Expression of accessory genes in Salmonella requires the presence of the Gre factors.

Genomic studies with Salmonella enterica serovar Typhimurium reveal a crucial role of horizontal gene transfer (HGT) in the acquisition of accessory cellular functions involved in host-interaction. Many virulence genes are located in genomic islands, plasmids and prophages. GreA and GreB proteins, Gre factors, interact transiently with the RNA polymerase alleviating backtracked complexes during transcription elongation. The overall effect of Gre factors depletion in Salmonella expression profile was studied. Both proteins are functionally redundant since only when both Gre factors were depleted a major effect in gene expression was detected. Remarkably, the accessory gene pool is particularly sensitive to the lack of Gre factors, with 18.6% of accessory genes stimulated by the Gre factors versus 4.4% of core genome genes. Gre factors involvement is particularly relevant for the expression of genes located in genomic islands. Our data reveal that Gre factors are required for the expression of accessory genes.

Intranasal Administration of Sugarcane Ash Causes Chronic Kidney Disease in Rats.

Background. Silica nanoparticles found in sugarcane ash have been postulated to be a toxicant contributing to chronic kidney disease of unknown etiology (CKDu). However, while the administration of manufactured silica nanoparticles is known to cause chronic tubulointerstitial disease in rats, the effect of administering sugarcane ash on kidney pathology remains unknown. Here we investigate whether sugarcane ash can induce CKD in rats. Methods. Sugarcane ash was administered for 13 weeks into the nares of rats (5 mg/day for 5d/week), and blood, urine and kidney tissues were collected at 13 weeks (at the end of ash administration) and in a separate group of rats at 24 weeks (11 weeks after stopping ash administration). Kidney histology was evaluated, and inflammation and fibrosis (collagen deposition) measured. Results. Sugarcane ash exposure led to the accumulation of silica in the kidneys, lungs, liver and spleen of rats. Mild proteinuria developed although renal function was largely maintained. However, biopsies showed focal glomeruli with segmental glomerulosclerosis, and tubulointerstitial inflammation and fibrosis that tended to worsen even after the ash administration had been stopped. Staining for the lysosomal marker, LAMP-1, showed decreased staining in ash administered rats consistent with lysosomal activation. Conclusion. Sugarcane ash containing silica nanoparticles can cause CKD in rats.

Polarized sorting of Patched enables cytoneme-mediated Hedgehog reception in the Drosophila wing disc.

Hedgehog (Hh) signal molecules play a fundamental role in development, adult stem cell maintenance and cancer. Hh can signal at a distance, and we have proposed that its graded distribution across Drosophila epithelia is mediated by filopodia-like structures called cytonemes. Hh reception by Patched (Ptc) happens at discrete sites along presenting and receiving cytonemes, reminiscent of synaptic processes. Here, we show that a vesicle fusion mechanism mediated by SNARE proteins is required for Ptc placement at contact sites. Transport of Ptc to these sites requires multivesicular bodies (MVBs) formation via ESCRT machinery, in a manner different to that regulating Ptc/Hh lysosomal degradation after reception. These MVBs include extracellular vesicle (EV) markers and, accordingly, Ptc is detected in the purified exosomal fraction from cultured cells. Blockage of Ptc trafficking and fusion to basolateral membranes result in low levels of Ptc presentation for reception, causing an extended and flattened Hh gradient.

Effectiveness of multiple health behavior change interventions in reducing symptoms of anxiety in the adult population: A systematic review and meta-analysis of randomized controlled trials.

There is limited evidence regarding the effectiveness of preventive interventions for anxiety disorders. We aim to test the effectiveness of multiple health behavior change (MHBC) interventions in the reduction of symptoms of anxiety in the adult population. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted by searching the most relevant databases and registry platforms in the area. Reference lists of included articles and relevant systematic reviews and meta-analyses of MHBC interventions that examined anxiety or depression as outcomes were also manually searched. To identify RCTs that evaluated preventive interventions, we excluded studies in which the target population included only patients meeting the diagnostic criteria for anxiety disorders. To pool results, the standardized mean difference (SMD) was calculated using the random effects model. Sensitivity, subgroup and meta-regression analyses were performed. Forty-six RCTs were included in the qualitative synthesis, and 34 RCTs were included in the meta-analysis. Thirty RCTs were focused on promoting healthy diet and physical activity, whereas the other 16 studies also focused on smoking cessation. The pooled SMD was small (-0.183; 95% CI -0.276 to -0.091) but significant (p < 0.001). The effect became non-significant when only studies with a low risk of bias were included. There was substantial and significant heterogeneity between the studies. There is currently insufficient evidence regarding the effectiveness of MHBC interventions to reduce symptoms of anxiety in the adult population.

