For over two decades, immunologists and biomaterials scientists have co‐existed in parallel world with the rationale of understanding the molecular profile of immune responses to vaccination, ...implantation, and treating incurable diseases. Much of the field of biomaterial‐based immunotherapy has relied on evaluating model antigens such as chicken egg ovalbumin in mouse models but their relevance to humans has been point of much discussion. Nevertheless, such model antigens have provided important insights into the mechanisms of immune regulation and served as a proof‐of‐concept for plethora of biomaterial‐based vaccines. After years of extensive development of numerous biomaterials for immunomodulation, it is only recently that an experimental scaffold vaccine implanted beneath the skin has begun to use the human model to study the immune responses to cancer vaccination by co‐delivering patient‐derived tumor lysates and immunomodulatory proteins. If successful, this scaffold vaccine will change the way we approached untreatable cancers, but more importantly, will allow a faster and more rational translation of therapeutic regimes to other cancers, chronic infections, and autoimmune diseases. Most materials reviews have focused on immunomodulatory adjuvants and micro‐nano‐particles. Here we provide an insight into emerging hydrogel and scaffold based immunomodulatory approaches that continue to demonstrate efficacy against immune associated diseases.
Biomedical researchers and clinicians have been continuously shifting focus towards engineered approaches at multiple length‐scales that could target organs like lymph nodes, lymphoid residing cells and their intracellular compartments, function as surrogate lymphoid‐like tissues, and deliver multiple biomolecules that could modulate the extent of the immune response. Here we discuss emerging hydrogel and scaffold‐based strategies for fighting against cancer, infections, and autoimmune diseases as well creating immune cell microenvironments.
Infectious diseases, including the coronavirus disease 2019 (COVID-19) pandemic that has brought the world to a standstill, are emerging at an unprecedented rate with a substantial impact on public ...health and global economies. For many life-threatening global infectious diseases, such as human immunodeficiency virus (HIV) infection, malaria and influenza, effective vaccinations are still lacking. There are numerous roadblocks to developing new vaccines, including a limited understanding of immune correlates of protection to these global infections. To induce a reproducible, strong immune response against difficult pathogens, sophisticated nanovaccine technologies are under investigation. In contrast to conventional vaccines, nanovaccines provide improved access to lymph nodes, optimal packing and presentation of antigens, and induction of a persistent immune response. This Review provides a perspective on the global trends in emerging nanoscale vaccines for infectious diseases and describes the biological, experimental and logistical problems associated with their development, and how immunoengineering can be leveraged to overcome these challenges.
Sepsis is a rapidly progressing, life threatening immune response triggered by infection that affects millions worldwide each year. Current clinical diagnosis relies on broad physiological parameters ...and time consuming lab-based cell culture. If proper treatment is not provided, cases of sepsis can drastically increase in severity over the course of a few hours. Development of new point of care tools for sepsis has the potential to improve diagnostic speed and accuracy, leading to prompt administration of appropriate therapeutics, thereby reducing healthcare costs and improving patient outcomes. In this review we examine developing and commercially available technologies to assess the feasibility of rapid, accurate sepsis diagnosis, with emphasis on point of care.
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Organogenesis and morphogenesis have informed our understanding of physiology, pathophysiology, and avenues to create new curative and regenerative therapies. Thus far, this ...understanding has been hindered by the lack of a physiologically relevant yet accessible model that affords biological control. Recently, three-dimensional ex vivo cellular cultures created through cellular self-assembly under natural extracellular matrix cues or through biomaterial-based directed assembly have been shown to physically resemble and recapture some functionality of target organs. These “organoids” have garnered momentum for their applications in modeling human development and disease, drug screening, and future therapy design or even organ replacement. This review first discusses the self-organizing organoids as materials with emergent properties and their advantages and limitations. We subsequently describe biomaterials-based strategies used to afford more control of the organoid’s microenvironment and ensuing cellular composition and organization. In this review, we also offer our perspective on how multifunctional biomaterials with precise spatial and temporal control could ultimately bridge the gap between in vitro organoid platforms and their in vivo counterparts.
Several notable reviews have highlighted PSC-derived organoids and 3D aggregates, including embryoid bodies, from a development and cellular assembly perspective. The focus of this review is to highlight the materials-based approaches that cells, including PSCs and others, adopt for self-assembly and the controlled development of complex tissues, such as that of the brain, gut, and immune system.
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•MtRuvX is a dimer in the asymmetric unit and each monomer has an RNase H fold.•MtRuvX has an intrinsic ATPase activity which is stimulated by DNA.•MtRuvX displays higher affinity to ...branched DNA species and RNA.•The Holliday junction cleavage activity is tightly coupled to ATP hydrolysis.•ATP hydrolysis switches MtRuvX to a DNA/RNA non-sequence specific endonuclease.
Much of our understanding of the homologous recombination (HR) machinery hinges on studies using Escherichia coli as a model organism. Interestingly enough, studies on the HR machinery in different bacterial species casts doubt on the universality of the E. coli paradigm. The human pathogen Mycobacterium tuberculosis encodes two Holliday junction (HJ)‐resolvase paralogues, namely RuvC and RuvX; however, insights into their structural features and functional relevance is still limited. Here, we report on structure-guided functional studies of the M. tuberculosis RuvX HJ resolvase (MtRuvX). The crystalline MtRuvX is a dimer in the asymmetric unit, and each monomer has a RNAse H fold vis-à-vis RuvC-like nucleases. Interestingly, MtRuvX also contains some unique features, including the residues essential for ATP binding/coordination of Mg2+ ions. Indeed, MtRuvX exhibited an intrinsic, robust ATPase activity, which was further accentuated by DNA cofactors. Structure-guided substitutions of single residues at the ATP binding/Mg2+coordination sites while markedly attenuating the ATPase activity completely abrogated HJ cleavage, indicating an unanticipated relationship between ATP hydrolysis and DNA cleavage. However, the affinity of ATPase-deficient mutants for the HJ was not impaired. Contrary to RuvC, MtRuvX exhibits relaxed substrate specificity, cleaving a variety of branched DNA/RNA substrates. Notably, ATP hydrolysis plays a regulatory role, rendering MtRuvX from a canonical HJ resolvase to a DNA/RNA non-sequence specific endonuclease, indicating a link between HJ resolvase and nucleic acid metabolism. These findings provide novel insights into the structure and dual-functional activities of MtRuvX, and suggest that it may play an important role in DNA/RNA metabolism.
The study explored the polycyclic aromatic hydrocarbon tolerance of indigenous biosurfactant producing microorganisms. Three bacterial species were isolated from crude oil contaminated sites of ...Haldia, West Bengal. The three species were screened for biosurfactant production and identified by 16S rRNA sequencing as Brevundimonas sp. IITISM 11, Pseudomonas sp. IITISM 19 and Pseudomonas sp. IITISM 24. The strains showed emulsification activities of 51%, 57% and 63%, respectively. The purified biosurfactants were characterised using FT-IR, GC-MS and NMR spectroscopy and found to have structural similarities to glycolipopeptides, cyclic lipopeptides and glycolipids. The biosurfactants produced were found to be stable under a wide range of temperature (0–100 °C), pH (4–12) and salinity (up to 20% NaCl). Moreover, the strains displayed tolerance to high concentrations (275 mg/L) of anthracene and fluorene and showed a good amount of cell surface hydrophobicity with different hydrocarbons. The study reports the production and characterisation of biosurfactant by Brevundimonas sp. for the first time. Additionally, the kinetic parameters of the bacterial strains grown on up to 300 mg/L concentration of anthracene and fluorene, ranged between 0.0131 and 0.0156 µmax (h−1), while the Ks(mg/L) ranged between 59.28 and 102.66 for Monod’s Model. For Haldane-Andrew’s model, µmax (h−1) varied between 0.0168 and 0.0198. The inhibition constant was highest for Pseudomonas sp. IITISM 19 on anthracene and Brevundimonas sp. IITISM 11 on fluorene. The findings of the study suggest that indigenous biosurfactant producing strains have tolerance to high PAH concentrations and can be exploited for bioremediation purposes.
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•First report of biosurfactant production by Brevundimonas sp. and its characterization.•Isolation of indigenous strains which utilize crude oil as a source of carbon.•Bacterial tolerance to 300 mg/l of anthracene and fluorene.•High Inhibition constant values in Haldane -Andrews Kinetics indicate greater tolerance to three-ringed PAHs.•Biosurfactants produced by the strains was stable at a wide range of pH, temperature and salinity.
•Importance and challenges of relay coordination in Microgrid.•Overview of different adaptive schemes opted for relay coordination.•Different optimization techniques which have been used for the ...calculation of relay settings.•Evolvement of algorithms from conventional to Hybrid methods which combines two different metaheuristic methods to solve a complex, non- linear optimization problem in an efficient way for optimized relay coordination.•Future directions of research for further modifications possible in Algorithms are stated at the end.
