SPARCLE, a p53-induced lncRNA, controls apoptosis after genotoxic stress by promoting PARP-1 cleavage.

p53, master transcriptional regulator of the genotoxic stress response, controls cell-cycle arrest and apoptosis following DNA damage. Here, we identify a p53-induced lncRNA suicidal PARP-1 cleavage enhancer (SPARCLE) adjacent to miR-34b/c required for p53-mediated apoptosis. SPARCLE is a ∼770-nt, nuclear lncRNA induced 1 day after DNA damage. Despite low expression (<16 copies/cell), SPARCLE deletion increases DNA repair and reduces DNA-damage-induced apoptosis as much as p53 deficiency, while its overexpression restores apoptosis in p53-deficient cells. SPARCLE does not alter gene expression. SPARCLE binds to PARP-1 with nanomolar affinity and causes apoptosis by acting as a caspase-3 cofactor for PARP-1 cleavage, which separates PARP-1's N-terminal (NT) DNA-binding domain from its catalytic domains. NT-PARP-1 inhibits DNA repair. Expressing NT-PARP-1 in SPARCLE-deficient cells increases unrepaired DNA damage and restores apoptosis after DNA damage. Thus, SPARCLE enhances p53-induced apoptosis by promoting PARP-1 cleavage, which interferes with DNA-damage repair.

Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1.

Chronic inflammatory diseases are associated with altered hematopoiesis that could result in neutrophilia and anemia. Here we report that genetic or chemical manipulation of different inflammasome components altered the differentiation of hematopoietic stem and progenitor cells (HSPC) in zebrafish. Although the inflammasome was dispensable for the emergence of HSPC, it was intrinsically required for their myeloid differentiation. In addition, Gata1 transcript and protein amounts increased in inflammasome-deficient larvae, enforcing erythropoiesis and inhibiting myelopoiesis. This mechanism is evolutionarily conserved, since pharmacological inhibition of the inflammasome altered erythroid differentiation of human erythroleukemic K562 cells. In addition, caspase-1 inhibition rapidly upregulated GATA1 protein in mouse HSPC promoting their erythroid differentiation. Importantly, pharmacological inhibition of the inflammasome rescued zebrafish disease models of neutrophilic inflammation and anemia. These results indicate that the inflammasome plays a major role in the pathogenesis of neutrophilia and anemia of chronic diseases and reveal druggable targets for therapeutic interventions.

Maf1 phosphorylation is regulated through the action of prefoldin-like Bud27 on PP4 phosphatase in Saccharomyces cerevisiae.

Bud27 is a prefoldin-like protein that participates in transcriptional regulation mediated by the three RNA polymerases in Saccharomyces cerevisiae. Lack of Bud27 significantly affects RNA pol III transcription, although the involved mechanisms have not been characterized. Here, we show that Bud27 regulates the phosphorylation state of the RNA pol III transcriptional repressor, Maf1, influences its nuclear localization, and likely its activity. We demonstrate that Bud27 is associated with the Maf1 main phosphatase PP4 in vivo, and that this interaction is required for proper Maf1 dephosphorylation. Lack of Bud27 decreases the interaction among PP4 and Maf1, Maf1 dephosphorylation, and its nuclear entry. Our data uncover a new nuclear function of Bud27, identify PP4 as a novel Bud27 interactor and demonstrate the effect of this prefoldin-like protein on the posttranslational regulation of Maf1. Finally, our data reveal a broader effect of Bud27 on PP4 activity by influencing, at least, the phosphorylation of Rad53.

Augmenting astrophysical scaling relations with machine learning: Application to reducing the Sunyaev-Zeldovich flux-mass scatter.

