Characterization of USP11 as a novel regulator of Hypoxia inducible factor a

207 p.Adaptation to hypoxia is a puzzling and tightly regulated challenge. This adaptability involves a severe gene expression rewiring, which is mainly triggered by the Hypoxia Inducible transcription Factor (HIF). Canonically, the regulation of the hypoxia signalling pathway mostly relies on HIF-¿ subunit, which has been described to be exquisitely regulated through the Ubiquitin Proteasome System (UPS).Because of the Ub conjugation¿ crucial role in the hypoxia pathway and in light with DUBs being druggable enzymes, we carried out an unbiased loss-of function screen to identify new DUBs modulating HIF signalling. Using this strategy, we identified 12 novel hypoxia-related DUBs. In this project, we have validated the hit candidates and further focused on USP11 characterization. We have shown that USP11 is required to sustain hypoxia-driven signalling. Indeed, USP11 binds the mRNA-binding protein, hnRNPD, forming a ribonucleoprotein complex that controls HIF1A mRNA turnover by hnRNPD-mediated interaction with HIF1A 3¿UTR. Consistent with the decrease in HIF1A mRNA upon hypoxia, we have shown that hypoxia inhibits USP11 activity and promotes hnRNPD/p37 nuclear accumulation. Therefore, USP11-mediated HIF1A post-transcriptional regulation reveals a new mechanism to fine tune HIF signalling and hypoxia adaptation, and might represent a new opportunity to understand the pathology of Lyme disease.CICBioGUNE RedHypo

On the eigenstate equivalent circuit for lossy asymmetric two-ports and its applications

An equivalent-circuit topology for two-port lossy non-symmetric reciprocal networks is presented [1]. The circuit topology is based on the eigenstate decomposition. The proposed circuit consists of two immittances and two transformers with a single complex turns ratio, as shown in Fig. 1. The only three complex parameters of the circuit are obtained from the eigenvalues and eigenvectors of the admittance or impedance matrix of the network in a straightforward way. The real parts of its immittances are always positive. Thus, the circuit is a powerful candidate for modeling asymmetric structures since it preserves some of the valuable properties of the symmetric lattice network: ability to separate the eigenstates and realizability of the real parts of the immittances. Indeed, it degenerates in the classic lattice network if the structure is symmetric. Two direct applications of the circuit are proposed. The first one is the design of asymmetric unit cells of leaky-wave antennas. A model can be found for the behavior of the two-port as a function of the degree of asymmetry using the proposed equivalent circuit topology. The new design methodology is simple and general, unlike the one proposed in [2]. The second application is the analysis and modeling of lossless and lossy bi-periodic scatterers [3]. It significantly simplifies their design, since it reduces the number of elements with respect to other equivalent circuits. Due to the capability of decomposition into the eigenexcitations of the structure, the circuit provides an important physical insight. For different structures, the admittances have been successfully modeled using a few positive and frequency-independent RLC elements

An equivalent-circuit topology for lossy non-symmetric reciprocal two-ports

An equivalent-circuit topology for two-port lossy non-symmetric reciprocal networks is proposed. The circuit topology is based on the eigenstate decomposition. The proposed circuit consists of two immittances and two transformers with a single complex turns ratio, all obtained from the eigenvalues and eigenvectors of the admittance or impedance matrix of the network in a straightforward way. The interconnection of the circuit elements is simple and compact, and the real parts of its immittances are always positive. To verify its behavior, the equivalent circuit of two different leaky-wave antenna unit cells is extracted: a series-fed coupled patch radiating element, and the complementary strip-slot. Simulated and measured data are provided for the study cases, highlighting the satisfactory behavior of the equivalent circuit over a very broad bandwidth. A simple asymmetry model is also proposed that can be used advantageously in the analysis and design of non-symmetric two-ports, like unit cells of leaky-wave antennas.This work was supported in part by the Spanish Ministerio de Educación, Cultura y Deporte (Programa para la Formación del Profesorado Universitario) under Grant FPU15/0645; in part by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (Contrato Juan de la Cierva-Incorporación) under Grant IJC2018-038 440-I; and in part by the MCIU, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) (Programa Estatal de I+D+i Orientada a los Retos de la Sociedad) under Grant RTI2018-097 098-J-I00

Time-Domain Characterization of Nematic Liquid Crystals Using Additive Manufacturing Microstrip Lines.

