Leucine rich repeat-malectin receptor kinases IGP1/CORK1, IGP3 and IGP4 are required for arabidopsis immune responses triggered by ß-1,4-D-Xylo-oligosaccharides from plant cell walls.

Pattern-Triggered Immunity (PTI) in plants is activated upon recognition by Pattern Recognition Receptors (PRRs) of Damage- and Microbe-Associated Molecular Patterns (DAMPs and MAMPs) from plants or microorganisms, respectively. An increasing number of identified DAMPs/MAMPs are carbohydrates from plant cell walls and microbial extracellular layers, which are perceived by plant PRRs, such as LysM and Leucine Rich Repeat-Malectin (LRR-MAL) receptor kinases (RKs). LysM-RKs (e.g. CERK1, LYK4 and LYK5) are needed for recognition of fungal MAMP chitohexaose (ß-1,4-D-(GlcNAc)6, CHI6), whereas IGP1/CORK1, IGP3 and IGP4 LRR-MAL RKs are required for perception of ß-glucans, like cellotriose (ß-1,4-D-(Glc)3, CEL3) and mixed-linked glucans. We have explored the diversity of carbohydrates perceived by Arabidopsis thaliana seedlings by determining PTI responses upon treatment with different oligosaccharides and polysaccharides. These analyses revealed that plant oligosaccharides from xylans [ß-1,4-D-(xylose)4 (XYL4)], glucuronoxylans and α-1,4-glucans, and polysaccharides from plants and seaweeds activate PTI. Cross-elicitation experiments of XYL4 with other glycans showed that the mechanism of recognition of XYL4 and the DAMP 33-α-L-arabinofuranosyl-xylotetraose (XA3XX) shares some features with that of CEL3 but differs from that of CHI6. Notably, XYL4 and XA3XX perception is impaired in igp1/cork1, igp3 and igp4 mutants, and almost not affected in cerk1 lyk4 lyk5 triple mutant. XYL4 perception is conserved in different plant species since XYL4 pre-treatment triggers enhanced disease resistance in tomato to Pseudomonas syringae pv tomato DC3000 and PTI responses in wheat. These results expand the number of glycans triggering plant immunity and support IGP1/CORK1, IGP3 and IGP4 relevance in Arabidopsis thaliana glycans perception and PTI activation. Significance Statement: The characterization of plant immune mechanisms involved in the perception of carbohydrate-based structures recognized as DAMPs/MAMPs is needed to further understand plant disease resistance modulation. We show here that IGP1/CORK1, IGP3 and IGP4 LRR-MAL RKs are required for the perception of carbohydrate-based DAMPs ß-1,4-D-(xylose)4 (XYL4) and 33-α-L-arabinofuranosyl-xylotetraose (XA3XX), further expanding the function of these LRR-MAL RKs in plant glycan perception and immune activation.

Mitogen-activated protein kinase phosphatase 1 controls broad spectrum disease resistance in Arabidopsis thaliana through diverse mechanisms of immune activation.