O-versus S-Metal Coordination of the Thiocarboxylate Group: An NMR Study of the Two Tautomeric Forms of the Ga(III)-Photoxenobactin E Complex.

Photoxenobactin E (1) is a natural product with an unusual thiocarboxylic acid terminus recently isolated from an entomopathogenic bacterium. The biosynthetic gene cluster associated with photoxenobactin E, and other reported derivatives, is very similar to that of piscibactin, the siderophore responsible for the iron uptake among bacteria of the Vibrionaceae family, including potential human pathogens. Here, the reisolation of 1 from the fish pathogen Vibrio anguillarum RV22 cultured under iron deprivation, its ability to chelate Ga(III), and the full NMR spectroscopic characterization of the Ga(III)-photoxenobactin E complex are presented. Our results show that Ga(III)-photoxenobactin E in solution exists in a thiol-thione tautomeric equilibrium, where Ga(III) is coordinated through the sulfur (thiol form) or oxygen (thione form) atoms of the thiocarboxylate group. This report represents the first NMR study of the chemical exchange between the thiol and thione forms associated with thiocarboxylate-Ga(III) coordination, including the kinetics of the interconversion process associated with this tautomeric exchange. These findings show significant implications for ligand design as they illustrate the potential of the thiocarboxylate group as a versatile donor for hard metal ions such as Ga(III).

Global prevalence of perinatal depression and anxiety during the COVID-19 pandemic: An umbrella review and meta-analytic synthesis.

INTRODUCTION: The prevalence of depression and anxiety symptoms in pregnant and postpartum women during the COVID-19 pandemic was assessed by several systematic reviews (SRs) and meta-analyses which provided contrasting and different results. We aimed to summarize the evidence relating to the global prevalence of anxiety and depression among pregnant and postpartum women during the COVID-19 pandemic. MATERIAL AND METHODS: An umbrella review of SRs and meta-analyses was performed. Searches were conducted in electronic databases up to April 2023. SRs and meta-analyses reporting the prevalence of perinatal anxiety and depression during the COVID-19 pandemic were selected for eligibility. Primary studies extracted from eligible meta-analyses were included in the quantitative synthesis. The research protocol was registered on PROSPERO (CRD42020173125). RESULTS: A total of 25 SRs (198 primary studies) and 12 meta-analyses (129 primary studies) were included in the qualitative and quantitative synthesis, respectively. Studies involved data from five continents and 45 countries. The pooled prevalence of antenatal and postpartum depression was 29% (n = 55; 95% CI: 25%-33%) and 26% (n = 54; 95% CI: 23%-30%), respectively. In the case of anxiety, the pooled antenatal and postnatal prevalence was 31% (n = 44; 95% CI: 26%-37%; n = 16; 95% CI: 24%-39%). Differences emerged between continents, with Africa having the highest prevalence of perinatal depression and Oceania and Europe having the highest prevalence of antenatal and postnatal anxiety. The prevalence also varied depending on the assessment tools, especially for antenatal anxiety. A medium-high quality of the studies was observed. One SR assessed strength-of-evidence, reporting very low strength. CONCLUSIONS: During the COVID-19 pandemic, depression and anxiety were common, affecting almost one in three perinatal women globally. A high heterogeneity and a risk of publication bias were found, partially due to the variety of assessment tools and cut-offs. The results may not be generalized to minorities. Studies on the prevalence of clinical diagnoses are needed. Based on our results it is not possible to firmly affirm that the COVID-19 pandemic was the main factor that directly increased perinatal depression and anxiety during the past few years. Future studies should study other factors' impact.

Health burden of sugarcane burning on agricultural workers and nearby communities.

