Validation of the Artificial Intelligence Prognostic Scoring System for Myelodysplastic Syndromes in chronic myelomonocytic leukaemia: A novel approach for improved risk stratification.

Chronic myelomonocytic leukaemia (CMML) is a rare haematological disorder characterized by monocytosis and dysplastic changes in myeloid cell lineages. Accurate risk stratification is essential for guiding treatment decisions and assessing prognosis. This study aimed to validate the Artificial Intelligence Prognostic Scoring System for Myelodysplastic Syndromes (AIPSS-MDS) in CMML and to assess its performance compared with traditional scores using data from a Spanish registry (n = 1343) and a Taiwanese hospital (n = 75). In the Spanish cohort, the AIPSS-MDS accurately predicted overall survival (OS) and leukaemia-free survival (LFS), outperforming the Revised-IPSS score. Similarly, in the Taiwanese cohort, the AIPSS-MDS demonstrated accurate predictions for OS and LFS, showing superiority over the IPSS score and performing better than the CPSS and molecular CPSS scores in differentiating patient outcomes. The consistent performance of the AIPSS-MDS across both cohorts highlights its generalizability. Its adoption as a valuable tool for personalized treatment decision-making in CMML enables clinicians to identify high-risk patients who may benefit from different therapeutic interventions. Future studies should explore the integration of genetic information into the AIPSS-MDS to further refine risk stratification in CMML and improve patient outcomes.

Selective Photooxidation of Valencene and Thymol with Nano-TiO2 and O2 as Oxidant.

The selective photocatalytic oxidation with O2 as oxidant of valencene and thymol was evaluated using nanostructured TiO2 under UV-Vis radiation at atmospheric conditions. The effect of the morphology and optical properties of TiO2 nanotubes and aminate nanoparticles was studied. Different scavengers were used to detect the presence of positive holes (h+), electrons (e-), hydroxyl radicals (•OH), and the superoxide radical anion (O2-) during the photooxidation reaction. Superoxide anion radical is the main oxidizing specie formed, which is responsible for the selective formation of nootkatone and thymoquinone using aminated TiO2 nanoparticles under 400 nm radiation.

Multi-sensorial perceptions of risk: the aesthetics behind (muco)cutaneous leishmaniasis-related stigma in Ecuador.

Previous research on the stigma associated with cutaneous leishmaniasis, a vector-transmitted parasitic disease, focuses on aesthetic appearance affectation as the leading cause of stigmatisation. However, Indigenous populations in the hinterland of Amazonian Ecuador trigger stigma expressions by recognising (muco)cutaneous leishmaniasis, primarily through atypical smell, followed by the odd voice sound, appearance and taste. This empirical way of recognising symptoms relies on embodied forms of identifying a disease, contrasting the Western supremacy of visuality and demanding to be understood via multi-sensorial anthropology. Through ethnographic research and data retrieved from eighty-three semistructured interviews and fifteen focus groups in seven Ecuadorian ethnic groups - including six Indigenous groups in the Amazon region - this paper analyses how the sensorium is a health thermometer. Findings reveal that differentiated cultural responses to a sense of peril, contagion and social (self)rejection, understood as stigma expressions, are linked to the holistic approach to health (or well-being) shared by Indigenous populations. In forest societies, well-being is explained through successful (non-)human relationships, and disease permeates through bodies that lack balanced relations.

Abnormal innate and learned behavior induced by neuron-microglia miscommunication is related to CA3 reconfiguration.

Neuron-microglia communication through the Cx3cr1-Cx3cl1 axis is essential for the development and refinement of neural circuits, which determine their function into adulthood. In the present work we set out to extend the behavioral characterization of Cx3cr1-/- mice evaluating innate behaviors and spatial navigation, both dependent on hippocampal function. Our results show that Cx3cr1-deficient mice, which show some changes in microglial and synaptic terminals morphology and density, exhibit alterations in activities of daily living and in the rapid encoding of novel spatial information that, nonetheless, improves with training. A neural substrate for these cognitive deficiencies was found in the form of synaptic dysfunction in the CA3 region of the hippocampus, with a marked impact on the mossy fiber (MF) pathway. A network analysis of the CA3 microcircuit reveals the effect of these synaptic alterations on the functional connectivity among CA3 neurons with diminished strength and topological reorganization in Cx3cr1-deficient mice. Neonatal population activity of the CA3 region in Cx3cr1-deficient mice shows a marked reorganization around the giant depolarizing potentials, the first form of network-driven activity of the hippocampus, suggesting that alterations found in adult subjects arise early on in postnatal development, a critical period of microglia-dependent neural circuit refinement. Our results show that interruption of the Cx3cr1-Cx3cl1/neuron-microglia axis leads to changes in CA3 configuration that affect innate and learned behaviors.