Complex astrophysical systems often exhibit low-scatter relations between observable properties (e.g., luminosity, velocity dispersion, oscillation period). These scaling relations illuminate the underlying physics, and can provide observational tools for estimating masses and distances. Machine learning can provide a fast and systematic way to search for new scaling relations (or for simple extensions to existing relations) in abstract high-dimensional parameter spaces. We use a machine learning tool called symbolic regression (SR), which models patterns in a dataset in the form of analytic equations. We focus on the Sunyaev-Zeldovich flux-cluster mass relation (YSZ - M), the scatter in which affects inference of cosmological parameters from cluster abundance data. Using SR on the data from the IllustrisTNG hydrodynamical simulation, we find a new proxy for cluster mass which combines YSZ and concentration of ionized gas (cgas): M ∝ Yconc3/5 ≡ YSZ3/5(1 - A cgas). Yconc reduces the scatter in the predicted M by ∼20 - 30% for large clusters (M ≳ 1014 h-1 M⊙), as compared to using just YSZ. We show that the dependence on cgas is linked to cores of clusters exhibiting larger scatter than their outskirts. Finally, we test Yconc on clusters from CAMELS simulations and show that Yconc is robust against variations in cosmology, subgrid physics, and cosmic variance. Our results and methodology can be useful for accurate multiwavelength cluster mass estimation from upcoming CMB and X-ray surveys like ACT, SO, eROSITA and CMB-S4.

NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death.

Several studies have revealed a correlation between chronic inflammation and nicotinamide adenine dinucleotide (NAD+) metabolism, but the precise mechanism involved is unknown. Here, we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation, and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly(ADP-ribose) (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases, and reactive oxygen species (ROS) scavenging all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased the expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of NAMPT and PARP activity, together with AIFM1 nuclear translocation, was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death.

Inflammation in Development and Aging: Insights from the Zebrafish Model.

Zebrafish are an emergent animal model to study human diseases due to their significant genetic similarity to humans, swift development, and genetic manipulability. Their utility extends to the exploration of the involvement of inflammation in host defense, immune responses, and tissue regeneration. Additionally, the zebrafish model system facilitates prompt screening of chemical compounds that affect inflammation. This study explored the diverse roles of inflammatory pathways in zebrafish development and aging. Serving as a crucial model, zebrafish provides insights into the intricate interplay of inflammation in both developmental and aging contexts. The evidence presented suggests that the same inflammatory signaling pathways often play instructive or beneficial roles during embryogenesis and are associated with malignancies in adults.

Phylogeographic patterns of Cyphocharax from trans-Andean rivers and northward expansion to lower Central America (Teleostei, Curimatidae).

Phylogenetic analyses of mitochondrial and nuclear data of 31 specimens of Cyphocharax from trans-Andean rivers support the presence of one lineage of Cyphocharax aspilos in Lago Maracaibo and three cryptic lineages of Cyphocharax magdalenae: (1) Cauca-Magdalena and Ranchería, (2) León and Atrato, and (3) Chucunaque-Tuira, Santa María, and Chiriquí basins of Central America. Results suggest that the Serranía del Perijá facilitated Late Miocene cladogenetic events, whereas post-Isthmian C. magdalenae expansion was enabled by gene flow across the lower Magdalena valley and Central American lowlands. Time-calibrated phylogenetics indicate that the C. magdalenae colonized lower Central America in the Pliocene (3.7 MYA; Ma), the divergence Atrato-Magdalena occurred in Late Pliocene (3.0 Ma) and the split Ranchería-Magdalena during the Middle Pleistocene (1.3 Ma). Updated geographic distribution data support the hypothesis that the Cordillera de Talamanca functions as a barrier to northward expansion of C. magdalenae in Central America.

Identification of mutants with increased variation in cell size at onset of mitosis in fission yeast.

Fission yeast cells divide at a similar cell length with little variation about the mean. This is thought to be the result of a control mechanism that senses size and corrects for any deviations by advancing or delaying onset of mitosis. Gene deletions that advance cells into mitosis at a smaller size or delay cells entering mitosis have led to the identification of genes potentially involved in this mechanism. However, the molecular basis of this control is still not understood. In this work, we have screened for genes that when deleted increase the variability in size of dividing cells. The strongest candidate identified in this screen was mga2 The mga2 deletion strain shows a greater variation in cell length at division, with a coefficient of variation (CV) of 15-24%, while the wild-type strain has a CV of 5-8%. Furthermore, unlike wild-type cells, the mga2 deletion cells are unable to correct cell size deviations within one cell cycle. We show that the mga2 gene genetically interacts with nem1 and influences the nuclear membrane and the nuclear-cytoplasmic transport of CDK regulators.