Sugarcane is the most widely cultivated crop in the world, with equatorial developing nations performing most of this agriculture. Burning sugarcane is a common practice to facilitate harvest, producing extremely high volumes of respirable particulate matter in the process. These emissions are known to have deleterious effects on agricultural workers and nearby communities, but the extent of this exposure and potential toxicity remain poorly characterized. As the epidemicof chronic kidney disease of an unknown etiology (CKDu) and its associated mortality continue to increase along with respiratory distress, there is an urgent need to investigate the causes, determine viable interventions to mitigate disease andimprove outcomes for groups experiencing disproportionate impact. The goal of this review is to establish the state of available literature, summarize what is known in terms of human health risk, and provide recommendations for what areas should be prioritized in research.

Characteristics of Prescreened Patients Who Did Not Participate in the Zoster Eye Disease Study.

PURPOSE: The Zoster Eye Disease Study (ZEDS) is a multicenter randomized clinical trial (RCT) funded by the National Eye Institute aiming to determine the efficacy of suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) that enrolled fewer participants than planned (527/780, 67.6%). Understanding reasons for nonparticipation of likely eligible prescreened patients provides insights into patient populations that are not represented by ZEDS and barriers in clinical trials. METHODS: In this retrospective cohort study, HZO adults likely eligible for ZEDS with a history of a typical rash and a medical record within the past year of an episode of epithelial or stromal keratitis or iritis were prescreened at activated Participating Clinical Centers from 2017 to 2022 using a standard prescreening log. De-identified data including demographic information, reasons for exclusion because of ineligibility, and patient refusal were retrospectively entered into REDCap and analyzed. RESULTS: Prescreening logs with reasons for nonconsent (1244/1706, 72.9%) were included in the data set. Patients were excluded from the study (915/1244, 73.6%) because they did not meet all inclusion criteria (619/915, 67.7%) or met an exclusion criterion (296/915, 32.3%). Among the 12 exclusion criteria for the ZEDS study, immunocompromise (76/296, 25.7%) and renal insufficiency (50/296, 16.9%) were most frequently reported. Patient refusal to participate (327/1,244, 26.3%) was common. CONCLUSION: The most common reasons for ineligibility were immunocompromise and renal insufficiency. There may be benefits to long-term antiviral use in these populations not captured in ZEDS. A quarter (26.3%) of prescreened patients refused participation, showing the substantial impact of patient preferences on trial participation.

Limited effects of culling on the behavior of invasive lionfish (Pterois miles) in the Mediterranean.

Invasive species pose serious threats to ecosystems. To reduce ecological and economic consequences of invasions, efforts are made to control invaders and evaluating the effects of such efforts is paramount. Lionfishes (Pterois volitans and Pterois miles) are native to the Indo-Pacific Ocean and pose a major threat to local ecosystems in the invaded Atlantic and Mediterranean. Culling via spearfishing is a widespread measure to limit lionfish population size in invaded ranges. However, like most hunted fishes, lionfish alter their behavior after repeated culling, potentially decreasing the effectiveness of future culls. Previous studies on lionfish in the Caribbean have shown that lionfish are less bold after repeated culling. However, the impact of culling on lionfish in their newest invasive range, the Mediterranean, remains enigmatic. To determine the behavioral changes in response to culling in this second area of invasion, we tested for effects of culling on the behavior of lionfish in Cyprus, a region heavily impacted by the lionfish invasion in the Mediterranean. We compared the response of lionfish to an approaching free diver holding a metal pole (imitating a spear fisher) between protected areas where spearfishing is restricted and areas where culls are frequently conducted. We also assessed whether activity, hiding pattern, and site fidelity differed between these culled and unculled sites. Overall, we found limited effects of culling on the traits measured, indicating surprising resistance to culling-induced behavioral changes in Mediterranean lionfish. Future studies should monitor invasive lionfish population densities and the effects of culling in more detail to tailor management plans and reduce the negative effects of these fish in specific invaded ranges.

Burn Resuscitation Practices in North America: Results of the Acute Burn ResUscitation Multicenter Prospective Trial (ABRUPT).

