Defining the tipping point: a complex cellular life/death balance in corals in response to stress.
Ontology highlight
ABSTRACT:
SUBMITTER: Ainsworth TD
PROVIDER: S-EPMC3240979 | biostudies-other | 2011
REPOSITORIES: biostudies-other
Similar Datasets
Project description:BackgroundAlthough risk factors for poor outcomes and complications have been studied, there remain limited objective criteria to guide surgeons about the timing of arthroplasty. The purpose of this study was to further characterize the tipping-point scores for a group of patient-reported outcome measures (PROMs) in patients undergoing primary shoulder arthroplasty.MethodsWe retrospectively reviewed 5670 primary shoulder arthroplasties (1833 anatomic total shoulder arthroplasties and 3837 reverse shoulder arthroplasties [RSAs]) performed over a 10-year period. Preoperative range of motion, PROMs (American Shoulder and Elbow Surgeons, Simple Shoulder Test, and Shoulder Pain and Disability Index scores), and Constant scores were evaluated. The tipping point for each PROM was evaluated. Univariate and multivariate analyses were performed to assess risk factors for lower tipping points.ResultsPatients undergoing RSA demonstrated lower tipping points for all range-of-motion parameters as well as American Shoulder and Elbow Surgeons, Shoulder Pain and Disability Index, and Simple Shoulder Test scores. Female sex was predictive of a lower tipping point prior to shoulder arthroplasty, regardless of implant type. When the total shoulder arthroplasty subgroup was evaluated, both female sex and a higher body mass index were shown to be associated with a lower tipping point.DiscussionThe choice to undergo shoulder arthroplasty is a multifactorial decision that encompasses both physical and social factors. Female patients and patients undergoing RSA are more likely to accept slightly worse shoulder function prior to making the decision to undergo shoulder arthroplasty.
| S-EPMC6928298 | biostudies-literature
Project description:Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E2 biosythesis favors CD103+ dendritic cell activation that primes a Tc1-polarized CD8+ T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E2 blockade as a strategy to harness ICD.
| S-EPMC7721802 | biostudies-literature
Project description:Coral reefs are in global decline, converting from dominance by coral to dominance by seaweed. Once seaweeds become abundant, coral recovery is suppressed unless herbivores return to remove seaweeds, and corals then recruit. Variance in the recovery of fishes and corals is not well understood. We show that juveniles of both corals and fishes are repelled by chemical cues from fished, seaweed-dominated reefs but attracted to cues from coral-dominated areas where fishing is prohibited. Chemical cues of specific seaweeds from degraded reefs repulsed recruits, and cues from specific corals that are typical of healthy reefs attracted recruits. Juveniles were present at but behaviorally avoided recruiting to degraded reefs dominated by seaweeds. For recovery, degraded reefs may need to be managed to produce cues that attract, rather than repel, recruiting corals and fishes.
| S-EPMC4470392 | biostudies-literature
Project description:Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 2–10 µM Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p <0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the importance of characterizing molecular mechanisms around the tipping point of adverse responses to better inform HTS paradigms.
2016-04-28 | GSE80733 | GEO
Project description:Understanding tipping point dynamics in harvested ecosystems is of crucial importance for sustainable resource management because ignoring their existence imperils social-ecological systems that depend on them. Fisheries collapses provide the best known examples for realizing tipping points with catastrophic ecological, economic and social consequences. However, present-day fisheries management systems still largely ignore the potential of their resources to exhibit such abrupt changes towards irreversible low productive states. Using a combination of statistical changepoint analysis and stochastic cusp modelling, here we show that Western Baltic cod is beyond such a tipping point caused by unsustainable exploitation levels that failed to account for changing environmental conditions. Furthermore, climate change stabilizes a novel and likely irreversible low productivity state of this fish stock that is not adapted to a fast warming environment. We hence argue that ignorance of non-linear resource dynamics has caused the demise of an economically and culturally important social-ecological system which calls for better adaptation of fisheries systems to climate change.
| S-EPMC8275682 | biostudies-literature
Project description:Acute and chronic cutaneous wounds pose a significant health and economic burden. Cutaneous wound healing is a complex process that occurs in four distinct, yet overlapping, highly coordinated stages: hemostasis, inflammation, proliferation, and remodeling. Postnatal wound healing is reparative, which can lead to the formation of scar tissue. Regenerative wound healing occurs during fetal development and in restricted postnatal tissues. This process can restore the wound to an uninjured state by producing new skin cells from stem cell reservoirs, resulting in healing with minimal or no scarring. Focusing on the pathophysiology of acute burn wounds, this review highlights reparative and regenerative healing mechanisms (including the role of cells, signaling molecules, and the extracellular matrix) and discusses how components of regenerative healing are being used to drive the development of novel approaches and therapeutics aimed at improving clinical outcomes. Important components of regenerative healing, such as stem cells, growth factors, and decellularized dermal matrices, are all being evaluated to recapitulate more closely the natural regenerative healing process. Impact Statement Acute wounds from thermal injury are common; they exert substantial physical and psychological effects on a patient and result in significant morbidity and mortality. This review provides a detailed overview of the mechanisms of reparative and regenerative wound healing; discusses the key cell types, signaling molecules, and molecular targets that influence these important biological pathways; and highlights current therapeutic approaches aimed at promoting regenerative wound healing. An increased understanding of the underlying mechanisms of reparative and regenerative healing will contribute to the development of innovative strategies for the clinical treatment of patients with severe burns.