Main olfactory bulb reconfiguration by prolonged passive olfactory experience correlates with increased brain-derived neurotrophic factor and improved innate olfaction.

The main olfactory bulb (MOB) is highly plastic and constantly reconfiguring its function and structure depending on sensory experience. Despite the extensive evidence of anatomical, functional and behavioural changes in the olfactory system induced by highly variable olfactory experiences, it is still unknown whether prolonged passive odour experience could reconfigure the MOB at its input and network activity levels and whether these changes impact innate olfaction. Here, by measuring odour-induced glomerular activation, MOB network activity and innate olfactory behaviours, we described a profound MOB reconfiguration induced by prolonged passive olfactory experience in adult animals that impacts MOB input integration at the glomerular layer including an increase in the activated glomerular area and signal intensity, which is combined with a refinement in the number of activated glomeruli and less-overlapped glomerular maps. We also found that prolonged passive olfactory experience dramatically changes MOB population activity in the presence and absence of odours, which is reflected as a decrease in slow oscillations (<12 Hz) and an increase in fast oscillations (>12 Hz). All these functional changes in awake and anaesthetized mice correlate with an increase in brain-derived neurotrophic factor (BDNF) and with improved innate olfactory responses such as habituation/dishabituation and innate preference/avoidance. Our study shows that prolonged passive olfactory experience in adult animals produces a dramatic reconfiguration of the MOB network, possibly driven by BDNF, that improves innate olfactory responses.

Configuration and dynamics of dominant inspiratory multineuronal activity patterns during eupnea and gasping generation in vitro.

The pre-Bötzinger complex (preBötC), located within the ventral respiratory column, produces inspiratory bursts in varying degrees of synchronization/amplitude. This wide range of population burst patterns reflects the flexibility of the preBötC neurons, which is expressed in variations in the onset/offset times of their activations and their activity during the population bursts, with respiratory neurons exhibiting a large cycle-to-cycle timing jitter both at the population activity onset and at the population activity peak, suggesting that respiratory neurons are stochastically activated before and during the inspiratory bursts. However, it is still unknown whether this stochasticity is maintained while evaluating the coactivity of respiratory neuronal ensembles. Moreover, the preBötC topology also remains unknown. In this study, by simultaneously recording tens of preBötC neurons and using coactivation analysis during the inspiratory periods, we found that the preBötC has a scale-free configuration (mixture of not many highly connected nodes, hubs, with abundant poorly connected elements) exhibiting the rich-club phenomenon (hubs more likely interconnected with each other). PreBötC neurons also produce multineuronal activity patterns (MAPs) that are highly stable and change during the hypoxia-induced reconfiguration. Moreover, preBötC contains a coactivating core network shared by all its MAPs. Finally, we found a distinctive pattern of sequential coactivation of core network neurons at the beginning of the inspiratory periods, indicating that, when evaluated at the multicellular level, the coactivation of respiratory neurons seems not to be stochastic.NEW & NOTEWORTHY By means of multielectrode recordings of preBötC neurons, we evaluated their configuration in normoxia and hypoxia, finding that the preBötC exhibits a scale-free configuration with a rich-club phenomenon. preBötC neurons produce multineuronal activity patterns that are highly stable but change during hypoxia. The preBötC contains a coactivating core network that exhibit a distinctive pattern of coactivation at the beginning of inspirations. These results reveal some network basis of inspiratory rhythm generation and its reconfiguration during hypoxia.

