HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion.

Enhanced expression of the cold-shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and in vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 cold induction remains elusive. To identify temperature-dependent modulators of RBM3, we performed a genome-wide CRISPR-Cas9 knockout screen using RBM3-reporter human iPSC-derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense-mediated decay. Importantly, we show that HNRNPH1 mediates this cold-dependent exon skipping via its thermosensitive interaction with a G-rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies.

Topoisomerase II poisons inhibit vertebrate DNA replication through distinct mechanisms.

Topoisomerase II (TOP2) unlinks chromosomes during vertebrate DNA replication. TOP2 "poisons" are widely used chemotherapeutics that stabilize TOP2 complexes on DNA, leading to cytotoxic DNA breaks. However, it is unclear how these drugs affect DNA replication, which is a major target of TOP2 poisons. Using Xenopus egg extracts, we show that the TOP2 poisons etoposide and doxorubicin both inhibit DNA replication through different mechanisms. Etoposide induces TOP2-dependent DNA breaks and TOP2-dependent fork stalling by trapping TOP2 behind replication forks. In contrast, doxorubicin does not lead to appreciable break formation and instead intercalates into parental DNA to stall replication forks independently of TOP2. In human cells, etoposide stalls forks in a TOP2-dependent manner, while doxorubicin stalls forks independently of TOP2. However, both drugs exhibit TOP2-dependent cytotoxicity. Thus, etoposide and doxorubicin inhibit DNA replication through distinct mechanisms despite shared genetic requirements for cytotoxicity.

Diverse microtubule-targeted anticancer agents kill cells by inducing chromosome missegregation on multipolar spindles.

Microtubule-targeted agents are commonly used for cancer treatment, though many patients do not benefit. Microtubule-targeted drugs were assumed to elicit anticancer activity via mitotic arrest because they cause cell death following mitotic arrest in cell culture. However, we recently demonstrated that intratumoral paclitaxel concentrations are insufficient to induce mitotic arrest and rather induce chromosomal instability (CIN) via multipolar mitotic spindles. Here, we show in metastatic breast cancer and relevant human cellular models that this mechanism is conserved among clinically useful microtubule poisons. While multipolar divisions typically produce inviable progeny, multipolar spindles can be focused into near-normal bipolar spindles at any stage of mitosis. Using a novel method to quantify the rate of CIN, we demonstrate that cell death positively correlates with net loss of DNA. Spindle focusing decreases CIN and causes resistance to diverse microtubule poisons, which can be counteracted by addition of a drug that increases CIN without affecting spindle polarity. These results demonstrate conserved mechanisms of action and resistance for diverse microtubule-targeted agents. Trial registration: clinicaltrials.gov, NCT03393741.

The Histone Chaperone FACT Coordinates H2A.X-Dependent Signaling and Repair of DNA Damage.

Safeguarding cell function and identity following a genotoxic stress challenge entails a tight coordination of DNA damage signaling and repair with chromatin maintenance. How this coordination is achieved and with what impact on chromatin integrity remains elusive. Here, we address these questions by investigating the mechanisms governing the distribution in mammalian chromatin of the histone variant H2A.X, a central player in damage signaling. We reveal that H2A.X is deposited de novo at sites of DNA damage in a repair-coupled manner, whereas the H2A.Z variant is evicted, thus reshaping the chromatin landscape at repair sites. Our mechanistic studies further identify the histone chaperone FACT (facilitates chromatin transcription) as responsible for the deposition of newly synthesized H2A.X. Functionally, we demonstrate that FACT potentiates H2A.X-dependent signaling of DNA damage. We propose that new H2A.X deposition in chromatin reflects DNA damage experience and may help tailor DNA damage signaling to repair progression.

Selection on Visual Opsin Genes in Diurnal Neotropical Frogs and Loss of the SWS2 Opsin in Poison Frogs.

