Mixed Reality for a collective and adaptive mental health metaverse.

This research paper explores the significant transformative potential of Mixed Reality (MR) technology as enabler of the metaverse, specifically aimed at enhancing mental health therapies. The emerging world of the metaverse, a multiuser, adaptive, three-dimensional digital space, paired with the interactive and immersive benefits of MR technology, promises a paradigm shift in how mental health support is delivered. Unlike traditional platforms, MR allows for therapy within the comfort of the user's familiar surroundings, while incorporating the benefits of social collaboration and interactions. The metaverse environment fosters heightened personalization and deeper user engagement, thereby offering a more tailored approach to computerized therapy. Beyond its immersive capabilities, MR offers potential for real-time, smart adaptations to the users' psycho-physiological state, targeting unique patients' needs on a diverse spectrum of therapeutic techniques, thus broadening the scope of mental health support. Furthermore, it opens avenues for continuous emotional support in everyday life situations. This research discusses the benefits and potentials of integrating MR within a mental health metaverse, highlighting how this innovative approach could significantly complement traditional therapeutic methods, fostering improved treatment efficacy, focusing on social and collective experiences, and increasing patient engagement.

Different Markov chains modulate visual stimuli processing in a Go-Go experiment in 2D, 3D, and augmented reality.

The introduction of Augmented Reality (AR) has attracted several developments, although the people's experience of AR has not been clearly studied or contrasted with the human experience in 2D and 3D environments. Here, the directional task was applied in 2D, 3D, and AR using simplified stimulus in video games to determine whether there is a difference in human answer reaction time prediction using context stimulus. Testing of the directional task adapted was also done. Research question: Are the main differences between 2D, 3D, and AR able to be predicted using Markov chains? Methods: A computer was fitted with a digital acquisition card in order to record, test and validate the reaction time (RT) of participants attached to the arranged RT for the theory of Markov chain probability. A Markov chain analysis was performed on the participants' data. Subsequently, the way certain factors influenced participants RT amongst the three tasks time on the accuracy of the participants was sought in the three tasks (environments) were statistically tested using ANOVA. Results: Markov chains of order 1 and 2 successfully reproduced the average reaction time by participants in 3D and AR tasks, having only 2D tasks with the variance predicted with the current state. Moreover, a clear explanation of delayed RT in every environment was done. Mood and coffee did not show significant differences in RTs on a simplified videogame. Gender differences were found in 3D, where endogenous directional goals are in 3D, but no gender differences appeared in AR where exogenous AR buttons can explain the larger RT that compensate for the gender difference. Our results suggest that unconscious preparation of selective choices is not restricted to current motor preparation. Instead, decisions in different environments and gender evolve from the dynamics of preceding cognitive activity can fit and improve neurocomputational models.

The Spheres & Shield Maze Task: A Virtual Reality Serious Game for the Assessment of Risk Taking in Decision Making.

Risk taking (RT) is an essential component in decision-making process that depicts the propensity to make risky decisions. RT assessment has traditionally focused on self-report questionnaires. These classical tools have shown clear distance from real-life responses. Behavioral tasks assess human behavior with more fidelity, but still show some limitations related to transferability. A way to overcome these constraints is to take advantage from virtual reality (VR), to recreate real-simulated situations that might arise from performance-based assessments, supporting RT research. This article presents results of a pilot study in which 41 individuals explored a gamified VR environment: the Spheres & Shield Maze Task (SSMT). By eliciting implicit behavioral measures, we found relationships between scores obtained in the SSMT and self-reported risk-related constructs, as engagement in risky behaviors and marijuana consumption. We conclude that decontextualized Virtual Reality Serious Games are appropriate to assess RT, since they could be used as a cross-disciplinary tool to assess individuals' capabilities under the stealth assessment paradigm.

Virtual Reality as a New Approach for Risk Taking Assessment.

Understanding how people behave when facing hazardous situations, how intrinsic and extrinsic factors influence the risk taking (RT) decision making process and to what extent it is possible to modify their reactions externally, are questions that have long interested academics and society in general. In the spheres, among others, of Occupational Safety and Health (OSH), the military, finance and sociology, this topic has multidisciplinary implications because we all constantly face RT situations. Researchers have hitherto assessed RT profiles by conducting questionnaires prior to and after the presentation of stimuli; however, this can lead to the production of biased, non-realistic, RT profiles. This is due to the reflexive nature of choosing an answer in a questionnaire, which is remote from the reactive, emotional and impulsive decision making processes inherent to real, risky situations. One way to address this question is to exploit VR capabilities to generate immersive environments that recreate realistic seeming but simulated hazardous situations. We propose VR as the next-generation tool to study RT processes, taking advantage of the big four families of metrics which can provide objective assessment methods with high ecological validity: the real-world risks approach (high presence VR environments triggering real-world reactions), embodied interactions (more natural interactions eliciting more natural behaviors), stealth assessment (unnoticed real-time assessments offering efficient behavioral metrics) and physiological real-time measurement (physiological signals avoiding subjective bias). Additionally, VR can provide an invaluable tool, after the assessment phase, to train in skills related to RT due to its transferability to real-world situations.