The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities.

Neuroendocrine neoplasms (NENs) comprise a highly heterogeneous group of tumors arising from the diffuse neuroendocrine system. NENs mainly originate in gastrointestinal, pancreatic, and pulmonary tissues, and despite being rare, show rising incidence. The molecular mechanisms underlying NEN development are still poorly understood, although recent studies are unveiling their genomic, epigenomic and transcriptomic landscapes. RNA was originally considered as an intermediary between DNA and protein. Today, compelling evidence underscores the regulatory relevance of RNA processing, while new RNA molecules emerge with key functional roles in core cell processes. Indeed, correct functioning of the interrelated complementary processes comprising RNA biology, its processing, transport, and surveillance, is essential to ensure adequate cell homeostasis, and its misfunction is related to cancer at multiple levels. This review is focused on the dysregulation of RNA biology in NENs. In particular, we survey alterations in the splicing process and available information implicating the main RNA species and processes in NENs pathology, including their role as biomarkers, and their functionality and targetability. Understanding how NENs precisely (mis)behave requires a profound knowledge at every layer of their heterogeneity, to help improve NEN management. RNA biology provides a wide spectrum of previously unexplored processes and molecules that open new avenues for NEN detection, classification and treatment. The current molecular biology era is rapidly evolving to facilitate a detailed comprehension of cancer biology and is enabling the arrival of personalized, predictive and precision medicine to rare tumors like NENs.

Ultrasound-Based Recovery of Anti-Inflammatory and Antimicrobial Extracts of the Acidophilic Microalga Coccomyxa onubensis.

In the present study, the recovery of valuable molecules of proven anti-inflammatory and antimicrobial activity of the acidophilic microalga Coccomyxa onubensis (C. onubensis) were evaluated using green technologies based on ultrasound-assisted extraction (UAE). Using a factorial design (3 × 2) based on response surface methodology and Pareto charts, two types of ultrasonic equipment (bath and probe) were evaluated to recover valuable compounds, including the major terpenoid of C. onubensis, lutein, and the antimicrobial activity of the microalgal extracts obtained under optimal ultrasound conditions (desirability function) was evaluated versus conventional extraction. Significant differences in lutein recovery were observed between ultrasonic bath and ultrasonic probe and conventional extraction. Furthermore, the antimicrobial activity displayed by C. onubensis UAE-based extracts was greater than that obtained in solvent-based extracts, highlighting the effects of the extracts against pathogens such as Enterococcus hirae and Bacillus subtilis, followed by Staphylococcus aureus and Escherichia coli. In addition, gas chromatography-mass spectrometry was performed to detect valuable anti-inflammatory and antimicrobial biomolecules present in the optimal C. onubensis extracts, which revealed that phytol, sterol-like, terpenoid, and even fatty acid structures could also be responsible for the antibacterial activities of the extracts. Moreover, UAE displayed a positive effect on the recovery of valuable molecules, improving biocidal effects. Our study results facilitate the use of green technology as a good tool in algal bioprocess engineering, improving energy consumption and minimizing environmental impacts and process costs, as well as provide a valuable product for applications in the field of biotechnology.

RNA Pol II Assembly Affects ncRNA Expression.

RNA pol II assembly occurs in the cytoplasm before translocation of the enzyme to the nucleus. Affecting this assembly influences mRNA transcription in the nucleus and mRNA decay in the cytoplasm. However, very little is known about the consequences on ncRNA synthesis. In this work, we show that impairment of RNA pol II assembly leads to a decrease in cryptic non-coding RNAs (preferentially CUTs and SUTs). This alteration is partially restored upon overcoming the assembly defect. Notably, this drop in ncRNAs is only partially dependent on the nuclear exosome, which suggests a major specific effect of enzyme assembly. Our data also point out a defect in transcription termination, which leads us to propose that CTD phosphatase Rtr1 could be involved in this process.