Laser photo-thermal therapy of epithelial carcinoma using pterin-6-carboxylic acid conjugated gold nanoparticles.

Gold nanoparticles functionalized with folic acid toward the internalization into cancer cells have received considerable attention recently. Folic acid is recognized by folate receptors, which are overexpressed in several cancer cells; it is limited in normal cells. In this work, pterin-6-carboxylic acid is proposed as an agonist of folic acid since the pterin-6-carboxylic acid structure has a pterin moiety, the same as folic acid that is recognized by the folate receptor. Here a simple photochemical synthesis of gold nanoparticles functionalized with pterin-6-carboxylic acid is studied. These conjugates were used to cause photothermal damage of HeLa cells irradiating with a diode laser of 808 nm. Pterin-6-carboxylic acid-conjugated gold nanoparticles caused the death of the cell after near-infrared irradiation, dose-dependently. These results indicate a possible internalization of AuNPs via folate receptor-mediated endocytosis due to the recognition or interaction between the folate receptors of HeLa cells and pterin, P6CA.

'Most at risk' for COVID19? The imperative to expand the definition from biological to social factors for equity.

First recognized in December 2019, the Coronavirus Disease 2019 (COVID19) was declared a global pandemic by the World Health Organization on March 11, 2020. To date, the most utilized definition of 'most at risk' for COVID19 morbidity and mortality has focused on biological susceptibility to the virus. This paper argues that this dominant biomedical definition has neglected the 'fundamental social causes' of disease, constraining the effectiveness of prevention and mitigation measures; and exacerbating COVID19 morbidity and mortality for population groups living in marginalizing circumstances. It is clear - even at this early stage of the pandemic - that inequitable social conditions lead to both more infections and worse outcomes. Expanding the definition of 'most at risk' to include social factors is critical to implementing equitable interventions and saving lives. Prioritizing populations with social conditions is necessary for more effective control of the epidemic in its next phase; and should become standard in the planning for, and prevention and mitigation of all health conditions. Reversing disparities and health inequities is only possible through an expansion of our 'most-at-risk' definition to also include social factors.

Circuitry and Synaptic Dysfunction in Alzheimer's Disease: A New Tau Hypothesis.

For more than five decades, the field of Alzheimer's disease (AD) has focused on two main hypotheses positing amyloid-beta (Aß) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

Collaborative Filtering to Predict Sensor Array Values in Large IoT Networks.

Internet of Things (IoT) projects are increasing in size over time, and some of them are growing to reach the whole world. Sensor arrays are deployed world-wide and their data is sent to the cloud, making use of the Internet. These huge networks can be used to improve the quality of life of the humanity by continuously monitoring many useful indicators, like the health of the users, the air quality or the population movements. Nevertheless, in this scalable context, a percentage of the sensor data readings can fail due to several reasons like sensor reliabilities, network quality of service or extreme weather conditions, among others. Moreover, sensors are not homogeneously replaced and readings from some areas can be more precise than others. In order to address this problem, in this paper we propose to use collaborative filtering techniques to predict missing readings, by making use of the whole set of collected data from the IoT network. State of the art recommender systems methods have been chosen to accomplish this task, and two real sensor array datasets and a synthetic dataset have been used to test this idea. Experiments have been carried out varying the percentage of failed sensors. Results show a good level of prediction accuracy which, as expected, decreases as the failure rate increases. Results also point out a failure rate threshold below which is better to make use of memory-based approaches, and above which is better to choose model-based methods.

Phosphorylation of Tau protein correlates with changes in hippocampal theta oscillations and reduces hippocampal excitability in Alzheimer's model.

Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine-treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.

Single amyloid-beta injection exacerbates 4-aminopyridine-induced seizures and changes synaptic coupling in the hippocampus.