Amphibians are ideal for studying visual system evolution because their biphasic (aquatic and terrestrial) life history and ecological diversity expose them to a broad range of visual conditions. Here, we evaluate signatures of selection on visual opsin genes across Neotropical anurans and focus on three diurnal clades that are well-known for the concurrence of conspicuous colors and chemical defense (i.e., aposematism): poison frogs (Dendrobatidae), Harlequin toads (Bufonidae: Atelopus), and pumpkin toadlets (Brachycephalidae: Brachycephalus). We found evidence of positive selection on 44 amino acid sites in LWS, SWS1, SWS2, and RH1 opsin genes, of which one in LWS and two in RH1 have been previously identified as spectral tuning sites in other vertebrates. Given that anurans have mostly nocturnal habits, the patterns of selection revealed new sites that might be important in spectral tuning for frogs, potentially for adaptation to diurnal habits and for color-based intraspecific communication. Furthermore, we provide evidence that SWS2, normally expressed in rod cells in frogs and some salamanders, has likely been lost in the ancestor of Dendrobatidae, suggesting that under low-light levels, dendrobatids have inferior wavelength discrimination compared to other frogs. This loss might follow the origin of diurnal activity in dendrobatids and could have implications for their behavior. Our analyses show that assessments of opsin diversification in across taxa could expand our understanding of the role of sensory system evolution in ecological adaptation.

Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis.

The antimicrobial resistance crisis requires the introduction of novel antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target pathogens and harms the microbiome. This is especially true for Mycobacterium tuberculosis, where treatment requires a 6-month course of antibiotics. Here we show that a novel antimicrobial from Photorhabdus noenieputensis, which we named evybactin, is a potent and selective antibiotic acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site overlapping with synthetic thiophene poisons. Given the conserved nature of DNA gyrase, the observed selectivity against M. tuberculosis is puzzling. We found that evybactin is smuggled into the cell by a promiscuous transporter of hydrophilic compounds, BacA. Evybactin is the first, but likely not the only, antimicrobial compound found to employ this unusual mechanism of selectivity.

Multiple Routes to Color Convergence in a Radiation of Neotropical Poison Frogs.

Convergent evolution is defined as the independent evolution of similar phenotypes in different lineages. Its existence underscores the importance of external selection pressures in evolutionary history, revealing how functionally similar adaptations can evolve in response to persistent ecological challenges through a diversity of evolutionary routes. However, many examples of convergence, particularly among closely related species, involve parallel changes in the same genes or developmental pathways, raising the possibility that homology at deeper mechanistic levels is an important facilitator of phenotypic convergence. Using the genus Ranitomeya, a young, color-diverse radiation of Neotropical poison frogs, we set out to 1) provide a phylogenetic framework for this group, 2) leverage this framework to determine if color phenotypes are convergent, and 3) to characterize the underlying coloration mechanisms to test whether color convergence occurred through the same or different physical mechanisms. We generated a phylogeny for Ranitomeya using ultraconserved elements and investigated the physical mechanisms underlying bright coloration, focusing on skin pigments. Using phylogenetic comparative methods, we identified several instances of color convergence, involving several gains and losses of carotenoid and pterin pigments. We also found a compelling example of nonparallel convergence, where, in one lineage, red coloration evolved through the red pterin pigment drosopterin, and in another lineage through red ketocarotenoids. Additionally, in another lineage, "reddish" coloration evolved predominantly through structural color mechanisms. Our study demonstrates that, even within a radiation of closely related species, convergent evolution can occur through both parallel and nonparallel mechanisms, challenging the assumption that similar phenotypes among close relatives evolve through the same mechanisms.

Suicide poisoning mortality: a comparison of the national poison data system and centers for disease control national dataset.

The America's Poison Centres National Poison Data System (NPDS) is set up for the active surveillance of voluntarily reported poisoning cases in near real-time. The Centres for Disease Control and Prevention (CDC)'s Wide-ranging Online Data for Epidemiologic Research (WONDER) database is final national mortality data from state registries. We compared suicide poisoning deaths in both datasets from 2000 to 2020 and tested their relationship using a simple linear regression model. Mean annual suicide poisoning deaths during the review period were 699 (SD 145) in NPDS, and 6150 (SD 577) in WONDER. NPDS annual cases averaged 11% of cases recorded in WONDER (SD 2%; Range 8%-16%). The regression coefficient for the linear relationship between annual deaths recorded in both datasets was 0.18 (p-value<0.001, R2=0.51). The rapidly available NPDS data on fatal self-poisoning may provide sentinel surveillance regarding self-poisonings, but do not reliably predict final national data on suicide poisoning.

Application of Hemoperfusion in the Treatment of Acute Poisoning.

