Endogenous Triggers Research Articles

An endogenous cluster of target-directed microRNA degradation sites induces decay of distinct microRNA families.

While much is known about miRNA biogenesis and canonical miRNA targeting, relatively less is understood about miRNA decay. The major miRNA decay pathway in metazoans is mediated through target-directed miRNA degradation (TDMD), in which certain RNAs can 'trigger' miRNA decay. All known triggers for TDMD base pair with the miRNA seed, and extensively base pair on the miRNA 3 prime end, a pattern that supposedly induces a TDMD-competent conformational change of Argonaute (Ago), allowing for miRNA turnover. Here, we utilized Ago1-CLASH to find that the Drosophila transcript Kah contains at least two triggers, a 'trigger cluster', against miR-9b and the miR-279 family. One of these triggers contains minimal/non-canonical 3 prime end base pairing but is still sufficient to induce TDMD of the entire miR-279 family. We found that these clustered triggers likely lack cooperativity, the minimal 3' pairing is required for miR-279 family turnover, and probed the in-cell RNA structure of the Kah trigger cluster. Overall, this study expands the list of endogenous triggers and the unexpectedly complex regulatory network governing miRNA degradation.

Abstract 4132149: Elevated Levels of Plasma Mitochondrial DNA Damage-Associated Molecular Patterns (DAMPS) in Humans and Dogs with Heart Failure and Reduced Ejection Fraction

Background: Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with increased inflammatory response that contributes to progressive worsening of the HF state. Potential endogenous triggers of this process include damage-associated molecular patterns (DAMPs). DAMPs originate from within cells following tissue stress or injury and activate pattern recognition receptors of the immune system, triggering an inflammatory response. Mitochondria are the major cell organelles that release DAMPs into the circulation. Chronic HF is associated with multi-organ mitochondrial dysfunction and cell injury and death. Purpose: The present study sought to quantify differences in mitochondrial DNA (mtDNA) DAMPs in the setting of HFrEF in humans and dogs compared to normal humans and dogs. Methods: Plasma samples were obtained from 9 HFrEF patients with left ventricular ejection fraction (LVEF) ≤35% and 9 age-matched healthy subjects, and from 6 dogs with coronary microembolization-induced HF (LVEF ≤35%) and 6 normal dogs. DNA fragments were isolated from 1 ml of plasma using a commercially available kit. Quantitative PCR and specifically designed primers were used to measure the amount of DNA in plasma from COX1 (cytochrome c oxidase subunit 1), ND1 (NADH dehydrogenase subunit 1) and ND6 (NADH dehydrogenase subunit 6) using an Applied Biosystems 7500 Fast-PCR unit. The relative abundances of plasma mtDNA DAMPs were expressed as threshold cycles (C T ). Results: Compared to normal human subjects, mtDNA DAMPs levels of COX1 , ND1 and ND6 in plasma of HFrEF patients was 4-fold, 9-fold and 8-fold greater, respectively. Similarly, compared to normal dogs, mtDNA DAMPs levels of COX1 , ND1 and ND6 in plasma of HFrEF dogs was increased 48-fold, 12-fold and 4-fold, respectively. Conclusions: These findings indicate a marked increase of mtDNA DAMPs in plasma of humans and dogs with HFrEF. The increase of mtDNA DAMPs is consistent with the elevated systemic inflammatory state of HFrEF. The results underscore mitochondrial abnormalities as integral players in the progressive worsening of HFrEF.

Chemoselective Reagents for the Traceless Bioreversible Modification of Native Proteins.

Nature utilizes bioreversible post-translational modifications (PTMs) to spatiotemporally diversify protein function. Mimicking Nature's approach, chemists have developed a variety of chemoselective regents for traceless, bioreversible modification of native proteins. These strategies have found utility in the development of reversible covalent inhibitors and degraders as well as the synthesis of functional protein conjugates for delivery into cells. This Viewpoint provides a snapshot of such tools, which currently cover Cys, Ser, Thr, Lys, Asp, and Glu residues and the N terminus. Additionally, we explore how bioreversible reagents, originally developed by research communities with differing objectives, can be utilized synergistically. Looking forward, we discuss the need for developing bioreversible reagents for labeling His, Tyr, Arg, Trp, Asn, Gln, and Met residues and the C-terminus as well as the installation of dynamic PTMs. Finally, to broaden the applicability of these tools, we point out the importance of developing modular release scaffolds with tunable release times and responsiveness to multiple endogenous triggers. We anticipate that this Viewpoint will catalyze further research and technological breakthroughs in this rapidly evolving field.