Accumulation of amyloid-beta (Aß) in temporal lobe structures, including the hippocampus, is related to a variety of Alzheimer's disease symptoms and seems to be involved in the induction of neural network hyperexcitability and even seizures. Still, a direct evaluation of the pro-epileptogenic effects of Aß in vivo, and of the underlying mechanisms, is missing. Thus, we tested whether the intracisternal injection of Aß modulates 4-aminopyridine (4AP)-induced epileptiform activity, hippocampal network function, and its synaptic coupling. When tested 3 weeks after its administration, Aß (but not its vehicle) reduces the latency for 4AP-induced seizures, increases the number of generalized seizures, exacerbates the time to fully recover from seizures, and favors seizure-induced death. These pro-epileptogenic effects of Aß correlate with a reduction in the power of the spontaneous hippocampal network activity, involving all frequency bands in vivo and only the theta band (4-10 Hz) in vitro. The pro-epileptogenic effects of Aß also correlate with a reduction of the Schaffer-collateral CA1 synaptic coupling in vitro, which is exacerbated by the sequential bath application of 4-AP and Aß. In summary, Aß produces long-lasting pro-epileptic effects that can be due to alterations in the hippocampal circuit, impacting its coordinated network activity and its synaptic efficiency. It is likely that normalizing synaptic coupling and/or coordinated neural network activity (i.e., theta activity) may contribute not only to improve cognitive function in Alzheimer's disease but also to avoid hyperexcitation in conditions of amyloidosis.

Sudden Intrabulbar Amyloid Increase Simultaneously Disrupts Olfactory Bulb Oscillations and Odor Detection.

There seems to be a correlation between soluble amyloid beta protein (Aß) accumulation in the main olfactory bulb (OB) and smell deterioration in both Alzheimer's disease (AD) patients and animal models. Moreover, this loss of smell appears to be related to alterations in neural network activity in several olfactory-related circuits, including the OB, as has been observed in anesthetized animals and brain slices. It is possible that there is a correlation between these two pathological phenomena, but a direct and simultaneous evaluation of the acute and direct effect of Aß on OB activity while animals are actually smelling has not been performed. Thus, here, we tested the effects of acute intrabulbar injection of Aß at a low dose (200 pmol) on the OB local field potential before and during the presence of a hidden piece of smelly food. Our results show that Aß decreases the power of OB network activity while impairing the animal's ability to reach the hidden food. We found a strong relationship between the power of the OB oscillations and the correlation between OBs and the olfactory detection test scores. These findings provide a direct link between Aß-induced OB network dysfunction and smell loss in rodents, which could be extrapolated to AD patients.

Modelling antisepsis using defined populations of facultative and anaerobic wound pathogens grown in a basally perfused biofilm model.

An in vitro model was developed to assess the effects of topical antimicrobials on taxonomically defined wound biofilms. Biofilms were exposed over seven days to povidone-iodine, silver acetate or polyhexamethylene biguanide (PHMB) at concentrations used in wound dressings. The rank order of tolerance in multi-species biofilms, based on an analysis of the average bacterial counts over time was P. aeruginosa > methicillin-resistant Staphylococcus aureus (MRSA) > B. fragilis > S. pyogenes. The rank order of effectiveness for the antimicrobials in the biofilm model was povidone-iodine > PHMB > silver acetate. None of the test compounds eradicated P. aeruginosa or MRSA from the biofilms although all compounds except silver acetate eliminated S. pyogenes. Antimicrobial effectiveness against bacteria grown in multi-species biofilms did not correlate with planktonic susceptibility. Defined biofilm populations of mixed-species wound pathogens could be maintained in the basal perfusion model, facilitating the efficacy testing of treatments regimens and potential dressings against multi-species biofilms composed of wound isolates.

Physically Demanding Labor and Health Among Indigenous Women in the Ecuadorian Highlands.

Physically demanding work carried out during long workdays affects women's health. In rural and agrarian societies, women perform a variety of domestic and productive tasks, often from dawn to dusk, with little or no leisure time. This paper presents the results of a survey of indigenous women in six rural communities in the Ecuadorian highlands. It was conducted to measure the amount of time women spend on physically demanding work in the context of food security, parity outcomes, and access to prenatal health care. The findings demonstrate that these women work very long workdays and also experience food insecurity and poor access to prenatal health care.

Neural Network Reconfigurations: Changes of the Respiratory Network by Hypoxia as an Example.

