Resident macrophage-dependent immune cell scaffolds drive anti-bacterial defense in the peritoneal cavity.

Peritoneal immune cells reside unanchored within the peritoneal fluid in homeostasis. Here, we examined the mechanisms that control bacterial infection in the peritoneum using a mouse model of abdominal sepsis following intraperitoneal Escherichia coli infection. Whole-mount immunofluorescence and confocal microscopy of the peritoneal wall and omentum revealed that large peritoneal macrophages (LPMs) rapidly cleared bacteria and adhered to the mesothelium, forming multilayered cellular aggregates composed by sequentially recruited LPMs, B1 cells, neutrophils, and monocyte-derived cells (moCs). The formation of resident macrophage aggregates (resMφ-aggregates) required LPMs and thrombin-dependent fibrin polymerization. E. coli infection triggered LPM pyroptosis and release of inflammatory mediators. Resolution of these potentially inflammatory aggregates required LPM-mediated recruitment of moCs, which were essential for fibrinolysis-mediated resMφ-aggregate disaggregation and the prevention of peritoneal overt inflammation. Thus, resMφ-aggregates provide a physical scaffold that enables the efficient control of peritoneal infection, with implications for antimicrobial immunity in other body cavities, such as the pleural cavity or brain ventricles.

Inflammatory Ly6Chigh Monocytes Protect against Candidiasis through IL-15-Driven NK Cell/Neutrophil Activation.

Neutrophils play a crucial role in defense against systemic candidiasis, a disease associated with a high mortality rate in patients receiving immunosuppressive therapy, although the early immune mechanisms that boost the candidacidal activity of neutrophils remain to be defined in depth. Here, we used a murine model of systemic candidiasis to explore the role of inflammatory Ly6Chigh monocytes in NK cell-mediated neutrophil activation during the innate immune response against C. albicans. We found that efficient anti-Candida immunity required a collaborative response between the spleen and kidney, which relied on type I interferon-dependent IL-15 production by spleen inflammatory Ly6Chigh monocytes to drive efficient activation and GM-CSF release by spleen NK cells; this in turn was necessary to boost the Candida killing potential of kidney neutrophils. Our findings unveil a role for IL-15 as a critical mediator in defense against systemic candidiasis and hold promise for the design of IL-15-based antifungal immunotherapies.

Estimated Population-Level Impact of Pneumococcal Conjugate Vaccines Against All-Cause Pneumonia Mortality Among Unvaccinated in 5 Latin American Countries.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) provide strong direct protection in children, while limited data are available on their indirect effect on mortality among older age groups. This multicountry study aimed to assess the population-level impact of pediatric PCVs on all-cause pneumonia mortality among children ≥5 years of age, and invasive pneumococcal disease (IPD) cases in Chile. METHODS: Demographic and mortality data from Argentina, Brazil, Chile, Colombia, and Mexico were collected considering the ≥ 5-year-old population, from 2000 to 2019, with 1 795 789 deaths due to all-cause pneumonia. IPD cases in Chile were also evaluated. Time series models were employed to evaluate changes in all-cause pneumonia deaths during the postvaccination period, with other causes of death used as synthetic controls for unrelated temporal trends. RESULTS: No significant change in death rates due to all-cause pneumonia was detected following PCV introduction among most age groups and countries. The proportion of IPD cases caused by vaccine serotypes decreased from 29% (2012) to 6% (2022) among people aged ≥65 years in Chile. DISCUSSION: While an effect of PCV against pneumonia deaths (a broad clinical definition that may not be specific enough to measure indirect effects) was not detected, evidence of indirect PCV impact was observed among vaccine-type-specific IPD cases.

Cardiorespiratory interactions during the transitional period in extremely preterm infants: a narrative review.