| S-EPMC9587785 | biostudies-literature
Project description:Nicotinamide adenine dinucleotide (NAD+), the essential cofactor derived from vitamin B3, is both a coenzyme in redox enzymatic processes and substrate in non-redox events; processes that are intimately implicated in all essential bioenergetics. A decrease in intracellular NAD+ levels is known to cause multiple metabolic complications and age-related disorders. One NAD+ precursor is dihydronicotinamide riboside (NRH), which increases NAD+ levels more potently in both cultured cells and mice than current supplementation strategies with nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) or vitamin B3 (nicotinamide and niacin). However, the consequences of extreme boosts in NAD+ levels are not fully understood. Here, we demonstrate the cell-specific effects of acute NRH exposure in mammalian cells. Hepatocellular carcinoma (HepG3) cells show dose-dependent cytotoxicity when supplemented with 100-1000 μM NRH. Cytotoxicity was not observed in human embryonic kidney (HEK293T) cells over the same dose range of NRH. PUMA and BAX mediate the cell-specific cytotoxicity of NRH in HepG3. When supplementing HepG3 with 100 μM NRH, a significant increase in ROS was observed concurrent with changes in the NAD(P)H and GSH/GSSG pools. NRH altered mitochondrial membrane potential, increased mitochondrial superoxide formation, and induced mitochondrial DNA damage in those cells. NRH also caused metabolic dysregulation, altering mitochondrial respiration. Altogether, we demonstrated the detrimental consequences of an extreme boost of the total NAD (NAD+ + NADH) pool through NRH supplementation in HepG3. The cell-specific effects are likely mediated through the different metabolic fate of NRH in these cells, which warrants further study in other systemic models.
| S-EPMC7652347 | biostudies-literature
Project description:Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a "Yin-Yang" counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the "Yin-Yang" homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.
| S-EPMC9832009 | biostudies-literature
Project description:Cold-water corals (CWCs) are the engineers of complex ecosystems forming unique biodiversity hotspots in the deep sea. They are expected to suffer dramatically from future environmental changes in the oceans such as ocean warming, food depletion, deoxygenation, and acidification. However, over the last decades of intense deep-sea research, no extinction event of a CWC ecosystem is documented, leaving quite some uncertainty on their sensitivity to these environmental parameters. Paleoceanographic reconstructions offer the opportunity to align the on- and offsets of CWC proliferation to environmental parameters. Here, we present the synthesis of 6 case studies from the North Atlantic Ocean and the Mediterranean Sea, revealing that food supply controlled by export production and turbulent hydrodynamics at the seabed exerted the strongest impact on coral vitality during the past 20,000 years, whereas locally low oxygen concentrations in the bottom water can act as an additional relevant stressor. The fate of CWCs in a changing ocean will largely depend on how these oceanographic processes will be modulated. Future ocean deoxygenation may be compensated regionally where the food delivery and food quality are optimal.
| S-EPMC9119455 | biostudies-literature
Project description:Background Chronic kidney disease (CKD) is the progressive loss of renal function. Although advances have been made in understanding the progression of CKD, key molecular events in complex pathophysiological mechanisms that mark each stage of renal failure remain largely unknown. Changes in plasma protein profiles in different disease stages are important for identification of early diagnostic markers and potential therapeutic targets. The goal of this study was to determine the molecular profile of each CKD stage (from 1 to 5), aiming to specifically point out markedly expressed or downregulated proteins. Methods We performed a cross-sectional shotgun-proteomic study of plasma proteome across CKD stages and compared them to healthy controls. After sample pooling and heparin-column purification we analysed proteomes from healthy to CKD stage 1 through 5 participants’ plasma by liquid-chromatography/mass-spectrometry. Results We identified 298 proteins in all study groups, as well as several outliers. Our results indicate that key events, that may later affect the course of disease progression and the overall pathophysiological background, are most pronounced in CKD stage 2, with an emphasis on inflammation, lipoprotein metabolism, angiogenesis and tissue regeneration. Conclusions Our data is consistent with multiple previous studies in CKD research, but also uncovers previously unknown CKD mediators and brings forth several novel potential protein-candidates which might have a significant impact on the development of diagnostic and therapeutic strategies for CKD. We hypothesize that CKD stage 2 is the tipping point in disease progression and a suitable point in disease course for the development of therapeutic solutions.
2022-08-12 | PXD033427 | Pride