Adaptive Response Research Articles

TG6050, an oncolytic vaccinia virus encoding interleukin-12 and anti-CTLA-4 antibody, favors tumor regression via profound immune remodeling of the tumor microenvironment

BackgroundTG6050 was designed as an improved oncolytic vector, combining the intrinsic properties of vaccinia virus to selectively replicate in tumors with the tumor-restricted expression of recombinant immune effectors to modify...

Pushing the limits: expanding the temperature tolerance of a coral photosymbiont through differing selection regimes.

Coral thermal bleaching resilience can be improved by enhancing photosymbiont thermal tolerance via experimental evolution. While successful for some strains, selection under stable temperatures was ineffective at increasing the thermal threshold of an already thermo-tolerant photosymbiont (Durusdinium trenchii). Corals from environments with fluctuating temperatures tend to have comparatively high heat tolerance. Therefore, we investigated whether exposure to temperature oscillations can raise the upper thermal limit of D. trenchii. We exposed a D. trenchii strain to stable and fluctuating temperature profiles, which varied in oscillation frequency. After 2.1 yr (54-73 generations), we characterised the adaptive responses under the various experimental evolution treatments by constructing thermal performance curves of growth from 21 to 31°C for the heat-evolved and wild-type lineages. Additionally, the accumulation of extracellular reactive oxygen species, photophysiology, photosynthesis and respiration rates were assessed under increasing temperatures. Of the fluctuating temperature profiles investigated, selection under the most frequent oscillations (diurnal) induced the greatest widening of D. trenchii's thermal niche. Continuous selection under elevated temperatures induced the only increase in thermal optimum and a degree of generalism. Our findings demonstrate how differing levels of thermal homogeneity during selection drive unique adaptive responses to heat in a coral photosymbiont.

HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2’s transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

MIS 3 innovative behavior and highland occupation during a stable wet episode in the Lake Tana paleoclimate record, Ethiopia

Securely dated archaeological sites from key regions and periods are critical for understanding early modern human adaptive responses to past environmental change. Here, we report new radiocarbon dates of > 42,000 cal years BP for an intensive human occupation of Gorgora rockshelter in the Ethiopian Highlands. We also document the development of innovative technologies and symbolic behaviors starting around this time. The evidenced occupation and behavioral patterns coincide with the onset and persistence of a stable wet phase in the geographically proximate high-resolution core record of Lake Tana. Range expansion into montane habitats and the subsequent development of innovative technologies and behaviors are consistent with population dispersal waves within Africa and beyond during wetter phases ~ 60–40 thousand years ago (ka).

Pre- and post-surgery: advancements in artificial intelligence and machine learning models for enhancing patient management in infective endocarditis.

Infective endocarditis (IE) is a severe infection of the inner lining of the heart, known as the endocardium. It is characterized by a range of symptoms and has a complicated pattern of occurrence, leading to a significant number of deaths. IE poses significant diagnostic and treatment difficulties. This evaluation examines the utilization of artificial intelligence (AI) and machine learning (ML) models in addressing information extraction (IE) management. It focuses on the most recent advancements and possible applications. Through this paper, we observe that AI/ML can significantly enhance and outperform traditional diagnostic methods leading to more accurate risk stratification, personalized therapies as well and real-time monitoring facilities. For example, early postsurgical mortality prediction models like SYSUPMIE achieved 'very good' area under the curve (AUROC) values exceeding 0.81. Additionally, AI/ML has improved diagnostic accuracy for prosthetic valve endocarditis, with PET-ML models increasing sensitivity from 59% to 72% when integrated into ESC criteria and reaching a high specificity of 83%. Furthermore, inflammatory biomarkers such as IL-15 and CCL4 have been identified as predictive markers, showing 91% accuracy in forecasting mortality, and identifying high-risk patients with specific CRP, IL-15, and CCL4 levels. Even simpler ML models, like Naïve Bayes, demonstrated an excellent accuracy of 92.30% in death rate prediction following valvular surgery for IE patients. Furthermore, this review provides a vital assessment of the advantages and disadvantages of such AI/ML models, such as better-quality decision support approaches like adaptive response systems on one hand, and data privacy threats or ethical concerns on the other hand. In conclusion, Al and ML must continue, through multi-centric and validated research, to advance cardiovascular medicine, and overcome implementation challenges to boost patient outcomes and healthcare delivery.

