Piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. In vitro antiviral activity evaluation against Zika and Dengue viruses.

Since 2011 Direct Acting antivirals (DAAs) drugs targeting different non-structural (NS) viral proteins (NS3, NS5A or NS5B inhibitors) have been approved for clinical use in HCV therapies. However, currently there are not licensed therapeutics to treat Flavivirus infections and the only licensed DENV vaccine, Dengvaxia, is restricted to patients with preexisting DENV immunity. Similarly to NS5 polymerase, the NS3 catalytic region is evolutionarily conserved among the Flaviviridae family sharing strong structural similarity with other proteases belonging to this family and therefore is an attractive target for the development of pan-flavivirus therapeutics. In this work we present a library of 34 piperazine-derived small molecules as potential Flaviviridae NS3 protease inhibitors. The library was developed through a privileged structures-based design and then biologically screened using a live virus phenotypic assay to determine the half-maximal inhibitor concentration (IC50) of each compound against ZIKV and DENV. Two lead compounds, 42 and 44, with promising broad-spectrum activity against ZIKV (IC50 6.6 µM and 1.9 µM respectively) and DENV (IC50 6.7 µM and 1.4 µM respectively) and a good security profile were identified. Besides, molecular docking calculations were performed to provide insights about key interactions with residues in NS3 proteases' active sites.

Crisis de los Colegios Mayores de la Universidad de Salamanca (siglos XVIII–XX). Su vinculación con la Diputación (siglo XIX) / Crisis of the Colleges of the University of Salamanca (XVIII-XX centuries). Its link with the Diputación (XIX century)

Este trabajo constituye un relato histórico de los Colegios Mayores salmantinos. Para ello, se han revisado algunos documentos existentes en el Archivo de la Universidad de Salamanca y copias notariales de documentos inéditos custodiados por la Diputación Provincial. A pesar de que la historia de estos Colegios Mayores suele formar parte de numerosos trabajos relativos a la historia de la Universidad salmantina, el examen de dichos documentos le ha permitido al autor realizar rigurosos comentarios, que aportan originalidad en el conocimiento de este tema. (AU)

This review constitutes a historical account of the Salamanca Major Colleges. To do this, some existing documents in the Archive of the University of Salamanca and notarized copies of unpublished documents kept by the Provincial Council have been reviewed. Despite the fact that the history of these Halls of Residence is usually part of the numerous works related to the history of the University of Salamanca, the examination of these documents has allowed the author to make rigurous comments that provide originality in the knowledge of this subject. (AU)

Vinculación del virólogo profesor Adolfo García Sastre con la Universidad de Salamanca y con la Real Academia Nacional de Farmacia / Relationship of the virologist professor Adolfo García Sastre with the University of Salamanca and the Royal National Academy of Pharmacy

Se detallan y comentan algunos datos biográficos relativos al virólogo Profesor Adolfo García Sastre correspondientes a su etapa como estudiante en la Facultad de Biología de la Universidad de Salamanca, durante los cursos finales de su Licenciatura (años 1981-1986), así como a los siguientes en que realizó su Tesis de Licenciatura (Tesina) en 1986, y Doctorado (1986-1990), en el Departamento de Bioquímica y Biología Molecular de dicha Facultad (Director: Prof. J.A. Cabezas); habiendo obtenido en ambas las máximas calificaciones y el Premio Extraordinario en la de Doctorado. También se resumen las líneas de investigación que cultivó en Salamanca hasta 1991 en colaboración con el director de ambas Tesis (el Profesor Titular Enrique Villar), el Profesor J.A. Cabezas y, a veces, otros. Los resultados obtenidos, así como los derivados de su breve etapa inmediata en el Instituto Pasteur de Paris, en coordinación con el Departamento salmantino, fueron publicados en revistas de Virología o de Bioquímica de gran prestigio y presentados en congresos nacionales e internacionales. Posteriormente, en su etapa americana en el Mount Sinai de Nueva York, entró en contacto con el Profesor Mariano Esteban, entonces trabajando en el Downstate Medical Center de New York, SUNY, y ambos, conjuntamente con el grupo del New York University (NYU) dirigido por Ruth Nussenweig y Fidel Zavala, llevaron a cabo experimentos seminales de inmunología que abrieron las bases a la combinación de vacunas en protocolos prime/boost y activación de linfocitos TCD8+ con resultado de alta eficacia frente a patógenos. Estos protocolos están siendo implementados en numerosos ensayos preclínicos y clínicos. La contribución del Prof. García Sastre a la ciencia está actualmente en fase exponencial, abriendo nuevos horizontes en el entendimiento de la biología molecular de virus emergentes, su patología, interacción virus-hospedador y desarrollando nuevos procedimientos de control viral. (AU)

