Development and validation of a methodology to measure exhaled carbon dioxide (co2) and control indoor air renewal

The measurement of carbon dioxide (CO2) has emerged as a cost-effective and straightforward technique for indirectly managing indoor air quality, aiding in the reduction of the potentially pathogen-laden aerosol concentrations to which we are exposed. Unfortunately, inadequate practices often limit the interpretation of CO2 levels and neglect methodologies that ensure proper air renewal. This study presents a novel methodology for measuring and controlling indoor CO2 levels in shared spaces, comprising four stages: analysis, diagnosis, correction protocols, and monitoring/control/surveillance (MCS). This methodology underwent validation in practical settings, including a cultural center (representing spaces with uniform activities) and 40 commercial spaces (with diverse activities) in Zaragoza, Spain. The results indicate the feasibility of swiftly implementing measures to enhance shared air renewal, with the immediate opening of doors and windows being the most direct solution. The proposed methodology is practical and has the potential to mitigate the risk of the aerosol transmission of respiratory diseases. Consequently, we anticipate that this work will contribute to establishing methodological foundations for CO2 measurement as a valuable, standardized, and reliable tool

SARS-CoV-2 Droplet and Airborne Transmission Heterogeneity

The spread dynamics of the SARS-CoV-2 virus have not yet been fully understood after two years of the pandemic. The virus’s global spread represented a unique scenario for advancing infectious disease research. Consequently, mechanistic epidemiological theories were quickly dismissed, and more attention was paid to other approaches that considered heterogeneity in the spread. One of the most critical advances in aerial pathogens transmission was the global acceptance of the airborne model, where the airway is presented as the epicenter of the spread of the disease. Although the aerodynamics and persistence of the SARS-CoV-2 virus in the air have been extensively studied, the actual probability of contagion is still unknown. In this work, the individual heterogeneity in the transmission of 22 patients infected with COVID-19 was analyzed by close contact (cough samples) and air (environmental samples). Viral RNA was detected in 2/19 cough samples from patient subgroups, with a mean Ct (Cycle Threshold in Quantitative Polymerase Chain Reaction analysis) of 25.7 ± 7.0. Nevertheless, viral RNA was only detected in air samples from 1/8 patients, with an average Ct of 25.0 ± 4.0. Viral load in cough samples ranged from 7.3 × 105 to 8.7 × 108 copies/mL among patients, while concentrations between 1.1–4.8 copies/m3 were found in air, consistent with other reports in the literature. In patients undergoing follow-up, no viral load was found (neither in coughs nor in the air) after the third day of symptoms, which could help define quarantine periods in infected individuals. In addition, it was found that the patient’s Ct should not be considered an indicator of infectiousness, since it could not be correlated with the viral load disseminated. The results of this work are in line with proposed hypotheses of superspreaders, which can attribute part of the heterogeneity of the spread to the oversized emission of a small percentage of infected people

EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal Adenocarcinoma

SummaryClinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, development of pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53-defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic

Spheresomes are the main extracellular vesicles in low-grade gliomas

Cancer progression and its impact on treatment response and prognosis is deeply regulated by tumour microenvironment (TME). Cancer cells are in constant communication and modulate TME through several mechanisms, including transfer of tumour-promoting cargos through extracellular vesicles (EVs) or oncogenic signal detection by primary cilia. Spheresomes are a specific EV that arise from rough endoplasmic reticulum–Golgi vesicles. They accumulate beneath cell membrane and are released to the extracellular medium through multivesicular spheres. This study describes spheresomes in low-grade gliomas using electron microscopy. We found that spheresomes are more frequent than exosomes in these tumours and can cross the blood–brain barrier. Moreover, the distinct biogenesis processes of these EVs result in unique cargo profiles, suggesting different functional roles. We also identified primary cilia in these tumours. These findings collectively contribute to our understanding of glioma progression and metastasis

Senescence in premalignant tumours

Oncogene-induced senescence is a cellular response that may be crucial for protection against cancer development1,2, but its investigation has so far been restricted to cultured cells that have been manipulated to overexpress an oncogene. Here we analyse tumours initiated by an endogenous oncogene, ras, and show that senescent cells exist in premalignant tumours but not in malignant ones. Senescence is therefore a defining feature of premalignant tumours that could prove valuable in the diagnosis and prognosis of cancer

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas G12V/G12V mice. HRas G12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRas G12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRas G12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments

Quantum Computing for High-Energy Physics: State of the Art and Challenges. Summary of the QC4HEP Working Group