Endogenous and exogeneous stimuli-triggered reactive oxygen species evoke long-lived carbon monoxide to fight against lung cancer

Reactive oxygen species (ROS)-associated anticancer approaches usually suffer from two limitations, i.e., insufficient ROS level and short ROS half-life. Nevertheless, no report has synchronously addressed both concerns yet. Herein, a multichannel actions-enabled nanotherapeutic platform using hollow manganese dioxide (H-MnO2) carriers to load chlorin e6 (Ce6) sonosensitizer and CO donor (e.g., Mn2(CO)10) has been constructed to maximumly elevate ROS level and trigger cascade catalysis to produce CO. Therein, intratumoral H2O2 and ultrasound as endogenous and exogeneous triggers stimulate H-MnO2 and Ce6 to produce •OH and 1O2, respectively. The further cascade reaction between ROS and Mn2(CO)10 proceeds to release CO, converting short-lived ROS into long-lived CO. Contributed by them, such a maximumly-elevated ROS accumulation and long-lived CO release successfully suppresses the progression, recurrence and metastasis of lung cancer with a prolonged survival rate. More significantly, proteomic and genomic investigations uncover that the CO-induced activation of AKT signaling pathway, NRF-2 phosphorylation and HMOX-1 overexpression induce mitochondrial dysfunction to boost anti-tumor consequences. Thus, this cascade catalysis strategy can behave as a general means to enrich ROS and trigger CO release against refractory cancers.Graphic

The dimorphic diaspore model Aethionema arabicum (Brassicaceae): Distinct molecular and morphological control of responses to parental and germination temperatures.

Plants in habitats with unpredictable conditions often have diversified bet-hedging strategies that ensure fitness over a wider range of variable environmental factors. A striking example is the diaspore (seed and fruit) heteromorphism that evolved to maximize species survival in Aethionema arabicum (Brassicaceae) in which external and endogenous triggers allow the production of two distinct diaspores on the same plant. Using this dimorphic diaspore model, we identified contrasting molecular, biophysical, and ecophysiological mechanisms in the germination responses to different temperatures of the mucilaginous seeds (M+ seed morphs), the dispersed indehiscent fruits (IND fruit morphs), and the bare non-mucilaginous M- seeds obtained by pericarp (fruit coat) removal from IND fruits. Large-scale comparative transcriptome and hormone analyses of M+ seeds, IND fruits, and M- seeds provided comprehensive datasets for their distinct thermal responses. Morph-specific differences in co-expressed gene modules in seeds, as well as in seed and pericarp hormone contents, identified a role of the IND pericarp in imposing coat dormancy by generating hypoxia affecting abscisic acid (ABA) sensitivity. This involved expression of morph-specific transcription factors, hypoxia response, and cell wall remodeling genes, as well as altered ABA metabolism, transport, and signaling. Parental temperature affected ABA contents and ABA-related gene expression and altered IND pericarp biomechanical properties. Elucidating the molecular framework underlying the diaspore heteromorphism can provide insight into developmental responses to globally changing temperatures.

The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity.

From studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease. We have seen cohesion in results from clinical studies in CAPS patients, exvivo studies of human cells and murine cells, and invivo murine models leading to our understanding of the downstream pathways, cytokine secretion, and cell death pathways that has solidified the role of autoinflammation in the pathogenesis of human disease. Recent advances in our understanding of the structure of the inflammasome have provided ways for us to visualize normal and mutant protein function and pharmacologic inhibition. The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein.

