Dissecting the signaling of the MAP3 Kinases TAK1 and MEKK3 for the treatment of pancreatic cancer

Pancreatic cancer (PC) remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century. The MAP3K pathway is one of most important pathways that regulate the aggressiveness of PC. In particular, MAP3Ks act by regulating NFkB and YAP/TAZ signaling, two of the most well characterized pathways sustaining the chemoresistance and EMT features of this cancer. We focused our attention on two members of the MAP3K pathway, the TGF-\u3b2-activated kinase 1 (TAK1) and the Mitogen-Activated protein kinase kinase kinase 3 (MEKK3) with the aim to understand whether and how they could impact on YAP/TAZ. We showed that TAK1 silencing affects the HIPPO pathway by modulating YAP/TAZ protein levels. We reported for the first time that TAK1 can regulate the stability of YAP/TAZ, independently on its kinase activity, by modulating the expression of E3-ubiquitin ligases, such as TRAF6 and ITCH/AIP4. Moreover, based on a recent report showing that the pharmacological inhibition of GSK3 caused a reduction of TAK1 levels, we treated our cells with GSK3 inhibitors and we observed a reduction of both TAK1 and YAP/TAZ proteins, as well as YAP/TAZ regulated genes. Pharmacological silencing of TAK1 impaired YAP/TAZ-regulated features, such as proliferation and migration. As for MEKK3, we knocked out its expression in different cellular models by CRISPR-Cas9 technology. Then, we assessed the impact of MEKK3 knock-out (MEKK3 KO) on the aggressiveness of PC. We observed a decrease of proliferation and colony formation ability in MEKK3 KO cells. Simultaneously, we observed that MEKK3 KO affects the YAP/TAZ target genes expression, without altering YAP/TAZ protein levels or the NFkB pathway. The emerging role of YAP/TAZ in orchestrating the development and the sustainment of PC opens the need for the discovery of drugs to inhibit their activities but, so far, no specific inhibitors of YAP/TAZ have been identified. Our data open the path for targeting the YAP/TAZ pathway through pharmacological inhibition of GSK3/TAK1 and MEKK3

Can we trust in Sars-CoV-2 rapid antigen testing? Preliminary results from a paediatric cohort in the emergency department

BACKGROUND: Rapid identification of Covid-19 in the paediatric emergency department is critical; Antigen tests are fast but poorly investigated in children. AIMS: To investigate Sars-CoV-2 antigen rapid test in children. METHODS: We compare the performance of LumiraDx with molecular tests in a paediatric emergency department. RESULTS: A retrospective cohort of 191 patients with AT and PCR tests performed in the same episode was analysed; 16% resulted positive for Sars-CoV-2. Using the PCR test as the gold standard, we calculated antigen testing overall sensitivity of 94.1%, specificity of 91.9%, and NPV of 99.4%. Only one false-negative test was found. CONCLUSIONS: AT may be helpful in the initial screening of patients at PED

Joint Individual-Group Modeling for Tracking

We present a novel probabilistic framework that jointly models individuals and groups for tracking. Managing groups is challenging, primarily because of their nonlinear dynamics and complex layout which lead to repeated splitting and merging events. The proposed approach assumes a tight relation of mutual support between the modeling of individuals and groups, promoting the idea that groups are better modeled if individuals are considered and vice versa. This concept is translated in a mathematical model using a decentralized particle filtering framework which deals with a joint individual-group state space. The model factorizes the joint space into two dependent subspaces, where individuals and groups share the knowledge of the joint individual-group distribution. The assignment of people to the different groups (and thus group initialization, split and merge) is implemented by two alternative strategies: using classifiers trained beforehand on statistics of group configurations, and through online learning of a Dirichlet process mixture model, assuming that no training data is available before tracking. These strategies lead to two different methods that can be used on top of any person detector (simulated using the ground truth in our experiments). We provide convincing results on two recent challenging tracking benchmarks

A strategy to identify breakdown location in MITICA test facility: results of high voltage test campaign

The Acceleration Grid Power Supply of the MITICA test facility in Padova (Italy) is currently under commissioning. The power conversion system, the DC generator, and the High Voltage equipment have been individually commissioned, whereas the integration tests are ongoing. It is a challenging process due to the unconventional application, to the variety of different electrical technologies involved and to the complexity of the interfaces. During the integrated tests of the power supplies the achievement of 700kV stable operation has been demonstrated for the first time in a Neutral Beam Injector, but an unexpected event occurred, most likely a breakdown in the HV part, which resulted in a fault of the DC generator. A subsequent test using an auxiliary power supply was performed to check the voltage withstanding capability of the HV plant, but another breakdown occurred at around 1MV. This paper describes the activity performed to identify the location of the breakdowns affecting the integrated tests. A test campaign has been devised with increased diagnostic capabilities and specific strategy conceived to trigger intentional breakdowns in specific locations and collect measurement patterns for different cases. The results of the campaign will be presented and the current understanding of the issue will be described, with a view on future tests and further improvements of diagnostics

Demographic Histories of ERV-K in Humans, Chimpanzees and Rhesus Monkeys

We detected 19 complete endogenous retroviruses of the K family in the genome of rhesus monkey (Macaca mulatta; RhERV-K) and 12 full length elements in the genome of the common chimpanzee (Pan troglodytes; CERV-K). These sequences were compared with 55 human HERV-K and 20 CERV-K reported previously, producing a total data set of 106 full-length ERV-K genomes. Overall, 61% of the human elements compared to 21% of the chimpanzee and 47% of rhesus elements had estimated integration times less than 4.5 million years before present (MYBP), with an average integration times of 7.8 MYBP, 13.4 MYBP and 10.3 MYBP for HERV-K, CERV-K and RhERV-K, respectively. By excluding those ERV-K sequences generated by chromosomal duplication, we used 63 of the 106 elements to compare the population dynamics of ERV-K among species. This analysis indicated that both HERV-K and RhERV-K had similar demographic histories, including markedly smaller effective population sizes, compared to CERV-K. We propose that these differing ERV-K dynamics reflect underlying differences in the evolutionary ecology of the host species, such that host ecology and demography represent important determinants of ERV-K dynamics