A new dromiid crab (Crustacea, Brachyura, Dromioidea) from the Upper Eocene of Huesca (Aragón, northern Spain).

A new genus and species of brachyuran crab from the Upper Eocene (Priabonian) strata in Basa Valley (Huesca, northern Spain) assignable to the superfamily Dromioidea, Basadromia longifrons n. gen., n. sp., adds to current knowledge of the morphological diversity and geographical-stratigraphical distribution of the superfamily. The main characters of the new form, such as the orbitofrontal construction with two median teeth and an rostral tooth situated in a lower plane, two minor frontal (inner orbital) teeth, well-marked cervical and branchial grooves, general carapace outline, and the shape and distribution of dorsal regions, confirm placement in Dromioidea. Unique features, such as the four conspicuous frontal teeth, lateral margins of carapace with small, subtle spines, the reduced length of the posterior margin, disposition of dorsal grooves, and peculiar shape and distribution of the dorsal regions (mainly protogastric and epibranchial), warrants the erection of a new genus and new species. In the absence of ventral features the new taxon is tentatively assigned to the family Dromiidae after detailed comparison with both fossil and extant members.

Computer-aided structure-based design of multitarget leads for Alzheimer's disease.

Alzheimer's disease is a neurodegenerative pathology with unmet clinical needs. A highly desirable approach to this syndrome would be to find a single lead that could bind to some or all of the selected biomolecules that participate in the amyloid cascade, the most accepted route for Alzheimer disease genesis. In order to circumvent the challenge posed by the sizable differences in the binding sites of the molecular targets, we propose a computer-assisted protocol based on a pharmacophore and a set of required interactions with the targets that allows for the automated screening of candidates. We used a combination of docking and molecular dynamics protocols in order to discard nonbinders, optimize the best candidates, and provide a rationale for their potential as inhibitors. To provide a proof of concept, we proceeded to screen the literature and databases, a task that allowed us to identify a set of carbazole-containing compounds that initially showed affinity only for the cholinergic targets in our experimental assays. Two cycles of design based on our protocol led to a new set of analogues that were synthesized and assayed. The assay results revealed that the designed inhibitors had improved affinities for BACE-1 by more than 3 orders of magnitude and also displayed amyloid aggregation inhibition and affinity for AChE and BuChE, a result that led us to a group of multitarget amyloid cascade inhibitors that also could have a positive effect at the cholinergic level.

Effect of pH and ligand charge state on BACE-1 fragment docking performance.

In this work we propose a protocol for estimating the effect of pH on the docking performance to BACE-1, which affords the charge state of the inhibitor as well as the protonation state of all ionisable residues in the protein at a given pH value. To the best of our knowledge, this is the first report of a protocol predicting the BACE-1 ligand docking poses not only at the neutral pH at which most crystallographic structures were obtained, but also at the optimal pH of the enzyme (in the acidic range), at which most of the BACE-1 binding affinity assays are performed. We have applied this protocol to a set of 23 fragment-like BACE-1 ligands that span four orders of magnitude in their binding affinities. The pK a values of the BACE-1 acidic residues deviate substantially from the estimates for model compounds in solution and display a ligand dependent variability, especially in the case of the catalytic Asp dyad residues. This outcome should have a strong bearing on the design of protocols for docking based BACE-1 screening campaigns. Finally, we were able to find an explanation for the poor docking success rate of some fragments based on the availability of anchoring points, a rationale that could help to improve hit rates in BACE-1 screening campaigns.

On the active site protonation state in aspartic proteases: implications for drug design.

