Repertoire Of Responses Research Articles

Evidence for broad cross-reactivity of the SARS-CoV-2 NSP12-directed CD4+ T-cell response with pre-primed responses directed against common cold coronaviruses.

The nonstructural protein 12 (NSP12) of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has a high sequence identity with common cold coronaviruses (CCC). Here, we comprehensively assessed the breadth and specificity of the NSP12-specific T-cell response after in vitro T-cell expansion with 185 overlapping 15-mer peptides covering the entire SARS-CoV-2 NSP12 at single-peptide resolution in a cohort of 27 coronavirus disease 2019 (COVID-19) patients. Samples of nine uninfected seronegative individuals, as well as five pre-pandemic controls, were also examined to assess potential cross-reactivity with CCCs. Surprisingly, there was a comparable breadth of individual NSP12 peptide-specific CD4+ T-cell responses between COVID-19 patients (mean: 12.82 responses; range: 0-25) and seronegative controls including pre-pandemic samples (mean: 12.71 responses; range: 0-21). However, the NSP12-specific T-cell responses detected in acute COVID-19 patients were on average of a higher magnitude. The most frequently detected CD4+ T-cell peptide specificities in COVID-19 patients were aa236-250 (37%) and aa246-260 (44%), whereas the peptide specificities aa686-700 (50%) and aa741-755 (36%), were the most frequently detected in seronegative controls. In CCC-specific peptide-expanded T-cell cultures of seronegative individuals, the corresponding SARS-CoV-2 NSP12 peptide specificities also elicited responses in vitro. However, the NSP12 peptide-specific CD4+ T-cell response repertoire only partially overlapped in patients analyzed longitudinally before and after a SARS-CoV-2 infection. The results of the current study indicate the presence of pre-primed, cross-reactive CCC-specific T-cell responses targeting conserved regions of SARS-CoV-2, but they also underline the complexity of the analysis and the limited understanding of the role of the SARS-CoV-2 specific T-cell response and cross-reactivity with the CCCs.

Delayed B-cell maturation with extra-follicular B-cell response and broad autoantibody repertoire are characteristic B-cell dysregulation signatures in patients with multi-lineage cytopenia

IntroductionMulti-lineage cytopenia (m-IC) are increasingly recognized as presenting manifestation of inborn errors immunity (IEI). Although around 40% of these patients are associated with known IEI, the underlying immune anomalies at onset of m-IC are poorly understood. Recently, we published a unique immune signature characterized by abnormal expansion of circulating T-follicular helper cells (cTfh), increased T-cell activation and decreased naïve CD4+ T (Kumar et.al Blood 2022). Despite our improved understanding of T-cell immune abnormalities, the underlying B-cell dysfunction is largely undefined at onset of m-IC. MethodsIn this study, we enrolled 20 patients with pES, 30 patients with chronic ITP (cITP) and 18 healthy controls (HCs). High dimensional B cell immunophenotyping was performed to assess B-cell maturation, extrafollicular B cell development, and autoreactivity. Autoantibody profiling was performed using human protein microarrays. Multiplex immunofluorescence staining of lymph nodes was performed to evaluate germinal center reaction. ResultsWe observed that patients with m-IC had increased frequency of CD10+ immature B cells in comparison to cITP and HCs. Despite an expansion of cTfh and elevated levels of plasma CXCL13, we observed decreased frequency of CSMB which suggests underlying defects in B-cell maturation. While canonical B-cell maturation was defective, we noticed aberrant extrafollicular B-cell development characterized by significantly higher proportion of DN2 (CD11c+CD21low) and decreased proportion of DN1 (CD21+ CD11c-) populations (Figure 1A). However, the frequency of parent population i.e., double negative (DN) (IgD- CD27-) B-cells was similar across the cohorts. In addition, we also noted decreased proportion of CXCR5+ B cells in 30% of patients and overall skewed CXCR5 expression on B versus T cells. Furthermore, we noted increase in autoreactivity in B cells as evident by increase in proportion of 9G4+ B cells. To further assess auto-antibody driven pathophysiology, we evaluated the auto-antibody repertoire and found broad auto-antibody repertoire targeting several biological processes (Figure 1B). [Display omitted] ConclusionsTaken together, our findings identified broad B-cell immune abnormalities along with unique auto-antibody repertoire in patients with m-IC. In addition to enhancing our current knowledge of disease pathology, the utility of these findings could further help in disease monitoring and evaluating response to the therapeutics.

