectionally segregated into 2 functionally different units of gyri and sulci.

Control of Heterologous Simian Immunodeficiency Virus SIVsmE660 Infection by DNA and Protein Coimmunization Regimens Combined with Different Toll-Like-Receptor-4-Based Adjuvants in Macaques.

We developed a method of simultaneous vaccination with DNA and protein resulting in robust and durable cellular and humoral immune responses with efficient dissemination to mucosal sites and protection against simian immunodeficiency virus (SIV) infection. To further optimize the DNA-protein coimmunization regimen, we tested a SIVmac251-based vaccine formulated with either of two Toll-like receptor 4 (TLR4) ligand-based liposomal adjuvant formulations (TLR4 plus TLR7 [TLR4+7] or TLR4 plus QS21 [TLR4+QS21]) in macaques. Although both vaccines induced humoral responses of similar magnitudes, they differed in their functional quality, including broader neutralizing activity and effector functions in the TLR4+7 group. Upon repeated heterologous SIVsmE660 challenge, a trend of delayed viral acquisition was found in vaccinees compared to controls, which reached statistical significance in animals with the TRIM-5α-resistant (TRIM-5α R) allele. Vaccinees were preferentially infected by an SIVsmE660 transmitted/founder virus carrying neutralization-resistant A/K mutations at residues 45 and 47 in Env, demonstrating a strong vaccine-induced sieve effect. In addition, the delay in virus acquisition directly correlated with SIVsmE660-specific neutralizing antibodies. The presence of mucosal V1V2 IgG binding antibodies correlated with a significantly decreased risk of virus acquisition in both TRIM-5α R and TRIM-5α-moderate/sensitive (TRIM-5α M/S) animals, although this vaccine effect was more prominent in animals with the TRIM-5α R allele. These data support the combined contribution of immune responses and genetic background to vaccine efficacy. Humoral responses targeting V2 and SIV-specific T cell responses correlated with viremia control. In conclusion, the combination of DNA and gp120 Env protein vaccine regimens using two different adjuvants induced durable and potent cellular and humoral responses contributing to a lower risk of infection by heterologous SIV challenge.IMPORTANCE An effective AIDS vaccine continues to be of paramount importance for the control of the pandemic, and it has been proven to be an elusive target. Vaccine efficacy trials and macaque challenge studies indicate that protection may be the result of combinations of many parameters. We show that a combination of DNA and protein vaccinations applied at the same time provides rapid and robust cellular and humoral immune responses and evidence for a reduced risk of infection. Vaccine-induced neutralizing antibodies and Env V2-specific antibodies at mucosal sites contribute to the delay of SIVsmE660 acquisition, and genetic makeup (TRIM-5α) affects the effectiveness of the vaccine. These data are important for the design of better vaccines and may also affect other vaccine platforms.

Self-organized interdependence among populations promotes cooperation by means of coevolution.

We show that self-organized interdependence promotes the evolution of cooperation in interdependent networks. The evolution of connections between networks occurs according to the following rule: if a player often wins against its opponent (regardless of its strategy), it is allowed to form an external link with the corresponding partner in another network to obtain additional benefit; otherwise, the opportunity to increase its benefit is lost. Through numerical simulation, it is unveiled that cooperation can be significantly promoted due to interdependent network reciprocity. Interestingly, the synchronization of evolutionary processes emerges on both networks, and individuals can take advantage of interdependent network reciprocity when both the strategies and the coevolving times in the two networks are synchronous.

Latent source mining in FMRI via restricted Boltzmann machine.

Blind source separation (BSS) is commonly used in functional magnetic resonance imaging (fMRI) data analysis. Recently, BSS models based on restricted Boltzmann machine (RBM), one of the building blocks of deep learning models, have been shown to improve brain network identification compared to conventional single matrix factorization models such as independent component analysis (ICA). These models, however, trained RBM on fMRI volumes, and are hence challenged by model complexity and limited training set. In this article, we propose to apply RBM to fMRI time courses instead of volumes for BSS. The proposed method not only interprets fMRI time courses explicitly to take advantages of deep learning models in latent feature learning but also substantially reduces model complexity and increases the scale of training set to improve training efficiency. Our experimental results based on Human Connectome Project (HCP) datasets demonstrated the superiority of the proposed method over ICA and the one that applied RBM to fMRI volumes in identifying task-related components, resulted in more accurate and specific representations of task-related activations. Moreover, our method separated out components representing intermixed effects between task events, which could reflect inherent interactions among functionally connected brain regions. Our study demonstrates the value of RBM in mining complex structures embedded in large-scale fMRI data and its potential as a building block for deeper models in fMRI data analysis.

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV.