Neural networks, including the respiratory network, can undergo a reconfiguration process by just changing the number, the connectivity or the activity of their elements. Those elements can be either brain regions or neurons, which constitute the building blocks of macrocircuits and microcircuits, respectively. The reconfiguration processes can also involve changes in the number of connections and/or the strength between the elements of the network. These changes allow neural networks to acquire different topologies to perform a variety of functions or change their responses as a consequence of physiological or pathological conditions. Thus, neural networks are not hardwired entities, but they constitute flexible circuits that can be constantly reconfigured in response to a variety of stimuli. Here, we are going to review several examples of these processes with special emphasis on the reconfiguration of the respiratory rhythm generator in response to different patterns of hypoxia, which can lead to changes in respiratory patterns or lasting changes in frequency and/or amplitude.

Microglia modulate respiratory rhythm generation and autoresuscitation.

Inflammation has been linked to the induction of apneas and Sudden Infant Death Syndrome, whereas proinflammatory mediators inhibit breathing when applied peripherally or directly into the CNS. Considering that peripheral inflammation can activate microglia in the CNS and that this cell type can directly release all proinflammatory mediators that modulate breathing, it is likely that microglia can modulate breathing generation. It might do so also in hypoxia, since microglia are sensitive to hypoxia, and peripheral proinflammatory conditions affect gasping generation and autoresuscitation. Here, we tested whether microglial activation or inhibition affected respiratory rhythm generation. By measuring breathing as well as the activity of the respiratory rhythm generator (the preBötzinger complex), we found that several microglial activators or inhibitors, applied intracisternally in vivo or in the recording bath in vitro, affect the generation of the respiratory rhythms both in normoxia and hypoxia. Furthermore, microglial activation with lipopolysaccharide affected the ability of the animals to autoresuscitate after hypoxic conditions, an effect that is blocked when lipopolysaccharide is co-applied with the microglial inhibitor minocycline. Moreover, we found that the modulation of respiratory rhythm generation induced in vitro by microglial inhibitors was reproduced by microglial depletion. In conclusion, our data show that microglia can modulate respiratory rhythm generation and autoresuscitation.

Pharmacological Tools to Study the Role of Astrocytes in Neural Network Functions.

Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte's influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction.

Bosutinib shows low cross intolerance, in chronic myeloid leukemia patients treated in fourth line. Results of the Spanish compassionate use program.

The role of bosutinib as rescue treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients after failing three previous tyrosine kinase inhibitors (TKIs) is currently unknown. We report here the largest series (to our knowledge) of patients treated with bosutinib in fourth-line, after retrospectively reviewing 30 patients in chronic phase, and pretreated with imatinib, nilotinib, and dasatinib. With a median follow up of 11.1 months, the probability to either maintain or improve their CCyR response was 56.6% (17/30) and 11 patients (36.7%) achieved or maintained their baseline MMR. In patients not having baseline CCyR, the probabilities of obtaining CCyR, MMR, and MR4.5 were 13, 11, and 14%, respectively. The probabilities of obtaining MMR and deep molecular response MR4.5 in patients with baseline CCyR were 40.0% (6/15) and 20.0% (3/15). At 20 months, progression-free survival was 73%. Grade 3-4 hematological toxicities were more frequent in resistant than intolerant patients (45.4 vs. 0.0%). Nonhematological toxicities were also more frequent in resistant patients, being diarrhea the most conspicuous one. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKI's.

Systems toxicology: modelling biomarkers of glutathione homeostasis and paracetamol metabolism.

One aim of systems toxicology is to deliver mechanistic, mathematically rigorous, models integrating biochemical and pharmacological processes that result in toxicity to enhance the assessment of the risk posed to humans by drugs and other xenobiotics. The benefits of such 'in silico' models would be in enabling the rapid and robust prediction of the effects of compounds over a range of exposures, improving in vitro-in vivo correlations and the translation from preclinical species to humans. Systems toxicology models of organ toxicities that result in high attrition rates during drug discovery and development, or post-marketing withdrawals (e.g., drug-induced liver injury (DILI)) should facilitate the discovery of safe new drugs. Here, systems toxicology as applied to the effects of paracetamol (acetaminophen, N-acetyl-para-aminophenol (APAP)) is used to exemplify the potential of the approach.