Abstract 2257: Activation and clonotypic expansion of the native T cell repertoire identifies durable response to CD19 CAR T cell therapy

Abstract Background: Axicabtagene ciloleucel (Axi-cel), a CD19 directed CAR T cell therapy, results in durable response in a subset of patients with relapsed/refractory large B cell lymphoma (LBCL) in the absence of persistent circulating CAR T cells. Aim: We postulated that long-term efficacy of CAR T therapy depends on the downstream triggering of native T cell immunity. We performed single-cell transcriptomics of longitudinal peripheral blood (PB) samples and RNAseq of tumor samples from patients of the ZUMA 1 Axi-cel study. Methods: Single cell immunoprofiling (5’ expression + V(D)J, 10x Genomics) was performed on PB mononuclear cell samples from ZUMA-1 patients (N=32), collected at leukapheresis, 4 weeks, 6 and 12 months post Axi-cel infusion. RNAseq was performed on FFPE lymphoma samples (N=17). Patients were divided into 3 groups: non-responders, relapsed within 1 year from CAR T infusion, and long-term responders. A total of 405,775 cells passed quality check, capturing 73 cellular populations. Results: Long-term responders presented a distinct T cell landscape with increased CD8 T cells and CD8/CD4 ratios prior to CAR T therapy, compared to the other groups, with similar trends observed across time points. They also presented an increased abundance of 3 distinct CD8 T cell populations: (a) cells expressing cytotoxic and NK cell markers, (b) CD8 T effector memory cells characterized by CXCR4, TGFB1, and BCL3, and (c) proinflammatory CD8 T cells. In contrast, patients with early relapse showed increased levels of regulatory T cells pre-/post-CAR T infusion and lower abundance of CD4 cytotoxic T cells.Comparisons of the TCR repertoire pre-/post-CAR T demonstrated a greater clonal expansion of cytotoxic CD4 and CD8 T cell populations in the long-term responders, with high similarity of expanded clones post CAR T. Shared PB T cell clones and tumor antigen sequences derived from the RNAseq samples suggest an antigen-specific response driven by common epitopes. In contrast to the lack of expansion of T reg clones in responders, relapsed patients demonstrated high T reg-clonal expansion 6 months post treatment.Monocyte and NK cells were less prevalent in responders before treatment, driven by differences in phagocytic monocyte and inhibitory NK cell abundance. Modeling the interaction between monocyte and effector cell populations based on ligand receptor expression was suggestive of negative immunoregulatory impact on the T cell populations. Conclusion: The application of single-cell immunoprofiling on longitudinal samples from ZUMA-1 patients demonstrated distinct cellular and clonal profiles among long-term responders. These findings confirm our hypothesis of an important role for the native immune cell repertoire in response to CAR T therapeutics and can be utilized to further our understanding but also to potentially inform patient stratification, management, and treatment. Citation Format: Dimitra Karagkouni, Giulia Cheloni, Yered Pita-Juarez, Daniela Torres, Eleni Kanata, Zachary Avigan, Jessica Liegel, Dina Stroopinsky, Brodie Miles, Gayatri Tiwari, Jenny Kim, Mike Mattie, Jacalyn Rosenblatt, David Avigan, Ioannis Vlachos. Activation and clonotypic expansion of the native T cell repertoire identifies durable response to CD19 CAR T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2257.

Abstract 6667: Pan-cancer assessment of tumour and peripheral T-cell receptor repertoire dynamics in patients treated with immune checkpoint inhibitors