Improving the Salt Tolerance of “Old Limachino Tomato” by Using a New Salt-Tolerant Rootstock

Salinity is a major constraint limiting the yield of tomatoes. However, grafting strategies may help to overcome the salt toxicity of this important horticultural species if appropriate rootstocks are identified. The present study aimed to test a new rootstock, JUPAFORT1, obtained by crossing the glycophyte Solanum lycopersicum (cv. Poncho Negro) with the halophyte wild-related species Solanum chilense to improve the salinity tolerance of the Chilean tomato landrace Old Limachino Tomato (OLT). Intact OLT plants were exposed to 0, 80, or 160 mM of NaCl for 21 days at the vegetative stage and compared with self-grafted (L/L) and Limachino plants grafted on JUPAFORT1 rootstock (L/R) under a completely randomized design. JUPAFORT1 increased OLT scion vigor in the absence of salt but did not significantly increase fresh weight under stress conditions. However, JUPAFORT1 confers to the scion an anisohydric behavior contrasting with the isohydric behavior of L and L/L plants as indicated by measurements of stomatal conductance; L/R plants were able to maintain their metabolic status despite a slight decrease in the leaf’s relative water content. JUPAFORT1 rootstock also enabled the maintenance of photosynthetic pigment concentrations in the scion in contrast to L and L/L plants, which exhibited a decrease in photosynthetic pigments under stress conditions. L/R plants encountered oxidative stress at the highest stress intensity (160 mM of NaCl) only, while L and L/L plants suffered from oxidative damage at a lower dose (80 mM of NaCl). L/R plants behaved as includer plants and did not sequester Na+ in the root system, in contrast to L and L/L, which behaved as excluder plants retaining Na+ in the root system to avoid its translocation to the shoots. The expression of genes coding for ion transporters (HKT1.1, HKT1.2, LKT1, SKOR, SOS2, and SOS3) in the root system was not modified by salinity in L/R. In contrast, their expression varied in response to salinity in L and L/L. Overall, L/R plants exhibited higher physiological stability than L/L or L plants in response to an increasing NaCl dose and did not require additional energy investment to trigger an adaptative response to salinity. This suggests that the constitutive salinity tolerance of the halophyte S. chilense was maintained in the interspecific rootstock. JUPAFORT1 issued from S. lycopersicum x S. chilense may thus improve salt-stress resilience in OLT tomatoes. Additional studies are required to identify the molecular components involved in the root-to-shoot signaling pathway in this promising material.

Separable nanocomposite hydrogel microneedles for intradermal and sustained delivery of antigens to enhance adaptive immune responses

Vaccines play a critical role in combating infectious diseases and cancers, yet improving their efficacy remains challenging. Here, we introduce a separable nanocomposite hydrogel microneedle (NHMN) patch designed for intradermal and sustained delivery of ovalbumin (OVA), a model antigen, to enhance adaptive immune responses. The NHMN patch consists of an array of OVA-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite (LAP), supported by a hyaluronic acid backing. The incorporation of LAP not only enhances the mechanical strength of the pure hydrogel microneedles but also significantly prolongs OVA release. Furthermore, in vitro cell experiments demonstrate that NHMNs effectively activate dendritic cells without compromising cell viability. Upon skin penetration, NHMNs detach from the backing as the hyaluronic acid rapidly dissolves upon contact with the skin interstitial fluid, thereby acting as antigen reservoirs to release antigens to abundant skin dendritic cells. NHMNs containing 0.5% w/v LAP achieved a 15-day OVA release in vivo. Immunization studies demonstrate that the intradermal and sustained release of OVA via NHMNs elicited stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. Given its easy to use, painless and minimally invasive features, the NHMN patch shows promise in improving vaccination accessibility and efficacy against a range of diseases. Statement of significanceThe study introduces a separable nanocomposite hydrogel microneedle (NHMN) patch. This patch consists of an array of ovalbumin (OVA, a model antigen)-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite, with a hyaluronic acid backing, designed for intradermal and sustained delivery of antigens. This patch addresses several key challenges in traditional vaccination methods, including poor antigen uptake and presentation, and rapid systematic clearance. The incorporation of laponite enhances mechanical strength of microneedles, promotes dendritic cell activation, and significantly slows down antigen release. NHMN-based vaccination elicits stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. This NHMN patch holds great potential for improving the efficacy, accessibility, and patient comfort of vaccinations against a range of diseases.

Whence and wherefore IgE?

