Fat-specific FUS-DDIT3-transgenic mice establish PPARgamma inactivation is required to liposarcoma development.

Peer reviewe

Origin of the Urease Inhibition of Metschnikowia pulcherrima Extracts: Comparative Assays with Synthetic Pulcherriminic Acid and Cyclo-dileucine

The objective of this work was to determine whether pulcherriminic acid was responsible for the urease inhibition activity of the extracts of the yeast Metschnikowia pulcherrima. Pulcherriminic acid was synthesized through a seven-step pathway from l-leucine, starting with the thermal cyclodimerization of l-leucine to the corresponding 2,5-diketopiperazine, followed by oxidation to the 2,5-dichloropyrazine through three consecutive steps without purification of the intermediates, oxidation to the corresponding di-N-oxide, dechlorination by nucleophilic aromatic substitution with benzyloxide, and deprotection with trifluoroacetic acid without isolation of an intermediate. The urease inhibition assay showed 57 ± 2.3% inhibition of the urease activity at 500 ppm of pulcherriminic acid, much lower than the percent inhibition obtain with the extract, in which pulcherriminic acid was not detected. The cyclic dimer of l-leucine was present in the extract, and its inhibitory capacity was also tested, showing a percent inhibition of 56.1 ± 6.11% of the urease activity at 400 ppm, again much lower than the percent inhibition of the extract. This work demonstrates that the inhibitory capacity of the extracts of the yeast M. pulcherrima is not due to either only pulcherriminic acid or only its cyclic dipeptide precursor

Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain

The development of clinica lpractice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance withr regard to adverse drug reactions.The poten-tial of pharmacogenomicbiomarkers has been extensively investigated in recent years.However,several barriers to implementing the use of pharmacogenomics testing exist.We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of majorgene/drug pairs.Of 11 potential barriers,the highest importance was attributed to lack of institutional support for pharmacogenomic stesting,and to the issues related to the lack of guidelines.Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen.In this perspective article,we compare the relative importance of 29 gene/drugpairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutic sstudy,and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testingThe work in the author’s laboratory is financed by Grants PS09/00943, PS09/00469, RETICS RIRAAF RD07/0064/0016, and CIBERehd from Instituto de Salud CarlosIII,Madrid, Spain, and by Grants GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Unio

The mechanistic foundation of Weber’s law

[Abstract] Although Weber's law is the most firmly established regularity in sensation, no principled way has been identified to choose between its many proposed explanations. We investigated Weber's law by training rats to discriminate the relative intensity of sounds at the two ears at various absolute levels. These experiments revealed the existence of a psychophysical regularity, which we term time-intensity equivalence in discrimination (TIED), describing how reaction times change as a function of absolute level. The TIED enables the mathematical specification of the computational basis of Weber's law, placing strict requirements on how stimulus intensity is encoded in the stochastic activity of sensory neurons and revealing that discriminative choices must be based on bounded exact accumulation of evidence. We further demonstrate that this mechanism is not only necessary for the TIED to hold but is also sufficient to provide a virtually complete quantitative description of the behavior of the rats

The architectural drawing: a method of building analysis, a study of unique buildings