This paper presents a method for effectively characterizing the dielectric permittivity of nematic liquid crystals across a broad frequency range. These materials show significant potential for reconfigurable devices operating in microwave and millimeter-wave frequencies. To achieve this goal, an additive manufacturing technique is used to create a microstrip line that can be filled with liquid that acts as its substrate. The liquid crystal (LC) is then biased to modulate its permittivity. After manufacturing, a time-gating approach is used to extract the permittivity, eliminating the need for in-fixture calibration, such as Thru-Reflect-Line (TRL). Finally, the approach is validated through simulations and experimental results, which closely align with those reported using other methods in the bibliography.Funding for open access charge: Universidad de Málaga / CBUA. This project has received funding from the MCIU/AEI/FEDER under grants RTI2018-097098-J-I00 (Programa Estatal de I+D+i Orientada a los Retos de la Sociedad) and PID2022-141193OB-I00 (Programa Estatal para Impulsar la Investigacion Científico-Técnica y su Transferencia), and also by the Regional Government under grant PY20 00452 (PAIDI 2020). It has also been supported by the MCIU under grant FPU20/03240 and the program NextGenerationEU Margarita Salas, and by the European Union under the program Horizon Europe Marie Skłodowska-Curie Actions with grant 101110031. Funding for open access charge: Universidad de Málaga / CBU

Bordetella hinzii Endocarditis, A Clinical Case Not Previously Described

Objective: To review infections by Bordetella hinzii. Materials and methods: A 79-year-old male patient, with a chronic aortic valve biological prosthesis, presented to hospital because of fever. First examinations were normal. However, 72 hours later B. hinzii was isolated in blood cultures, and so meropenem was prescribed. Nevertheless, fever and B. hinzii bacteraemia were still present 7 days later. Results: The transoesophageal echocardiogram revealed an enlarged image suggesting a periprosthetic abscess, confirmed with a PET-CT scan. The patient was sent for cardiac surgery, and biopsy samples confirmed the presence of B. hinzii. Conclusion: There are very few cases of B. hinzii infection in humans. Ours is the first described case of B. hinzii endocarditis

Radioresistance of mesenchymal glioblastoma initiating cells correlates with patient outcome and is associated with activation of inflammatory program

Glioblastoma (GBM) still remains an incurable disease being radiotherapy (RT) the mainstay treatment. Glioblastoma intra-tumoral heterogeneity and GlioblastomaInitiating Cells (GICs) challenge the design of effective therapies. We investigated GICs and non-GICs response to RT in a paired in-vitro model and addressed molecular programs activated in GICs after RT. Established GICs heterogeneously expressed several GICs markers and displayed a mesenchymal signature. Upon fractionated RT, GICs reported higher radioresistance compared to non-GICs and showed lower α- and β-values, according to the Linear Quadratic Model interpretation of the survival curves. Moreover, a significant correlation was observed between GICs radiosensitivity and patient disease-free survival. Transcriptome analysis of GICs after acquisition of a radioresistant phenotype reported significant activation of Proneural-to-Mesenchymal transition (PMT) and pro-inflammatory pathways, being STAT3 and IL6 the major players. Our findings support a leading role of mesenchymal GICs in defining patient response to RT and provide the grounds for targeted therapies based on the blockade of inflammatory pathways to overcome GBM radioresistance

Role of rare earth sites and vacancies in the anomalous compression of modulated scheelite tungstates

X-ray powder diffraction experiments at high pressures combining conventional sources and synchrotron radiation, together with theoretical simulations have allowed us to study the anomalous compression of the entire α-RE2(WO4)3 (RE = La-Ho) family with modulated scheelite structure (α phase). The investigated class of materials is of great interest due to their peculiar structural behavior with temperature and pressure, which is highly sought after for specialized high-tech applications. Experimental data were analyzed using full-profile refinements and were complemented with computational methods based on density functional theory (DFT) total energy calculations for a subset of the samples investigated. An unusual change in the compression curves of the lattice parameters a, c, and β was observed in both the experiments and theoretical simulations. In particular, in all the studied compounds the lattice parameter a decreased with pressure to a minimum value and then increased upon further compression. Pressure evolution of the experimental x-ray diffraction (XRD) patterns and cell parameters is correlated with the ionic radius of the rare earth element: (1) the lighter La-Nd tungstates underwent two phase transitions, and both transition pressures decreased as the rare earth's ionic radius increased. The XRD patterns of the first high pressure phase could be indexed with propagation vectors parallel to the a axis (tripling the unit cell). At higher pressures, the lattice parameters for the second phase (referred to as the preamorphous phase) showed little variation with pressure. (2) The heavier tungstates, from Sm to Dy, undergo a transition to the preamorphous phase without any intermediate phase. The reversibility of both phase transitions was investigated. DFT calculations support this unusual response of the crystal structures under pressure and shed light on the structural mechanism of negative linear compressibility (NLC) and the resulting softening. The pressure dependence of the structural modifications is related to tilting, along with small elongation and alignment, of the WO2−4 tetrahedrons. These changes correlate with those in the alternating RE…RE…RE chains and blocks of cationic vacancies arranged along the a axis. Possible stacking defects, which emerge between them, helped to explain this anomalous compression and the pressure induced amorphization. Such mechanisms were compared with other ferroelastic families of molybdates, niobates, vanadates, and other compounds with similar structural motifs classified as having “hinge frames.

Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma

Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in vivo studies, the activity of the triple combination of PIM447 + pomalidomide + dexamethasone (PIM-Pd) in multiple myeloma. Results: Our results show that the PIM-Pd combination exerts a potent anti-myeloma effect in vitro and in vivo, where it markedly delays tumor growth and prolongs survival of treated mice. Mechanism of action studies performed in vitro and on mice tumor samples suggest that the combination PIM-Pd inhibits protein translation processes through the convergent inhibition of c-Myc and mTORC1, which subsequently disrupts the function of eIF4E. Interestingly the MM pro-survival factor IRF4 is also downregulated after PIM-Pd treatment. As a whole, all these molecular changes would promote cell cycle arrest and deregulation of metabolic pathways, including glycolysis and lipid biosynthesis, leading to inhibition of myeloma cell proliferation. Conclusions: Altogether, our data support the clinical evaluation of the triple combination PIM-Pd for the treatment of patients with multiple myeloma.This work was supported by funding from Spanish FIS (PI15/00067, PI15/02156 and PI18/01600) and FEDER, AECC (GCB120981SAN), Junta de Castilla y León, Consejería de Sanidad (GRS 862/A/13 and BIO/SA05/14), Fundación Memoria de D. Samuel Solórzano Barruso of the University of Salamanca (FS/22-2015), Fundación Ramón Areces (FRA16/003), Sociedad Española de Hematología y Hemoterapia and Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León. E.M.O. was supported by an Inplant grant from IDIVAL. T.P. is supported by a grant from AECC (INVES18043PAÍN)

Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bor tezomib and dexamethasone

Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.This work was in part funded by the Spanish ISCIII-FIS (PI 15/0067 and PI15/02156) and FEDER, the Spanish RTICC (RD12/0036/0058), "Asociación Española Contra el Cancer" (AECC, GCB120981SAN), the regional Council from “Castilla y León” (GRS 1175/A/15 and FIC335U14) and a research grant from Pharmamar SAU. MMS were also supported by the Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León, Spain. A-A López-Iglesias was supported by a grant from the Spanish Society of Hematology and Hemotherapy.Peer Reviewe

PI3K-regulated Glycine N-methyltransferase is required for the development of prostate cancer

[EN] Glycine N-Methyltransferase (GNMT) is a metabolic enzyme that integrates metabolism and epigenetic regulation. The product of GNMT, sarcosine, has been proposed as a prostate cancer biomarker. This enzyme is predominantly expressed in the liver, brain, pancreas, and prostate tissue, where it exhibits distinct regulation. Whereas genetic alterations in GNMT have been associated to prostate cancer risk, its causal contribution to the development of this disease is limited to cell line-based studies and correlative human analyses. Here we integrate human studies, genetic mouse modeling, and cellular systems to characterize the regulation and function of GNMT in prostate cancer. We report that this enzyme is repressed upon activation of the oncogenic Phosphoinositide-3-kinase (PI3K) pathway, which adds complexity to its reported dependency on androgen signaling. Importantly, we demonstrate that expression of GNMT is required for the onset of invasive prostate cancer in a genetic mouse model. Altogether, our results provide further support of the heavy oncogenic signal-dependent regulation of GNMT in prostate cancer.We are grateful to the Carracedo lab for valuable input, to Drs. Ana M. Aransay, James D. Sutherland and F. Elortza for technical advice, and Drs. Michelle Clasquin, Katie Sellers and Katya Marjon at Agios Pharmaceuticals for performing, processing and analyzing the metabolomics experiments. We thank the Basque Biobank for Research (BIOEF) for the support with prostate specimen acquisition and management. A.A-A. was funded by the Basque Government (predoctoral fellowship). V.T. is funded by Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (BIO15/CA/052), the AECC J.P. Bizkaia, the Basque Department of Health (2016111109) and the MICINN RTI2018-097267-B-I00. I.M. is supported by Fundación Cris Contra el Cáncer (PR_TPD_2020-19). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the department of education (IKERTALDE IT1106-16) and health (RIS3), the BBVA foundation, the MICINN (SAF2016-79381-R; PID2019-108787RB-I00 (FEDER/EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks RED2018-102769-T), the AECC (GCTRA18006CARR), Vencer el Cáncer Foundation, La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/ and the European Research Council (Starting Grant 336343, PoC 754627, Consolidator Grant 819242). CIBERONC was co-funded with FEDER funds and funded by ISCIII. We are grateful for the support of Mondravember and Movembergara. A.E. was supported by MCIN/AEI/10.13039/501100011033 and the EU programme NextGenerationEU/PRTR (IJC2020-043583-I). The work of JM Mato was supported by NIH grant R01CA172086 and SAF2017-88041-R. EB is funded by the MICINN (BFU2016-76872-R (FEDER/EU), PID2019-108112RB-I00, and Excellence Networks SAF2017-90794-REDT)