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Poly- and per-fluoroalkyl substances (PFAS) are synthetic environmentally persistent chemicals. Despite the phaseout of specific PFAS, their inherent stability has resulted in ubiquitous and enduring environmental contamination. PFAS bioaccumulation has been reported globally with omnipresence in most populations wherein they have been associated with a range of negative health effects, including strong associations with increased instances of testicular cancer and reductions in overall semen quality. To elucidate the biological basis of such effects, we employed an acute in vitro exposure model in which the spermatozoa of adult male mice were exposed to a cocktail of PFAS chemicals at environmentally relevant concentrations. We hypothesized that direct PFAS treatment of spermatozoa would induce reactive oxygen species generation and compromise the functional profile and DNA integrity of exposed cells. Despite this, post-exposure functional testing revealed that short-term PFAS exposure (3 h) did not elicit a cytotoxic effect, nor did it overtly influence the functional profile, capacitation rate, or the in vitro fertilization ability of spermatozoa. PFAS treatment of spermatozoa did, however, result in a significant delay in the developmental progression of the day 4 pre-implantation embryos produced in vitro. This developmental delay could not be attributed to a loss of sperm DNA integrity, DNA damage, or elevated levels of intracellular reactive oxygen species. When considered together, the results presented here raise the intriguing prospect that spermatozoa exposed to a short-term PFAS exposure period potentially harbor an alternate stress signal that is delivered to the embryo upon fertilization.

Earthquake is one of the natural disasters that affects the buildings and communities in developing countries. It causes different levels of damages to the buildings, making them uninhabitable for a period of time, called downtime (DT). This paper proposes a Fuzzy Logic hierarchical method to estimate the downtime of residential buildings in developing countries after an earthquake. The use of expert-based systems allows quantifying the indicators involved in the model using descriptive knowledge instead of hard data, accounting also for the uncertainties that may affect the analysis. The applicability of the methodology is illustrated using the information gathered after the 2015 Gorkha, Nepal, earthquake as a case study. On April 25, 2015, Nepal was hit by the Mw 7.8 Gorkha earthquake, which damaged and destroyed more than 500.000 residential buildings. Information obtained from a Rapid Visual Damage Assessment (RVDA) is used through a hierarchical scheme to evaluate the building damageability. Sensitivity analysis based on Sobol method is implemented to evaluate the importance of parameters gathered in the RVDA for building damage estimation. The findings of this work may be used to estimate the restoration time of damaged buildings in developing countries and to plan preventive safety measures.

BACKGROUND: Pediatric diffuse midline gliomas (DMGs) are incurable childhood cancers. The imipridone ONC201 has shown early clinical efficacy in a subset of DMGs. However, the anticancer mechanisms of ONC201 and its derivative ONC206 have not been fully described in DMGs. METHODS: DMG models including primary human in vitro (n = 18) and in vivo (murine and zebrafish) models, and patient (n = 20) frozen and FFPE specimens were used. Drug-target engagement was evaluated using in silico ChemPLP and in vitro thermal shift assay. Drug toxicity and neurotoxicity were assessed in zebrafish models. Seahorse XF Cell Mito Stress Test, MitoSOX and TMRM assays, and electron microscopy imaging were used to assess metabolic signatures. Cell lineage differentiation and drug-altered pathways were defined using bulk and single-cell RNA-seq. RESULTS: ONC201 and ONC206 reduce viability of DMG cells in nM concentrations and extend survival of DMG PDX models (ONC201: 117 days, P = .01; ONC206: 113 days, P = .001). ONC206 is 10X more potent than ONC201 in vitro and combination treatment was the most efficacious at prolonging survival in vivo (125 days, P = .02). Thermal shift assay confirmed that both drugs bind to ClpP, with ONC206 exhibiting a higher binding affinity as assessed by in silico ChemPLP. ClpP activation by both drugs results in impaired tumor cell metabolism, mitochondrial damage, ROS production, activation of integrative stress response (ISR), and apoptosis in vitro and in vivo. Strikingly, imipridone treatment triggered a lineage shift from a proliferative, oligodendrocyte precursor-like state to a mature, astrocyte-like state. CONCLUSION: Targeting mitochondrial metabolism and ISR activation effectively impairs DMG tumorigenicity. These results supported the initiation of two pediatric clinical trials (NCT05009992, NCT04732065).