Rescue of acute poisoning is a race against time, and it is particularly important to remove toxic substances in time. Traditional methods include gastric lavage, promoting elimination, chelating agents, and other treatments. Hemoperfusion is a common blood purification technique. In the clinical practice of acute poisoning, hemoperfusion can directly remove toxic substances through its unique adsorption effect, showing its excellent efficacy. This paper reviews the experience of hemoperfusion in the treatment of various drug overdoses, pesticides, biological toxins, and industrial poisons, even drug addiction. It is hoped to provide a reference for clinicians in acute poisoning rescue.

The 200-Year Timeline on Botulinum Toxin: From Biologic Poison to Wonder Drug.

The history of botulinum toxin dates back to the late 1700s, when food preparation, storage, and later canning practices led to outbreaks of botulism across Europe and the United States. It is from these initial incidents that the remarkable discovery of botulinum toxin was eventually made, sparking over 200 years of further scientific inquiry and medical innovation. To date, 6 botulinum toxin products have been commercialized in North America with numerous indications across the specialties of ophthalmology, neurology, urology, dermatology, plastic surgery, and otolaryngology. This article traces the key moments and important players in the remarkable journey of this biologic poison and wonder drug. J Drugs Dermatol. 2024;23(1) doi:10.36849/JDD.7288.

Prediction the prognosis of the poisoned patients undergoing hemodialysis using machine learning algorithms.

BACKGROUND: Hemodialysis is a life-saving treatment used to eliminate toxins and metabolites from the body during poisoning. Despite its effectiveness, there needs to be more research on this method precisely, with most studies focusing on specific poisoning. This study aims to bridge the existing knowledge gap by developing a machine-learning prediction model for forecasting the prognosis of the poisoned patient undergoing hemodialysis. METHODS: Using a registry database from 2016 to 2022, this study conducted a retrospective cohort study at Loghman Hakim Hospital. First, the relief feature selection algorithm was used to identify the most important variables influencing the prognosis of poisoned patients undergoing hemodialysis. Second, four machine learning algorithms, including extreme gradient boosting (XGBoost), histgradient boosting (HGB), k-nearest neighbors (KNN), and adaptive boosting (AdaBoost), were trained to construct predictive models for predicting the prognosis of poisoned patients undergoing hemodialysis. Finally, the performance of paired feature selection and machine learning (ML) algorithm were evaluated to select the best models using five evaluation metrics including accuracy, sensitivity, specificity the area under the curve (AUC), and f1-score. RESULT: The study comprised 980 patients in total. The experimental results showed that ten variables had a significant influence on prognosis outcomes including age, intubation, acidity (PH), previous medical history, bicarbonate (HCO3), Glasgow coma scale (GCS), intensive care unit (ICU) admission, acute kidney injury, and potassium. Out of the four models evaluated, the HGB classifier stood out with superior results on the test dataset. It achieved an impressive mean classification accuracy of 94.8%, a mean specificity of 93.5 a mean sensitivity of 94%, a mean F-score of 89.2%, and a mean receiver operating characteristic (ROC) of 92%. CONCLUSION: ML-based predictive models can predict the prognosis of poisoned patients undergoing hemodialysis with high performance. The developed ML models demonstrate valuable potential for providing frontline clinicians with data-driven, evidence-based tools to guide time-sensitive prognosis evaluations and care decisions for poisoned patients in need of hemodialysis. Further large-scale multi-center studies are warranted to validate the efficacy of these models across diverse populations.

Exercise and Atrial Fibrillation: The Dose Makes the Poison? A Narrative Review.

"All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison" (Paracelsus, ~ 1538 AD). This well-known quote seems to aptly summarize the current understanding of the interaction between exercise and atrial fibrillation (AF). A host of data strongly suggests that regular exercise has a protective effect against developing AF. A small but well-conducted group of trials also demonstrates beneficial effects of exercise in the treatment of AF. Recently, however, potentially detrimental effects of large volumes of high-intensity exercise on the probability of developing AF have moved into the sports-cardiological focus. This effect is well documented for elite athletes; data regarding the general population is less clear. This review presents the current data regarding the protective, therapeutic and potentially risk-enhancing effects of exercise regarding AF. The authors demonstrate that the benefits are clear and strongly outweigh the potential disadvantages.

A potential cost of evolving epibatidine resistance in poison frogs.