Autonomous behaviour and the limits of human volition

Humans and some other animals can autonomously generate action choices that contribute to solving complex problems. However, experimental investigations of the cognitive bases of human autonomy are challenging, because experimental paradigms typically constrain behaviour using controlled contexts, and elicit behaviour by external triggers. In contrast, autonomy and freedom imply unconstrained behaviour initiated by endogenous triggers. Here we propose a new theoretical construct of adaptive autonomy, meaning the capacity to make behavioural choices that are free from constraints of both immediate external triggers and of routine response patterns, but nevertheless show appropriate coordination with the environment. Participants (N = 152) played a competitive game in which they had to choose the right time to act, in the face of an opponent who punished (in separate blocks) either choice biases (such as always responding early), sequential patterns of action timing across trials (such as early, late, early, late…), or predictable action-outcome dependence (such as win-stay, lose-shift). Adaptive autonomy was quantified as the ability to maintain performance when each of these influences on action selection was punished. We found that participants could become free from habitual choices regarding when to act and could also become free from sequential action patterns. However, they were not able to free themselves from influences of action-outcome dependence, even when these resulted in poor performance. These results point to a new concept of autonomous behaviour as flexible adaptation of voluntary action choices in a way that avoids stereotypy. In a sequential analysis, we also demonstrated that participants increased their reliance on belief learning in which they attempt to understand the competitor's beliefs and intentions, when transition bias and reinforcement bias were punished. Taken together, our study points to a cognitive mechanism of adaptive autonomy in which competitive interactions with other agents could promote both social cognition and volition in the form of non-stereotyped action choices.

Geographic variability in the seasonality of euphausiid diel vertical migrations among three locations in coastal British Columbia, Canada

Abstract Diel vertical migration (DVM) is a behaviour observed across zooplankton taxa in marine and limnetic systems worldwide. DVM influences biogeochemical cycling and carbon drawdown in oceanic systems and alters prey availability for zooplanktivorous species. DVM has been well studied among zooplankton, and many exogenous and endogenous triggers as well as adaptive significances have been hypothesized. However, second-order variability in DVM timing, the deviation of DVM times to respective dawn and dusk times throughout the year, is a less-studied phenomenon that can help identify the factors influencing migration timing as well as demonstrate the changes of DVM behaviours within and across systems. Here, we quantified seasonal trends in second-order variability of DVM timing of euphausiids at Brooks Peninsula, Clayoquot Canyon, and Saanich Inlet near Vancouver Island, British Columbia, Canada, over multiple years using upward-facing moored echosounders. We used generalized additive mixed models to characterize this seasonality. DVM timing relative to civil twilight times showed strong seasonality at all locations, with euphausiids remaining near the surface longer than expected in spring and summer, and shorter than expected in winter. Euphausiids spent less time near the surface at Brooks Peninsula and Clayoquot Canyon than at Saanich Inlet throughout the year. Increased primary productivity in Saanich Inlet, which reduced light penetration and hid euphausiids from visual predators, likely drove this difference. Our findings confirm that proper understanding of DVM behaviours must account for seasonal variability due to context-specific oceanographic and ecological parameters. This is particularly pertinent when attempting to model the biogeochemical or predator–prey interactions influenced by DVM behaviours.

Mitochondrial DNA Copy Number Drives the Penetrance of Acute Intermittent Porphyria.

No published study has investigated the mitochondrial count in patients suffering from acute intermittent porphyria (AIP). In order to determine whether mitochondrial content can influence the pathogenesis of porphyria, we measured the mitochondrial DNA (mtDNA) copy number in the peripheral blood cells of 34 patients and 37 healthy individuals. We found that all AIP patients had a low number of mitochondria, likely as a result of a protective mechanism against an inherited heme synthesis deficiency. Furthermore, we identified a close correlation between disease penetrance and decreases in the mitochondrial content and serum levels of PERM1, a marker of mitochondrial biogenesis. In a healthy individual, mitochondrial count is usually modulated to fit its ability to respond to various environmental stressors and bioenergetic demands. In AIP patients, coincidentally, the phenotype only manifests in response to endogenous and exogenous triggers factors. Therefore, these new findings suggest that a deficiency in mitochondrial proliferation could affect the individual responsiveness to stimuli, providing a new explanation for the variability in the clinical manifestations of porphyria. However, the metabolic and/or genetic factors responsible for this impairment remain to be identified. In conclusion, both mtDNA copy number per cell and mitochondrial biogenesis seem to play a role in either inhibiting or promoting disease expression. They could serve as two novel biomarkers for porphyria.