Abstract Introduction: Clinical benefit from Immune Checkpoint Blockade (ICB) is a function of local T-cell specificity for tumor-associated antigens. However, overcoming local T-cell dysfunction necessitates systemic immunity engagement. Therefore, studying the dynamics of both local and peripheral T-cell repertoires in response to ICB is required to identify features of T-cell repertoires associated with pathological response. Methods: We conducted TCRβ-sequencing on tumor-residing T-cells (n=59), Peripheral Blood Mononuclear Cells (PBMCs) (n=306) and cell-free DNA (cfDNA) (n=73) from pre- and multiple on-ICB timepoints collected from patients enrolled in the pan-cancer INvestigator-initiated Phase II Study of Pembrolizumab Immunological Response Evaluation (INSPIRE; NCT02644369) trial. To assess specificity-agnostic shifts in TCR repertoires, we first compared TCR diversity and clonal expansion in longitudinal tumor and PBMC samples. Then, to temporally track the specificity-associated features of local and systemic TCR repertoires, we leveraged a Graph Neural Network (GNN) model that took in unique TCRβ chains as nodes. The connectivity between the nodes was defined by multi-relational edges that represented VJ-gene usage and GLIPHII-identified (Grouping Lymphocyte Interactions by Paratope Hotspots) specificities derived from a compendium of TCR sequences with empirically confirmed specificities. Results: While absolute diversity and clonal expansion values in baseline tumor (n=33) were not associated with response to ICB, changes in these values were informative between pre- and on-ICB tumors. All patients (n=4) with low baseline tumor TCR diversity and lack of clonotypic re-structuring in tumor TCR repertoire on-ICB had either progressive or short-term stable disease. Furthermore, pairwise comparison of pre- and on-ICB tumors for each patient (n=17) revealed that all the patients, irrespective of their pathological response, experienced emergence of new TCR clonotypes (i.e., clonal replacement) in response to ICB, suggesting only a minority of these TCRs might consist of tumor-associated clonotypes. Patients with clinical benefit also had higher degree of GLIPHII-identified clustering at baseline tumor, highlighting the role of both specificity-agnostic and specificity-centric TCR analysis in determining the response to ICB. Analysis of TCR sequences in blood plasma found cfDNA contains a small number of TCR sequences (median 32, range 12-89) enriched for TCRs found in matched tumor tissues, suggesting that cfDNA TCR repertoire may provide an indirect measurement of tumor-residing T-cells. Conclusions: TCR diversity and functional clonal annotation are emerging biomarkers of ICB response and cfDNA TCR repertoire can potentially be exploited for clinical diagnostics and monitoring. Citation Format: Shirin Soleimani, Ben X. Wang, Stephanie Pedersen, Jenna Eagles, Jacob Brick, Marcus O. Butler, Scott V. Bratman, Lillian L. Siu, Pamela S. Ohashi, Trevor J. Pugh. Pan-cancer assessment of tumour and peripheral T-cell receptor repertoire dynamics in patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6667.

A Qualitative Exploration of Parenting Adolescents in Indonesia

To explore how parents of Indonesian adolescents conceptualize adolescence and to identify the challenges faced in parenting adolescents, focusing on parents from different sociodemographic backgrounds. Focus group discussions (FGD) were undertaken with parents of adolescents aged 10-18years old from different sociodemographic backgrounds (urban high socioeconomic; urban low socioeconomic; rural low socioeconomic) using a semi-structured interview guide. Content and thematic analysis were assisted by Nvivo version 12.6.0. Forty-three parents participated in four FGD. All parents recognized that adolescence was a distinct developmental stage, reflected in changing behaviors, escalation of peer influences and sexual development. Parents from poor, rural backgrounds had relatively limited understanding of the emerging capabilities of adolescents and had a narrow repertoire of responses to challenging behaviors, with heavy reliance on religious rules and punishment. Parents from higher socioeconomic backgrounds displayed a wider range of warmer, more engaging approaches that they reported using to shape their children's behaviors. These findings highlight opportunities to enhance parenting skills, which appear most warranted in parents of adolescents from disadvantaged backgrounds. Embedding basic adolescent parenting information within community programs appears indicated, and enhancing religious leaders' understanding of different approaches to parenting could be helpful in more religious communities.

Quantifying human performance in chess

From sports to science, the recent availability of large-scale data has allowed to gain insights on the drivers of human innovation and success in a variety of domains. Here we quantify human performance in the popular game of chess by leveraging a very large dataset comprising of over 120 million games between almost 1 million players. We find that individuals encounter hot streaks of repeated success, longer for beginners than for expert players, and even longer cold streaks of unsatisfying performance. Skilled players can be distinguished from the others based on their gaming behaviour. Differences appear from the very first moves of the game, with experts tending to specialize and repeat the same openings while beginners explore and diversify more. However, experts experience a broader response repertoire, and display a deeper understanding of different variations within the same line. Over time, the opening diversity of a player tends to decrease, hinting at the development of individual playing styles. Nevertheless, we find that players are often not able to recognize their most successful openings. Overall, our work contributes to quantifying human performance in competitive settings, providing a first large-scale quantitative analysis of individual careers in chess, helping unveil the determinants separating elite from beginner performance.

Response diversity as a sustainability strategy

Financial advisers recommend a diverse portfolio to respond to market fluctuations across sectors. Similarly, nature has evolved a diverse portfolio of species to maintain ecosystem function amid environmental fluctuations. In urban planning, public health, transport and communications, food production, and other domains, however, this feature often seems ignored. As we enter an era of unprecedented turbulence at the planetary level, we argue that ample responses to this new reality — that is, response diversity — can no longer be taken for granted and must be actively designed and managed. We describe here what response diversity is, how it is expressed and how it can be enhanced and lost. A varied repertoire of responses helps manage fluctuations, as in markets. This Perspective argues that society needs to strengthen the diversity of options for responding to disruptions, exploring how this response diversity is expressed, how it can be built and lost, and what we can do to promote it.

CD161 Characterizes an Inflamed Subset of Cytotoxic T Lymphocytes Associated with Prolonged Survival in Human Papillomavirus-Driven Oropharyngeal Cancer.

Human papillomavirus (HPV)-driven oropharyngeal carcinoma (OPSCC) is distinct from tobacco- or alcohol-associated OPSCC and has a unique immune landscape. Studies have supported the heterogeneity of T cells, accompanied by a broad repertoire of T-cell responses, within tumors driven by HPV infection. However, the phenotype and function of these HPV-related T cells remain unclear. Using a combination of single-cell RNA sequencing, flow cytometry, pharmacologic inhibition, and immunofluorescence staining, we explored the prognostic implication of HPV-related T cells and further validated our findings in two independent cohorts. Cytotoxic T lymphocytes (CTL) within OPSCC displayed a spectrum of transcriptional signatures. Among which, we identified CD161 receptor, encoded by KLRB1, as a potential marker to distinguish the CTL subsets in HPV-positive OPSCC with a divergent evolutionary trajectory. In-depth analysis revealed that CD161+ CTLs exhibited a more robust immune response over the CD161- counterparts and a T cell-inflamed phenotype that could be further reinvigorated by immune-checkpoint blockade. Despite the high expression of exhaustion markers, reinforcement of CD161+ CTL reactivity was expected to boost immune responses, considering their functional reversibility. We further confirmed that the high level of intratumoral CD161+ CTLs associated with a favorable treatment response and prolonged overall survival. Therefore, our research not only provides an insight into the immune landscape of HPV-driven OPSCC but also sheds light on a special subset of CTLs with prognostic and therapeutic significance.

What comes after crises? Key elements and insights into feedback amplifying community self-organization

In face of complex socio-environmental issues experienced in different social-ecological systems, we ask if comprehensive lessons could be learned from cases of community self-organization that were successful in solving collective problems at the local level. Considering that the trajectory of each community is unique and self-organization develops in distinctive settings, we sought to identify the common elements shared by six case studies in Brazil and investigate how they interact (i.e., if they generate feedback that amplifies self-organization), synthesizing the lessons drawn from each case so they may be applied to other contexts. In all cases, community self-organization provided good conditions to overcome crisis and led to desirable changes regarding the problem in question. We explored the underlying mechanisms of successful community self-organization from a social-ecological and community resilience standpoint and identified six elements in common: ability and/or willingness to find opportunities in crisis; partnerships with external actors; human and social capital within the community; generation of income opportunities and/or guarantee of rights; existence of spaces that favor social interaction; and agency oriented to collective mobilization and problem solving. Elements were interconnected and often reinforced one another, generating amplifying feedback, which is seen in the repetition and improvement of practices and attitudes over time and space. Agency was a prominent catalyst for self-organization by generating amplifying feedback that positively affected other elements; it was an element of the feedback chain reinforced by the benefits reaped at the individual level. When collective interests prevailed over individual ones, it was less likely to generate feedback that inhibited self-organization. We argued that ordinary relationships related to different cultural practices and livelihoods were important exercises of collective action that provided communities with a repertoire of responses that could be activated in times of crisis, thus enhancing their capacity to self-organize.

El sentido de pertenencia, identidad y agencia de docentes del ILE en sedes regionales


 
 
 This article presents the results of research based on a life-history narrative research of the complexities involved in being a university teacher at a regional campus. Nine English as a Foreign Language (EFL) university instructors participated in this study. The data were analyzed and organized by following the three-dimensional, temporal-relational perspective on teacher agency offered by the ecological approach. Findings suggest that factors from the past that gave instructors a broad repertoire of responses to engage and act mainly included participants’ institutional and community belonging. Power differentials and the need for association and recognition stood out in participants’ stories.
 
 

Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy.

Post translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy. A citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model. We show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide. We propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach.

Cross-reactivity of SARS-CoV-2- and influenza A-specific T cells in individuals exposed to SARS-CoV-2.

Cross-reactive immunity between SARS-CoV-2 and other related coronaviruses has been well-documented, and it may play a role in preventing severe COVID-19. Epidemiological studies early in the pandemic showed a geographical association between high influenza vaccination rates and lower incidence of SARS-CoV-2 infection. We, therefore, analyzed whether exposure to influenza A virus (IAV) antigens could influence the T cell repertoire in response to SARS-CoV-2, indicating a heterologous immune response between these 2 unrelated viruses. Using artificial antigen-presenting cells (aAPCs) combined with real-time reverse-transcription PCR (RT-qPCR), we developed a sensitive assay to quickly screen for antigen-specific T cell responses and detected a significant correlation between responses to SARS-CoV-2 epitopes and IAV dominant epitope (M158-66). Further analysis showed that some COVID-19 convalescent donors exhibited both T cell receptor (TCR) specificity and functional cytokine responses to multiple SARS-CoV-2 epitopes and M158-66. Utilizing an aAPC-based stimulation/expansion assay, we detected cross-reactive T cells with specificity to SARS-CoV-2 and IAV. In addition, TCR sequencing of the cross-reactive and IAV-specific T cells revealed similarities between the TCR repertoires of the two populations. These results indicate that heterologous immunity shaped by our exposure to other unrelated endemic viruses may affect our immune response to novel viruses such as SARS-CoV-2.

E-government performance in democracies versus autocracies

PurposeThis study aims to examine the relationship between political regimes and e-government performance, with a focus on governments’ perspectives of e-government. First, the authors use United Nations (UN) E-government Development Index (EGDI) to establish the current patterns of e-government performance across different regime types, and then develop their own typology of the various perspectives of different political regime types to e-government adopted in the literature. The purpose of this study is to explore the relationship between e-government performance and regime types.Design/methodology/approachThis study adopts a mixed-method research approach that involves quantitative (statistical databases) as well as qualitative (interviews) methods to go beyond the statistics and obtain interpretations of explored patterns of e-government performance and regime types. The research instruments for this study include the Jupyter open-source software used for drawing the relevant correlations, and validating the results using expert interviews.FindingsThe results of the analysis support the research hypothesis that democracies have better e-government implementation than autocracies. The findings suggest that the type of a political regime has an influence on the conceptualization of e-government, the implementation of its practices and subsequently the assessment of its performance.Research limitations/implicationsThis study relies on the UN EGDI and data from previous literature. the UN Index only measures the supply side of government outputs without taking into consideration their impact on citizens, which does not provide a holistic view of the whole picture. Therefore, the UN EGDI rankings do not necessarily imply citizen satisfaction or improved e-government.Practical implicationsFrom a practice point of view, this study gives information to government leaders as well as technical experts on how the political regime influences the government’s performance in e-government. In fact, this paper bridges the gap between theory and practice by calling policymakers to take different regime worldviews and motivations into consideration before setting e-government strategies or even assessing e-government performance. Considering the current global digital transformation, it should be ensured that practitioners take these regime specifications into consideration. In the long term, the results of this research will prove that setting up e-government or e-participation platforms is not enough as technology alone is not enough to strengthen democracy or let alone stimulate citizen engagement. When dealing with e-government initiatives, the focus should be broadened beyond the technological aspect and take the social and political motivations of governments into consideration.Social implicationsFrom a theoretical standpoint, this study calls for a more holistic e-government performance indicator that could take the regime perspectives into consideration and integrate them into its evaluation process. An indicator that can accommodate the different objectives pursued by different regime types. This could also be achieved by setting two indicators with each one matching the perspective of the specific regime type, which takes us to Ashby’s “Law of Requisite Variety” (1991). The Law of Requisite Variety states that “the system must possess as much regulatory variety as can be expected from the environment” (Ashby, 1956). This law has some implications for this study. It implies that the regime worldview influences the requisite variety depending on the political context where e-government is being implemented. Because we have two regime worldviews, we need to have at least two responses (in this case indicators) that consider the variety of political contexts. Therefore, through appreciating the differences between these two worldviews, this study recommends using the Law of Requisite Variety to investigate the influence of political regimes on e-government. In the same way, in our repertoire of responses, we should not assume that one discipline has the answer but have a variety of cross-disciplinary responses.Originality/valueThe contribution of this study lies in going beyond the statistical analyses of the UN EGDI to come up with possible interpretations of the reasons why political regimes differ in their e-government performance and what could be the reasons behind such variations. Based on analyzing correlations between e-participation performance and regime types, and interviews with experts, two different e-government perspectives could be identified: one for democracies and one for autocracies. Through identifying the relationship between these perspectives and the e-government performance of each regime type, this study provides governments and policy makers with new evidence that different regime types have different motivations for developing their e-government performance. Hence, e-government policies and strategies ought to match particular political contexts.