BACKGROUND: Some dendrobatid poison frogs sequester the toxin epibatidine as a defense against predators. We previously identified an amino acid substitution (S108C) at a highly conserved site in a nicotinic acetylcholine receptor ß2 subunit of dendrobatid frogs that decreases sensitivity to epibatidine in the brain-expressing α4ß2 receptor. Introduction of S108C to the orthologous high-sensitivity human receptor similarly decreased sensitivity to epibatidine but also decreased sensitivity to acetylcholine, a potential cost if this were to occur in dendrobatids. This decrease in the acetylcholine sensitivity manifested as a biphasic acetylcholine concentration-response curve consistent with the addition of low-sensitivity receptors. Surprisingly, the addition of the ß2 S108C into the α4ß2 receptor of the dendrobatid Epipedobates anthonyi did not change acetylcholine sensitivity, appearing cost-free. We proposed that toxin-bearing dendrobatids may have additional amino acid substitutions protecting their receptors from alterations in acetylcholine sensitivity. To test this, in the current study, we compared the dendrobatid receptor to its homologs from two non-dendrobatid frogs. RESULTS: The introduction of S108C into the α4ß2 receptors of two non-dendrobatid frogs also does not affect acetylcholine sensitivity suggesting no additional dendrobatid-specific substitutions. However, S108C decreased the magnitude of neurotransmitter-induced currents in Epipedobates and the non-dendrobatid frogs. We confirmed that decreased current resulted from fewer receptors in the plasma membrane in Epipedobates using radiolabeled antibodies against the receptors. To test whether S108C alteration of acetylcholine sensitivity in the human receptor was due to (1) adding low-sensitivity binding sites by changing stoichiometry or (2) converting existing high- to low-sensitivity binding sites with no stoichiometric alteration, we made concatenated α4ß2 receptors in stoichiometry with only high-sensitivity sites. S108C substitutions decreased maximal current and number of immunolabeled receptors but no longer altered acetylcholine sensitivity. CONCLUSIONS: The most parsimonious explanation of our current and previous work is that the S108C substitution renders the ß2 subunit less efficient in assembling/trafficking, thereby decreasing the number of receptors in the plasma membrane. Thus, while ß2 S108C protects dendrobatids against sequestered epibatidine, it incurs a potential physiological cost of disrupted α4ß2 receptor function.

Range and Pasture Plants Likely to Poison Horses.

Range and pasture toxic plants can poison horses. Many of these plants are noxious weeds that can dominate plant populations and replace healthy forages. Poisoning is often difficult to diagnose as the resulting plant-induced disease is similar to other infectious, toxic, and nutritional diseases. Identifying potentially problem plants, and observing what plants horses are eating, is essential in determining the risk of poisoning. If the risk is significant, it can drive management to invest in strategies to avoid exposure, animal disease, and suffering.

Dessert or Poison? The Roles of Glycosylation in Alzheimer's, Parkinson's, Huntington's Disease, and Amyotrophic Lateral Sclerosis.

Ministry of Education and Key Laboratory of Neurons and glial cells of the central nervous system (CNS) are modified by glycosylation and rely on glycosylation to achieve normal neural function. Neurodegenerative disease is a common disease of the elderly, affecting their healthy life span and quality of life, and no effective treatment is currently available. Recent research implies that various glycosylation traits are altered during neurodegenerative diseases, suggesting a potential implication of glycosylation in disease pathology. Herein, we summarized the current knowledge about glycosylation associated with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS) pathogenesis, focusing on their promising functional avenues. Moreover, we collected research aimed at highlighting the need for such studies to provide a wealth of disease-related glycosylation information that will help us better understand the pathophysiological mechanisms and hopefully specific glycosylation information to provide further diagnostic and therapeutic directions for neurodegenerative diseases.

XRCC1 counteracts poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib, and a clinical alkylating agent, temozolomide, by promoting the removal of trapped PARP1 from broken DNA.

Base excision repair (BER) removes damaged bases by generating single-strand breaks (SSBs), gap-filling by DNA polymerase ß (POLß), and resealing SSBs. A base-damaging agent, methyl methanesulfonate (MMS) is widely used to study BER. BER increases cellular tolerance to MMS, anti-cancer base-damaging drugs, temozolomide, carmustine, and lomustine, and to clinical poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib. The poisons stabilize PARP1/SSB complexes, inhibiting access of BER factors to SSBs. PARP1 and XRCC1 collaboratively promote SSB resealing by recruiting POLß to SSBs, but XRCC1-/- cells are much more sensitive to MMS than PARP1-/- cells. We recently report that the PARP1 loss in XRCC1-/- cells restores their MMS tolerance and conclude that XPCC1 facilitates the release of PARP1 from SSBs by maintaining its autoPARylation. We here show that the PARP1 loss in XRCC1-/- cells also restores their tolerance to the three anti-cancer base-damaging drugs, although they and MMS induce different sets of base damage. We reveal the synthetic lethality of the XRCC1-/- mutation, but not POLß-/- , with olaparib and talazoparib, indicating that XRCC1 is a unique BER factor in suppressing toxic PARP1/SSB complex and can suppress even when PARP1 catalysis is inhibited. In conclusion, XRCC1 suppresses the PARP1/SSB complex via PARP1 catalysis-dependent and independent mechanisms.

