Summary Alzheimer's disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has ...stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimer's pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.
The thymus hosts the development of a specific type of adaptive immune cells called T cells. T cells orchestrate the adaptive immune response through recognition of antigen by the highly variable ...T-cell receptor (TCR). T-cell development is a tightly coordinated process comprising lineage commitment, somatic recombination of Tcr gene loci and selection for functional, but non-self-reactive TCRs, all interspersed with massive proliferation and cell death. Thus, the thymus produces a pool of T cells throughout life capable of responding to virtually any exogenous attack while preserving the body through self-tolerance. The thymus has been of considerable interest to both immunologists and theoretical biologists due to its multi-scale quantitative properties, bridging molecular binding, population dynamics and polyclonal repertoire specificity. Here, we review experimental strategies aimed at revealing quantitative and dynamic properties of T-cell development and how they have been implemented in mathematical modeling strategies that were reported to help understand the flexible dynamics of the highly dividing and dying thymic cell populations. Furthermore, we summarize the current challenges to estimating
cellular dynamics and to reaching a next-generation multi-scale picture of T-cell development.
The equilibrium properties of allocation algorithms for networks with a large number of nodes with finite capacity are investigated. Every node receives a flow of requests. When a request arrives at ...a saturated node, i.e. a node whose capacity is fully utilized, an allocation algorithm may attempt to reallocate the request to a non-saturated node. For the algorithms considered, the reallocation comes at a price: either extra capacity is required in the system, or the processing time of a reallocated request is increased. The paper analyzes the properties of the equilibrium points of the associated asymptotic dynamical system when the number of nodes gets large. At this occasion the classical model of Gibbens, Hunt, and Kelly (1990) in this domain is revisited. The absence of known Lyapunov functions for the corresponding dynamical system significantly complicates the analysis. Several techniques are used. Analytic and scaling methods are used to identify the equilibrium points. We identify the subset of parameters for which the limiting stochastic model of these networks has multiple equilibrium points. Probabilistic approaches are used to prove the stability of some of them. A criterion of exponential stability with the spectral gap of the associated linear operator of equilibrium points is also obtained.
The process of recombination between variable (V), diversity (D), and joining (J) immunoglobulin (Ig) gene segments determines an individual's naive Ig repertoire and, consequently, (auto)antigen ...recognition. VDJ recombination follows probabilistic rules that can be modeled statistically. So far, it remains unknown whether VDJ recombination rules differ between individuals. If these rules differed, identical (auto)antigen-specific Ig sequences would be generated with individual-specific probabilities, signifying that the available Ig sequence space is individual specific. We devised a sensitivity-tested distance measure that enables inter-individual comparison of VDJ recombination models. We discovered, accounting for several sources of noise as well as allelic variation in Ig sequencing data, that not only unrelated individuals but also human monozygotic twins and even inbred mice possess statistically distinguishable immunoglobulin recombination models. This suggests that, in addition to genetic, there is also nongenetic modulation of VDJ recombination. We demonstrate that population-wide individualized VDJ recombination can result in orders of magnitude of difference in the probability to generate (auto)antigen-specific Ig sequences. Our findings have implications for immune receptor-based individualized medicine approaches relevant to vaccination, infection, and autoimmunity.
In this paper, we propose a holistic AI-based pharmacovigilance optimization approach using patient’s social media data. Instead of focusing on the detection and identification of Adverse Drug Events ...(ADE) in social media posts in single time points, we propose a holistic approach that looks at the evolution of different user behavior indicators in time. We examine various NLP-based indicators such as word frequency, semantic similarity, Adverse Drug Reactions mentions, and sentiment analysis. We introduce a classification approach to identify normal vs. abnormal time periods based on patient comments. This approach, along with user behavior indicators, can optimize the pharmacovigilance process by flagging the need for immediate attention and further investigation. We specifically focus on the Levothyrox® case in France, which sparked media attention due to changes in the medication formula and affected patient behavior on medical forums. For classification, we propose a deep learning architecture called Word Cloud Convolutional Neural Network (WC-CNN), trained on word clouds from patient comments. We evaluate different temporal resolutions and NLP pre-processing techniques, finding that monthly resolution and the proposed indicators can effectively detect new safety signals, with an accuracy of 75%. We have made the code open source, available via github.
•Non-supervised approach for pharmacovigilance from patients behavior on social media.•NLP-based indicators from patients’ reviews for pharmacovigilance optimization.•CNN architecture trained on word clouds from patient comments to detect abnormal periods.
A protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact ...on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens. Immunodominance is a challenge for the development of vaccines to mutating viruses, and for the development of broadly neutralizing antibodies. The extent by which antigens with different levels of immunogenicity compete for the induction of high affinity antibodies and therefore contribute to immunodominance is not known.