Towards a political economy of violence: Property and revanchism in West Thessaloniki

Encompassing data from a year-long field-based work in the neighborhood of Ksiladika, Thessaloniki in Northern Greece, I divulge a campaign of vigilant evictions of migrant squatters by local property owners. To contextualize this vigilant violence historically, I point to the distinct trajectory of the Greek property regime, carved by the minimal involvement of the state in welfare provision, the role of the family as a welfare substitute and a valorized norm hybridizing familism with a laissez-faire ethos linked to the possession of (residential) assets. Geographically, I marry Wacquant’s conceptualization of advanced urban marginality with rent gap theory to unearth the specificity of Ksiladika, a space at once relegated yet loaded with the promise of revaluation. I suggest that this violence is linked with what local impoverished landholders perceive as an opened rent gap that is what drives their pursuit to reorganize space according to the dictates of the markets as a way to secure, valorize and restore their property with its attendant meanings vis-a-vis the social reproduction squeeze brought about the economic restructuring of the Greek economy. Advancing Wacquant’s conceptualization of advanced urban marginality as an effect of the neoliberal state crafting on a global scale I suggest (i) that the schematization of a neoliberal Janus-like centaur state that performs liberalism for the privileged and punitive paternalism for those at the social bottom needs due to the expanding zone of precarity is no longer reserved for the marginalized and (ii) that neoliberal governing is attained not merely by the penal apparatus of the state, but via a diversified repertoire of state responses, including the governing through the precarized subjects who internalize the postulates of the ideology of self-reliance mediated through possession of (residential) assets in times when the resource is scarce.

Good jobs, scam jobs: Detecting, normalizing, and internalizing online job scams during the COVID-19 pandemic

Good jobs that allow remote work have enabled white-collar professionals to stay home during COVID-19, but for precarious workers, online advertisements for work-from-home employment are often scams. In this article, based on in-depth interviews conducted between April and July 2020 with nearly 200 precarious workers, we find that precarious workers regularly encountered fraudulent job advertisements via digital media. Drawing on Swidler’s concepts of the cultural tool kit and cultural logic, we find that in this time of uncertainty, workers defaulted to the focus on personal responsibility that is inherent in insecurity culture. Following the cultural logic of personal responsibility, job seekers did not place blame on job search websites for allowing the scams to be posted, but normalized the situation, deploying a scam detection repertoire in response. In addition, the discovery that advertised “good jobs” are often scams affecting workers’ desire to continue job hunting and perceptions of potential future success.

Giftedness as Trait vs. State

ABSTRACT Giftedness is usually conceived of in trait-like terms. But it often is expressed in the world in state-like terms—in response to challenging but often unpredictable situations where it is unclear who will rise to the challenges or even how we could know in advance who would be able to address the challenges at hand. Whereas traits tend to be stable, long term, and somewhat predictable in their manifestations, states tend to be unstable, often short term, and frequently unpredictable in the ways they manifest themselves. This article introduces the concept of state-giftedness. Because state-giftedness is not easily identifiable, everyone needs to be taught how to respond to the unexpected and unpredictable situations that will be consequential for their and others’ lives. Because of the unpredictability, these will be situations for which a ready repertoire of responses is neither available nor easily constructed.

Visualizing Staphylococcus aureus pathogenic membrane modification within the host infection environment by multimodal imaging mass spectrometry

Bacterial pathogens have evolved virulence factors to colonize, replicate, and disseminate within the vertebrate host. Although there is an expanding body of literature describing how bacterial pathogens regulate their virulence repertoire in response to environmental signals, it is challenging to directly visualize virulence response within the host tissue microenvironment. Multimodal imaging approaches enable visualization of host-pathogen molecular interactions. Here we demonstrate multimodal integration of high spatial resolution imaging mass spectrometry and microscopy to visualize Staphylococcus aureus envelope modifications within infected murine and human tissues. Data-driven image fusion of fluorescent bacterial reporters and matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance imaging mass spectrometry uncovered S. aureus lysyl-phosphatidylglycerol lipids, localizing to select bacterial communities within infected tissue. Absence of lysyl-phosphatidylglycerols is associated with decreased pathogenicity during vertebrate colonization as these lipids provide protection against the innate immune system. The presence of distinct staphylococcal lysyl-phosphatidylglycerol distributions within murine and human infections suggests a heterogeneous, spatially oriented microbial response to host defenses.