Old poisons, new signaling molecules: the case of hydrogen cyanide.

The high phenotypic plasticity developed by plants includes rapid responses and adaptations to aggressive or changing environments. To achieve this, they evolved extremely efficient mechanisms of signaling mediated by a wide range of molecules, including small signal molecules. Among them, hydrogen cyanide (HCN) has been largely ignored due to its toxic characteristics. However, not only is it present in living organisms, but it has been shown that it serves several functions in all kingdoms of life. Research using model plants has changed the traditional point of view, and it has been demonstrated that HCN plays a positive role in the plant response to pathogens independently of its toxicity. Indeed, HCN induces a response aimed at protecting the plant from pathogen attack, and the HCN is provided either exogenously (in vitro or by some cyanogenic bacteria species present in the rhizosphere) or endogenously (in reactions involving ethylene, camalexin, or other cyanide-containing compounds). The contribution of different mechanisms to HCN function, including a new post-translational modification of cysteines in proteins, namely S-cyanylation, is discussed here. This work opens up an expanding 'HCN field' of research related to plants and other organisms.

Investigating signal modalities of aposematism in a poison frog.

Aposematic species combine a conspicuous signal with a secondary defence, the majority of which are studied in the context of a visual signal. While multimodality of the aposematic signal appears to be common in invertebrate species, we know very little about the presence or absence of multimodality in vertebrates. Here, we examine the possibility of multimodality of aposematism in the green-and-black poison frog, Dendrobates auratus. Using a non-visual predator (the cat-eyed snake, Leptodeira annulata) and extractions of chemicals in frog skins, we test whether there is sufficient non-visual information for predators to avoid this aposematic species without using visual cues. We found that experienced predators avoid chemicals in this poison frog's skin by olfactory cues alone in trials with live frogs and extracts from captive poison frogs, whereas extracts from wild poison frogs did not lead to avoidance behaviours in predators. Further, in our limited sampling, naïve predators demonstrate no avoidance. This not only indicates that predators can make informed decisions from the frog's odour, but also indicates that avoidance based on olfactory cue is a learned response.

Fierce poison to others: the phenomenon of bacterial dependence on antibiotics.

Beyond the development of resistance, the effects of antibiotics on bacteria and microbial communities are complex and far from exhaustively studied. In the context of the current global antimicrobial resistance crisis, understanding the adaptive and physiological responses of bacteria to antimicrobials is of paramount importance along with the development of new therapies. Bacterial dependence on antibiotics is a phenomenon in which antimicrobials instead of eliminating the pathogens actually provide a boost for their growth. This trait comprises an extreme example of the complexities of responses elicited by microorganisms to these drugs. This compelling evolutionary trait was readily described along with the first wave of antibiotics use and dependence to various antimicrobials has been reported. Nevertheless, current molecular characterizations have been focused on dependence on vancomycin, linezolid and colistin, three critically important antibiotics frequently used as last resource therapy for multi resistant pathogens. Outstanding advances have been made in understanding the molecular basis for the dependence to vancomycin, including specific mutations involved. Regarding linezolid and colistin, the general physiological components affected by the dependence, namely ribosomes and membrane function respectively, have been established. Nonetheless the implications of antibiotic dependence in clinically relevant features, such as virulence, epidemics, relationship with development of resistance, diagnostics and therapy effectiveness require clarification. This review presents a brief introduction of the phenomenon of bacterial dependence to antibiotics and a summary on early and current research concerning the basis for this trait. Furthermore, the available information on the effect of dependence in key clinical aspects is discussed. The studies performed so far underline the need to fully disclose the biological and clinical significance of this trait in pathogens to successfully assess its role in resistance and to design adjusted therapies.