Aspartic proteases (AP) are a family of important hydrolytic enzymes in medicinal chemistry, since many of its members have become therapeutical targets for a wide variety of diseases from AIDS to Alzheimer. The enzymatic activity of these proteins is driven by the Asp dyad, a pair of active site Asp residues that participate in the hydrolysis of peptides. Hence, the protonation state of these and other acidic residues present in these enzymes determines the catalytic rate and the affinity for an inhibitor at a given pH. In the present work we have reviewed the effect of the protonation states of the titratable residues in AP's both on catalysis and inhibition in this family of enzymes. The first section focuses on the details of the catalytic reaction mechanism picture brought about by a large number of kinetic, crystallographic and computational chemistry analyses. The results indicate that although the mechanism is similar in both retroviral and eukaryotic enzymes, there are some clear differences. For instance, while in the former family branch the binding of the substrate induces a mono-ionic charge state for the Asp dyad, this charge state seems to be already present in the unbound state of the eukaryotic enzymes. In this section we have explored as well the possible existence of low barrier hydrogen bonds (LBHB's) in the enzymatic path. Catalytic rate enhancement in AP's could in part be explained by the lowering of the barrier for proton transfer in a hydrogen bond from donor to acceptor, which is a typical feature of LBHB's. Review of the published work indicates that the experimental support for this type of bonds is rather scarce and it may be more probable in the first stages of the hydrolytic mechanism in retroviral proteases. The second section deals with the effect of active site protonation state on inhibitor binding. The design of highly potent AP inhibitors, that could be the basis for drug leads require a deep knowledge of the protonation state of the active site residues induced by their presence. This vital issue has been tackled by experimental techniques like NMR, X-ray crystallography, calorimetric and binding kinetic techniques. Recently, we have developed a protocol that combines monitoring the pH effect on binding affinities by SPR methods and rationalization of the results by molecular mechanics based calculations. We have used this combined method on BACE-1 and HIV-1 PR, two important therapeutic targets. Our calculations are able to reproduce the inhibitor binding trends to either enzyme upon a pH increase. The results indicate that inhibitors that differ in the Asp dyad binding fragments will present different binding affinity trends upon a pH increase. Our calculations have enabled us to predict the protonation states at different pH values that underlie the above mentioned trends. We have found out that these results have many implications not only for in silico hit screening campaigns aimed at finding high affinity binders, but also (in the case of BACE-1) for the discovery of cell active compounds.

Experimental and 'in silico' analysis of the effect of pH on HIV-1 protease inhibitor affinity: implications for the charge state of the protein ionogenic groups.

The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations. Moreover, our calculations are able to pinpoint the possible changes in the charged state of the protein binding site and of the inhibitor that underlie the observed effects of the pH on binding affinity. The combination of SPR and molecular mechanics calculations has afforded novel insights into the pH dependence of inhibitor interactions with their target. This work raises the possibility of designing inhibitors with different pH binding affinity profiles to the ones described here.

On a possible neutral charge state for the catalytic dyad in ß-secretase when bound to hydroxyethylene transition state analogue inhibitors.

ß-Secretase is one of the aspartic proteases involved in the formation of amyloid plaques in Alzheimer's disease patients. Our previous results using a combination of surface plasmon resonance experiments with molecular modeling calculations suggested that the Asp dyad in ß-secretase bound to hydroxylethylene containing inhibitors adopts a neutral charged state. In this work, we show that the Asp dyad diprotonated state reproduced the binding ranking of a set of these inhibitors better than alternative protonation states.

Effect of the protonation state of the titratable residues on the inhibitor affinity to BACE-1.

BACE-1 is one of the aspartic proteases involved in the cleavage of beta amyloid peptide, an initial step in the formation of amyloid plaques whose toxicity induces neuron death in Alzheimer's disease patients. One of the central issues in the search of novel BACE-1 inhibitors is the optimum pH for the binding of inhibitors to the enzyme. It is known that the enzyme has optimal catalytic activity at acidic pH, while cell active inhibitors may bind optimally at higher pH. In this work we determine the effect of the pH on the affinities of a set of inhibitors, with a variety of chemical motifs, for the ectodomain region of BACE-1 by a surface plasmon resonance (SPR) biosensor based assay. In order to understand the molecular interactions that underlie the diverse optimum pH for the binding of the various inhibitors as observed experimentally, we have calculated the titration curves for a set of BACE-1 ligand complexes. The results indicate that the pK(a) values of the titratable residues of the protein depend on the nature of the ligand involved, in disagreement with previous work. The enzyme-inhibitor structures with the resulting protonation states at pH values 4.5 and 7.4 served as the starting point for the prediction of the pH-dependent binding ranking. Our calculations reproduced the entire affinity ranking observed upon pH increase and most of the binding trends among inhibitors, especially at low pH. Finally, our cell-based assays indicate a possible correlation between high inhibitor affinity at both acidic and neutral pH values, with optimal cell response, a result that may open new venues for the search of potent BACE-1 inhibitors that are active at the cellular level.