Despite the near ubiquitous presence of Ig-based antibodies in vertebrates, IgE is unique to mammals. How and why it emerged remains mysterious. IgE expression is greatly constrained compared to other IgH isotypes. While other IgH isotypes are relatively abundant, soluble IgE has a truncated half-life, and IgE plasma cells are mostly short-lived. Despite its rarity, IgE is consequential and can trigger life-threatening anaphylaxis. IgE production reflects a dynamic steady state with IgG memory B cells feeding short-lived IgE production. Emerging evidence suggests that IgE may also potentially be produced in longer-lived plasma cells as well, perhaps as an aberrancy stemming from its evolutionary roots from an antibody isotype that likely functioned more like IgG. As a late derivative of an ancient systemic antibody system, the benefits of IgE in mammals likely stems from the antibody system's adaptive recognition and response capability. However, the tendency for massive, systemic, and long-lived production, common to IgH isotypes like IgG, were likely not a good fit for IgE. The evolutionary derivation of IgE from an antibody system that for millions of years was good at antigen de-sensitization to now functioning as a highly specialized antigen-sensitization function required heavy restrictions on antibody production-insufficiency of which may contribute to allergic disease.

Bioinformatic elucidation of conserved epitopes to design a potential vaccine candidate against existing and emerging SARS-CoV-2 variants of concern

The COVID-19 pandemic caused by SARS-CoV-2 poses a significant adverse effects on health and economy globally. Due to mutations in genome, COVID-19 vaccine efficacy decreases. We used immuno-informatics to design a multi-epitope-based vaccine (MEV) candidate for SARS-CoV-2 variants of concern (VOCs). Hence, we predicted binders/epitopes MHC-I, CD8+, MHC-II, CD4+, and CTLs from spike, membrane and envelope proteins of VOCs. In addition, we assessed the conservation of these binders and epitopes across different VOCs. Subsequently, we designed MEV by combining the predicted CTL and CD4+ epitopes from spike protein, peptide linkers, and an adjuvant. Further, we evaluated the binding of MEV candidate against immune receptors namely HLA class I histocompatibility antigen, HLA class II histocompatibility antigen, and TLR4, achieving binding scores of -1265.3, -1330.7, and -1337.9. Molecular dynamics and normal mode analysis revealed stable docking complexes. Moreover, immune simulation suggested MEV candidate elicits both innate and adaptive immune response. We anticipate that this conserved MEV candidate will provide protection from VOCs and emerging strains.

Shear-thickening-fluid-based meta-material for adaptive impact response

Lattice and Triply-Periodic-Minimal-Surface (TPMS) structures are widely employed in different engineering disciplines, combining interesting designs with optimal mechanical properties thanks to the capabilities of Additive Manufacturing. In this framework, a technique based on filling a 3D-printed flexible structure with a shear-thickening fluid (STF) is proposed to improve the mechanical response of the resulting bi-phase composite under impact loads in the low-velocity regime up to around 3 m/s. Test data indicate that once the critical shear rate threshold for the fluid is reached, the STF-filled structure can effectively smooth the peak acceleration by 50%, decrease the penetration depth and significantly enhance the energy absorption capability by a remarkable 85%. The proposed hybrid composite paves the way to novel functional applications, exploiting the adaptive behavior of non-Newtonian fillers. To this end, a Finite-Element model is proposed to further investigate and optimize the underlying fluid-structure interaction responsible for improvement of the dynamic compressive response.

B cells secrete functional antigen-specific IgG antibodies on extracellular vesicles

B cells and the antibodies they produce are critical in host defense against pathogens and contribute to various immune-mediated diseases. B cells responding to activating signals in vitro release extracellular vesicles (EV) that carry surface antibodies, yet B cell production of EVs that express antibodies and their function in vivo is incompletely understood. Using transgenic mice expressing the Cre recombinase in B cells switching to IgG1 to induce expression of fusion proteins between emerald green fluorescent protein (emGFP) and the EV tetraspanin CD63 as a model, we identify emGFP expression in B cells responding to foreign antigen in vivo and characterize the emGFP+ EVs they release. Our data suggests that emGFP+ germinal center B cells undergoing immunoglobulin class switching to express IgG and their progeny memory B cells and plasma cells, also emGFP+, are sources of circulating antigen-specific IgG+ EVs. Furthermore, using a mouse model of influenza virus infection, we find that IgG+ EVs specific for the influenza hemagglutinin antigen protect against virus infection. In addition, crossing the B cell Cre driver EV reporter mice onto the Nba2 lupus-prone strain revealed increased circulating emGFP+ EVs that expressed surface IgG against nuclear antigens linked to autoimmunity. These data identify EVs loaded with antibodies as a novel route for antibody secretion in B cells that contribute to adaptive immune responses, with important implications for different functions of IgG+ EVs in infection and autoimmunity.

Is inflammatory change associated with psychological risk and resilience in high-risk military personnel?

IntroductionIn military populations, the potential for under-reporting of Post-traumatic Stress Disorder (PTSD) symptoms and challenges in recognising early changes can make it difficult to detect an emerging disorder. However, early...