Quantum computers offer an intriguing path for a paradigmatic change of computing in the natural sciences and beyond, with the potential for achieving a so-called quantum advantage, namely a significant (in some cases exponential) speed-up of numerical simulations. The rapid development of hardware devices with various realizations of qubits enables the execution of small scale but representative applications on quantum computers. In particular, the high-energy physics community plays a pivotal role in accessing the power of quantum computing, since the field is a driving source for challenging computational problems. This concerns, on the theoretical side, the exploration of models which are very hard or even impossible to address with classical techniques and, on the experimental side, the enormous data challenge of newly emerging experiments, such as the upgrade of the Large Hadron Collider. In this roadmap paper, led by CERN, DESY and IBM, we provide the status of high-energy physics quantum computations and give examples for theoretical and experimental target benchmark applications, which can be addressed in the near future. Having the IBM 100 x 100 challenge in mind, where possible, we also provide resource estimates for the examples given using error mitigated quantum computing

A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition

11 páginas, 8 figuras, 2 tablas.-- et al.Germline activation of H-RAS oncogenes is the primary cause of Costello syndrome (CS), a neuro-cardio-facio-cutaneous developmental syndrome. Here we describe the generation of a mouse model of CS by introduction of an oncogenic Gly12Val mutation in the mouse H-Ras locus using homologous recombination in ES cells. Germline expression of the endogenous H-RasG12V oncogene, even in homozygosis, resulted in hyperplasia of the mammary gland. However, development of tumors in these mice was rare. H-RasG12V mutant mice closely phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. These mice also displayed alterations in the homeostasis of the cardiovascular system, including development of systemic hypertension, extensive vascular remodeling, and fibrosis in both the heart and the kidneys. This phenotype was age dependent and was a consequence of the abnormal upregulation of the renin-Ang II system. Treatment with captopril, an inhibitor of Ang II biosynthesis, prevented development of the hypertension condition, vascular remodeling, and heart and kidney fibrosis. In addition, it partially alleviated the observed cardiomyopathies. These mice should help in elucidating the etiology of CS symptoms, identifying additional defects, and evaluating potential therapeutic strategies.This work was supported by grants from the Spanish Ministry of Education and Science to M. Barbacid (SAF2003-05172 and SAF2004-20477-E) and X.R. Bustelo (SAF2006-01789); from the VI Framework Programme of the European Union to M. Barbacid (LSHC-CT-2004-503438, LSHG-CT-2007-037665, and LSHGCT-2006-037188); from the National Cancer Institute, NIH, to X.R. Bustelo (5R01-CA73735-10); from the Fondo de Investigación Sanitaria to C. Guerra (PI042124); from the Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, to X.R. Bustelo (RD06/0020/0001); from the Autonomous Community of Madrid to M. Barbacid (GR/SAL/0587/2004) and C. Guerra (GR/SAL/0349/2004); from the Autonomous Government of Castilla-León to X.R. Bustelo (SA053A05); and from the Fundación de la Mutua Madrileña de Automóviles to M. Barbacid. All Spanish funding to X.R. Bustelo is cosponsored by the European Union FEDER program. A.J. Schuhmacher is supported by a FPU fellowship from the Spanish Ministerio de Educación y Ciencia (MEC). V. Sauzeau is partially supported by a Juan de la Cierva postdoctoral contract from the MEC.Peer Reviewe

Germline expression of H-RasG12V causes neurological deficits associated to Costello syndrome

Costello syndrome (CS) is a rare congenital disorder caused by germline activation of H-Ras oncogenes. A mouse model of CS generated by introduction of an oncogenic Gly12Val mutation in the mouse H-Ras locus using homologous recombination in embryonic stem (ES) cells has been recently described. These mice phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. We investigated here their neurological and behavioral phenotype. The analysis of H-RasG12V mice revealed phenotypes that resembled the hyperemotivity, hypersensibility and cognitive impairments observed in children with CS. Stronger neurological deficits were found in the analysis of mice homozygous for this mutation than in the analysis of heterozygous mice, suggesting the existence of a gene dose effect. These mice represent the first mouse model for CS, offering an experimental tool to study the molecular and physiological alterations underlying the neurological manifestations of CS and to test new therapies aimed at preventing or ameliorating the cognitive and emotional impairments associated to this condition.This work was supported by grants from the Spanish Ministry of Education and Science to A.B. (BFU2005-00286 and SAF2005-24584-E), the European Commission to A.B. (MEXT-CT-2003-509550), the Fondo de Investigación Sanitaria to C.G. (PI042124), the Autonomous Community of Madrid to C.G. (GR/SAL/0349/2004), and Fundació La Marató de TV3 and Fundación Ramón Areces to A.B. J.V. is supported by a FPI fellowship from the Generalitat Valenciana and A.J.S. is supported by a FPU fellowship from the Spanish Ministry of Education and Science.Peer Reviewe