While machine learning techniques have been applied within the context of fusion for predicting plasma disruptions in tokamaks, they are typically interpreted with a simple 'yes/no' prediction or ...perhaps a probability forecast. These techniques take input signals, which could be real-time signals from machine diagnostics, to make a prediction of whether a transient event will occur. A major criticism of these methods is that, due to the nature of machine learning, there is no clear correlation between the input signals and the output prediction result. Here is proposed a simple method that could be applied to any existing prediction model to determine how sensitive the state of a plasma is at any given time with respect to the input signals. This is accomplished by computing the gradient of the decision function, which effectively identifies the quickest path away from a disruption as a function of the input signals and therefore could be used in a plasma control setting to avoid them. A numerical example is provided for illustration based on a support vector machine model, and the application to real data is left as an open opportunity.
Anti-HIV-1 broadly neutralizing antibodies (BnAbs) exhibit an impressive capacity to protect against chimeric SIV-HIV (SHIV) challenges in macaques and potently reduce viremia in both SHIV-infected ...macaques and HIV-1-infected humans. There is a body of evidence suggesting Fc-mediated functions of anti-HIV-1 binding antibodies are important in protecting from infection and controlling viremia. The degree to which the efficacy of BnAbs is assisted by Fc-mediated functions is of great interest. Challenge experiments with the older generation BnAb b12 showed that mutating the Fc region to abrogate Fcγ receptor binding reduced protective efficacy in macaques. Similar data have been generated with newer BnAbs using murine models of HIV-1. In addition, the degree to which therapeutically administered BnAbs reduce viremia suggests that elimination of infected cells through Fc-mediated functions may contribute to their efficacy. Fc-mediated functions that eliminate infected cells may be particularly important for challenge systems involving cell-associated virus. Herein we review data regarding the importance of Fc-mediated functions of BnAbs in mediating protective immunity and control of viremia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
STUDY DESIGNRetrospective study of 150 IVDs. OBJECTIVEAssessment of costume algorithm ability to delineate the IAF and NP on routine T2 images. SUMMARY OF BACKGROUND DATACentral hyperintense region ...on T2-weighted MR images of normal lumbar IVDs represents a combination of IAF and NP. Ability to identify NP as distinct from IAF can help improve our understanding of IVD morphology in-vivo. METHODSSagittal T2-weighted TSE MR images of 150 lumbar IVDs from 25 patients were analyzed. MR images were processed using a custom algorithm that markedly increased the signal intensity of structures with inherent signal intensity within 2 defined intensity thresholds. Signal intensity and contrast-to- noise ratio between outer annulus fibrosus, IAF, and NP were assessed at baseline and after processing. To assess consistency of underlying T2 differences, similar analysis was done on 108 discs from 18 patients in whom additional sagittal T2-weighted STIR images were available. RESULTSFollowing image processing, apparent IAF and NP were rendered visible in 86% and 84.3% IVDs on T2-weighted TSE and STIR images respectively. While signal intensity of these 2 regions was inherently different (P< 0.001) before processing on TSE and STIR images, their visualization was facilitated by a significant increase (P<0.001) in contrast-to-noise ratio after processing. Nonvisualization of NP was associated with disc degeneration (P<0.001). CONCLUSIONInherent differences exist in signal intensities of normal NP and IAF on T2-weighted MR images. Accentuating these differences using image postprocessing techniques can render these 2 structures visible.
HIV-1 conceals epitopes of its envelope glycoproteins (Env) recognized by antibody (Ab)-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These Abs, including anti-coreceptor binding site ...(CoRBS) and anti-cluster A antibodies, preferentially recognize Env in its "open" conformation. The binding of anti-CoRBS Abs has been shown to induce conformational changes that further open Env, allowing interaction of anti-cluster A antibodies. We explored the possibility that CoRBS Abs synergize with anti-cluster A Abs to engage Fc-gamma receptors to mediate ADCC. We found that binding of anti-CoRBS and anti-cluster A Abs to the same gp120 is required for interaction with soluble dimeric FcγRIIIa in enzyme-linked immunosorbent assays (ELISAs). We also found that Fc regions of both Abs are required to optimally engage FcγRIIIa and mediate robust ADCC. Taken together, our results indicate that these two families of Abs act together in a sequential and synergistic fashion to promote FcγRIIIa engagement and ADCC.