Local differences in robustness to ocean acidification.

Ocean acidification (OA) caused by increased atmospheric carbon dioxide is affecting marine systems a globally and is more extreme in coastal waters. A wealth of research to determine how species will be affected by OA, now and in the future, is emerging. Most studies are discrete and generally do not include the full life cycle of animals. Studies that include the potential for adaptation responses of animals from areas with different environmental conditions and the most vulnerable life stages are needed. Therefore, we conducted experiments with the widely-distributed blue mussel, Mytilus edulis, from populations regularly exposed to different OA conditions. Mussels experienced experimental conditions prior to spawning, through embryonic and larval development, a highly vulnerable stage. Survivorship to metamorphosis of larvae from all populations was negatively affected by extreme OA conditions (pH 7.3, Ωar, 0.39, pCO2 2479.74), but, surprisingly, responses to Mid OA (pH 7.6, Ωar 0.77, pCO21167.13) and Low OA (pH 7.9, Ωar 1.53, pCO2 514.50) varied among populations. Two populations were robust and showed no effect of OA on survivorship in this range. One population displayed the expected negative effect on survivorship with increased OA. Unexpectedly survivorship in the fourth population was highest under Mid OA conditions. There were also significant differences in development time among populations that were unaffected by OA. These results suggest that adaptation to OA may already be present in some populations and emphasizes the importance of testing animals from different populations to see the potential for adaptation to OA.

Hepatitis E virus: from innate sensing to adaptive immune responses.

Hepatitis E virus (HEV) infections are a major cause of acute viral hepatitis in humans worldwide. In immunocompetent individuals, the majority of HEV infections remain asymptomatic and lead to spontaneous clearance of the virus, and only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis. However, HEV infections can cause up to 30% mortality in pregnant women, become chronic in immunocompromised patients and cause extrahepatic manifestations. A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes. In this Review, we summarize key components of the innate and adaptive immune responses to HEV, including the underlying immunological mechanisms of HEV associated with acute and chronic liver failure and interactions between T cell and B cell responses. In addition, we discuss the current status of vaccines against HEV and raise outstanding questions regarding the immune responses induced by HEV and treatment of the disease, highlighting areas for future investigation.

Physiological and performance adaptations to beta alanine supplementation and short sprint interval training in volleyball players

This study aimed to elucidate the impact of combining Beta-Alanine (BA) supplementation with short sprint interval training on cardiorespiratory fitness, anaerobic power, and bio-motor abilities in volleyball players. Twenty young male athletes were randomly divided into 2 equal groups and performed 8 weeks of short sprint interval training while supplementing 4.8 g daily BA or placebo (polydextrose). The players were evaluated for volleyball-specific bio-motor abilities (vertical jump, horizontal jump, spike jump, block jump, 10-m linear sprint, and T-test change of direction speed) and physiological parameters (cardiorespiratory fitness and anaerobic power) pre- and post-intervention. Both groups demonstrated significant (p ≤ 0.05) improvements in all measured variables over time. A time-regimen interaction was observed in jumping ability enhancement from pre- to post-training, wherein BA elicited more significant changes in both vertical and horizontal jumps compared to the placebo. Analyzing residuals in changes and the coefficient of variations (CV) in mean group changes demonstrated that BA supplementation results in uniformly inducing adaptive changes among individuals. Therefore, in light of these results, it is recommended that coaches and trainers take into consideration the utilization of BA as an ergogenic aid to enhance the vertical and horizontal jumps of volleyball players and increase the homogeneity in adaptive responses over the training period.

Research progress of T cell autophagy in autoimmune diseases.

T cells, as a major lymphocyte population involved in the adaptive immune response, play an important immunomodulatory role in the early stages of autoimmune diseases. Autophagy is a cellular catabolism mediated by lysosomes. Autophagy maintains cell homeostasis by recycling degraded cytoplasmic components and damaged organelles. Autophagy has a protective effect on cells and plays an important role in regulating T cell development, activation, proliferation and differentiation. Autophagy mediates the participation of T cells in the acquired immune response and plays a key role in antigen processing as well as in the maintenance of T cell homeostasis. In autoimmune diseases, dysregulated autophagy of T cells largely influences the pathological changes. Therefore, it is of great significance to study how T cells play a role in the immune mechanism of autoimmune diseases through autophagy pathway to guide the clinical treatment of diseases.

Melatonin regulates endoplasmic reticulum stress in diverse pathophysiological contexts: A comprehensive mechanistic review.