HIV sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the HIV proteome are hurdles in the development of an effective AIDS vaccine. An HIV-derived conserved element (CE) p24gag plasmid DNA (pDNA) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. By homology to the HIV immunogen, seven CE were identified in SIV p27Gag Analysis of 31 rhesus macaques vaccinated with full-length SIV gag pDNA showed inefficient induction (58% response rate) of cellular responses targeting these CE. In contrast, all 14 macaques immunized with SIV p27CE pDNA developed robust T cell responses recognizing CE. Vaccination with p27CE pDNA was also critical for the efficient induction and increased the frequency of Ag-specific T cells with cytotoxic potential (granzyme B+ CD107a+) targeting subdominant CE epitopes, compared with the responses elicited by the p57gag pDNA vaccine. Following p27CE pDNA priming, two booster regimens, gag pDNA or codelivery of p27CE+gag pDNA, significantly increased the levels of CE-specific T cells. However, the CE+gag pDNA booster vaccination elicited significantly broader CE epitope recognition, and thus, a more profound alteration of the immunodominance hierarchy. Vaccination with HIV molecules showed that CE+gag pDNA booster regimen further expanded the breadth of HIV CE responses. Hence, SIV/HIV vaccine regimens comprising CE pDNA prime and CE+gag pDNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth.

Distinct Cerebellar Contributions to Cognitive-Perceptual Dynamics During Natural Viewing.

The crucial role of the cerebellum in motor learning and coordination is very well known. Considerable interest has recently shifted toward its contribution to nonmotor tasks, such as working memory, emotion, and language. However, the cognitive role and functional subdivisions of the cerebellum, particularly in dynamic, ecologically realistic contexts, are not yet established. By analyzing functional neuroimaging data acquired while participants viewed a short dramatic movie, we found that posterior and inferior cerebellar regions are reliably engaged in dynamic perceptual and affective processes with no explicit motor component. These cerebellar regions show significant relevance to visual salience and unexpected turning points of the movie. Our results demonstrate that distinct functional subdivisions of the cerebellum are robustly engaged in real-life cognitive processes, playing specific roles through a dynamic interaction with higher order regions in the cerebral cortex.

Test-retest reliability of functional connectivity networks during naturalistic fMRI paradigms.

Functional connectivity analysis has become a powerful tool for probing the human brain function and its breakdown in neuropsychiatry disorders. So far, most studies adopted resting-state paradigm to examine functional connectivity networks in the brain, thanks to its low demand and high tolerance that are essential for clinical studies. However, the test-retest reliability of resting-state connectivity measures is moderate, potentially due to its low behavioral constraint. On the other hand, naturalistic neuroimaging paradigms, an emerging approach for cognitive neuroscience with high ecological validity, could potentially improve the reliability of functional connectivity measures. To test this hypothesis, we characterized the test-retest reliability of functional connectivity measures during a natural viewing condition, and benchmarked it against resting-state connectivity measures acquired within the same functional magnetic resonance imaging (fMRI) session. We found that the reliability of connectivity and graph theoretical measures of brain networks is significantly improved during natural viewing conditions over resting-state conditions, with an average increase of almost 50% across various connectivity measures. Not only sensory networks for audio-visual processing become more reliable, higher order brain networks, such as default mode and attention networks, but also appear to show higher reliability during natural viewing. Our results support the use of natural viewing paradigms in estimating functional connectivity of brain networks, and have important implications for clinical application of fMRI. Hum Brain Mapp 38:2226-2241, 2017. © 2017 Wiley Periodicals, Inc.

Network-selective vulnerability of the human cerebellum to Alzheimer's disease and frontotemporal dementia.

SEE SCHMAHMANN DOI101093/BRAIN/AWW064 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Neurodegenerative diseases are associated with distinct and distributed patterns of atrophy in the cerebral cortex. Emerging evidence suggests that these atrophy patterns resemble intrinsic connectivity networks in the healthy brain, supporting the network-based degeneration framework where neuropathology spreads across connectivity networks. An intriguing yet untested possibility is that the cerebellar circuits, which share extensive connections with the cerebral cortex, could be selectively targeted by major neurodegenerative diseases. Here we examined the structural atrophy in the cerebellum across common types of neurodegenerative diseases, and characterized the functional connectivity patterns of these cerebellar atrophy regions. Our results showed that Alzheimer's disease and frontotemporal dementia are associated with distinct and circumscribed atrophy in the cerebellum. These cerebellar atrophied regions share robust and selective intrinsic connectivity with the atrophied regions in the cerebral cortex. These findings for the first time demonstrated the selective vulnerability of the cerebellum to common neurodegenerative disease, extending the network-based degeneration framework to the cerebellum. Our work also has direct implications on the cerebellar contribution to the cognitive and affective processes that are compromised in neurodegeneration as well as the practice of using the cerebellum as reference region for ligand neuroimaging studies.