We give some biographical details of the virologist Professor Adolfo Garcia Sastre, as a Graduate student (1981-1986) in the Biology School of University of Salamanca and during his PhD Thesis (1986-1990) in the Department of Biochemistry and Molecular Biology (Chairman Prof J.A. Cabezas), under the supervision of Prof. Enrique Villlar and obtaining the highest academic marks. The research lines that he established in collaboration with his Thesis director, with Prof. J.A Cabezas and others, as well as his results during his stay at the Pasteur Institute in Paris, are also highlighted. His findings in this period were published in prestigious Virology and Biochemistry journals and presented at national and international meetings. Thereafter, when he moved to Mount Sinai in New York, he met Prof Mariano Esteban, then working at Downstate Medical Center in New York, SUNY, and both, in collaboration with the group of Prof. Ruth Nussenzweig and Fidel Zavala at New York University, set up seminal immunological studies that are the basis for combined vaccination approaches, prime/boost and activation of CD8+ T cells, now widely used in preclinical and clinical studies. The scientific research contributions of Prof. García Sastre are growing at an exponential rate, opening new horizons in understanding the molecular biology of emerging viruses, their pathology, virus-host cell interactions and strategies of virus control. (AU)

Colaboración hispano-alemana en Bioquímica mantenida por miembros de la Real Academia Nacional de Farmacia y por otros bioquímicos españoles / Spanish-German collaboration in Biochemistry maintained by members of the Royal Academy National of Pharmacy and by other Spanish biochemists

Considerada la Bioquímica alemana como la pionera en el mundo, ya en la etapa inicial de la misma, hacia 1872, se estableció la primera vinculación entre el Profesor alemán fundador de esta disciplina, Felix von Hoppe-Seyler, y el Catedrático español de Química Orgánica Laureano Calderón Arana. Después, algunos de los Catedráticos de la recién establecida asignatura de Química Biológica, cuya enseñanza se impartía únicamente en la Facultad de Farmacia madrileña para los alumnos de Doctorado (común a Farmacia, Medicina y Ciencias), mantuvieron esta relación, aunque menos intensa, con sus colegas germanos. Pero, a partir de 1928, el que sería Premio Nobel, Dr. Severo Ochoa, trabajó durante largos periodos en prestigiosos Departamentos de Berlín y Heidelberg. Y ya en época reciente, bioquímicos pertenecientes a la Real Academia Nacional de Farmacia (RANF) han continuado esta vinculación colaborando en diversos Departamentos alemanes. Por otro lado, bioquímicos germanos han impartido conferencias en Universidades españolas, invitados por sus colegas hispanos, además de hacerlo en congresos o simposios en España. Asimismo, algunos de ellos han sido miembros de la RANF. (AU)

German can be considered as world pioneer in the development of Biochemistry. Its founder, Prof. Felix von Hoppe-Seyler, established contacts with the Spanish Professor of Organic Chemistry, Laureano Calderón Arana, since the onset of this subject around 1872. Later, some other Professors of the newly created Química Biológica, which was taught only at the Faculty of Pharmacy in Madrid as a subject common to doctoral students in Pharmacy, Medicine and Science, maintained a connection, albeit minor, with their German colleagues. From 1928, Dr. Severo Ochoa, who would subsequently win a Nobel Prize, worked for long periods in the prestigious Departments at Berlin and Heidelberg. More recently, other biochemists, members of the Royal Academy National of Pharmacy (RANF), have followed this connection with several German Departments. Furthermore, German biochemists have delivered lectures in Spanish Universities invited by their Spanish colleagues, in addition to their participation in Spanish symposia. Moreover, several German biochemists have been RANF members. (AU)