Concept of microgrids (MGs) have gained significant attention in order to enhance the resilience and efficiency of modern Power Systems. MG offers bi-directional power flow so an effective protection and control becomes a vital requirement to ensure the reliable operation of MGs. Relay coordination being an integral part of the protection system, plays a critical role in prevention of power disturbances and equipment damage due to the presence of bi-directional power flow. This review paper focuses on the optimization of relay coordination in MGs, and highlights the importance of adaptive and intelligent approaches involved for the efficacy of MG operation. This paper overviews different schemes used to adapt while determining the DOCRs settings with different contingencies considered. The paper depicts the key challenges associated with relay coordination in MGs; varying fault currents, and bidirectional power flows. To overcome these challenges, recent researches have explored advanced techniques that includes intelligent algorithms to operate on collected real-time data. Additionally, the impact of communication technologies for relay coordination in real-time has been discussed for Grid connected and Islanded mode of operation. This review covers a wide range of optimization methods such as; Traditional, Meta-Heuristic, and Hybrid algorithms, which allows adaptive and reliable protection schemes during different modes of MG operations.
Abstract
Informal care can exert adverse effects on the mental health of young people. Bullying victimisation is an important determinant of mental disorders. Young carers are at elevated risk of ...bullying. We quantify the mental health effects of informal care among Australian adolescents and the extent to which these effects are transmitted through school bullying. We used data from the Longitudinal Study of Australian Children. Participants were classified as non-carers, light carers (caring for < 10 h/week) and moderate-to-heavy carers (caring for 10 + h/week). Mental health was measured using the Kessler Psychological Distress Scale (K10). Using a counterfactual approach to mediation analysis, total effects (TE) of informal care on mental health were decomposed into natural direct effects (NDE—mental health effects not transmitted through school bullying) and natural indirect effects (NIE—mental health effects transmitted through school bullying). The TE of informal caring was 0.71 (95%CI − 0.03, 1.49) for light carers and 1.72 (95%CI 0.45, 3.02) for moderate-to-heavy carers. While school bullying explained 27% of the TE among moderate-to-heavy carers (NIE: 0.46; 95%CI 0.12, 0.91) there was weak evidence of mediation for light carers. Our findings indicate that the mental health effects of moderate-to-heavy caregiving can be reduced by school bullying interventions.
The EZH2 histone methyltransferase is required for B cells to form germinal centers (GC). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A ...(p21
). Deletion of Cdkn1a rescues the GC reaction in Ezh2
mice. Using a 3D B cell follicular organoid system that mimics the GC reaction, we show that depletion of EZH2 suppresses G1 to S phase transition of GC B cells in a Cdkn1a-dependent manner. GC B cells of Cdkn1a
Ezh2
mice have high levels of phospho-Rb, indicating that loss of Cdkn1a enables progression of cell cycle. Moreover, the transcription factor E2F1 induces EZH2 during the GC reaction. E2f1
mice manifest impaired GC responses, which is rescued by restoring EZH2 expression, thus defining a positive feedback loop in which EZH2 controls GC B cell proliferation by suppressing CDKN1A, enabling cell cycle progression with a concomitant phosphorylation of Rb and release of E2F1.The histone methyltransferase EZH2 silences genes by generating H3K27me3 marks. Here the authors use a 3D GC organoid and show EZH2 mediates germinal centre (GC) formation through epigenetic silencing of CDKN1A and release of cell cycle checkpoints.
Abstract
Optical trapping and patterning cells or microscopic particles is fascinating. We developed a light sheet-based optical tweezer to trap dielectric particles and live HeLa cells. The ...technique requires the generation of a tightly focussed diffraction-limited light-sheet realized by a combination of cylindrical lens and high NA objective lens. The resultant field is a focussed line (along
x
-axis) perpendicular to the beam propagation direction (
z
-axis). This is unlike traditional optical tweezers that are fundamentally point-traps and can trap one particle at a time. Several spherical beads undergoing Brownian motion in the solution are trapped by the lightsheet gradient potential, and the time (to reach trap-centre) is estimated from the video captured at 230 frames/s. High-speed imaging of beads with increasing laser power shows a steady increase in trap stiffness with a maximum of 0.00118 pN/nm at 52.5 mW. This is order less than the traditional point-traps, and hence may be suitable for applications requiring delicate optical forces. On the brighter side, light sheet tweezer (LOT) can simultaneously trap multiple objects with the distinct ability to manipulate them in the transverse (
xy
) plane via translation and rotation. However, the trapped beads displayed free movement along the light-sheet axis (
x
-axis), exhibiting a single degree of freedom. Furthermore, the tweezer is used to trap and pattern live HeLa cells in various shapes and structures. Subsequently, the cells were cultured for a prolonged period of time (> 18 h), and cell viability was ascertained. We anticipate that LOT can be used to study constrained dynamics of microscopic particles and help understand the patterned cell growth that has implications in optical imaging, microscopy, and cell biology.
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