P2X7 Receptor Regulates Collagen Expression in Human Intestinal Fibroblasts: Relevance in Intestinal Fibrosis.

Intestinal fibrosis is a common complication that affects more than 50% of Crohn´s Disease (CD) patients. There is no pharmacological treatment against this complication, with surgery being the only option. Due to the unknown role of P2X7 in intestinal fibrosis, we aim to analyze the relevance of this receptor in CD complications. Surgical resections from CD and non-Inflammatory Bowel Disease (IBD) patients were obtained. Intestinal fibrosis was induced with two different murine models: heterotopic transplant model and chronic-DSS colitis in wild-type and P2X7-/- mice. Human small intestine fibroblasts (HSIFs) were transfected with an siRNA against P2X7 and treated with TGF-ß. A gene and protein expression of P2X7 receptor was significantly increased in CD compared to non-IBD patients. The lack of P2X7 in mice provoked an enhanced collagen deposition and increased expression of several profibrotic markers in both murine models of intestinal fibrosis. Furthermore, P2X7-/- mice exhibited a higher expression of proinflammatory cytokines and a lower expression of M2 macrophage markers. Moreover, the transient silencing of the P2X7 receptor in HSIFs significantly induced the expression of Col1a1 and potentiated the expression of Col4 and Col5a1 after TGF-ß treatment. P2X7 regulates collagen expression in human intestinal fibroblasts, while the lack of this receptor aggravates intestinal fibrosis.

An approach for evaluating the bioavailability and risk assessment of potentially toxic elements using edible and inedible plants-the Remance (Panama) mining area as a model.

Mining affects the environment, particularly through the persistence of accumulation of tailings materials; this is aggravated under tropical climatic conditions, which favours the release of potentially toxic elements (PTEs) bioavailable to the local flora and fauna and supposing a risk to human health. The Remance gold mine (Panamá), exploited intermittently for more than 100 years, and has remained derelict for over 20 years. Within the area live farmers who carry out subsistence agriculture and livestock activities. The objective of this study has been to study the transference of PTEs in the local agricultural soil-plants system, with the goal of identifying their bioavailability to perform a human risk assessment. The results obtained of the Bioaccumulation coefficient in local plants show very weak to strong absorption of As (< 0.001-1.50), Hg (< 0.001-2.38), Sb (0.01-7.83), Cu (0.02-2.89), and Zn (0.06-5.32). In the case of Cu in grass (18.3 mg kg-1) and plants (16.9 mg kg-1) the concentrations exceed the maximum authorised value in animal nutrition for ruminants (10 mg kg-1). The risk to human health for edible plants exceeds the non-carcinogenic risk for rice, corn, cassava, and tea leaves for Sb (HQ 19.450, 18.304, 6.075, 1.830, respectively), the carcinogenic risk for Cu (CR = 2.3 × 10-3, 7.7 × 10 -4, 1.1 × 10-3, 1.0 × 10-3, respectively), and the carcinogenic risk for As in rice, corn and tea leaves (CR = 8 × 10-5, 3 × 10-5, 3 × 10-5, respectively). Urgent measures are needed to alleviate these effects.

Prefoldin-like Bud27 influences the transcription of ribosomal components and ribosome biogenesis in Saccharomyces cerevisiae.

Understanding the functional connection that occurs for the three nuclear RNA polymerases to synthesize ribosome components during the ribosome biogenesis process has been the focal point of extensive research. To preserve correct homeostasis on the production of ribosomal components, cells might require the existence of proteins that target a common subunit of these RNA polymerases to impact their respective activities. This work describes how the yeast prefoldin-like Bud27 protein, which physically interacts with the Rpb5 common subunit of the three RNA polymerases, is able to modulate the transcription mediated by the RNA polymerase I, likely by influencing transcription elongation, the transcription of the RNA polymerase III, and the processing of ribosomal RNA. Bud27 also regulates both RNA polymerase II-dependent transcription of ribosomal proteins and ribosome biogenesis regulon genes, likely by occupying their DNA ORFs, and the processing of the corresponding mRNAs. With RNA polymerase II, this association occurs in a transcription rate-dependent manner. Our data also indicate that Bud27 inactivation alters the phosphorylation kinetics of ribosomal protein S6, a readout of TORC1 activity. We conclude that Bud27 impacts the homeostasis of the ribosome biogenesis process by regulating the activity of the three RNA polymerases and, in this way, the synthesis of ribosomal components. This quite likely occurs through a functional connection of Bud27 with the TOR signaling pathway.