Glicoconjugados (estructura, funciones biológicas, actividad patológica, utilización terapéutica) / Glycoconjugates (structures, biological functions, pathological activity, therapeutic use)

Se conocen principalmente algunas peculiaridades funcionales, muy importantes, de los ácidos siálicos denominados N-acetilneuramínico (NeuAc) y N-glicolilneuramínico (NeuGc), por ser agentes que participan en actividades fisiológicas o en procesos patológicos cada vez más investigados en seres humanos. Dichos ácidos forman parte de los glicoconjugados. Los glicoconjugados son moléculas resultantes de la unión fuerte, covalente, entre glúcidos y proteínas o entre glúcidos y lípidos. La desregulación de la actividad de enzimas que catalizan procesos metabólicos vinculados a los glicoconjugados produce anomalías en la estructura química de estos compuestos que impiden el desarrollo normal de la correspondiente función biológica. Tales anomalías pueden afectar a las rutas biosintéticas (desórdenes congénitos de glicosilación) o a las rutas catabólicas (anomalías por almacenamiento causadas por enzimas lisosómicas). Por fortuna, actualmente se dispone de agentes que son glicoconjugados o están relacionados con ellos que facilitan la prevención o la curación de enfermedades como la gripe, el SIDA, el cáncer, etc. Últimamente se ha intensificado la investigación con finalidad terapéutica mediante nuevos enfoques inmunológicos o genéticos relativos a los glicoconjugados, según se indica en este artículo. (AU)

Mainly N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc) exhibit very important peculiarities in certain biological (both physiological and pathological) processes. These acids are components of the glycoconjugates. Glycoconjugates are molecules resulting of the covalent link between carbohydrates and proteins or between carbohydrates and lipids. The disregulation of enzymes which catalyse the metabolic processess related to glycoconjugates produces anomalies in the chemical structure of these compounds which preclude their normal biological function, by abnormalities in the biosynthetic route (Congenital Disorders of Glycosylation) or abnormalities in the catabolic way (Lysosomal Storage Disorders). Fortunately, several agents related to glycoconjugates are now available to prevent or heal illness such as influenza, AIDS, cancer, etc. In this wiew, the research on immunological and genetic features of glycoconjugates with a therapeutic finality has been recently increased, as shown in this paper. (AU)

Components of case management in caring for patients with dementia: a mixed-methods study.

BACKGROUND: Case management has shown improvements in some health outcomes for dementia patients and their families. However, despite its benefits the components of case management in order to provide effective patient and family care remain unknown at present. Thus, the aim of this study is to identify the specific components of case management in caring for patients with dementia and to determine the necessary intensity of its deployment to enhance outcomes for these patients and their caregivers. METHODS: Mixed-methods study with a qualitative phase to characterise forms of service provision, according to the case management components involved, followed by a quantitative phase to analyse the correlations between different patterns of service provision, adverse events in patients and caregiver overload. This study will be based on the variables described in the RANGE.COM register. DISCUSSION: This research is expected to achieve a reproducible, evaluable set of interventions that can be modelled to optimise case management effectiveness for patients with dementia. Interactions between patients with dementia, their family caregivers and case management healthcare services, the components of these interactions and their association with the conditions of the individuals concerned are issues of great interest in the field of case management, which is constantly evolving.

Prediction of platelet counts with ROTEM-sigma in cardiac surgery.

BACKGROUND: Excessive bleeding is common after cardiac surgery. According to transfusion algorithms based on ROTEM results (TEM International Inc., Munich, Germany), platelet transfusion is recommended when FIBTEM amplitude is normal and EXTEM amplitude is reduced. The aim of this study was to evaluate whether ROTEM (TEM International Inc.) parameters may predict accurately platelet counts in cardiac surgery patients, and to determine which of these parameters is the most useful for predicting platelet counts. METHODS: In this retrospective single center study data from 83 patients who underwent cardiac surgery were reviewed. We analyzed the results of patients for whom ROTEM (TEM International Inc.) and conventional laboratory tests were performed simultaneously. The derived ROTEM (TEM International Inc.) parameter PLTEM was used to estimate platelet count; PLTEM is calculated by subtracting FIBTEM from EXTEM. Correlation between ROTEM (TEM International Inc.) variables and platelet counts were determined. Logistic regression analyses were performed to predict platelet counts. RESULTS: ROTEM A5 values show a high linear correlation with MCF values. PLTEM has a strong linear correlation with platelet counts. According to our results for PLTEM A5<32 mm the probability of platelet count <150×109/L is 100%, for PLTEM A5<27 mm the probability of platelet count <100×109/L is nearly 80%, and for PLTEM A5<22 the probability of platelet count <75×109/L is 70%. CONCLUSIONS: This study demonstrates the reliability of considering early ROTEM (TEM International Inc.) results and the feasibility of using PLTEM A5 to predict platelet counts and so, improve our ability to decide the need of platelet transfusion in cardiac surgery patients.

Intraoperative complexity and risk factors associated with conversion to open surgery during laparoscopic cholecystectomy in eight hospitals in Mexico City.

BACKGROUND: The conversion to open surgery (COS) during the Laparoscopic Cholecystectomy (LC) is reported to occur at a rate of 10-15%. Some preoperative risk factors (RF) have been postulated; however, few studies have evaluated these factors and the intraoperative complexity with the COS rate. The aim of the study was to evaluate the preoperative RF and intraoperative complexity using the Parkland grading scale (PGS) with the COS rate in LC. METHODS: A retrospective study was done evaluating the demographic and surgical variables from the patients and LC videos from 8 different hospitals of Mexico City from December 2018 to January 2020. The evaluation of the PGS was done by 2 surgeons (one MI and one HPB surgeon); the PGS was also categorized as Non-Complex LC (nCLC, PGS1-2) and Complex LC (CLC, PGS 3-5). Logistic regression was used to evaluate the association of this factors with the COS rate. RESULTS: 430 LC were analyzed; 358 (78.61%) were women, 261 (60.7%) were elective and 169(39.3%) urgent LC, the mean age was 44.06 (SD ± 13.16) years. 21 (4.8%) LC were COS; the mean age of this group was 55 (SD ± 12.95), 3 (0.7%) were nCLC and 18 (4.19%) CLC, mean PGS of 3.76 (SD ± 1.09), the mean time to COS was 48.67 (SD ± 41.9), the estimated blood loss (EBL) was 258 (SD ± 260.22) and 6 (1.4%) intraoperative BDI were recognized on this group. Univariate analysis showed a significant association with the COS with male sex, older age, age > 45 years, presence of comorbidities, a higher PGS, a CLC, higher EBL and possible BDI; multivariate analysis produced a model using male sex, age, presence of comorbidities and a CLC with a 0.809 area under the ROC curve. CONCLUSION: The recognition of the associated RF and a CLC can guide the surgeon to establish preoperative and bailout strategies during the procedure, recognizing a higher risk of COS and its higher morbidity.

Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation.

The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m2), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.

Crisis de los Colegios Mayores de la Universidad de Salamanca (siglos XVIII–XX). Su vinculación con la Diputación (siglo XIX) / Crisis of the Colleges of the University of Salamanca (XVIII-XX centuries). Its link with the Diputación (XIX century)

Este trabajo constituye un relato histórico de los Colegios Mayores salmantinos. Para ello, se han revisado algunos documentos existentes en el Archivo de la Universidad de Salamanca y copias notariales de documentos inéditos custodiados por la Diputación Provincial. A pesar de que la historia de estos Colegios Mayores suele formar parte de numerosos trabajos relativos a la historia de la Universidad salmantina, el examen de dichos documentos le ha permitido al autor realizar rigurosos comentarios, que aportan originalidad en el conocimiento de este tema. (AU)

This review constitutes a historical account of the Salamanca Major Colleges. To do this, some existing documents in the Archive of the University of Salamanca and notarized copies of unpublished documents kept by the Provincial Council have been reviewed. Despite the fact that the history of these Halls of Residence is usually part of the numerous works related to the history of the University of Salamanca, the examination of these documents has allowed the author to make rigurous comments that provide originality in the knowledge of this subject. (AU)

White Button Mushroom Extracts Modulate Hepatic Fibrosis Progression, Inflammation, and Oxidative Stress In Vitro and in LDLR-/- Mice.

Liver fibrosis can be caused by non-alcoholic steatohepatitis (NASH), among other conditions. We performed a study to analyze the effects of a nontoxic, water-soluble extract of the edible mushroom Agaricus bisporus (AB) as a potential inhibitor of fibrosis progression in vitro using human hepatic stellate cell (LX2) cultures and in vivo in LDLR-/- mice. Treatment of LX2 cells with the AB extract reduced the levels of fibrotic and oxidative-related markers and increased the levels of GATA4 expression. In LDLR-/- mice with high-fat diet (HFD)-induced liver fibrosis and inflammation, the progression of fibrosis, oxidative stress, inflammation, and apoptosis were prevented by AB extract treatment. Moreover, in the mouse model, AB extract could exert an antiatherogenic effect. These data suggest that AB mushroom extract seems to exert protective effects by alleviating inflammation and oxidative stress during the progression of liver fibrosis, possibly due to a decrease in Toll-like receptor 4 (TLR4) expression and a reduction in Nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we observed a potential atheroprotective effect in our mouse model.

Explanatory Factors of Burnout in a Sample of Workers with Disabilities from the Special Employment Centres (SEC) of the Amica Association, Spain.

BACKGROUND: we have based our study on the fact that the labour market is progressively becoming more accessible for people with disabilities. This investigation aims to identify the factors that contribute to high levels of work-related stress in a group of disabled individuals in order to develop policies to prevent it and promote the health of the workforce. METHODS: 131 workers from two Special Employment Centres (SECs) of the Amica Association in Cantabria (Spain) participated in the study. Sociodemographic and job-related variables were collected using a questionnaire. Work-related stress was evaluated using the Maslach Burnout Inventory General Survey (MBI-GS), which analyzes emotional exhaustion, cynicism and personal efficacy. RESULTS: the main explanatory factors for higher levels of emotional exhaustion were more than 5 years of service in the company (OR 3.235-IC 95% 1.392-7.519; p = 0.006) and bad job satisfaction (OR 7.615-IC 95% 2.467-23.503; p = 0.0001); higher levels of cynicism were also explained by bad job satisfaction (OR 8.599-IC 95% 2.481-29.799; p = 0.001). CONCLUSIONS: future research is needed to facilitate the design of company policies and promote the well-being of the disabled population in the workplace, to avoid pathological conditions such as burnout syndrome.

Vinculación del virólogo profesor Adolfo García Sastre con la Universidad de Salamanca y con la Real Academia Nacional de Farmacia / Relationship of the virologist professor Adolfo García Sastre with the University of Salamanca and the Royal National Academy of Pharmacy

Se detallan y comentan algunos datos biográficos relativos al virólogo Profesor Adolfo García Sastre correspondientes a su etapa como estudiante en la Facultad de Biología de la Universidad de Salamanca, durante los cursos finales de su Licenciatura (años 1981-1986), así como a los siguientes en que realizó su Tesis de Licenciatura (Tesina) en 1986,y Doctorado (1986-1990), en el Departamento de Bioquímica y Biología Molecular de dicha Facultad (Director: Prof.J.A. Cabezas); habiendo obtenido en ambas las máximas calificaciones y el Premio Extraordinario en la de Doctorado. También se resumen las líneas de investigación que cultivó en Salamanca hasta 1991 en colaboración con el director de ambas Tesis (el Profesor Titular Enrique Villar), el Profesor J.A. Cabezas y, a veces, otros. Los resultados obtenidos, así como los derivados de su breve etapa inmediata en el Instituto Pasteur de Paris, en coordinación con el Departamentos almantino, fueron publicados en revistas de Virología o de Bioquímica de gran prestigio y presentados en congresos nacionales e internacionales. Posteriormente, en su etapa americana en el Mount Sinai de Nueva York, entró en contacto con el Profesor Mariano Esteban, entonces trabajando en el Down state Medical Center de New York, SUNY, y ambos, conjuntamente con el grupo del New York University (NYU) dirigido por Ruth Nussenweig y Fidel Zavala, llevaron a cabo experimentos seminales de inmunología que abrieron las bases a la combinación de vacunas en protocolos prime/boosty activación de linfocitos TCD8+ con resultado de alta eficacia frente a patógenos. Estos protocolos están siendo implementados en numerosos ensayos preclínicos y clínicos. La contribución del Prof. García Sastre a la ciencia está actualmente en fase exponencial, abriendo nuevos horizontes en el entendimiento de la biología molecular de virus emergentes, su patología, interacción virus-hospedador y desarrollando nuevos procedimientos de control viral

Se detallan y comentan algunos datos biográficos relativos al virólogo Profesor Adolfo García Sastre correspondientes in the Biology School of University of Salamanca and during his PhD Thesis (1986-1990) in the Department of Biochemistry and Molecular Biology (Chairman Prof J.A. Cabezas), under the supervision of Prof. Enrique Villlar and obtaining the highest academic marks. The research lines that he established in collaboration with his Thesis director, with Prof.J.A Cabezas and others, as well as his results during his stay at the Pasteur Institute in Paris, are also highlighted. His findings in this period were published in prestigious Virology and Biochemistry journals and presented at national and international meetings. Thereafter, when he moved to Mount Sinai in New York, he met Prof Mariano Esteban, then working at Downstate Medical Center in New York, SUNY, and both, in collaboration with the group of Prof. Ruth Nus-senzweig and Fidel Zavala at New York University, set up seminal immunological studies that are the basis for combined vaccination approaches, prime/boost and activation of CD8+ T cells, now widely used in preclinical and clinical studies. The scientific research contributions of Prof. García Sastre are growing at an exponential rate, opening new horizon sin understanding the molecular biology of emerging viruses, their pathology virus-host cell interactions and strategies of virus control

Delta-gamma phase-amplitude coupling as a biomarker of postictal generalized EEG suppression.

Postictal generalized EEG suppression is the state of suppression of electrical activity at the end of a seizure. Prolongation of this state has been associated with increased risk of sudden unexpected death in epilepsy, making characterization of underlying electrical rhythmic activity during postictal suppression an important step in improving epilepsy treatment. Phase-amplitude coupling in EEG reflects cognitive coding within brain networks and some of those codes highlight epileptic activity; therefore, we hypothesized that there are distinct phase-amplitude coupling features in the postictal suppression state that can provide an improved estimate of this state in the context of patient risk for sudden unexpected death in epilepsy. We used both intracranial and scalp EEG data from eleven patients (six male, five female; age range 21-41 years) containing 25 seizures, to identify frequency dynamics, both in the ictal and postictal EEG suppression states. Cross-frequency coupling analysis identified that during seizures there was a gradual decrease of phase frequency in the coupling between delta (0.5-4 Hz) and gamma (30+ Hz), which was followed by an increased coupling between the phase of 0.5-1.5 Hz signal and amplitude of 30-50 Hz signal in the postictal state as compared to the pre-seizure baseline. This marker was consistent across patients. Then, using these postictal-specific features, an unsupervised state classifier-a hidden Markov model-was able to reliably classify four distinct states of seizure episodes, including a postictal suppression state. Furthermore, a connectome analysis of the postictal suppression states showed increased information flow within the network during postictal suppression states as compared to the pre-seizure baseline, suggesting enhanced network communication. When the same tools were applied to the EEG of an epilepsy patient who died unexpectedly, ictal coupling dynamics disappeared and postictal phase-amplitude coupling remained constant throughout. Overall, our findings suggest that there are active postictal networks, as defined through coupling dynamics that can be used to objectively classify the postictal suppression state; furthermore, in a case study of sudden unexpected death in epilepsy, the network does not show ictal-like phase-amplitude coupling features despite the presence of convulsive seizures, and instead demonstrates activity similar to postictal. The postictal suppression state is a period of elevated network activity as compared to the baseline activity which can provide key insights into the epileptic pathology.

Transitions between neocortical seizure and non-seizure-like states and their association with presynaptic glutamate release.

The transition between seizure and non-seizure states in neocortical epileptic networks is governed by distinct underlying dynamical processes. Based on the gamma distribution of seizure and inter-seizure durations, over time, seizures are highly likely to self-terminate; whereas, inter-seizure durations have a low chance of transitioning back into a seizure state. Yet, the chance of a state transition could be formed by multiple overlapping, unknown synaptic mechanisms. To identify the relationship between the underlying synaptic mechanisms and the chance of seizure-state transitions, we analyzed the skewed histograms of seizure durations in human intracranial EEG and seizure-like events (SLEs) in local field potential activity from mouse neocortical slices, using an objective method for seizure state classification. While seizures and SLE durations were demonstrated to have a unimodal distribution (gamma distribution shape parameter >1), suggesting a high likelihood of terminating, inter-SLE intervals were shown to have an asymptotic exponential distribution (gamma distribution shape parameter <1), suggesting lower probability of cessation. Then, to test cellular mechanisms for these distributions, we studied the modulation of synaptic neurotransmission during, and between, the in vitro SLEs. Using simultaneous local field potential and whole-cell voltage clamp recordings, we found a suppression of presynaptic glutamate release at SLE termination, as demonstrated by electrically- and optogenetically-evoked excitatory postsynaptic currents (EPSCs), and focal hypertonic sucrose application. Adenosine A1 receptor blockade interfered with the suppression of this release, changing the inter-SLE shape parameter from asymptotic exponential to unimodal, altering the chance of state transition occurrence with time. These findings reveal a critical role for presynaptic glutamate release in determining the chance of neocortical seizure state transitions.

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging.

Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2ß, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice. Fibrotic, lipid, and oxidative reduction in liver tissues of mice was more pronounced in those old KO NLRP3 mice than in the younger ones, despite their greater liver damage. These results suggest that absence of the NLRP3 inflammasome attenuates age-related liver fibrotic pathology in mice, suggesting that pharmacological targeting may be beneficial.

Colaboración hispano-alemana en Bioquímica mantenida por miembros de la Real Academia Nacional de Farmacia y por otros bioquímicos españoles / Spanish-German collaboration in Biochemistry maintained by members of the Royal Academy National of Pharmacy and by other Spanish biochemists

Considerada la Bioquímica alemana como la pionera en el mundo, ya en la etapa inicial de la misma, hacia 1872, se estableció la primera vinculación entre el Profesor alemán fundador de esta disciplina, Felix von Hoppe-Seyler, y el Catedrático español de Química Orgánica Laureano Calderón Arana. Después, algunos de los Catedráticos de la recién establecida asignatura de Química Biológica, cuya enseñanza se impartía únicamente en la Facultad de Farmacia madrileña para los alumnos de Doctorado (común a Farmacia, Medicina y Ciencias), mantuvieron esta relación, aunque menos intensa, con sus colegas germanos. Pero, a partir de 1928, el que sería Premio Nobel, Dr. Severo Ochoa, trabajó durante largos periodos en prestigiosos Departamentos de Berlín y Heidelberg. Y ya en época reciente, bioquímicos pertenecientes a la Real Academia Nacional de Farmacia (RANF) han continuado esta vinculación colaborando en diversos Departamentos alemanes. Por otro lado, bioquímicos germanos han impartido conferencias en Universidades españolas, invitados por sus colegas hispanos, además de hacerlo en congresos o simposios en España. Asimismo, algunos de ellos han sido miembros de la RANF

German can be considered as world pioneer in the development of Biochemistry. Its founder, Prof. Felix von Hoppe-Seyler, established contacts with the Spanish Professor of Organic Chemistry, Laureano Calderón Arana, since the onset of this subject around 1872. Later, some other Professors of the newly created Química Biológica, which was taught only at the Faculty of Pharmacy in Madrid as a subject common to doctoral students in Pharmacy, Medicine and Science, maintained a connection, albeit minor, with their German colleagues. From 1928, Dr. Severo Ochoa, who would subsequently win a Nobel Prize, worked for long periods in the prestigious Departments at Berlin and Heidelberg. More recently, other biochemists, members of the Royal Academy National of Pharmacy (RANF), have followed this connection with several German Departments. Furthermore, German biochemists have delivered lectures in Spanish Universities invited by their Spanish colleagues, in addition to their participation in Spanish symposia. Moreover, several German biochemists have been RANF members