OBJECTIVES: ABRUPT was a prospective, noninterventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, to design a future prospective randomized trial. SUMMARY BACKGROUND DATA: No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation. METHODS: Patients ≥18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols. RESULTS: Of 379 enrollees, two-thirds (253) were resuscitated with albumin and one-third (126) were resuscitated with crystalloid alone. Albumin patients received more total fluid than Crystalloid patients (5.2 ± 2.3 vs 3.7 ± 1.7 mL/kg/% TBSA burn/24 hours), but patients in the Albumin Group were older, had larger burns, higher admission Sequential Organ Failure Assessment (SOFA) scores, and more inhalation injury. Albumin lowered the in-to-out (I/O) ratio and was started ≤12 hours in patients with the highest initial fluid requirements, given >12 hours with intermediate requirements, and avoided in patients who responded to crystalloid alone. CONCLUSIONS: Albumin use is associated with older age, larger and deeper burns, and more severe organ dysfunction at presentation. Albumin supplementation is started when initial crystalloid rates are above expected targets and improves the I/O ratio. The fluid received in the first 24 hours was at or above the Parkland Formula estimate.

Numerical analysis of micro-optics based single photon sources via a combined physical optics and rigorous simulations approach.

The use of 3D printed micro-optical components has enabled the miniaturization of various optical systems, including those based on single photon sources. However, in order to enhance their usability and performance, it is crucial to gain insights into the physical effects influencing these systems via computational approaches. As there is no universal numerical method which can be efficiently applied in all cases, combining different techniques becomes essential to reduce modeling and simulation effort. In this work, we investigate the integration of diverse numerical techniques to simulate and analyze optical systems consisting of single photon sources and 3D printed micro-optical components. By leveraging these tools, we primarily focus in evaluating the impact of different far-field spatial distributions and the underlying physical phenomena on the overall performance of a compound micro-optical system via the direct evaluation of a fiber in-coupling efficiency integral expression.

Climate change and nephrology.

Climate change should be of special concern for the nephrologist, as the kidney has a critical role in protecting the host from dehydration, but it is also a favorite target of heat stress and dehydration. Here we discuss how rising temperatures and extreme heat events may affect the kidney. The most severe presentation of heat stress is heat stroke, which can result in severe electrolyte disturbance and both acute and chronic kidney disease (CKD). However, lesser levels of heat stress also have multiple effects, including exacerbating kidney disease and precipitating cardiovascular events in subjects with established kidney disease. Heat stress can also increase the risk for kidney stones, cause multiple electrolyte abnormalities and induce both acute and chronic kidney disease. Recently there have been multiple epidemics of CKD of uncertain etiology in various regions of the world, including Mesoamerica, Sri Lanka, India and Thailand. There is increasing evidence that climate change and heat stress may play a contributory role in these conditions, although other causes, including toxins, could also be involved. As climate change worsens, the nephrologist should prepare for an increase in diseases associated with heat stress and dehydration.

High-CO2 Levels Rather than Acidification Restrict Emiliania huxleyi Growth and Performance.

The coccolithophore Emiliania huxleyi shows a variety of responses to ocean acidification (OA) and to high-CO2 concentrations, but there is still controversy on differentiating between these two factors when using different strains and culture methods. A heavily calcified type A strain isolated from the Norwegian Sea was selected and batch cultured in order to understand whether acclimation to OA was mediated mainly by CO2 or H+, and how it impacted cell growth performance, calcification, and physiological stress management. Emiliania huxleyi responded differently to each acidification method. CO2-enriched aeration (1200 µatm, pH 7.62) induced a negative effect on the cells when compared to acidification caused by decreasing pH alone (pH 7.60). The growth rates of the coccolithophore were more negatively affected by high pCO2 than by low pH without CO2 enrichment with respect to the control (400 µatm, pH 8.1). High CO2 also affected cell viability and promoted the accumulation of reactive oxygen species (ROS), which was not observed under low pH. This suggests a possible metabolic imbalance induced by high CO2 alone. In contrast, the affinity for carbon uptake was negatively affected by both low pH and high CO2. Photochemistry was only marginally affected by either acidification method when analysed by PAM fluorometry. The POC and PIC cellular quotas and the PIC:POC ratio shifted along the different phases of the cultures; consequently, calcification did not follow the same pattern observed in cell stress and growth performance. Specifically, acidification by HCl addition caused a higher proportion of severely deformed coccoliths, than CO2 enrichment. These results highlight the capacity of CO2 rather than acidification itself to generate metabolic stress, not reducing calcification.

Structural Requirements for Ga3+ Coordination in Synthetic Analogues of the Siderophore Piscibactin Deduced by Chemical Synthesis and Density Functional Theory Calculations.