The "open" CD4-bound conformation of HIV-1 envelope glycoproteins is the primary target of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies present in HIV-positive (HIV
) sera, such as anti-coreceptor binding site and anti-cluster A antibodies. Here we report that the binding of these two families of antibodies is required to engage FcγRIIIa and mediate ADCC.
The partial success of the RV144 trial re-energized the field of HIV vaccine research, which had stalled after vaccines based on neutralizing antibody and cytotoxic T cells had failed to induce ...protection. A large post-vaccine research effort has focused attention on the role of non-neutralizing antibodies in the protection afforded by the RV144 vaccine. These binding antibodies can initiate immune responses such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and combine elements of the adaptive and innate immune system in the form of antibodies and effector cells (including NK cells, monocytes and granulocytes). A complex interplay exists between the variable portion of the binding antibody and its HIV antigen target on one hand and the constant region of the antibody and the Fcγ-receptor of the effector cell on the other hand. Technical advances have revolutionized the abilities of scientist to detect the targets of non-neutralizing antibodies, including both envelope and non-envelope epitopes, and their role in forcing escape. Our understanding of the antibody characteristics (including IgG subclasses and Fc glycan profile) is providing valuable insights into their optimal structure and function. We expand on critical research on ADCC effector cells, particularly education of NK cells. We introduce the concept of HIV antibodydependent trogocytosis by monocytes as a potentially important aspect of HIV immunity. In summary, this review highlights recent advances in HIV-specific antibody immunity mediated through NK cells and monocytes.
The conformation of the HIV-1 envelope glycoprotein (Env) substantially impacts antibody recognition and antibody-dependent cellular cytotoxicity (ADCC) responses. In the absence of the CD4 receptor ...at the cell surface, primary Envs sample a "closed" conformation that occludes CD4-induced (CD4i) epitopes. The virus controls CD4 expression through the actions of Nef and Vpu accessory proteins, thus protecting infected cells from ADCC responses. However, gp120 shed from infected cells can bind to CD4 present on uninfected bystander cells, sensitizing them to ADCC mediated by CD4i antibodies (Abs). Therefore, we hypothesized that these bystander cells could impact the interpretation of ADCC measurements. To investigate this, we evaluated the ability of antibodies to CD4i epitopes and broadly neutralizing Abs (bNAbs) to mediate ADCC measured by five ADCC assays commonly used in the field. Our results indicate that the uninfected bystander cells coated with gp120 are efficiently recognized by the CD4i ligands but not the bNabs. Consequently, the uninfected bystander cells substantially affect
measurements made with ADCC assays that fail to identify responses against infected versus uninfected cells. Moreover, using an mRNA flow technique that detects productively infected cells, we found that the vast majority of HIV-1-infected cells in
cultures or
samples from HIV-1-infected individuals are CD4 negative and therefore do not expose significant levels of CD4i epitopes. Altogether, our results indicate that ADCC assays unable to differentiate responses against infected versus uninfected cells overestimate responses mediated by CD4i ligands.
Emerging evidence supports a role for antibody-dependent cellular cytotoxicity (ADCC) in protection against HIV-1 transmission and disease progression. However, there are conflicting reports regarding the ability of nonneutralizing antibodies targeting CD4-inducible (CD4i) Env epitopes to mediate ADCC. Here, we performed a side-by-side comparison of different methods currently being used in the field to measure ADCC responses to HIV-1. We found that assays which are unable to differentiate virus-infected from uninfected cells greatly overestimate ADCC responses mediated by antibodies to CD4i epitopes and underestimate responses mediated by broadly neutralizing antibodies (bNAbs). Our results strongly argue for the use of assays that measure ADCC against HIV-1-infected cells expressing physiologically relevant conformations of Env to evaluate correlates of protection in vaccine trials.
A considerable body of evidence suggests that Fc-dependent functions improve the capacity of broadly neutralizing antibodies (BnAbs) to protect against and control HIV-1 infection. This phenomenon, ...however, has not been formally tested in robust cell-associated macaque simian-human immunodeficiency virus (SHIV) models with newer-generation BnAbs. We studied both the WT BnAb PGT121 and a LALA mutant of PGT121 (which has impaired Fc-dependent functions) for their ability to protect pigtail macaques from an i.v. high-dose cell-associated SHIVSF162P3 challenge. We found that both WT and LALA PGT121 completely protected all 12 macaques studied. Further, partial depletion of NK cells, key mediators of Fc-dependent functions, did not abrogate the protective efficacy of PGT121 in 6 macaques. Additionally, in animals with established SHIVSF162P3 infection, SHIV viremia levels were equally rapidly reduced by LALA and WT PGT121. Our studies suggest that the potent neutralizing capacity of PGT121 renders the Fc-dependent functions of the Ab at least partially redundant. These findings have implications for Ab-mediated protection from and control of HIV-1 infection.
To test whether an image-processing algorithm can aid in visualization of mesial temporal sclerosis on magnetic resonance imaging by selectively increasing contrast-to-noise ratio (CNR) between ...abnormal hippocampus and normal brain.
In this Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study, baseline coronal fluid-attenuated inversion recovery images of 18 adults (10 females, eight males; mean age 41.2 years) with proven mesial temporal sclerosis were processed using a custom algorithm to produce corresponding enhanced images. Average (Hmean) and maximum (Hmax) CNR for abnormal hippocampus were calculated relative to normal ipsilateral white matter. CNR values for normal gray matter (GM) were similarly calculated using ipsilateral cingulate gyrus as the internal control. To evaluate effect of image processing on visual conspicuity of hippocampal signal alteration, a neuroradiologist masked to the side of hippocampal abnormality rated signal intensity (SI) of hippocampi on baseline and enhanced images using a five-point scale (definitely abnormal to definitely normal). Differences in Hmean, Hmax, GM, and SI ratings for abnormal hippocampi on baseline and enhanced images were assessed for statistical significance.
Both Hmean and Hmax were significantly higher in enhanced images as compared to baseline images (p < 0.0001 for both). There was no significant difference in the GM between baseline and enhanced images (p = 0.9375). SI ratings showed a more confident identification of abnormality on enhanced images (p = 0.0001).
Image-processing resulted in increased CNR of abnormal hippocampus without affecting the CNR of normal gray matter. This selective increase in conspicuity of abnormal hippocampus was associated with more confident identification of hippocampal signal alteration.
Antibody‐dependent cellular cytotoxicity levels reflect a formative interaction between killer cell immunoglobulin‐like receptor 3DL1 and the class I human leukocyte antigen Bw4 epitope.
Activating ...receptor‐mediated recognition of stress‐induced ligands or IgG antibody bridging of tumor or pathogen‐associated antigens to the FcγRIII CD16 triggers NK cells to kill transformed and infected cells with reduced HLA‐I expression. According to the licensing hypothesis, NK cells become competent for activating receptor‐mediated triggering after a formative encounter between a NK inhibitory receptor and its ligand. This general hypothesis is supported by murine and human studies, but to date, evidence of a role for such licensing in human ADCC is ambiguous. Inhibitory receptor interactions with HLA‐C promote NK cell ADCC licensing, but interactions between KIR3DL1 and its HLA‐Bw4 ligand may be insufficient. We investigated the impact of KIR3DL1 and HLA‐Bw4 coexpression on NK cell ADCC using a robust, genuine target system of antibody‐bearing EBV‐transformed B lymphocytes. Although numbers of KIR3DL1+ NK cells were similar in HLA‐Bw4+ and HLA‐Bw4– individuals, general levels of ADCC mediated against target cells were significantly higher in a group of HLA‐Bw4+KIR3DL1+ individuals than in a comparable HLA‐Bw4– group. Flow cytometry demonstrated directly that a significantly higher fraction of KIR3DL1+ NK cells derived from HLA‐Bw4+ compared with HLA‐Bw4– individuals produced IFN‐γ following stimulation with ADCC targets. Murine FcR‐bearing P815 target cells also triggered higher levels of CD16‐mediated cytotoxicity by NK cells from HLA‐Bw4+KIR3DL1+ individuals. These results indicate a prominent role for KIR3DL1/HLA‐Bw4 interactions in licensing NK cells for CD16‐mediated effector function.
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