Arabidopsis thaliana Mitogen-activated protein Kinase Phosphatase 1 (MKP1) negatively balances production of reactive oxygen species (ROS) triggered by Microbe-Associated Molecular Patterns (MAMPs) through uncharacterized mechanisms. Accordingly, ROS production is enhanced in mkp1 mutant after MAMP treatment. Moreover, mkp1 plants show a constitutive activation of immune responses and enhanced disease resistance to pathogens with distinct colonization styles, like the bacterium Pseudomonas syringae pv. tomato DC3000, the oomycete Hyaloperonospora arabidopsidis Noco2 and the necrotrophic fungus Plectosphaerella cucumerina BMM. The molecular basis of this ROS production and broad-spectrum disease resistance controlled by MKP1 have not been determined. Here, we show that the enhanced ROS production in mkp1 is not due to a direct interaction of MKP1 with the NADPH oxidase RBOHD, nor is it the result of the catalytic activity of MKP1 on RBHOD phosphorylation sites targeted by BOTRYTIS INDUCED KINASE 1 (BIK1) protein, a positive regulator of RBOHD-dependent ROS production. The analysis of bik1 mkp1 double mutant phenotypes suggested that MKP1 and BIK1 targets are different. Additionally, we showed that phosphorylation residues stabilizing MKP1 are essential for its functionality in immunity. To further decipher the molecular basis of disease resistance responses controlled by MKP1, we generated combinatory lines of mkp1-1 with plants impaired in defensive pathways required for disease resistance to pathogen: cyp79B2 cyp79B3 double mutant defective in synthesis of tryptophan-derived metabolites, NahG transgenic plant that does not accumulate salicylic acid, aba1-6 mutant impaired in abscisic acid (ABA) biosynthesis, and abi1 abi2 hab1 triple mutant impaired in proteins described as ROS sensors and that is hypersensitive to ABA. The analysis of these lines revealed that the enhanced resistance displayed by mkp1-1 is altered in distinct mutant combinations: mkp1-1 cyp79B2 cyp79B3 fully blocked mkp1-1 resistance to P. cucumerina, whereas mkp1-1 NahG displays partial susceptibility to H. arabidopsidis, and mkp1-1 NahG, mkp1-1 aba1-6 and mkp1-1 cyp79B2 cyp79B3 showed compromised resistance to P. syringae. These results suggest that MKP1 is a component of immune responses that does not directly interact with RBOHD but rather regulates the status of distinct defensive pathways required for disease resistance to pathogens with different lifestyles.

Asciminib for third-line treatment of chronic myeloid leukemia: Cost-effectiveness analysis based on treatment-free remission approach.

INTRODUCTION: The first targeted therapy in oncology, imatinib, revolutionized chronic myeloid leukemia (CML) treatment and spurred research in targeted therapies for various cancers. CML results from a chromosomal translocation, forming the BCR-ABL1 fusion gene. Asciminib has been recently approved for third-line refractory or intolerant patients. Treatment-free remission (TFR) is attainable with sustained deep molecular response (DMR) and this approach could be incorporated into pharmacoeconomic models. AIMS: To establish a cost-effectiveness model comparing asciminib to approved third-generation tyrosine kinase inhibitors (TKIs) (bosutinib and ponatinib) with a focus on achieving TFR. Additionally, the budgetary impact of incorporating asciminib as a therapeutic alternative is assessed. METHODS: This model is based on a Markov chain with 7 states. The condition for achieving TFR is to remain for 5 years in DMR state. Efficacy of the model was measured in QALYs, and the costs included in the base case analysis are based in Spain. A probabilistic (PSA) and deterministic analysis (DSA) were carried out to assess the variability of the model. There were achieved 2 independent models comparing asciminib vs bosutinib and asciminib vs ponatinib. RESULTS: Asciminib, when compared with ponatinib, is a cost-saving alternative, as efficacy is similar between alternatives, and asciminib have a lower cost of 30,275€. Asciminib showed 4.33 more QALYs and a higher cost (203,591€) than bosutinib, resulting in an ICER of €47,010.49 per QALY. PSA shows that the parameters with higher influence in the variability of the model were the probability of transitioning to BP and probabilities of achieving MMR and DMR. A one-way analysis reports that the drug cost has a higher influence on both models, and the discount rate significantly affects the asciminib vs bosutinib model. CONCLUSION: Asciminib broadens therapeutic choices for patient's refractory or intolerant to 2 prior lines of treatment in a cost-effectiveness manner. The costs of drugs significantly impact the overall cost of the disease, emphasizing the importance of the selected discount rates for each drug. Given the relatively low incidence of CML, the introduction of asciminib has a limited budgetary impact, warranting individualized decisions based on patient`s clinical characteristics.

Plant cell wall-mediated disease resistance: Current understanding and future perspectives.