Here, we perform
simulations of the GC response, using a structural representation of antigens with complex surface amino acid composition and topology. We generate antigens with complex domains of different levels of immunogenicity and perform simulations with combinations of these domains.
We found that GC dynamics were driven by the most immunogenic domain and immunodominance arose as affinity maturation to less immunogenic domain was inhibited. However, this inhibition was moderate since the less immunogenic domain exhibited a weak GC response in the absence of the most immunogenic domain. Less immunogenic domains reduced the dominance of GC responses to more immunogenic domains, albeit at a later time point.
The simulations suggest that increased vaccine valency may decrease immunodominance of the GC response to strongly immunogenic domains and therefore, act as a potential strategy for the natural induction of broadly neutralizing antibodies in GC reactions.
Germinal Centre Shutdown Arulraj, Theinmozhi; Binder, Sebastian C; Robert, Philippe A ...
Frontiers in immunology,
07/2021, Letnik:
12
Journal Article
Recenzirano
Odprti dostop
Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective ...antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, 'normal' GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question - what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.
Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as ...Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.
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•Direct killing of L. major by NO occurs only during the peak of the immune response•Efficient L. major proliferation requires newly recruited monocyte-derived cells•Loss of NO production increases both pathogen proliferation and monocyte recruitment•NO dampens L. major proliferation indirectly, limiting the pathogen’s cellular niche
Besides direct antimicrobial activity, nitric oxide (NO) can inhibit the entry of inflammatory cells into infected tissues. Intracellular pathogens can hijack such cells as niches for proliferation. Formaglio et al. show that restriction of proliferation-permissive host cell recruitment by NO represents a mechanism that controls Leishmania major infection.
Recently there has been a growing interest in employing serious games (SGs) for the assessment and rehabilitation of elderly people with mild cognitive impairment (MCI), Alzheimer's disease (AD), and ...related disorders. In the present study we examined the acceptability of 'Kitchen and cooking' - a SG developed in the context of the EU project VERVE (http://www.verveconsortium.eu/) - in these populations. In this game a cooking plot is employed to assess and stimulate executive functions (such as planning abilities) and praxis. The game is installed on a tablet, to be flexibly employed at home and in nursing homes. Twenty one elderly participants (9 MCI and 12 AD, including 14 outpatients and 7 patients living in nursing homes, as well as 11 apathetic and 10 non-apathetic) took part in a 1-month trail, including a clinical and neuropsychological assessment, and 4-week training where the participants were free to play as long as they wanted on a personal tablet. During the training, participants met once a week with a clinician in order to fill in self-report questionnaires assessing their overall game experience (including acceptability, motivation, and perceived emotions). The results of the self reports and of the data concerning game performance (e.g., time spent playing, number of errors, etc) confirm the overall acceptability of Kitchen and cooking for both patients with MCI and patients with AD and related disorders, and the utility to employ it for training purposes. Interestingly, the results confirm that the game is adapted also to apathetic patients.
Abstract To better understand how sleep/wake dysregulation affects Alzheimer’s disease (AD) we compared the cerebrospinal fluid (CSF) orexin and histamine levels from early to late phases of 82 ...patients with Alzheimer’s process including 41 probable AD with high level of evidence and 41 MCI due to AD (i.e 27 MCI due to AD-high likelihood and 14 MCI due to AD-intermediate likelihood) according to the NIA diagnosis criteria guidelines, 24 other neurological disorders (OND) and 24 controls. We determined the relationships between these biomarkers, the CSF amyloid-β42 , total-tau, phosphorylated-tau (p-tau) concentrations and the sleep profile based on clinical interview and sleep validated questionnaires (n=86). CSF orexin-A, but not histamine/tele-methylhistamine (HA/t-MHA) levels were higher in MCI due to AD and AD than OND and controls (p=0.0003). CSF orexin-A correlated to CSF amyloid-β42 within the Alzheimer process (p=0.03). This relation is not explained by age, gender, MMSE, total-tau, p-tau, histamine nor sleep parameters. Nighttime sleep duration was longer in MCI due to AD and AD patients than controls (p=0.004). In MCI due to AD, nighttime sleep duration was negatively correlated with CSF amyloid-β42 level and MMSE. To conclude, CSF orexin-A was upregulated in AD and correlated with amyloid-β42 level. No CSF HA and t-HMA level differences were observed within the Alzheimer’s process. Lower levels of CSF amyloid-β42 were associated with longer night-sleep duration in MCI due to AD patients. Our data suggested a change in the sleep-wake pattern at an early stage of the disease that needs further investigation to better understand the mechanistic interplay between sleep and Alzheimer.
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