Diffuse midline glioma (DMG) is a deadly pediatric and adolescent central nervous system (CNS) tumor localized along the midline structures of the brain atop the spinal cord. With a median overall survival (OS) of just 9-11-months, DMG is characterized by global hypomethylation of histone H3 at lysine 27 (H3K27me3), driven by recurring somatic mutations in H3 genes including, HIST1H3B/C (H3.1K27M) or H3F3A (H3.3K27M), or through overexpression of EZHIP in patients harboring wildtype H3. The recent World Health Organizations 5th Classification of CNS Tumors now designates DMG as, H3 K27-altered, suggesting that global H3K27me3 hypomethylation is a ubiquitous feature of DMG and drives devastating transcriptional programs for which there are no treatments. H3-alterations co-segregate with various other somatic driver mutations, highlighting the high-level of intertumoral heterogeneity of DMG. Furthermore, DMG is also characterized by very high-level intratumoral diversity with tumors harboring multiple subclones within each primary tumor. Each subclone contains their own combinations of driver and passenger lesions that continually evolve, making precision-based medicine challenging to successful execute. Whilst the intertumoral heterogeneity of DMG has been extensively investigated, this is yet to translate to an increase in patient survival. Conversely, our understanding of the non-genomic factors that drive the rapid growth and fatal nature of DMG, including endogenous and exogenous microenvironmental influences, neurological cues, and the posttranscriptional and posttranslational architecture of DMG remains enigmatic or at best, immature. However, these factors are likely to play a significant role in the complex biological sequelae that drives the disease. Here we summarize the heterogeneity of DMG and emphasize how analysis of the posttranslational architecture may improve treatment paradigms. We describe factors that contribute to treatment response and disease progression, as well as highlight the potential for pharmaco-proteogenomics (i.e., the integration of genomics, proteomics and pharmacology) in the management of this uniformly fatal cancer.

Abstract We develop a thermoelectric generator based on catalytic combustion and operating in the low power range (up to 10 W). Considering the target of small-scale thermoelectric generators, the additive technique was chosen as an enabling technology to customize the different parts of the presented device. The generator consists of a hexagonal shaped combustion chamber coupled to commercial thermoelectric modules, water-cooled at the cold side. Thanks to the components design, heat transfer across each part of the system is properly driven enhancing the thermal management of the system. Moreover, in order to improve the overall efficiency, exhausts outlet is designed to promote heat recovery. The generator is characterized achieving an electrical power output close to 9 W in continuous regime, with an overall efficiency of 3.55%. The compact size, the light weight, the simple design and the reliability in continuous operating conditions are all promising features of the device described. Furthermore, the materials chosen for the device can suggest a way to fabricate cheaper heat exchangers, actually one of the main costs of the device development.

BackgroundSlow pathway (SP) ablation is the cornerstone for atrioventricular nodal reentry tachycardia (AVNRT) treatment, and a low-voltage bridge offers a good target during mapping using low x-ray exposure. We aimed to assess a new tool to identify SP by activation mapping using the last CARTO3® version, i.e., CARTO PRIME® V7 (Biosense Webster, Diamond Bar, CA, USA)Methods and resultsRight atrial septum and triangle of Koch 3D-activation map were obtained from intracardiac contact mapping during low x-ray CARTO 3® procedure. In 60 patients (mean age 60.3 ± 14.7, 61% females) undergoing ablation for AVNRT, an automatic activation map using a DECANAV® mapping catheter and CARTO® Confidense™, Coherent, and FAM DX software modules were obtained. The SP was identified in all patients as the latest atrioventricular node activation area; RF catheter ablation (RFCA) in that region elicited junctional beats. The mean procedural time was 150.3 ± 48.3 min, the mean fluoroscopy time exposure was 2.9 ± 2 min, the mean dose-area product (DAP) was 16.5 ± 2.7 cGy/cm2. The mean number of RF applications was 3.9 ± 2, the mean ablation index was 428.6 ± 96.6, and the mean contact force was 8 ± 2.8 g. There were no adverse event during the procedure, and no AVNRT recurrences occurred during a mean follow-up of 14.3 ± 8.3 months.ConclusionAblation of the SP by automatic mapping using Confidense™, Coherent, and FAM DX software modules is an innovative, safe, and effective approach to AVNRT ablation. The CARTO3® V7 system shows on a 3D map the latest AV node activation area during sinus rhythm allowing low fluoroscopy time and highly effective RFCA.