Stereoselective total synthesis of several analogues of piscibactin (Pcb), the siderophore produced by different pathogenic Gram-negative bacteria, was performed. The acid-sensitive α-methylthiazoline moiety was replaced by a more stable thiazole ring, differing in the configuration of the OH group at the C-13 position. The ability of these Pcb analogues to form complexes with Ga3+ as a mimic of Fe3+ showed that the configuration of the hydroxyl group at C-13 as 13S is crucial for the chelation of Ga3+ to preserve the metal coordination, while the presence of a thiazole ring instead of the α-methylthiazoline moiety does not affect such coordination. A complete 1H and 13C NMR chemical shift assignment of the diastereoisomer mixtures around C9/C10 was done for diagnostic stereochemical disposition. Additionally, density functional theory calculations were performed not only for confirming the stereochemistry of the Ga3+ complex among the six possible diastereoisomers but also for deducing the ability of these to form octahedral coordination spheres with gallium. Finally, the lack of antimicrobial activity of Pcb and Pcb thiazole analogue Ga3+ complexes against Vibrio anguillarum agrees with one of the roles of siderophores in protecting pathogens from metal ion toxicity. The efficient metal coordination shown by this scaffold suggests its possible use as a starting point for the design of new chelating agents or vectors for the development of new antibacterials that exploit the "Trojan horse" strategy using the microbial iron uptake mechanisms. The results obtained will be of great help in the development of biotechnological applications for these types of compounds.

Advanced Methods for Natural Products Discovery: Bioactivity Screening, Dereplication, Metabolomics Profiling, Genomic Sequencing, Databases and Informatic Tools, and Structure Elucidation.

Natural Products (NP) are essential for the discovery of novel drugs and products for numerous biotechnological applications. The NP discovery process is expensive and time-consuming, having as major hurdles dereplication (early identification of known compounds) and structure elucidation, particularly the determination of the absolute configuration of metabolites with stereogenic centers. This review comprehensively focuses on recent technological and instrumental advances, highlighting the development of methods that alleviate these obstacles, paving the way for accelerating NP discovery towards biotechnological applications. Herein, we emphasize the most innovative high-throughput tools and methods for advancing bioactivity screening, NP chemical analysis, dereplication, metabolite profiling, metabolomics, genome sequencing and/or genomics approaches, databases, bioinformatics, chemoinformatics, and three-dimensional NP structure elucidation.

The IMBG Test for Evaluating the Pharmacodynamic Response to Immunosuppressive Therapy in Kidney Transplant Patients: Current Evidence and Future Applications.

Immunosuppressive drugs are widely used to prevent rejection after kidney transplantation. However, the pharmacological response to a given immunosuppressant can vary markedly between individuals, with some showing poor treatment responses and/or experiencing serious side effects. There is an unmet need for diagnostic tools that allow clinicians to individually tailor immunosuppressive therapy to a patient's immunological profile. The Immunobiogram (IMBG) is a novel blood-based in vitro diagnostic test that provides a pharmacodynamic readout of the immune response of individual patients to a range of immunosuppressants commonly used in kidney transplant recipients. Here, we discuss the current approaches used to measure the pharmacodynamic responses of individual patients to specific immunosuppressive drugs in vitro, which can then be correlated with patient's clinical outcomes. We also describe the procedure of the IMBG assay, and summarize the results obtained using the IMBG in different kidney transplant populations. Finally, we outline future directions and other novel applications of the IMBG, both in kidney transplant patients and other autoimmune diseases.

Antifungal Potential of Marine Organisms of the Yucatan Peninsula (Mexico) against Medically Important Candida spp.