The Association of Rpb4 with RNA Polymerase II Depends on CTD Ser5P Phosphatase Rtr1 and Influences mRNA Decay in Saccharomyces cerevisiae.

Rtr1 is an RNA polymerase II (RNA pol II) CTD-phosphatase that influences gene expression during the transition from transcription initiation to elongation and during transcription termination. Rtr1 interacts with the RNA pol II and this interaction depends on the phosphorylation state of the CTD of Rpb1, which may influence dissociation of the heterodimer Rpb4/7 during transcription. In addition, Rtr1 was proposed as an RNA pol II import factor in RNA pol II biogenesis and participates in mRNA decay by autoregulating the turnover of its own mRNA. Our work shows that Rtr1 acts in RNA pol II assembly by mediating the Rpb4/7 association with the rest of the enzyme. RTR1 deletion alters RNA pol II assembly and increases the amount of RNA pol II associated with the chromatin that lacks Rpb4, decreasing Rpb4-mRNA imprinting and, consequently, increasing mRNA stability. Thus, Rtr1 interplays RNA pol II biogenesis and mRNA decay regulation. Our data also indicate that Rtr1 mediates mRNA decay regulation more broadly than previously proposed by cooperating with Rpb4. Interestingly, our data include new layers in the mechanisms of gene regulation and in the crosstalk between mRNA synthesis and decay by demonstrating how the association of Rpb4/7 to the RNA pol II influences mRNA decay.

Senescence-Independent Anti-Inflammatory Activity of the Senolytic Drugs Dasatinib, Navitoclax, and Venetoclax in Zebrafish Models of Chronic Inflammation.

Telomere shortening is the main molecular mechanism of aging, but not the only one. The adaptive immune system also ages, and older organisms tend to develop a chronic pro-inflammatory status with low-grade inflammation characterized by chronic activation of the innate immune system, called inflammaging. One of the main stimuli that fuels inflammaging is a high nutrient intake, triggering a metabolic inflammation process called metainflammation. In this study, we report the anti-inflammatory activity of several senolytic drugs in the context of chronic inflammation, by using two different zebrafish models: (i) a chronic skin inflammation model with a hypomorphic mutation in spint1a, the gene encoding the serine protease inhibitor, kunitz-type, 1a (also known as hai1a) and (ii) a non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) model with inflammation induced by a high-fat diet. Our results show that, although these models do not manifest premature aging, the senolytic drugs dasatinib, navitoclax, and venetoclax have an anti-inflammatory effect that results in the amelioration of chronic inflammation.

Environmental challenges related to cyanidation in Central American gold mining; the Remance mine (Panama).

Mine tailings are a potential source of environmental pollution because they typically contain potentially toxic elements (PTEs) and the residue of chemical compounds used during extraction processes. The Remance gold mine (NW Panama) is a decommissioned mine with mining activity records dating from the 1800s and several periods of abandonment. Very little remediation work has been performed, and waste is exposed to climatic conditions. This study aimed to evaluate the PTEs and cyanide contents in mine waste after mining operations ceased some 20 years ago, and to evaluate the degree of pollution and the environmental risks they pose with the use of the Pollution Load Index (PLI) and the Ecological Risk Index (RI). Although the total cyanide (T-CN) concentration (1.4-1.9 mg kg-1) found in most of the study area falls within the limits of gold mining tailing values for American sites (1.5-23 mg kg-1), it is worth noting that the values of the tailings of the last used mining operation exceed it (25.2-518 mg kg-1) and persist at the site. The PLI and RI suggest that the tailings from the mine and mine gallery sediments represent a source of pollution for soils and surrounding areas given their high content of PTEs (As, Cu, Sb, Hg) and T-CN, which pose serious ecological risks for biota. Therefore, it is necessary to draw up a remediation plan for this area.