Abstract Our previous studies have shown that p53 isoform expression is altered in breast cancer and related to prognosis. In particular, a high ∆40p53:p53α ratio is associated with worse disease-free survival. In this manuscript, the influence of altered Δ40p53 and p53α levels on the response to standard of care DNA-damaging agents used in breast cancer treatment was investigated in vitro. Our results revealed that a high Δ40p53:p53α ratio causes cells to respond differently to doxorubicin and cisplatin treatments. Δ40p53 overexpression significantly impairs the cells’ sensitivity to doxorubicin through reducing apoptosis and DNA damage, whereas Δ40p53 knockdown has the opposite effect. Further, a high Δ40p53:p53α ratio inhibited the differential expression of several genes following doxorubicin and promoted DNA repair, impairing the cells’ canonical response. Overall, our results suggest that the response of breast cancer cells to standard of care DNA-damaging therapies is dependent on the expression of p53 isoforms, which may contribute to outcomes in breast cancer.

The Pleistocene Pampean Megafauna (PPM) may be considered as the assemblage consisting mainly of large mammals (i.e., bodymass ≥ 45 kg) that inhabited what is currently considered the Pampean Region during the Pleistocene and became extinct near the Pleistocene–Holocene transition. This contribution addresses several conceptual issues that may guide future efforts in its reconstruction and to consider potential consequences of its extinction. First, we approach the concept of megafauna by urging its explicit definition and contextualization in every investigation as a means of avoiding conceptual ambiguity. Second, we call attention to the risks of succumbing too readily to the temptation of employing a simplistic approach that assumes that extinct taxa had virtually the same biological requirements as those of their extant counterparts. We claim that within the PPM the abundance of taxa distantly related to or markedly distinct morphologically from their living counterparts poses significant challenges for understanding their paleobiology. Paleobiological interpretations need not be rigidly phylogenetically restricted, and phylogenetically based interpretations require critical assessment before their application. Third, we consider the paleoecology of the PPM from a metabolic perspective: as it was clearly dominated by allegedly hypometabolic megaherbivores (xenarthrans), there is no clear counterpart among living faunas. Fourth, we call attention to the fact that the loss of the PPM may have left in its wake an enduring but little-recognized legacy on the functioning of the contemporary ecosystem of the Pampean Region. Extinction of the PPM opened an enormous ecological chasm in the herbivore guild during the Holocene that persisted for about 6000 years, until it was filled, at least in part, by herds of cattle introduced since the sixteenth century.

The transformation of the energy sector, based on the development of low-carbon technologies, is essential to achieve climate neutrality. The Life Cycle Assessment (LCA) is a powerful methodology for assessing the environmental impact of energy technologies, which proves to be a useful tool for policy makers. The paper is a review of the main LCA studies of power generation systems performed over the past ten years aiming at comparing the energy technologies to identify those with the lowest impact on the environment, evaluated in terms of gCO2eq/kWh emissions. Screening criteria were established to include only studies of the highest qualitative significance. The authors decided to assign greater weight to emission values reported in more recent studies. For nuclear and renewable energy technologies, most of the emissions are related to the pre-operational phases. Notably, both nuclear and wind technologies, along with other renewable sources throughout their entire life cycle, exhibit significantly lower and less variable emissions compared with conventional gas- and coal-fired technologies.