Invasive fungal infections represent a global health threat. They are associated with high mortality and morbidity rates, partly due to the ineffectiveness of the available antifungal agents. The rampant increase in infections recalcitrant to the current antifungals has worsened this scenario and made the discovery of new and more effective antifungals a pressing health issue. In this study, 65 extracts from marine organisms of the Yucatan Peninsula, Mexico, were screened for antifungal activity against Candida albicans and Candida glabrata, two of the most prevalent fungal species that cause nosocomial invasive fungal infections worldwide. A total of 51 sponges, 13 ascidians and 1 gorgonian were collected from the coral reef and mangrove forest in the Yucatan Peninsula (Mexico) and extracted with organic solvents. Nine crude extracts showed potent antifungal activity, of which four extracts from the sponge species Aiolochroia crassa, Amphimedon compressa, Monanchora arbuscula and Agelas citrina had promising activity against Candida spp. Bioassay-guided fractionation of the M. arbuscula extract revealed the remarkable fungicidal activity of some fractions. Analysis of the chemical composition of one of the most active fractions by UHPLC-HRMS and NMR indicated the presence of mirabilin B and penaresidin B, and their contribution to the observed antifungal activity is discussed. Overall, this work highlights marine organisms of the Yucatan Peninsula as important reservoirs of natural products with promising fungicidal activity, which may greatly advance the treatment of invasive fungal infections, especially those afflicting immunosuppressed patients.

Datura stramonium Flowers as a Potential Natural Resource of Bioactive Molecules: Identification of Anti-Inflammatory Agents and Molecular Docking Analysis.

The present study investigated the antioxidant, antibacterial, antiviral and anti-inflammatory activities of different aerial parts (flowers, leaves and seeds) of Datura stramonium. The plant material was extracted with 80% methanol for about 24 h. The sensitivity to microorganisms analysis was performed by the microdilution technique. Antioxidant tests were performed by scavenging the DPPH and ABTS radicals, and by FRAP assay. Anti-inflammatory activity was evaluated through the inhibition of nitric oxide production in activated macrophage RAW 264.7 cells. Cell viability was assessed with an MTT assay. Results show that the flower extract revealed a powerful antimicrobial capacity against Gram-positive bacteria and strong antioxidant and anti-inflammatory activities. No significant cytotoxicity to activated macrophages was recorded. High resolution electrospray ionization mass spectrometry and nuclear magnetic resonance analysis identified two molecules with important anti-inflammatory effects: 12α-hydroxydaturametelin B and daturametelin B. Molecular docking analysis with both pro-inflammatory agents tumor necrosis factor alpha and interleukin-6 revealed that both compounds showed good binding features with the selected target proteins. Our results suggest that D. stramonium flower is a promising source of compounds with potential antioxidant, antibacterial, and anti-inflammatory activities. Isolated withanolide steroidal lactones from D. stramonium flower extract with promising anti-inflammatory activity have therapeutic potential against inflammatory disorders.

Inhaled silica nanoparticles cause chronic kidney disease in rats.

Silica nanoparticles (SiNPs) released during the burning of sugarcane have been postulated to have a role in chronic kidney disease of unknown etiology. We tested the hypothesis that pristine SiNPs of the size present in sugarcane might cause chronic kidney injury when administered through the lung in rats. We administered 200- or 300-nm amorphous SiNPs twice weekly (4 mg/dose), or vehicle by oropharyngeal aspiration for 13 wk to rats followed by euthanasia after an additional 13 wk (26 wk total). Tissues were evaluated for the presence of SiNPs and evidence of histological injury. Both sizes of SiNPs caused kidney damage, with early tubular injury and inflammation (at week 13) that continued to inflammation and chronic fibrosis at week 26 despite discontinuation of the SiNP administration. Both sizes of SiNPs caused local inflammation in the lung and kidney and were detected in the serum and urine at week 13, and the 200-nm particles were also localized to the kidney with no evidence of retention of the 300-nm particles. At week 26, there was some clearance of the 200-nm silica from the kidneys, and urinary levels of SiNPs were reduced but still significant in both 200- and 300 nm-exposed rats. In conclusion, inhaled SiNPs cause chronic kidney injury that progresses despite stopping the SiNP administration. These findings support the hypothesis that human exposure to amorphous silica nanoparticles found in burned sugarcane fields could have a participatory role in chronic kidney disease of unknown etiology.NEW & NOTEWORTHY Inhalation of silica nanoparticles (SiNPs) released during the burning of sugarcane has been postulated to have a role in chronic kidney disease of unknown etiology (CKDu). We administered 200- and 300-nm amorphous SiNPs to rats by aspiration and observed kidney damage with tubular injury and inflammation that persisted even after stopping the SiNP exposure. These findings support the hypothesis that human exposure to SiNPs found in sugarcane ash could have a participatory role CKDu.

Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program.

BACKGROUND: Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. METHODS: Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. RESULTS: Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. CONCLUSIONS: We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.