The aim of this educational innovation project is the study of the interesting building. In this case the exercises are focused in those similar tasks being currently performed by professionals. The detailed study of a building makes easier the understanding of it, as well as to analyze the building in all its dimensions. First of all, an initial assessment about knowledge and skills of the new students will be performed for the purpose of achieving an optimal adaptation. 1.-The Goals are: Study and analysis of interesting buildings ; Building as a study element for the future professionals in Building ; Analysis of the building elements like educational models, and documentation to be issued for educational purposes. 2. Description of the project and outcome phases Actions: An architectural survey (elevations and sections) of the Unique buildings will be produced ; - The selected buildings will be a nalyzed by producing the plans. Our plan is to use these types of activities to make the students perform similar works to those performed by professionals. In order to encourage the student s to participate in the educational process the following activities are proposed: a) With the aim students can get a better understanding on their achievements we address: - To do a self assessment; -To evaluate the exercises of other mates; -To comment corrections in public presentations; b) To motivate students for documenting the different topics of the subject program ; c) To identify practical exercises; d) To produce practical exercises; e) To increase the awareness of the students at the required exigency level as well as to be aware of their own failures; f) To gain a clear view of the objectives; g) To get a higher level of involvement and participation by the students; h) To acquire skills on finding and selecting, with valuable criteria the useful sources of information; i) To propose the elaboration of a monographic work to be realized in a team of students; j) To computerize the studied models for their publication in the existing educational platforms for the students. A subsequent application of them in the learning program of the Architectural Drawing I and II subjects ; k) To produce open information repositories to be available in the educational platforms. 3. Expected results: To improve and promote the team work in order to increase the exchange of knowledge’s and promote the integration of students in their future professional life. Incorporation of new t echnologies in the learning by: Applying new educational and assessment methodologies to be applied to the students and their works. We intend to continue progressing towards the convergence to the European Space of Higher Education. - The study of singular buildings and their realization on technical drawings by using learning systems with progressive difficulty level; This will allow extending the exercises in the program subject in the area of technical drawing systems and plans survey. This will help the student to know his city and is excellent way of helping us to bring students closer to the professional work, and thus making easier access to a job. What it is the fundamental objective of the university studies

The architectural drawing: a method of building analysis, a study of unique buildings

The aim of this educational innovation project is the study of the interesting building. In this case the exercises are focused in those similar tasks being currently performed by professionals. The detailed study of a building makes easier the understanding of it, as well as to analyze the building in all its dimensions. First of all, an initial assessment about knowledge and skills of the new students will be performed for the purpose of achieving an optimal adaptation. 1.-The Goals are: Study and analysis of interesting buildings ; Building as a study element for the future professionals in Building ; Analysis of the building elements like educational models, and documentation to be issued for educational purposes. 2. Description of the project and outcome phases Actions: An architectural survey (elevations and sections) of the Unique buildings will be produced ; - The selected buildings will be a nalyzed by producing the plans. Our plan is to use these types of activities to make the students perform similar works to those performed by professionals. In order to encourage the student s to participate in the educational process the following activities are proposed: a) With the aim students can get a better understanding on their achievements we address: - To do a self assessment; -To evaluate the exercises of other mates; -To comment corrections in public presentations; b) To motivate students for documenting the different topics of the subject program ; c) To identify practical exercises; d) To produce practical exercises; e) To increase the awareness of the students at the required exigency level as well as to be aware of their own failures; f) To gain a clear view of the objectives; g) To get a higher level of involvement and participation by the students; h) To acquire skills on finding and selecting, with valuable criteria the useful sources of information; i) To propose the elaboration of a monographic work to be realized in a team of students; j) To computerize the studied models for their publication in the existing educational platforms for the students. A subsequent application of them in the learning program of the Architectural Drawing I and II subjects ; k) To produce open information repositories to be available in the educational platforms. 3. Expected results: To improve and promote the team work in order to increase the exchange of knowledge’s and promote the integration of students in their future professional life. Incorporation of new t echnologies in the learning by: Applying new educational and assessment methodologies to be applied to the students and their works. We intend to continue progressing towards the convergence to the European Space of Higher Education. - The study of singular buildings and their realization on technical drawings by using learning systems with progressive difficulty level; This will allow extending the exercises in the program subject in the area of technical drawing systems and plans survey. This will help the student to know his city and is excellent way of helping us to bring students closer to the professional work, and thus making easier access to a job. What it is the fundamental objective of the university studies

Activation of p21 limits acute lung injury and induces early senescence after acid aspiration and mechanical ventilation

The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir/ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an anti-apoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence

Integrating clinical, molecular, proteomic and histopathological data within the tissue context : tissunomics

