In contrast to academic and popular accounts that present generational characteristics from the outside, in a top-down manner, we explore how Gen Z constructs, narrates, and projects itself in ...real-time on TikTok-a prominent social media platform, dominated by Gen Z, that provides a valuable window into youth experience and cultural production. Based on a thematic analysis of 1918 public videos tagged #GenZ, as well as salient comments posted on these videos, we aim to explore inductively how Gen Z collectively portrays itself on TikTok. Our findings illustrate how, via creative processes of both internal and external self-definition, Gen Z portrays itself as a generation of contrasts: powerful and self-assured, yet vulnerable and damaged. Videos embrace a playful self-reflexivity about time that embodies Gen Z's self-awareness, sense of unity, and collective spirit. This research contributes to our understanding of both generational identity and youth social media participation; sitting at the intersection of these two bodies of knowledge, it facilitates a nuanced understanding of youth self-representation, online collective expression, and multimodal communication practices on a critically understudied social media platform.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The role of the NAD+ network in host responses to infection
Abstract
Nicotinamide adenine dinucleotide (NAD+) is both a crucial coenzyme and a cosubstrate for various metabolic reactions in all ...living cells. Maintenance of NAD+ levels is essential for cell energy homeostasis, survival, proliferation and function. Mounting evidence points to NAD+ as one of the major modulators of immuno-metabolic circuits, thus regulating immune responses and functions. Recent studies delineate impaired host NAD+ metabolism during chronic infections and inflammation, suggesting NAD+ replenishment as an avenue to ameliorate deleterious inflammatory responses. Here, we discuss aspects of NAD+ biosynthesis and consumption, NAD+ biology during infections and how NAD+ metabolism can be intervened with pharmacologically to enhance the host’s immunological fitness against pathogens.
Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat ...Hodgkin lymphoma (HL).
We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety.
Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent.
Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
This Review outlines a practical approach to assessing and managing polyclonal hypergammaglobulinaemia in adults. Polyclonal hypergammaglobulinaemia is most commonly caused by liver disease, immune ...dysregulation, or inflammation, but can also provide an important diagnostic clue of rare diseases such as histiocyte disorders, autoimmune lymphoproliferative syndrome, Castleman disease, and IgG4-related disease. Causes of polyclonal hypergammaglobulinaemia can be divided into eight categories: liver disease, autoimmune disease and vasculitis, infection and inflammation, non-haematological malignancy, haematological disorders, IgG4-related disease, immunodeficiency syndromes, and iatrogenic (from immunoglobulin therapy). Measuring serum concentrations of C-reactive protein and IgG subclasses are helpful in diagnosis. IL-6-mediated inflammation, associated with persistently elevated C-reactive protein concentrations (≥30 mg/L), is an important driver of polyclonal hypergammaglobulinaemia in some cases. Although the presence of markedly elevated serum IgG4 concentrations (>5 g/L) is around 90% specific for diagnosing IgG4-related disease, mildly elevated serum IgG4 concentrations are seen in many conditions. In most cases, managing polyclonal hypergammaglobulinaemia simply involves treating the underlying condition. Rarely, however, polyclonal hypergammaglobulinaemia can lead to hyperviscosity, requiring plasmapheresis.
Successful infection depends on the ability of the pathogen to gain nutrients from the host. The extracellular pathogenic bacterium group A Streptococcus (GAS) causes a vast array of human diseases. ...By using the quorum-sensing sil system as a reporter, we found that, during adherence to host cells, GAS delivers streptolysin toxins, creating endoplasmic reticulum stress. This, in turn, increases asparagine (ASN) synthetase expression and the production of ASN. The released ASN is sensed by the bacteria, altering the expression of ∼17% of GAS genes of which about one-third are dependent on the two-component system TrxSR. The expression of the streptolysin toxins is strongly upregulated, whereas genes linked to proliferation are downregulated in ASN absence. Asparaginase, a widely used chemotherapeutic agent, arrests GAS growth in human blood and blocks GAS proliferation in a mouse model of human bacteremia. These results delineate a pathogenic pathway and propose a therapeutic strategy against GAS infections.
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•Group A streptococcus (GAS) induces ER stress and asparagine production•Asparagine alters GAS gene expression and increases bacterial multiplication•Expression of streptolysins causing ER stress is augmented in asparagine absence•Asparaginase inhibits GAS bacteremia
The human pathogen group A streptococcus delivers streptolysin toxins into host cells, triggering endoplasmic reticulum stress and production of asparagine. Asparagine is utilized by GAS to alter its own gene expression program and enhance proliferation, demonstrating how an extracellular pathogen manipulates host metabolism for its own benefit.
Sex differences in aging and longevity have been widely observed, with females consistently outliving males across human populations. However, the mechanisms driving these disparities remain poorly ...understood. In this study, we explored the influence of post‐pubertal testicular effects on sex differences in aging by prepubertally castrating genetically heterogeneous (UM‐HET3) mice, a unique mouse model that emulates human sex differences in age‐related mortality. Prepubertal castration eliminated the longevity disparity between sexes by reducing the elevated early‐ to mid‐life mortality rate observed in males and extending their median lifespan to match that of females. Additionally, castration extended the duration of body weight growth and attenuated the inverse correlation between early‐age body weight and lifespan in males, aligning their growth trajectories with those of females. Our findings suggest that post‐pubertal testicular actions in genetically diverse mice are primarily responsible for sex differences in longevity as well as growth trajectories. These findings offer a foundation for further investigation into the fundamental mechanisms driving sex‐specific aging patterns and the development of potential pro‐longevity interventions.
Males live shorter than females and experience higher mortality rates since early adulthood with no known definitive mechanisms. Here we found prepubertal castration eliminated sex differences in longevity and growth in a genetically heterogeneous mouse model, which indicates the presence of testes plays a causative role in these sex differences.
Recent genetic studies show that the Eph/ephrin bidirectional signaling pathway is associated with both congenital and age-related cataracts in mice and humans. We have investigated the molecular ...mechanisms of cataractogenesis and the roles of ephrin-A5 and EphA2 in the lens. Ephrin-A5 knockout ⁻/⁻ mice often display anterior polar cataracts while EphA2⁻/⁻ lenses show very mild cortical or nuclear cataracts at weaning age. The anterior polar cataract of ephrin-A5⁻/⁻ lenses is correlated with multilayers of aberrant cells that express alpha smooth muscle actin, a marker for mesenchymal cells. Only select fiber cells are altered in ephrin-A5⁻/⁻ lenses. Moreover, the disruption of membrane-associated β-catenin and E-cadherin junctions is observed in ephrin-A5⁻/⁻ lens central epithelial cells. In contrast, EphA2⁻/⁻ lenses display normal monolayer epithelium while disorganization is apparent in all lens fiber cells. Immunostaining of ephrin-A5 proteins, highly expressed in lens epithelial cells, were not colocalized with EphA2 proteins, mainly expressed in lens fiber cells. Besides the previously reported function of ephrin-A5 in lens fiber cells, this work suggests that ephrin-A5 regulates β-catenin signaling and E-cadherin to prevent lens anterior epithelial cells from undergoing the epithelial-to-mesenchymal transition while EphA2 is essential for controlling the organization of lens fiber cells through an unknown mechanism. Ephrin-A5 and EphA2 likely interacting with other members of Eph/ephrin family to play diverse functions in lens epithelial cells and/or fiber cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Different from other epithelia, the intestinal epithelium has the complex task of providing a barrier impeding the entry of toxins, food antigens, and microbes, while at the same time allowing for ...the transfer of nutrients, electrolytes, water, and microbial metabolites. These molecules/organisms are transported either transcellularly, crossing the apical and basolateral membranes of enterocytes, or paracellularly, passing through the space between enterocytes. Accordingly, the intestinal epithelium can affect energy metabolism, fluid balance, as well as immune response and tolerance. To help accomplish these complex tasks, the intestinal epithelium has evolved many sensing receptor mechanisms. Yet, their