Discrete Biochemical Systems Theory.

Almost every biomedical systems analysis requires early decisions regarding the choice of the most suitable representations to be used. De facto the most prevalent choice is a system of ordinary differential equations (ODEs). This framework is very popular because it is flexible and fairly easy to use. It is also supported by an enormous array of stand-alone programs for analysis, including many distinct numerical solvers that are implemented in the main programming languages. Having selected ODEs, the modeler must then choose a mathematical format for the equations. This selection is not trivial as nearly unlimited options exist and there is seldom objective guidance. The typical choices include ad hoc representations, default models like mass-action or Lotka-Volterra equations, and generic approximations. Within the realm of approximations, linear models are typically successful for analyses of engineered systems, but they are not as appropriate for biomedical phenomena, which often display nonlinear features such as saturation, threshold effects or limit cycle oscillations, and possibly even chaos. Power-law approximations are simple but overcome these limitations. They are the key ingredient of Biochemical Systems Theory (BST), which uses ODEs exclusively containing power-law representations for all processes within a model. BST models cover a vast repertoire of nonlinear responses and, at the same time, have structural properties that are advantageous for a wide range of analyses. Nonetheless, as all ODE models, the BST approach has limitations. In particular, it is not always straightforward to account for genuine discreteness, time delays, and stochastic processes. As a new option, we therefore propose here an alternative to BST in the form of discrete Biochemical Systems Theory (dBST). dBST models have the same generality and practicality as their BST-ODE counterparts, but they are readily implemented even in situations where ODEs struggle. As a case study, we illustrate dBST applied to the dynamics of the aryl hydrocarbon receptor (AhR), a signal transduction system that simultaneously involves time delays and stochasticity.

High-dimensional single-cell analysis of the immune response in multiple myeloma and profiling of the T cell repertoire in response to immunomodulatory treatment

Abstract Multiple myeloma is a largely incurable malignancy of plasma cells in the bone marrow. The standard of care for this disease has increasingly included the use of immunomodulatory drugs such as thalidomide and its derivatives. However, high-dimensional analysis of the immune response in multiple myeloma tumors and the resultant response to immunomodulatory treatment is lacking. Here, we present a single-cell multi-omic analysis of the immune response in refractory multiple myeloma patient tumors including profiling of CD8+ T cell antigen specificities. We also analyze changes in the T cell repertoire and gene expression following treatment of pomalidomide. We observe a contraction of the repertoire that includes the expansion of select clones within the repertoire. These results provide a clearer map of the immune response in multiple myeloma and how patients respond to immunomodulatory treatment. Supported by grants from CRI Lloyd J. Old STAR Program and NIH R33 IMAT 2018

Viewing the rare through public lenses: insights into dead calf carrying and other thanatological responses in Asian elephants using YouTube videos.

Documenting the behavioural repertoire of an animal species is important for understanding that species' natural history. Many behaviours such as mating, parturition and death may be observed only rarely in the wild due to the low frequency of occurrence, short duration and the species' elusiveness. Opportunistic documentation of rare behaviours is therefore valuable for deciphering the behavioural complexity in a species. In this context, digital platforms may serve as useful data sources for studying rare behaviours in animals. Using videos uploaded on YouTube, we document and construct a tentative repertoire of thanatological responses (death-related behaviours) in Asian elephants (Elephas maximus). The most frequently observed thanatological responses included postural changes, guarding/keeping vigil, touching, investigating the carcass, epimeletic behaviours and vocalizations. We also describe some infrequently observed behaviours, including carrying dead calves by adult females, re-assurance-like behaviours and attempts to support dying or dead conspecifics, some of which were only known anecdotally in Asian elephants. Our observations indicate the significance of open-source video data on digital platforms for gaining insights into rarely observed behaviours and support the accumulating evidence for higher cognitive abilities of Asian elephants in the context of comparative thanatology.