Using the Marked Power Spectrum to Detect the Signature of Neutrinos in Large-Scale Structure.

Cosmological neutrinos have their greatest influence in voids: These are the regions with the highest neutrino to dark matter density ratios. The marked power spectrum can be used to emphasize low-density regions over high-density regions and, therefore, is potentially much more sensitive than the power spectrum to the effects of neutrino masses. Using 22 000 N-body simulations from the Quijote suite, we quantify the information content in the marked power spectrum of the matter field and show that it outperforms the standard power spectrum by setting constraints improved by a factor larger than 2 on all cosmological parameters. The combination of marked and standard power spectra allows us to place a 4.3σ constraint on the minimum sum of the neutrino masses with a volume equal to 1 (Gpc h^{-1})^{3} and without cosmic microwave background priors. Combinations of different marked power spectra yield a 6σ constraint within the same conditions.

Searching for the Radiative Decay of the Cosmic Neutrino Background with Line-Intensity Mapping.

We study the possibility to use line-intensity mapping (LIM) to seek photons from the radiative decay of neutrinos in the cosmic neutrino background. The Standard Model prediction for the rate for these decays is extremely small, but it can be enhanced if new physics increases the neutrino electromagnetic moments. The decay photons will appear as an interloper of astrophysical spectral lines. We propose that the neutrino-decay line can be identified with anisotropies in LIM clustering and also with the voxel intensity distribution. Ongoing and future LIM experiments will have-depending on the neutrino hierarchy, transition, and experiment considered-a sensitivity to an effective electromagnetic transition moment ∼10^{-12}-10^{-8}(m_{i}c^{2}/0.1 eV)^{3/2}µ_{B}, where m_{i} is the mass of the decaying neutrino and µ_{B} is the Bohr magneton. This will be significantly more sensitive than cosmic microwave background spectral distortions, and it will be competitive with stellar cooling studies. As a by-product, we also report an analytic form of the one-point probability distribution function for neutrino-density fluctuations, obtained from the quijote simulations using symbolic regression.

Efficacy and safety of certolizumab pegol in pregnant women with uveitis. Recommendations on the management with immunosuppressive and biologic therapies in uveitis during pregnancy.

OBJECTIVES: Clinicians often face the challenge of providing effective and safe therapy for pregnant women with uveitis. Certolizumab pegol (CZP) differs from other anti-TNFα agents due to its limited placental transfer. In this study we assessed the efficacy of CZP in pregnant women with uveitis. We also provided information on outcomes of pregnant women and neonates exposed to CZP. METHODS: We carried out a multicentre study of women with uveitis who received CZP during pregnancy and their neonates. The main visual outcomes were visual acuity (VA), intraocular inflammation and corticosteroid-sparing effect. Pregnancy outcomes, maternal and neonatal infections and congenital malformations were also assessed. RESULTS: We studied 14 women (23 affected eyes); mean age of 34.3±5.5 years. The underlying diseases were spondyloarthritis (n=7), idiopathic (n=2), and Vogt-Koyanagi-Harada, rheumatoid arthritis, juvenile idiopathic arthritis, punctate inner choroidopathy and Behçet's disease (1 each). The patterns of ocular involvement were anterior (n=10), posterior (n=2), intermediate (n=1), panuveitis (n=1). Cystoid macular oedema was present in one patient (1 eye). Uveitis was bilateral in nine cases and chronic in seven patients. CZP was started before getting pregnant in ten patients and after conceiving in four. All patients achieved or maintained ocular remission throughout pregnancy. Fifteen healthy infants were born. Only one woman presented a mild infection during pregnancy. Neither infections nor malformations were observed in neonates after a follow-up of 6 months. Six infants were breastfed and all of them received scheduled vaccinations without complications. CONCLUSIONS: Certolizumab pegol is effective and safe in women with uveitis during pregnancy.