The endoplasmic reticulum (ER) is crucial for protein quality control, and disruptions in its function can lead to various diseases. ER stress triggers an adaptive response called the unfolded protein response (UPR), which can either restore cellular homeostasis or induce cell death. Melatonin, a safe and multifunctional compound, shows promise in controlling ER stress and could be a valuable therapeutic agent for managing the UPR. By regulating ER and mitochondrial functions, melatonin helps maintain cellular homeostasis via reduction of oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-associated sensors and downstream targets of the UPR, impacting cell death, autophagy, inflammation, molecular repair, among others. Crucially, this review explores the mechanistic role of melatonin on ER stress in various diseases including liver damage, neurodegeneration, reproductive disorders, pulmonary disease, cardiomyopathy, insulin resistance, renal dysfunction, and cancer. Interestingly, while it alleviates the burden of ER stress in most pathological contexts, it can paradoxically stimulate ER stress in cancer cells, highlighting its intricate involvement in cellular homeostasis. With numerous successful studies using in vivo and in vitro models, the continuation of clinical trials is imperative to fully explore melatonin's therapeutic potential in these conditions.

Experimental evolution in a warming world - the omics era.

A comprehensive understanding of the genetic mechanisms that shape species responses to thermal variation is essential for more accurate predictions of the impacts of climate change on biodiversity. Experimental evolution with high-throughput resequencing approaches (E&R) is a highly effective tool that has been increasingly employed to elucidate the genetic basis of adaptation. The number of thermal E&R studies is rising, yet there is a dearth of efforts to integrate this new wealth of knowledge. Here we review this literature showing how these studies have contributed to increase our understanding on the genetic basis of thermal adaptation. We identify two major trends: highly polygenic basis of thermal adaptation and general lack of consistency in candidate targets of selection between studies. These findings indicate that the adaptive responses to specific environments are rather independent. A review of the literature reveals several gaps in the existing research. Firstly, there is a paucity of studies done with organisms of diverse taxa. Secondly, there is a need to apply more dynamic and ecologically relevant thermal environments. Thirdly, there is a lack of studies that integrate genomic changes with changes in life-history and behavioural traits. Addressing these issues would allow a more in-depth understanding of the relationship between genotype and phenotype. We highlight key methodological aspects that can address some of the limitations and omissions identified. These include the need for greater standardisation of methodologies and the utilisation of new technologies focusing on the integration of genomic and phenotypic variation in the context of thermal adaptation.

The Impact of SIV-Induced Immunodeficiency on SARS-CoV-2 Disease, Viral Dynamics, and Antiviral Immune Response in a Nonhuman Primate Model of Coinfection.

The effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. In this pilot study, we exposed two pigtail macaques (PTMs) chronically infected with SIVmac239, exhibiting from very low to no CD4 T cells across all compartments, to SARS-CoV-2. We monitored the disease progression, viral replication, and evolution, and compared these outcomes with SIV-naïve PTMs infected with SARS-CoV-2. No overt signs of COVID-19 disease were observed in either animal, and the SARS-CoV-2 viral kinetics and evolution in the SIVmac239 PTMs were indistinguishable from those in the SIV-naïve PTMs in all sampled mucosal sites. However, the single-cell RNA sequencing of bronchoalveolar lavage cells revealed an infiltration of functionally inert monocytes after SARS-CoV-2 infection. Critically, neither of the SIV-infected PTMs mounted detectable anti-SARS-CoV-2 T-cell responses nor anti-SARS-CoV-2 binding or neutralizing antibodies. Thus, HIV-induced immunodeficiency alone may not be sufficient to drive the emergence of novel viral variants but may remove the ability of infected individuals to mount adaptive immune responses against SARS-CoV-2.

The Interactions of the Complement System with Human Cytomegalovirus.

The complement system is an evolutionarily ancient component of innate immunity that serves as an important first line of defense against pathogens, including viruses. In response to infection, the complement system can be activated by three distinct yet converging pathways (classical, lectin, and alternative) capable of engaging multiple antiviral host responses to confront acute, chronic, and recurrent viral infections. Complement can exert profound antiviral effects via multiple mechanisms including the induction of inflammation and chemotaxis to sites of infection, neutralization/opsonization of viruses and virally infected cells, and it can even shape adaptive immune responses. With millions of years of co-evolution and the ability to establish life-long infections, herpesviruses have evolved unique mechanisms to counter complement-mediated antiviral defenses, thus enabling their survival and replication within humans. This review aims to comprehensively summarize how human herpesviruses engage with the complement system and highlight our understanding of the role of complement in human cytomegalovirus (HCMV) infection, immunity, and viral replication. Herein we describe the novel and unorthodox roles of complement proteins beyond their roles in innate immunity and discuss gaps in knowledge and future directions of complement and HCMV research.