Beyond their function as structural barriers, plant cell walls are essential elements for the adaptation of plants to environmental conditions. Cell walls are dynamic structures whose composition and integrity can be altered in response to environmental challenges and developmental cues. These wall changes are perceived by plant sensors/receptors to trigger adaptative responses during development and upon stress perception. Plant cell wall damage caused by pathogen infection, wounding, or other stresses leads to the release of wall molecules, such as carbohydrates (glycans), that function as damage-associated molecular patterns (DAMPs). DAMPs are perceived by the extracellular ectodomains (ECDs) of pattern recognition receptors (PRRs) to activate pattern-triggered immunity (PTI) and disease resistance. Similarly, glycans released from the walls and extracellular layers of microorganisms interacting with plants are recognized as microbe-associated molecular patterns (MAMPs) by specific ECD-PRRs triggering PTI responses. The number of oligosaccharides DAMPs/MAMPs identified that are perceived by plants has increased in recent years. However, the structural mechanisms underlying glycan recognition by plant PRRs remain limited. Currently, this knowledge is mainly focused on receptors of the LysM-PRR family, which are involved in the perception of various molecules, such as chitooligosaccharides from fungi and lipo-chitooligosaccharides (i.e., Nod/MYC factors from bacteria and mycorrhiza, respectively) that trigger differential physiological responses. Nevertheless, additional families of plant PRRs have recently been implicated in oligosaccharide/polysaccharide recognition. These include receptor kinases (RKs) with leucine-rich repeat and Malectin domains in their ECDs (LRR-MAL RKs), Catharanthus roseus RECEPTOR-LIKE KINASE 1-LIKE group (CrRLK1L) with Malectin-like domains in their ECDs, as well as wall-associated kinases, lectin-RKs, and LRR-extensins. The characterization of structural basis of glycans recognition by these new plant receptors will shed light on their similarities with those of mammalians involved in glycan perception. The gained knowledge holds the potential to facilitate the development of sustainable, glycan-based crop protection solutions.

Advances in Understanding Fractals in Affective and Anxiety Disorders.

In this chapter, we review the research that has applied fractal measures to the study of the most common psychological disorders, that is, affective and anxiety disorders. Early studies focused on heart rate, but diverse measures have also been examined, from variations in subjective mood, or hand movements, to electroencephalogram or magnetoencephalogram data. In general, abnormal fractal dynamics in different physiological and behavioural outcomes have been observed in mental disorders. Despite the disparity of variables measured, fractal analysis has shown high sensitivity in discriminating patients from healthy controls. However, and because of this heterogeneity in measures, the results are not straightforward, and more studies are needed in this promising line.

Reproductive traits in Pura Raza Española mares manifest inbreeding depression from low levels of homozygosity.

Inbreeding depression is a genetic phenomenon associated with the loss of fitness and mean phenotypic performance due to mating between relatives. Historically, inbreeding coefficients have been estimated from pedigree information. However, the onset of genomic selection programs provides large datasets of individuals genotyped using SNP arrays, enabling more precise assessment of an individual's genomic-level inbreeding using genomic data. One of the traits most sensitive to issues stemming from increased inbreeding is reproduction. This is particularly important in equine, in which fertility is only moderate compared to other livestock species. To explore this further, we evaluated the effect of inbreeding on five reproductive traits (age at first foaling (AFF), average interval between foalings (AIF), total number of foalings (NF), productive life (PL) and reproductive efficiency (RE)) in Pura Raza Español mares using genomic data. Residual predicted phenotypes were obtained by purging these traits through the REML (wgResidual ) and ssGREML (gResidual ) approaches in reproductive data of 29,847 PRE mares using the BLUPF90+ program. Next, we used pedigree-based (Fped ) and ROH-based genomic (FROH ) inbreeding coefficients derived from 1018 animals genotyped with 61,271 SNPs to estimate the inbreeding depression (linear regression). Our results indicated significant levels of inbreeding depression for all reproductive traits, with the exception of the AIF trait when Fped was used. However, all traits were negatively affected by the increase in genomic inbreeding, and FROH was found to capture more inbreeding depression than Fped . Likewise, REML models (ssGREML) using genomic data for estimated predicted residual phenotypes resulted in higher variance explained by the model compared with the models not using genomics (REML). Finally, a segmented regression analysis was conducted to evaluate the effect of inbreeding depression, revealing that the levels of genealogical and genomic homozygosity do not manifest uniformly in reproductive traits. In contrast, the levels of inbreeding depression ranged from low to high as homozygosity increased. This analysis also showed that reproductive traits are very sensitive to inbreeding depression, even with relatively low levels of homozygosity.

Mutual information of multiple rhythms in schizophrenia.

Interactions between different cortical rhythms, such as slow and fast oscillations, have been hypothesized to underlie many cognitive functions. In patients diagnosed with schizophrenia, there is some evidence indicating that the interplay between slow and fast oscillations might be impaired or disrupted. In this study, we investigated multiple oscillatory interactions in schizophrenia using a novel approach based on information theory. This method allowed us to investigate interactions from a new perspective, where two or more rhythm interactions could be analyzed at the same time. We calculated the mutual information of multiple rhythms (MIMR) for EEG segments registered in resting state. Following previous studies, we focused on rhythm interactions between theta, alpha, and gamma. The results showed that, in general, MIMR was higher in patients than in controls for alpha-gamma and theta-gamma couplings. This finding of an increased coupling between slow and fast rhythms in schizophrenia may indicate complex interactions in the Default Mode Network (DMN) related to hyperactivation of internally guided cognition.

Designing an early selection morphological traits index for reproductive efficiency in Pura Raza Española mares.

The low rate of reproductive efficiency in horses may be linked to the equine industry's practice of maintaining breeding stock that stands out for its athletic or morphological performance but exhibits poor reproductive efficiency. In this study, the age at first foaling, age at last foaling, interval between first and second foaling, average interval between foaling, foaling number and reproductive efficiency, and their relationship with the morphological records in 19,758 Pura Raza Española (PRE) mares were analyzed. After a partial least squares analysis height at withers, lateral hock angle, dorsal-sternal diameter, perimeter of anterior cannon bone, angle of shoulder, thoracic perimeter, hip-stifle distance, and angle of croup were the most important traits related with reproductive traits in PRE mares. A multivariate animal model with both morphological and reproductive traits was applied, including age, geographical area, coat color, and average stud size in the decade of the mare's first foaling. The results indicate that reproductive selection is feasible, and is enhanced by the use of morphological traits, given the moderate to high magnitudes of heritability values in both types of traits, which oscillated between 0.1 (interval between first and second foaling) and 0.95 (height at withers). The resulting genetic parameters were used to develop a series of selection indexes based on morphological or morphological and reproductive combination traits to improve reproductive efficiency traits in PRE mares and thus compute the expected genetic response (EGR) for the different strategies. The increase in EGR, when comparing EGR using only reproductive traits as selection criteria vs. using a combined index of both morphological and reproductive traits, oscillated between 4.0% for the age at first foaling to 46.8% for the interval between first and second foaling. In addition, two precocity indexes showed positive EGR when the age at last foaling and the interval between first and second foaling, both with and without morphological traits, were used as selection criteria. Therefore, this analysis reveals that the preselection of reproductive traits based on morphological traits is possible in PRE mares. Ultimately, this knowledge will help breeders achieve genetic progress in reproductive traits, leading to healthier and more successful breeding outcomes in horses.

Historically in livestock production, employing combinations of traits as selection criteria for indirect selection of related traits has been a challenging task, particularly when this implies selection for reproductive traits based on the animal morphology. However, if the decision about animal selection is based on morphological traits that are quick and easy to obtain, in addition to early reproductive traits, selection responses can be improved and made earlier. This is particularly significant in sport horse breeds like the Pura Raza Española horse, which is primarily used for dressage competitions. Mares belonging to this breed commonly engage in several years of competition before transitioning to breeding, without the breeders having prior knowledge of their reproductive efficiency. Nonetheless, the availability of existing morphological information enables us to make informed decisions in this regard. While a selection index using morphology alone would not yield as good a response as direct selection for reproductive traits, there are cases, such as age at last foaling, where the correlated response can be very high. Our study further illustrates a substantial increase in selection response when morphological and reproductive traits are jointly included as selection criteria, with the aim of enhancing reproductive efficiency.

Unlocking New Avenues in Breast Cancer Treatment: The Synergy of Kinase Inhibitors and Immunotherapy.

Cancer is one of the world's most significant health problems today. Currently, breast cancer has globally surpassed lung cancer as the most commonly diagnosed cancer in women. In 2020, an estimated 2,261,419 new cases were diagnosed in women worldwide. Therefore, there is a need to understand the processes that can help us better treat this disease. In recent years, research in the fight against cancer has often been based on two treatment modalities. One of them is the use of protein kinase inhibitors, which have been instrumental in the development of new therapeutic strategies. Another crucial route is the use of immunotherapy, which has been touted as a great promise for cancer treatment. Protein kinase alterations can interfere with the effectiveness of other treatments, such as immunotherapy. In this review, we will analyze the role played by protein kinase alterations in breast cancer and their possible impact on the effectiveness of the response to immunotherapy treatments.

Análisis modal de fallos y efectos en las transferencias de pacientes de urgencias a hospitalización / Patient transfers from emergency departments to other in-hospital areas: a failure mode and effects analysis

Objetivo: Este estudio analiza en profundidad el proceso de transferencia de pacientes de urgencias a hospitalización y posibles fallos para evitar problemas de seguridad mediante la identificación de líneas de mejora. Método: Se conformó un grupo de trabajo multidisciplinar compuesto por profesionales asistenciales de urgencias y hospitalización de adultos que, mediante la metodología de análisis modal de fallos y efectos (AMFE), analizó pormenorizadamente el proceso de transferencia de pacientes de urgencias a hospitalización. Para los puntos críticos identificados se estableció el índice de prioridad del riesgo (IPR) en base a su gravedad, probabilidad de aparición y de detección. Resultados: Se identificaron 8 subprocesos y 14 puntos críticos que podrían generar fallos en el proceso de transferencia. Los aspectos relacionados con la administración de medicamentos y el proceso de identificación fueron los que obtuvieron mayores puntuaciones de IPR. Para todos ellos se establecieron acciones de mejora. Se elaboró un procedimiento específico de transferencia de pacientes entre estas áreas y un listado de verificación de ingresos en hospitalización. Conclusiones: Con la metodología AMFE se ha conseguido desgranar un proceso de especial vulnerabilidad como es la transferencia de pacientes de urgencias a hospitalización y definir acciones de mejora en aras de incrementar la seguridad de los pacientes. (AU)

Objectives: To perform an in-depth analysis of the process of transferring patients from an emergency department (ED) to other areas inside a hospital and identify possible points of failure and risk so that strategies for improvement can be developed. Methods: We formed a multidisciplinary group of ED and other personnel working with hospitalized adults. The group applied failure mode and effects analysis (FMEA) to understand the in-hospital transfer processes. A risk priority scoring system was then established to assess the seriousness of each risk and the likelihood it would appear and be detected. Results: We identified 8 transfer subprocesses and 14 critical points at which failures could occur. Processes related to administering medications and identifying patients were the components that received the highest risk priority scores. Improvement strategies were established for all risks. The group created a specific protocol for in-hospital transfers and a checklist to use during handovers. Conclusion: The FMEA method helped the group to identify points when there is risk of failure during patient transfers and to define ways to improve patient safety. (AU)

Patient transfers from emergency departments to other in-hospital areas: a failure mode and effects analysis. / Análisis modal de fallos y efectos en las transferencias de pacientes de urgencias a hospitalización.

OBJECTIVES: To perform an in-depth analysis of the process of transferring patients from an emergency department (ED) to other areas inside a hospital and identify possible points of failure and risk so that strategies for improvement can be developed. MATERIAL AND METHODS: We formed a multidisciplinary group of ED and other personnel working with hospitalized adults. The group applied failure mode and effects analysis (FMEA) to understand the in-hospital transfer processes. A risk priority scoring system was then established to assess the seriousness of each risk and the likelihood it would appear and be detected. RESULTS: We identified 8 transfer subprocesses and 14 critical points at which failures could occur. Processes related to administering medications and identifying patients were the components that received the highest risk priority scores. Improvement strategies were established for all risks. The group created a specific protocol for in-hospital transfers and a checklist to use during handovers. CONCLUSION: The FMEA method helped the group to identify points when there is risk of failure during patient transfers and to define ways to improve patient safety.

OBJETIVO: Este estudio analiza en profundidad el proceso de transferencia de pacientes de urgencias a hospitalización y posibles fallos para evitar problemas de seguridad mediante la identificación de líneas de mejora. METODO: Se conformó un grupo de trabajo multidisciplinar compuesto por profesionales asistenciales de urgencias y hospitalización de adultos que, mediante la metodología de análisis modal de fallos y efectos (AMFE), analizó pormenorizadamente el proceso de transferencia de pacientes de urgencias a hospitalización. Para los puntos críticos identificados se estableció el índice de prioridad del riesgo (IPR) en base a su gravedad, probabilidad de aparición y de detección. RESULTADOS: Se identificaron 8 subprocesos y 14 puntos críticos que podrían generar fallos en el proceso de transferencia. Los aspectos relacionados con la administración de medicamentos y el proceso de identificación fueron los que obtuvieron mayores puntuaciones de IPR. Para todos ellos se establecieron acciones de mejora. Se elaboró un procedimiento específico de transferencia de pacientes entre estas áreas y un listado de verificación de ingresos en hospitalización. CONCLUSIONES: Con la metodología AMFE se ha conseguido desgranar un proceso de especial vulnerabilidad como es la transferencia de pacientes de urgencias a hospitalización y definir acciones de mejora en aras de incrementar la seguridad de los pacientes.

Circulating miRNAs signature on breast cancer: the MCC-Spain project.

PURPOSE: To build models combining circulating microRNAs (miRNAs) able to identify women with breast cancer as well as different types of breast cancer, when comparing with controls without breast cancer. METHOD: miRNAs analysis was performed in two phases: screening phase, with a total n = 40 (10 controls and 30 BC cases) analyzed by Next Generation Sequencing, and validation phase, which included 131 controls and 269 cases. For this second phase, the miRNAs were selected combining the screening phase results and a revision of the literature. They were quantified using RT-PCR. Models were built using logistic regression with LASSO penalization. RESULTS: The model for all cases included seven miRNAs (miR-423-3p, miR-139-5p, miR-324-5p, miR-1299, miR-101-3p, miR-186-5p and miR-29a-3p); which had an area under the ROC curve of 0.73. The model for cases diagnosed via screening only took in one miRNA (miR-101-3p); the area under the ROC curve was 0.63. The model for disease-free cases in the follow-up had five miRNAs (miR-101-3p, miR-186-5p, miR-423-3p, miR-142-3p and miR-1299) and the area under the ROC curve was 0.73. Finally, the model for cases with active disease in the follow-up contained six miRNAs (miR-101-3p, miR-423-3p, miR-139-5p, miR-1307-3p, miR-331-3p and miR-21-3p) and its area under the ROC curve was 0.82. CONCLUSION: We present four models involving eleven miRNAs to differentiate healthy controls from different types of BC cases. Our models scarcely overlap with those previously reported.

Metabolomic Signatures of Exposure to Nitrate and Trihalomethanes in Drinking Water and Colorectal Cancer Risk in a Spanish Multicentric Study (MCC-Spain).

We investigated the metabolomic profile associated with exposure to trihalomethanes (THMs) and nitrate in drinking water and with colorectal cancer risk in 296 cases and 295 controls from the Multi Case-Control Spain project. Untargeted metabolomic analysis was conducted in blood samples using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. A variety of univariate and multivariate association analyses were conducted after data quality control, normalization, and imputation. Linear regression and partial least-squares analyses were conducted for chloroform, brominated THMs, total THMs, and nitrate among controls and for case-control status, together with a N-integration model discriminating colorectal cancer cases from controls through interrogation of correlations between the exposure variables and the metabolomic features. Results revealed a total of 568 metabolomic features associated with at least one water contaminant or colorectal cancer. Annotated metabolites and pathway analysis suggest a number of pathways as potentially involved in the link between exposure to these water contaminants and colorectal cancer, including nicotinamide, cytochrome P-450, and tyrosine metabolism. These findings provide insights into the underlying biological mechanisms and potential biomarkers associated with water contaminant exposure and colorectal cancer risk. Further research in this area is needed to better understand the causal relationship and the public health implications.

Examining Neural Connectivity in Schizophrenia Using Task-Based EEG: A Graph Theory Approach.

Schizophrenia (SZ) is a complex disorder characterized by a range of symptoms and behaviors that have significant consequences for individuals, families, and society in general. Electroencephalography (EEG) is a valuable tool for understanding the neural dynamics and functional abnormalities associated with schizophrenia. Research studies utilizing EEG have identified specific patterns of brain activity in individuals diagnosed with schizophrenia that may reflect disturbances in neural synchronization and information processing in cortical circuits. Considering the temporal dynamics of functional connectivity provides a more comprehensive understanding of brain networks' organization and how they change during different cognitive states. This temporal perspective would enhance our understanding of the underlying mechanisms of schizophrenia. In the present study, we will use measures based on graph theory to obtain dynamic and static indicators in order to evaluate differences in the functional connectivity of individuals diagnosed with SZ and healthy controls using an ecologically valid task. At the static level, patients showed alterations in their ability to segregate information, particularly in the default mode network (DMN). As for dynamic measures, patients showed reduced values in most metrics (segregation, integration, centrality, and resilience), reflecting a reduced number of dynamic states of brain networks. Our results show the utility of combining static and dynamic indicators of functional connectivity from EEG sensors.

Reconsidering the Use of Population Health Surveys for Monitoring of Mental Health.

Monitoring of the mental health status of the population and assessment of its determinants are 2 of the most relevant pillars of public mental health, and data from population health surveys could be instrumental to support them. Although these surveys could be an important and suitable resource for these purposes, due to different limitations and challenges, they are often relegated to the background behind other data sources, such as electronic health records. These limitations and challenges include those related to measurement properties and cross-cultural validity of the tools used for the assessment of mental disorders, their degree of representativeness, and possible difficulties in the linkage with other data sources. Successfully addressing these limitations could significantly increase the potential of health surveys in the monitoring of mental disorders and ultimately maximize the impact of the relevant policies to reduce their burden at the population level. The widespread use of data from population health surveys, ideally linked to electronic health records data, would enhance the quality of the information available for research, public mental health decision-making, and ultimately addressing the growing burden of mental disorders.

Pulsed magnetic field increases the effect of ultraviolet C radiation and thermal shock in aged yeasts / El campo magnético pulsado aumenta el efecto de la radiación ultravioleta C y el choque térmico en levaduras envejecidas

The study of the effects of the magnetic field (MF) on living matter continues to be a dilemma. Until now, the interaction mechanisms of MF with living matter that explain the observed phenomena are unknown. Despite the existing literature and the multiple effects described to date, there are few published articles that study the combined effect of MF with other physical agents during the cellular aging process. In this sense, the aim of this work is to study whether low frequency and intensity pulsed and sinusoidal MF exposure produce alterations in the cell killing effect of ultraviolet C (UVC) radiation and thermal shock during the chronological aging of S. cerevisiae. Yeast cells were exposed to 2.45 mT (50 Hz) sinusoidal MF and 1.5 mT (25 Hz) pulsed MF, during 40 days of aging, in combination with UVC radiation (50 J/m2) and/or thermal shock (52°C). Cell survival was evaluated by clonogenic assay. The exposure of yeast to pulsed MF produces an acceleration of aging, which is not observed in cells exposed to sinusoidal MF. The pulsed MF modifies the cellular response to damaging agents only in aged S. cerevisiae cells. In this sense, the pulsed MF applied increases the damage induced by UVC radiation and by thermal shock. In contrast, the sinusoidal MF used has no effect.(AU)

miR-28-based combination therapy impairs aggressive B cell lymphoma growth by rewiring DNA replication.

Diffuse large B cell lymphoma (DLBCL) is the most common aggressive B cell lymphoma and accounts for nearly 40% of cases of B cell non-Hodgkin lymphoma. DLBCL is generally treated with R-CHOP chemotherapy, but many patients do not respond or relapse after treatment. Here, we analyzed the therapeutic potential of the tumor suppressor microRNA-28 (miR-28) for DLBCL, alone and in combination with the Bruton's tyrosine kinase inhibitor ibrutinib. Combination therapy with miR-28 plus ibrutinib potentiated the anti-tumor effects of monotherapy with either agent by inducing a specific transcriptional cell-cycle arrest program that impairs DNA replication. The molecular actions of miR-28 and ibrutinib synergistically impair DNA replication by simultaneous inhibition of origin activation and fork progression. Moreover, we found that downregulation of the miR-28-plus-ibrutinib gene signature correlates with better survival of ABC-DLBCL patients. These results provide evidence for the effectiveness of a new miRNA-based ibrutinib combination therapy for DLBCL and unveil the miR-28-plus-ibrutinib gene signature as a new predictor of outcome in ABC-DLBCL patients.

Fractal dimension analysis of resting state functional networks in schizophrenia from EEG signals.

Fractal dimension (FD) has been revealed as a very useful tool in analyzing the changes in brain dynamics present in many neurological disorders. The fractal dimension index (FDI) is a measure of the spatiotemporal complexity of brain activations extracted from EEG signals induced by transcranial magnetic stimulation. In this study, we assess whether the FDI methodology can be also useful for analyzing resting state EEG signals, by characterizing the brain dynamic changes in different functional networks affected by schizophrenia, a mental disorder associated with dysfunction in the information flow dynamics in the spontaneous brain networks. We analyzed 31 resting-state EEG records of 150 s belonging to 20 healthy subjects (HC group) and 11 schizophrenia patients (SCZ group). Brain activations at each time sample were established by a thresholding process applied on the 15,002 sources modeled from the EEG signal. FDI was then computed individually in each resting-state functional network, averaging all the FDI values obtained using a sliding window of 1 s in the epoch. Compared to the HC group, significant lower values of FDI were obtained in the SCZ group for the auditory network (p < 0.05), the dorsal attention network (p < 0.05), and the salience network (p < 0.05). We found strong negative correlations (p < 0.01) between psychopathological scores and FDI in all resting-state networks analyzed, except the visual network. A receiver operating characteristic curve analysis also revealed that the FDI of the salience network performed very well as a potential feature for classifiers of schizophrenia, obtaining an area under curve value of 0.83. These results suggest that FDI is a promising method for assessing the complexity of the brain dynamics in different regions of interest, and from long resting-state EEG signals. Regarding the specific changes associated with schizophrenia in the dynamics of the spontaneous brain networks, FDI distinguished between patients and healthy subjects, and correlated to clinical variables.