La cirugía que he vivido (1932-1988) / The surgery is have lived (1932-1988)

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New insights on molybdenum suboxide: nature of carbons in isomerization reactions.

MoO3 transformations under isomerization process conditions were studied. The products obtained after different times under stream (H2/n-heptane mixture, 18.5 bar, at 370 degrees C) were characterized by X-ray diffraction, Raman spectroscopy, thermal analysis, and high-resolution transmission electron microscopy (HRTEM). Theoretical quantum calculations were carried out with the aim of understanding the paradox of the real active phase in isomerization reactions. Theoretical calculations predict the existence of a metallic-like MoO phase with a structure that matches the X-ray diffraction experimental results. From experimental and simulated HRTEM images it was possible to identify the presence of small MoO cubic crystallites inside MoOx matrix phases. These results also support the previously proposed idea that isomerization reactions take place as a result of the existence of a bifunctional catalyst. The Raman and thermo-programmed oxidation (TPO) analyses show the existence of at least two types of carbonaceous deposits which tend to increase its ordering with the increase of time under stream. The carbon K edge in electron energy loss spectroscopy (EELS) of a sample after 24 h under stream shows that these carbonaceous deposits consist of a mixture of sp2- and sp3-hybridized carbons.

DNA ploidy and cytonuclear area of peritumoral and paratumoral samples of mastectomy specimens: a useful prognostic marker?

OBJECTIVE: To investigate a possible relationship between DNA alterations in the "normal" residual mammary tissue of patients with breast cancer and survival. DESIGN: Prospective study. SETTING: University hospital, Spain. SUBJECTS: 162 patients operated on for breast cancer between 1991 and 1995. MAIN OUTCOME MEASURES: Cytology, histopathology, optic karyometry, DNA ploidy, and S-phase fraction measured by flow cytometry in peritumoral and paratumoral tissue. Mortality, and univariate analysis. RESULTS: DNA ploidy in peritumoral tissue was altered in 42 patients (26%), in 41 of whom the mean cytonuclear area was also altered. Of the 19 patients whose death within the study period was attributed to their cancer, 13 had peritumoral tissue in which both DNA ploidy and mean cytonuclear area were altered. On univariate analysis, there was significantly worse survival among the patients in whom both tumoral and peritumoral tissues were DNA aneuploid than among those in whom only tumoural tissue was DNA aneuploid (p < 0.0001). CONCLUSIONS: The presence of peritumoral or paratumoral tissue or both, with anomalous DNA content is associated with a reduced survival among women whose breast cancer has been treated by mastectomy. Additional studies including multivariate analysis are necessary to confirm our findings.

Frecuencia de parásitos gastrointestinales en animales domésticos diagnosticados en Yucatán, México / Frequency of gastrointestinal parasites in domestic animals, diagnosed in Yucatan, México

Introducción. Los parásitos gastrointestinales ocasionan grandes pérdidas a la producción y salud animal. La información generada en los laboratorios de diagnóstico ayudan en el conocimiento de las parasitosis y permiten diseñar programas de prevención, control y/o erradicación.Material y métodos. Se revisaron los archivos del laboratorio de Parasitología de la Facultad de Medicina Veterinaria y Zootecnia de la Universidad Autónoma de Yucatán, de marzo de 1984 a diciembre de 1999. Se obtuvo la información de las muestras de heces de animales domésticos que fueron remitidas y procesadas mediante la técnica de Flotación Centrifugada.Resultados. Se analizaron un total de 10689 muestras fecales, de las cuales 3827 fueron de bovinos, 1456 de caprinos, 544 de ovinos, 993 de caninos, 46 de felinos, 211 de aves, 3232 de porcinos y 380 de equinos. Los parásitos gastrointestinales más frecuentes en las distintas especies animales fueron los siguientes: bovinos: strongylida (60.64 por ciento) y coccidia (71.57 por ciento), cabras: strongylida (75.41 por ciento) y coccidia (93.40 por ciento), ovinos: strongylida (59.00 por ciento) y coccidia (91.17 por ciento), caninos: Ancylostoma sp (37.36 por ciento), felinos: Ancylostoma sp (32.61 por ciento), aves de corral: coccidia (53.00 por ciento), porcinos: coccidia (45.04 por ciento), y equinos: Strongylus sp (55.26 por ciento).Conclusión. Los animales domésticos del estado de Yucatán, México, se encuentran parasitados por una gran variedad de nemátodos, céstodos y protozoarios.