A life cycle view on unicorn start-ups: drivers of long-term high-growth

PurposeThe purpose of this study is to explore the exogenous and endogenous drivers of the high-growth of Unicorn start-ups along their life cycle, with a particular focus on Unicorns in the fintech industry.Design/methodology/approachThe study employs an explorative longitudinal analysis with a matched-pair of two cases of Unicorns start-ups with similar antecedent features to understand holistically drivers over the longer term.FindingsHigh-growth patterns over the longer term are the result of a combined industry- and company-life cycle perspective. Drivers and growth patterns vary significantly according to the time of entry in the industry and its development status. The findings are systematised within a set of propositions to be tested in future research.Research limitations/implicationsThe limitations lie in empirical evidence, as the analysis is limited to one-matched-pair. The revealed Unicorns' drivers for long-term growth might encourage future research to further investigate these drivers on a larger scale.Practical implicationsThe study offers practical recommendations for start-ups with high-growth ambitions and advice to policy makers regarding the development of tailor-made support programs.Originality/valueThe study significantly extends extant work on growth and high-growth by examining endogenous and exogenous triggers over time and by linking the Unicorn-life cycle to the industry life cycle, an approach which has, to the best of the authors’ knowledge, not yet been applied.

Inflammation, Autoinflammation and Autoimmunity in Inflammatory Bowel Diseases.

In this review, the role of innate and adaptive immunity in the pathogenesis of inflammatory bowel diseases (IBD) is reported. In IBD, an altered innate immunity is often found, with increased Th17 and decreased Treg cells infiltrating the intestinal mucosa. An associated increase in inflammatory cytokines, such as IL-1 and TNF-α, and a decrease in anti-inflammatory cytokines, such as IL-10, concur in favoring the persistent inflammation of the gut mucosa. Autoinflammation is highlighted with insights in the role of inflammasomes, which activation by exogenous or endogenous triggers might be favored by mutations of NOD and NLRP proteins. Autoimmunity mechanisms also take place in IBD pathogenesis and in this context of a persistent immune stimulation by bacterial antigens and antigens derived from intestinal cells degradation, the adaptive immune response takes place and results in antibodies and autoantibodies production, a frequent finding in these diseases. Inflammation, autoinflammation and autoimmunity concur in altering the mucus layer and enhancing intestinal permeability, which sustains the vicious cycle of further mucosal inflammation.

Enzyme-Triggered DNA Sensor Technology for Spatially-Controlled, Cell-Selective Molecular Imaging.