The integration of the internal and external milieu in the insula during dynamic emotional experiences.

Whilst external events trigger emotional responses, interoception (the perception of internal physiological states) is fundamental to core emotional experience. By combining high resolution functional neuroimaging with concurrent physiological recordings, we investigated the neural mechanisms of interoceptive integration during free listening to an emotionally salient audio film. We found that cardiac activity, a key interoceptive signal, was robustly synchronised across participants and centrally represented in the posterior insula. Effective connectivity analysis revealed that the anterior insula, specifically tuned to the emotionally salient moments of the audio stream, serves as an integration hub of interoceptive processing: interoceptive states represented in the posterior insula are integrated with exteroceptive representations by the anterior insula to highlight these emotionally salient moments. Our study for the first time demonstrates the insular hierarchy for interoceptive processing during natural emotional experience. These findings provide an ecologically-valid framework for elucidating the neural underpinnings of emotional deficits in neuropsychiatric disorders.

A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques.

BACKGROUND: None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs. METHODS: To overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1. RESULTS: Our approach identified 16 regions in Gag, Pol, Vif and Nef that were relatively conserved and predominantly targeted by individuals with reduced viral loads. These regions formed the basis of the HIVACAT T-cell Immunogen (HTI) sequence which is 529 amino acids in length, includes more than 50 optimally defined CD4(+) and CD8(+) T-cell epitopes restricted by a wide range of HLA class I and II molecules and covers viral sites where mutations led to a dramatic reduction in viral replicative fitness. In both, C57BL/6 mice and Indian rhesus macaques immunized with an HTI-expressing DNA plasmid (DNA.HTI) induced broad and balanced T-cell responses to several segments within Gag, Pol, and Vif. DNA.HTI induced robust CD4(+) and CD8(+) T cell responses that were increased by a booster vaccination using modified virus Ankara (MVA.HTI), expanding the DNA.HTI induced response to up to 3.2% IFN-γ T-cells in macaques. HTI-specific T cells showed a central and effector memory phenotype with a significant fraction of the IFN-γ(+) CD8(+) T cells being Granzyme B(+) and able to degranulate (CD107a(+)). CONCLUSIONS: These data demonstrate the immunogenicity of a novel HIV-1 T cell vaccine concept that induced broadly balanced responses to vulnerable sites of HIV-1 while avoiding the induction of responses to potential decoy targets that may divert effective T-cell responses towards variable and less protective viral determinants.

Fusing DTI and fMRI data: a survey of methods and applications.

The relationship between brain structure and function has been one of the centers of research in neuroimaging for decades. In recent years, diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) techniques have been widely available and popular in cognitive and clinical neurosciences for examining the brain's white matter (WM) micro-structures and gray matter (GM) functions, respectively. Given the intrinsic integration of WM/GM and the complementary information embedded in DTI/fMRI data, it is natural and well-justified to combine these two neuroimaging modalities together to investigate brain structure and function and their relationships simultaneously. In the past decade, there have been remarkable achievements of DTI/fMRI fusion methods and applications in neuroimaging and human brain mapping community. This survey paper aims to review recent advancements on methodologies and applications in incorporating multimodal DTI and fMRI data, and offer our perspectives on future research directions. We envision that effective fusion of DTI/fMRI techniques will play increasingly important roles in neuroimaging and brain sciences in the years to come.

Inferring functional interaction and transition patterns via dynamic Bayesian variable partition models.

Multivariate connectivity and functional dynamics have been of wide interest in the neuroimaging field, and a variety of methods have been developed to study functional interactions and dynamics. In contrast, the temporal dynamic transitions of multivariate functional interactions among brain networks, in particular, in resting state, have been much less explored. This article presents a novel dynamic Bayesian variable partition model (DBVPM) that simultaneously considers and models multivariate functional interactions and their dynamics via a unified Bayesian framework. The basic idea is to detect the temporal boundaries of piecewise quasi-stable functional interaction patterns, which are then modeled by representative signature patterns and whose temporal transitions are characterized by finite-state transition machines. Results on both simulated and experimental datasets demonstrated the effectiveness and accuracy of the DBVPM in dividing temporally transiting functional interaction patterns. The application of DBVPM on a post-traumatic stress disorder (PTSD) dataset revealed substantially different multivariate functional interaction signatures and temporal transitions in the default mode and emotion networks of PTSD patients, in comparison with those in healthy controls. This result demonstrated the utility of DBVPM in elucidating salient features that cannot be revealed by static pair-wise functional connectivity analysis.