roles and functions are only now beginning to be elucidated. This article explores one such sensing receptor mechanism, carried out by the extracellular calcium-sensing receptor (CaSR). In addition to its established function as a nutrient sensor, coordinating food digestion, nutrient absorption, and regulating energy metabolism, we present evidence for the emerging role of CaSR in the control of intestinal fluid homeostasis and immune balance. An additional role in the modulation of the enteric nerve activity and motility is also discussed. Clearly, CaSR has profound effects on many aspects of intestinal function. Nevertheless, more work is needed to fully understand all functions of CaSR in the intestine, including detailed mechanisms of action and specific pathways involved. Considering the essential roles CaSR plays in gastrointestinal physiology and immunology, research may lead to a translational opportunity for the development of novel therapies that are based on CaSR's unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators. It is possible that, through targeting of intestinal CaSR with a combination of specific nutrients, oral solutions that are both inexpensive and practical may be developed to help in conditioning the gut microenvironment and in maintaining digestive health.
•T cells significantly contribute to the immune response in Mtb infection.•The Mtb antigenic repertoire varies at different stages of Mtb infection.•Optimal antigen selection depends on several ...parameters.
Tuberculosis (TB) remains a global health challenge due to various factors, including delayed diagnoses leading to the spread of infection, limited efficacy of current vaccination strategies, and emergence of drug-resistant strains. Here, we explore the significance of Mycobacterium tuberculosis (Mtb)-specific antigens to overcome these challenges.
A narrative review exploring the dynamics of Mtb-specific antigens and the related T cell immune responses across the TB spectrum.
A variety of antigens are expressed at different stages of Mtb infection, driving its diverse antigenic landscape and associated T cell functional heterogeneity. Recent advances in high-coverage genomic and proteomic approaches may lead to the identification and characterization of antigens/epitopes within the context of TB.
Factors such as magnitude of memory response, cytokine profile, immunodominance, and conservation of epitopes should be emphasized as crucial parameters in assessing the potential efficacy of these antigens in diagnostics or vaccine research. Recognizing the antigenic repertoire of Mtb changes with the infection stage, it is important to assess the availability of different subsets of Mtb antigens across the spectrum of infection for more precise disease classifications. Targeting specific antigens holds promise as a pathway for developing specific immunological biomarkers to predict TB reactivation in populations.
The female survival advantage is a robust characteristic of human longevity. However, underlying mechanisms are not understood, and rodent models exhibiting a female advantage are lacking. Here, we ...report that the genetically heterogeneous (UM‐HET3) mice used by the National Institute on Aging Interventions Testing Program (ITP) are such a model. Analysis of age‐specific survival of 3,690 control ITP mice revealed a female survival advantage paralleling that of humans. As in humans, the female advantage in mice was greatest in early adulthood, peaking around 350 days of age and diminishing progressively thereafter. This persistent finding was observed at three geographically distinct sites and in six separate cohorts over a 10‐year period. Because males weigh more than females and bodyweight is often inversely related to lifespan, we examined sex differences in the relationship between bodyweight and survival. Although present in both sexes, the inverse relationship between bodyweight and longevity was much stronger in males, indicating that male mortality is more influenced by bodyweight than is female mortality. In addition, male survival varied more across site and cohort than female survival, suggesting greater resistance of females to environmental modulators of survival. Notably, at 24 months the relationship between bodyweight and longevity shifted from negative to positive in both sexes, similar to the human condition in advanced age. These results indicate that the UM‐HET3 mouse models the human female survival advantage and provide evidence for greater resilience of females to modulators of survival.
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