ConspectusWith unparalleled programmability, DNA has evolved as a powerful scaffold for engineering intricate and dynamic systems that can perform diverse tasks. By allowing serial detection of molecular targets in complex cellular milieus, increasingly sophisticated DNA sensors have not only promoted significant advances in unveiling the fundamental mechanisms of various pathophysiological processes but also provided a useful toolkit for disease diagnostics based on molecular signatures. Despite much progress, an inherent limitation of DNA-based sensors is that they often lack spatial control and cell-type selectivity for the sensing activity because of their "always active" design mechanism. Since most molecular targets of interests are not exclusive to disease cells, they are also shared by normal cells, the application of such biosensors for disease-specific imaging is limited by inadequate signal-to-background ratios due to indistinguishable signal response in both disease and normal cells. Therefore, imparting biosensors with spatial controllability remains a key issue to achieve molecular imaging with high sensitivity and cell specificity.As a biocatalyst, enzyme has been found to be closely related with the pathological conditions of numerous diseases. For example, many nucleases, protease, and kinases have been identified overexpressed in disease cells and considered as important biomarkers of cancer, inflammation, and neurological diseases. Recently, we have envisioned that such pathophysiology-associated enzymes could be leveraged as endogenous triggers to achieve spatial control over the molecular imaging activity of the DNA-based sensors with improved cell-specificity. In this Account, we outline the research efforts from our group on the development of endogenous enzyme-triggered, DNA-based sensor technology that enables spatially controlled, cell-type selective molecular imaging. With programmable DNA design and further engineering of enzymatically cleavable sites, a series of DNAzyme- and aptamer-based sensors have been developed for enzyme-controlled imaging of various molecular targets (e.g., metal ions and small molecules) in a cancer cell-selective manner. In particular, by introduction of PNA as bridge molecules to engineer DNA-based sensors with functional peptides, the conceptual design of protease-activated DNA biosensors has been established for spatioselective molecular imaging in cancer cells and extracellular tumor microenvironments. Furthermore, enzyme-triggered signal amplification approaches, such as enzymatically activated molecular beacon and catalytic hairpin assembly, have been developed for spatially selective RNA imaging in specific disease cells (e.g., inflammatory cells and cancer cells), which enables enhanced disease-site specificity and thus improved signal-to-background ratio. The signal amplification strategy is further expanded to cell-selective amplified imaging of non-RNA species through the combination with functional DNA design. Finally, the challenges and potential future directions in this burgeoning field are discussed. We hope this Account offers insights into rational design of enzymatically controlled, DNA-based sensor platforms for opening new frontiers in spatially resolved, cell-selective molecular imaging. We believe that the continuing advances in DNA-based molecular sensing technology together with the discoveries of diverse disease-associated enzymes will promise to usher a new era of diagnosis.

Topographic localization of migraine triggers and its association with headache frequency and severity

ObjectiveInternal biological rhythm with or without external trigger may precipitate migraine. Classifying exogenous and endogenous triggers to a topographic localization may help in understanding the migraine. We report topographic localization of migraine triggers and its influence on headache frequency and severity. Methods588 migraineurs, aged 16–69 years were included. Various endogenous and exogenous triggers were categorized to topographic localization- hypothalamic, pituitary, auditory, visual, somato-sensory, olfactory and gustatory. The relationship of topographic localization of triggers with episodic versus chronic migraine, and moderate versus severe headache were analyzed using univariate followed by multivariate analysis. ResultsAll migraineurs had triggers 584(99.9%) except 4(0.1%) patients. Presence of multiple triggers (99.4%), and combination of both endogenous and exogenous triggers (97.7%) was the rule. On topographic localization, hypothalamic trigger was the commonest (98.1%) followed by visual (84.1%), auditory (82.1%), somatosensory (76.1%), olfactory (26.2%), pituitary (24.1%), and gustatory (6.6%). 98.6% patients had combination of hypothalamic with pituitary triggers. Hypothalamic [Adjusted odds ratio (AOR) 4.50] and auditory triggers (AOR 0.34) independently predicted chronic migraine, and auditory (AOR 0.55) and gustatory (AOR 2.41) triggers predicted severity of headache. ConclusionHypothalamic triggers are the commonest suggesting an innate susceptibility of migraine. Auditory trigger may precipitate frequent and severe headache.

Confinement of Assemblies of Peptides by Chemical Reactions in Living Cells.

The self-assembly of peptides plays an important role in optics, catalysis, medicine, and disease treatment. In recent years, peptide-based materials have exhibited great potential for cancer therapy and disease imaging due to their excellent biocompatibility, structural tenability, and ease of functionality. Peptides could self-assemble into diverse nanostructures in vivo triggered by endogenous stimuli, which initiated chemical reactions and self-assembled to achieve desired biological functions in the tumor microenvironment. This concept introduces the utilization of endogenous triggers to construct functional nanostructures in vivo and their corresponding biological applications. After briefly discussing the representative example of chemical reactions induced self-assembly of peptides in the living system, we describe the several stimuli triggered self-assembly for constructing therapeutic assemblies and serving as an imaging probe. Finally, we give a brief outlook to discuss the future direction of this exciting new field.

Chapter 18 - Pediatric neuropsychiatric disorders with motor and nonmotor phenomena

The concept of pediatric autoimmune neuropsychiatric disorders associated with group A beta-hemolytic streptococcus (PANDAS) has become seminal since first introduced more than two decades ago. At the time of this writing, most neurologists, pediatricians, psychiatrists, and general pediatricians will probably have heard of this association or treated an affected child with PANDAS. The concept of an acute-onset, and typically self-limited, postinfectious autoimmune neuropsychiatric disorder resembling PANDAS manifesting vocal and motor tics and obsessive-compulsive disorder has broadened to other putative microbes and related endogenous and exogenous disease triggers. These disorders with common features of hypometabolism in the medial temporal lobe and hippocampus in brain 18fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (FDG PET-MRI), form a spectrum: with the neuropsychiatric disorder Tourette syndrome and PANDAS with its well-defined etiopathogenesis at one end, and pediatric abrupt-onset neuropsychiatric syndrome (PANS), alone or associated with specific bacterial and viral pathogens, at the other end. The designation of PANS in the absence of a specific trigger, as an exclusionary diagnosis, reflects the current problem in nosology.

Catalytic Biomaterials and Nanomedicines with Exogenous and Endogenous Activations.

Catalytic therapy can concurrently enhance therapeutic efficacy and decrease side effects by converting less toxic or nontoxic endogenous substances into various highly toxic reactive species (e.g., toxic radicals) to induce cell apoptosis/necrosis, which has been exploited to combat different types of diseases. As material science and nanotechnology evolve for application in disease therapies, a variety of catalytic biomaterials and nanomedicines have been elaborately designed and synthesized to mediate catalytic reactions and/or enhance the corresponding catalytic treatment efficacy. This review systematically summarizes, outlines, and discusses the state-of-the-art advances in the development and use of catalytic biomaterials and nanomedicines in diverse biomedical applications, particularly concentrating on their endogenous activators, exogenous stimuli (e.g., light, heat, ultrasound, and magnetic field), and the integration of endogenous and exogenous triggers to improve the efficacy of biomaterial/nanomedicine-enabled catalytic treatments. The biosafety and biocompatibility of various catalytic biomaterials and nanomedicines for biomedical applications are also discussed. Finally, the current challenges and future opportunities for advancement of catalytic biomaterials and nanomedicines are highlighted, aiming to boost their early fulfillment of practical clinical applications.

Molecular systems processes and cellular mechanisms-causing to itching tingling and aching in atopic dermatitis skin conditions and repercussions for innovative therapeutics

: Atopic dermatitis (AD) is a prolonged seditious, rabble rousing, and inflammatory—provocative skin disease. The subjects (i.e., patients) by means of atopic-dermatitis suffer incendiary lesions linked through extreme itching plus discomfort, and that is leading to sleep disorder (and also rarely apnea), weak mental and psychological health and also quality-of-life (QoL). : This study discusses the molecular systems processes/mechanisms causing to itching, tingling and irritation plus aching signs in atopic-dermatitis and examine the existing clinical, medical-advancement of therapies for mild-to-acute atopic-dermatitis. : The molecular pathology of AD contains abnormal immune, protected stimulation including substantial crisscross-talk amongst the skin and safe and neural cells/neuronal cells. Exogenous and endogenous triggers modulate stimulus of mediators including cytokine/chemokine expression/release by the skin and immune cells, which causes inflammation, skin barrier disruption, activation and growth of sensory neurons, itching and paining. These complex interactions among cell types are mediated primarily by cytokines, but also involve chemokines, neurotransmitters, lipids, proteases, antimicrobial peptides, and agonists of ion channels or various G protein–coupled receptors. : Patients with atopic dermatitis have a cytokine profile characterized by abnormal levels of interleukins 4,12,13,18,22,31 and 33; thymic stromal lymphopoietin; and interferon gamma. Cytokine receptors mainly signal through the Janus kinase/signal transducer and activator of transcription pathways. Among emerging novel therapeutics, several Janus kinase inhibitors are being developed for topical or (general nut systemic) systematic treatment of mild to acute AD tis as of their ability to regulate-cytokine countenance then make available. Janus-kinase hampers take the lead to variations in genetic representation which has positive impacts on provincial and general (universal) cytokine-release, and possibly additional intermediaries, so well regulating molecular-cellular-mechanisms accountable for irritation, itching, tingling followed by agony in AD. : This study explored the skin disorder in which the skin develops pink, inflamed plus wound.

Immunomodulatory role of mitochondrial DAMPs: a missing link in pathology?

In accordance with the endosymbiotic theory, mitochondrial components bear characteristic prokaryotic signatures, which act as immunomodulatory molecules when released into the extramitochondrial compartment. These endogenous immune triggers, called mitochondrial damage-associated molecular patterns (mtDAMPs), have been implicated in the pathogenesis of various diseases, yet their role remains largely unexplored. In this review, we summarise the available literature on mtDAMPs in diseases, with a special focus on respiratory diseases. We highlight the need to bolster mtDAMP research using a multipronged approach, to study their effect on specific cell types, receptors and machinery in pathologies. We emphasise the lacunae in the current understanding of mtDAMPs, particularly in their cellular release and the chemical modifications they undergo. Finally, we conclude by proposing additional effects of mtDAMPs in diseases, specifically their role in modulating the immune system.

The Developmental Transcription Factor p63 Is Redeployed to Drive Allergic Skin Inflammation through Phosphorylation by p38α.

Keratinocytes, the epithelial cells of the skin, reprogram their gene expression and produce immune effector molecules when exposed to environmental and endogenous triggers of inflammation. It remains unclear how keratinocytes process physiological signals generated during skin irritation and switch from a homeostatic to an inflammatory state. In this article, we show that the stress-activated protein kinase p38α is crucial for keratinocytes to prompt changes in their transcriptome upon cytokine stimulation and drive inflammation in allergen-exposed skin. p38α serves this function by phosphorylating p63, a transcription factor essential for the lineage identity and stemness of the skin epithelium. Phosphorylation by p38α alters the activity of p63 and redeploys this developmental transcription factor to a gene expression program linked to inflammation. Genetic ablation and pharmacological inhibition of p38α or the p38α-p63 target gene product MMP13 attenuate atopic dermatitis-like disease in mice. Our study reveals an epithelial molecular pathway promoting skin inflammation and actionable through treatment with topical small-molecule therapeutics.

Peptide-based bioactivated in vivo assembly nanomaterials and its biomedical applications: a review

Based on the self-assembly process occurring in the human body all the time, self-assembled nanomaterials were designed by the researchers. The self-assembled nanomaterials have controllability, biocompatibility and functional advantages in vivo. The self-assembled nanomaterials constructed in situ under a physiological environment display various biological characteristics which can be used for imaging, therapy, and broad clinical applications. In situ self-assembled nanomaterials can boost drug function, reduce toxic and side effects, prolong imaging time and enlarge signal-to-noise ratio. By using pathological conditions to trigger specific responses in vivo, well-ordered nanoaggregates can be spontaneously formed by multiple weak bonding interactions. The assembly shows higher accumulation and longer retention in situ. Endogenous triggers for in situ assembly, such as enzymes, pH, reactive oxygen species and ligand receptor interaction, can be used to transform the materials into a variety of controllable nanostructures including nanoparticles, nanofibers and gels through bioactivated in vivo assembly (BIVA) strategies. BIVA strategies can be applied for treatment, imaging or participate in the physiological activities of cells at the lesion site. This review summarized and prospected the design of self-assembled peptide materials based on BIVA technology and their biomedical applications. The nanostructures of the self-assembly enable some beneficial biological effects, such as assembly induced retention (AIR) effect, enhanced targeting effect, multivalent bond effect, and membrane disturbance. Thus, the BIVA nanotechnology is promising for efficient drug delivery, enhancement of targeting and treatment, as well as optimization of the biological distribution of drugs.