Malignant tumours show a marked degree of morphological, molecular and proteomic heterogeneity. This variability is closely related to microenvironmental factors and the location of the tumour. The activation of genetic alterations is very tissue-dependent and only few tumours have distinct genetic alterations. Importantly, the activation state of proteins and signaling factors is heterogeneous in the primary tumour and in metastases and recurrences. The molecular diagnosis based only on genetic alterations can lead to treatments with unpredictable responses, depending on the tumour location, such as the tumour response in melanomas versus colon carcinomas with mutations. Therefore, we understand that the correct evaluation of tumours requires a system that integrates both morphological, molecular and protein information in a clinical and pathological context, where intratumoral heterogeneity can be assessed. Thus, we propose the term 'tissunomics', where the diagnosis will be contextualised in each tumour based on the complementation of the pathological, molecular, protein expression, environmental cells and clinical data

Acceptance and knowledge of evolutionary theory among third-year university students in Spain

The theory of evolution is one of the greatest scientific achievements in the intellectual history of humankind, yet it is still contentious within certain social groups. Despite being as robust and evidence-based as any other notable scientific theory, some people show a strong reluctance to accept it. In this study, we used the Measure of Acceptance of the Theory of Evolution (MATE) and Knowledge of Evolution Exam (KEE) questionnaires with university students from four academic degree programs (Chemistry, English, History, and Biology) of ten universities from Spain to measure, respectively, acceptance and knowledge of evolutionary theory among third-year undergraduate students (nMATE = 978; nKEE = 981). Results show that acceptance of evolution is relatively high (87.2%), whereas knowledge of the theory is moderate (5.4 out of 10) although there are differences across degrees (Biology>Chemistry>History>English), and even among various universities (ranging from 4.71 to 5.81). Statistical analysis reveals that knowledge of evolutionary theory among Biology students is partially explained by the relative weight of evolutionary themes within the curriculum, suggesting that an increase in the number of hours dedicated to this topic could have a direct influence on students’ knowledge of it. We also found that religion may have a significant—although relatively small—negative influence on evolutionary theory acceptance. The moderate knowledge of evolution in our undergraduate students, together with the potential problem of acceptance in certain groups, suggests the need for a revision of the evolutionary concepts in the teaching curricula of our students since primary school.This work was supported by Xunta de Galicia (ED431C 2016-037), FONDOS FEDER (“unha maneira de facer Europa”), and Spain’s Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (CGL2016-75904-C2-1-P), Dr. Emilio Rolán-Alvarez

Real-life outcomes in biotypes of psychotic disorders based on neurocognitive performance

Producción CientíficaAiming at discerning potential biotypes within the psychotic syndrome, we have recently reported the possible existence of two clusters or biotypes across schizophrenia and bipolar disorder characterized by their cognitive performance using the Brief Assessment of Cognition in Schizophrenia (BACS) instrument and validated with independent biological and clinical indexes (Fernández-Linsenbarth et al. in Schizophr Res 229:102–111, 2021). In this previous work, the group with larger cognitive deficits (N = 93, including 69 chronic schizophrenia, 17 first episodes (FE) of schizophrenia and 7 bipolar disorder patients) showed smaller thalamus and hippocampus volume and hyper-synchronic electroencephalogram than the group with milder deficits (N = 105, including 58 chronic schizophrenia, 25 FE and 22 bipolar disorder patients). We predicted that if these biotypes indeed corresponded to different cognitive and biological substrates, their adaptation to real life would be different. To this end, in the present work we have followed up the patients’ population included in that work at 1st and 3rd years after the date of inclusion in the 2021 study and we report on the statistical comparisons of each clinical and real-life outcomes between them. The first cluster, with larger cognitive deficits and more severe biological alterations, showed during that period a decreased capacity for job tenure (1st and 3rd years), more admissions to a psychiatric ward (1st year) and a higher likelihood for quitting psychiatric follow-up (3rd year). Patients in the second cluster, with moderate cognitive deficits, were less compliant with prescribed treatment at the 3rd year. The differences in real-life outcomes may give additional external validity to that yielded by biological measurements to the described biotypes based on neurocognition.Instituto de Salud Carlos III (grant ID PI18/00178)Dirección Regional de Salud de Castilla y León (grant ID GRS 2121/A/2020)Junta de Castilla y León - predoctoral grants from the Consejería de Educación and the European Social Fund (grant IDs VA-183-18 to IFL and VA- 223-19 to RMBRS)Publicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCL