The PII-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions

PII, a homotrimeric very ancient and highly widespread (bacteria, archaea, plants) key sensor-transducer protein, conveys signals of abundance or poorness of carbon, energy and usable nitrogen, converting these signals into changes in the activities of channels, enzymes, or of gene expression. PII sensing is mediated by the PII allosteric effectors ATP, ADP (and, in some organisms, AMP), 2-oxoglutarate (2OG; it reflects carbon abundance and nitrogen scarcity) and, in many plants, L-glutamine. Cyanobacteria have been crucial for clarification of the structural bases of PII function and regulation. They are the subject of this review because the information gathered on them provides an overall structure-based view of a PII regulatory network. Studies on these organisms yielded a first structure of a PII complex with an enzyme, (N-acetyl-Lglutamate kinase, NAGK), deciphering how PII can cause enzyme activation, and how it promotes nitrogen stockpiling as arginine in cyanobacteria and plants. They have also revealed the first clear-cut mechanism by which PII can control gene expression. A small adaptor protein, PipX, is sequestered by PII when nitrogen is abundant and is released when is scarce, swapping partner by binding to the 2OG-activated transcriptional regulator NtcA, co-activating it. The structures of PII-NAGK, PII-PipX, PipX alone, of NtcA in inactive and 2OG-activated forms and as NtcA-2OG-PipX complex, explain structurally PII regulatory functions and reveal the changing shapes and interactions of the T-loops of PII depending on the partner and on the allosteric effectors bound to PII. Cyanobacterial studies have also revealed that in the PII-PipX complex PipX binds an additional transcriptional factor, PlmA, thus possibly expanding PipX roles beyond NtcA-dependency. Further exploration of these roles has revealed a functional interaction of PipX with PipY, a pyridoxal-phosphate (PLP) protein involved in PLP homeostasis whose mutations in the human ortholog cause epilepsy. Knowledge of cellular levels of the different components of this PII-PipX regulatory network and of KD values for some of the complexes provides the basic background for gross modeling of the system at high and low nitrogen abundance. The cyanobacterial network can guide searches for analogous components in other organisms, particularly of PipX functional analogs

The PII-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions

PII, a homotrimeric very ancient and highly widespread (bacteria, archaea, plants) key sensor-transducer protein, conveys signals of abundance or poorness of carbon, energy and usable nitrogen, converting these signals into changes in the activities of channels, enzymes, or of gene expression. PII sensing is mediated by the PII allosteric effectors ATP, ADP (and, in some organisms, AMP), 2-oxoglutarate (2OG; it reflects carbon abundance and nitrogen scarcity) and, in many plants, L-glutamine. Cyanobacteria have been crucial for clarification of the structural bases of PII function and regulation. They are the subject of this review because the information gathered on them provides an overall structure-based view of a PII regulatory network. Studies on these organisms yielded a first structure of a PII complex with an enzyme, (N-acetyl-Lglutamate kinase, NAGK), deciphering how PII can cause enzyme activation, and how it promotes nitrogen stockpiling as arginine in cyanobacteria and plants. They have also revealed the first clear-cut mechanism by which PII can control gene expression. A small adaptor protein, PipX, is sequestered by PII when nitrogen is abundant and is released when is scarce, swapping partner by binding to the 2OG-activated transcriptional regulator NtcA, co-activating it. The structures of PII-NAGK, PII-PipX, PipX alone, of NtcA in inactive and 2OG-activated forms and as NtcA-2OG-PipX complex, explain structurally PII regulatory functions and reveal the changing shapes and interactions of the T-loops of PII depending on the partner and on the allosteric effectors bound to PII. Cyanobacterial studies have also revealed that in the PII-PipX complex PipX binds an additional transcriptional factor, PlmA, thus possibly expanding PipX roles beyond NtcA-dependency. Further exploration of these roles has revealed a functional interaction of PipX with PipY, a pyridoxal-phosphate (PLP) protein involved in PLP homeostasis whose mutations in the human ortholog cause epilepsy. Knowledge of cellular levels of the different components of this PII-PipX regulatory network and of KD values for some of the complexes provides the basic background for gross modeling of the system at high and low nitrogen abundance. The cyanobacterial network can guide searches for analogous components in other organisms, particularly of PipX functional analogs.Supported by grants BFU2014-58229-P and BFU2017-84264-P from the Spanish Government

Reproductive desire in women with HIV infection in Spain, associated factors and motivations: A mixed-method study

Background: Antiretroviral therapy has created new expectations in the possibilities of procreation for persons living with HIV. Our objectives were to evaluate reproductive desire and to analyze the associated sociodemographic and clinical factors in HIV-infected women in the Spanish AIDS Research Network Cohort (CoRIS).Methods: A mixed qualitative-quantitative approach was designed. Women of reproductive age (18-45) included in CoRIS were interviewed by phone, and data were collected between November 2010 and June 2012 using a specifically designed questionnaire. Reproductive desire was defined as having a desire to be pregnant at present or having unprotected sex with the purpose of having children or wanting to have children in the near future.Results: Overall, 134 women were interviewed. Median age was 36 years (IQR 31-41), 55% were Spanish, and 35% were unemployed. 84% had been infected with HIV through unprotected sex, with a median time since diagnosis of 4.5 years (IQR 2.9-6.9). Reproductive desire was found in 49% of women and was associated with: 1) Age (women under 30 had higher reproductive desire than those aged 30-39; OR = 4.5, 95% CI 1.4-14.3); 2) having no children vs. already having children (OR = 3.2; 1.3-7.7 3); Being an immigrant (OR = 2.2; 1.0-5.0); and 4) Not receiving antiretroviral treatment (OR = 3.6; 1.1-12.1). The main reasons for wanting children were related to liking children and wanting to form a family. Reasons for not having children were HIV infection, older age and having children already. Half of the women had sought or received information about how to have a safe pregnancy, 87% had disclosed their serostatus to their family circle, and 39% reported having experienced discrimination due to HIV infection.Conclusions: The HIV-infected women interviewed in CoRIS have a high desire for children, and the factors associated with this desire are not fundamentally different from those of women in the general population. Maternity may even help them face a situation they still consider stigmatized and prefer not to disclose. Health-care protocols for handling HIV-positive women should incorporate specific interventions on sexual and reproductive health to help them fulfill their procreation desire and experience safe pregnanciesThe RIS cohort (CoRIS) is funded by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RIS C03/173

Vigilancia epidemiológica de la hepatitis B en España. Años 1997 a 2008

Se ha realizado un estudio epidemiológico descriptivo de la incidencia y mortalidad por hepatitis B en España con datos desde 1997 a 2008. Se han utilizado como fuentes de información el Sistema de Enfermedades de Declaración Obligatoria y el Sistema de Información Microbiológica, ambos integrados en la Red Nacional de Vigilancia Epidemiológica (RENAVE) junto con otras fuentes complementarias como son el Conjunto Mínimo Básico de Datos (Morbilidad Hospitalaria) y la Estadística de Causa de Muerte

Combining heart rate and systolic blood pressure to improve risk stratification in older patients with heart failure: Findings from the RICA Registry

Objectives: Heart rate (HR) and systolic blood pressure (SBP) are independent prognostic variables in patients with heart failure (HF). We evaluated if combining HR and SBP could improve prognostic assessment in older patients. Methods: Variables associated with all-cause mortality and readmission for HF during 9 months of follow-up were analyzed from the Spanish Heart Failure Registry (RICA). HR and SBP values were stratified in three combined groups. Results: We evaluated 1551 patients, 82 years and 56% women. Using HR strata of < 70 and ≥ 70 bpm we found mortality rates of 9.8 and 13.6%, respectively (hazard ratio 1.0 and 1.35). For SBP ≥ 140, 120–140 and < 120 mm Hg, mortality rates were 8.2, 10.4 and 20.3%. respectively (hazard ratio 1.0, 1.34 and 2.76). Using combined strata of HR < 70 bpm and SBP ≥ 140 mm Hg (n = 176; low-risk), HR < 70 and SBP < 140 + HR ≥ 70 and SBP < 120 (n = 1089; moderate-risk) and HR ≥ 70 and SBP < 120 (n = 286; high-risk) we found mortality rates of 4.5%, 11.0% and 24.0%, respectively. Multivariate Cox regression for all-cause mortality shows for low-, middle- and high-risk groups was 1 (reference), 1.93 (95% CI: 0.93–3.99, p = 0.077) and 4.32 (95% CI: 2.04–9.14, p < 0.001). BMI, NYHA, MDRD, hypertension and sodium were also independent prognostic factors. Conclusions: The combination provides better risk discrimination than use of HR and SBP alone and may provide a simple and reliable tool for risk assessment for older HF patients in clinical practice

The structural role of SARS-CoV-2 genetic background in the emergence and success of spike mutations: The case of the spike A222V mutation

The S:A222V point mutation, within the G clade, was characteristic of the 20E (EU1) SARS-CoV-2 variant identified in Spain in early summer 2020. This mutation has since reappeared in the Delta subvariant AY.4.2, raising questions about its specific effect on viral infection. We report combined serological, functional, structural and computational studies characterizing the impact of this mutation. Our results reveal that S:A222V promotes an increased RBD opening and slightly increases ACE2 binding as compared to the parent S:D614G clade. Finally, S:A222V does not reduce sera neutralization capacity, suggesting it does not affect vaccine effectiveness

Finding the underlying symmetries behind the fundamental components of matter

Capítulo 2.Unraveling the structure behind the components of matter and the fundamental laws governing their interactions is the ultimate goal of particle physics. One of the central questions in the Standard Model is the origin of the fermion family replication, which may point towards a hidden flavour symmetry. Many experiments will be soon addressing this issue by exploring the flavour sector with impressive sensitivities. Understanding other symmetries, such as CPT and lepton or baryon numbers, is also crucial, since their violation would have dramatic consequences for the shape of the underlying physics. Other open questions, such as the origin of the chiral character of the weak interactions, the stability of the particle that may constitute the dark matter of the Universe and the possible unification of the fundamental interactions at high energies, may also be associated to the existence of new symmetries and dynamics, possibly better described with a new mathematical language.Peer reviewe

Un ataque combinado químico, virológico, biofísico y estructural hace posible la obtención de nuevos inhibidores de entrada celular de SARS-CoV-2 y la caracterización de su mecanismo de inhibición

Resumen del trabajo presentado al 45º Congreso de la Sociedad Española de Bioquímica y Biología Molecular (SEBBM), celebrado en Zaragoza del 5 al 8 de septiembre de 2023.IBV-COVID19 Pipeline: C.Espinosa, N.Gougeard, M.P.Hernández-Sierra, A.Rubio-del-Campo, R.Ruiz-Partida, L.Villamayor.El virus SARS-CoV-2 causa el COVID-19 al infectar las células a través de la interacción de la proteína de su espícula (S) con el receptor celular enzima convertidora de angiotensina 2 (ACE2). Para buscar inhibidores de este paso clave en la infección viral, examinamos una biblioteca interna (IQM-CSIC, Madrid) de compuestos multivalentes derivados de triptófano, primero usando pseudopartículas de Virus de Estomatits Vesicular que expresaban S (I2SysBio, UV y CSIC, Valencia), identificando un compuesto como potente inhibidor de entrada no citotóxico. La optimización química (IQM-CSIC) generó otros dos potentes inhibidores de entrada no citotóxicos que, como 2, también inhibieron la entrada celular de SARS-CoV-2 genuino (I2SysBio). Los estudios con proteínas recombinantes puras (IBV-CSIC, Valencia) usando termofluor y termoforesis de microescala revelaron la unión de estos compuestos a S, y a su dominio de unión al receptor producido separadamente, probando interferencia con la interacción con ACE2. La criomicroscopía electrónica de S (IBV-CSIC), libre o unido al compuesto activo, arrojó luz sobre los mecanismos de inhibición por estos compuestos de la entrada viral a la célula. Esta actividad triinstitucional combinada ha identificado y caracterizado una nueva clase de inhibidores de entrada de SARS-CoV-2 de claro potencial preventivo o terapéutico de COVID-19.ECNextGeneration EUfund 2020/2094 de CSIC/PTI Salud Global; Crue/CSIC/Santander Fondo Supera Covid-19;CSIC-COV19-082; CIBERER-ISCIIICOV20/00437; Covid19-SCI/GValenciana (RG);PID2020- 120322RB-C21 (VR) y PID2020-116880GB-I00 (JLLl) Agenc. Estat Investig.Peer reviewe