We aimed to review the physiology and evidence behind cardiorespiratory interactions during the transitional circulation of extremely preterm infants with fragile physiology and to propose a framework for future research. Cord clamping strategies have a great impact on initial haemodynamic changes, and appropriate transition can be facilitated by establishing spontaneous ventilation before cord clamping. Mechanical ventilation modifies preterm transitional haemodynamics, with positive pressure ventilation affecting the right and left heart loading conditions. Pulmonary vascular resistances can be minimized by ventilating with optimal lung volumes at functional residual capacity, and other pulmonary vasodilator treatments such as inhaled nitric oxide can be used to improve ventilation/perfusion mismatch. Different cardiovascular drugs can be used to provide support during transition in this population, and it is important to understand both their cardiovascular and respiratory effects, in order to provide adequate support to vulnerable preterm infants and improve outcomes. Current available non-invasive bedside tools, such as near-infrared spectroscopy, targeted neonatal echocardiography, or lung ultrasound offer the opportunity to precisely monitor cardiorespiratory interactions in preterm infants. More research is needed in this field using precision medicine to strengthen the benefits and avoid the harms associated to early neonatal interventions. IMPACT: In extremely preterm infants, haemodynamic and respiratory transitions are deeply interconnected, and their changes have a key impact in the establishment of lung aireation and postnatal circulation. We describe how mechanical ventilation modifies heart loading conditions and pulmonary vascular resistances in preterm patients, and how hemodynamic interventions such as cord clamping strategies or cardiovascular drugs affect the infant respiratory status. Current available non-invasive bedside tools can help monitor cardiorespiratory interactions in preterm infants. We highlight the areas of research in which precision medicine can help strengthen the benefits and avoid the harms associated to early neonatal interventions.

Predicting the effectiveness of drugs used for treating cardiovascular conditions in newborn infants.

BACKGROUND: Cardiovascular support (CVS) treatment failure (TF) is associated with a poor prognosis in preterm infants. METHODS: Medical charts of infants with a birth weight <1500 g who received either dopamine (Dp) or dobutamine (Db), were reviewed. Treatment response (TR) occurred if blood pressure increased >3rd centile for gestational age or superior vena cava flow was maintained >55 ml/kg/min, with decreased lactate or less negative base excess, without additional CVS. A predictive model of Dp and Db on TR was designed and the impact of TR on survival was analyzed. RESULTS: Sixty-six infants (median gestational age 27.3 weeks, median birth weight 864 g) received Dp (n = 44) or Db (n = 22). TR occurred in 59% of the cases treated with Dp and 31% with Db, p = 0.04. Machine learning identified a model that correctly labeled Db response in 90% of the cases and Dp response in 61.4%. Sixteen infants died (9% of the TR group, 39% of the TF group; p = 0.004). Brain or gut morbidity-free survival was observed in 52% vs 30% in the TR and TF groups, respectively (p = 0.08). CONCLUSIONS: New predictive models can anticipate Db but not Dp effectiveness in preterm infants. These algorithms may help the clinicians in the decision-making process. IMPACT: Failure of cardiovascular support treatment increases the risk of mortality in very low birth weight infants. A predictive model built with machine learning techniques can help anticipate treatment response to dobutamine with high accuracy. Predictive models based on artificial intelligence may guide the clinicians in the decision-making process.

A recommendation for the use of electrical biosensing technology in neonatology.

Non-invasive cardiac output monitoring, via electrical biosensing technology (EBT), provides continuous, multi-parameter hemodynamic variable monitoring which may allow for timely identification of hemodynamic instability in some neonates, providing an opportunity for early intervention that may improve neonatal outcomes. EBT encompasses thoracic (TEBT) and whole body (WBEBT) methods. Despite the lack of relative accuracy of these technologies, as compared to transthoracic echocardiography, the use of these technologies in neonatology, both in the research and clinical arena, have increased dramatically over the last 30 years. The European Society of Pediatric Research Special Interest Group in Non-Invasive Cardiac Output Monitoring, a group of experienced neonatologists in the field of EBT, deemed it appropriate to provide recommendations for the use of TEBT and WBEBT in the field of neonatology. Although TEBT is not an accurate determinant of cardiac output or stroke volume, it may be useful for monitoring longitudinal changes of hemodynamic parameters. Few recommendations can be made for the use of TEBT in common neonatal clinical conditions. It is recommended not to use WBEBT to monitor cardiac output. The differences in technologies, study methodologies and data reporting should be addressed in ongoing research prior to introducing EBT into routine practice. IMPACT STATEMENT: TEBT is not recommended as an accurate determinant of cardiac output (CO) (or stroke volume (SV)). TEBT may be useful for monitoring longitudinal changes from baseline of hemodynamic parameters on an individual patient basis. TEBT-derived thoracic fluid content (TFC) longitudinal changes from baseline may be useful in monitoring progress in respiratory disorders and circulatory conditions affecting intrathoracic fluid volume. Currently there is insufficient evidence to make any recommendations regarding the use of WBEBT for CO monitoring in neonates. Further research is required in all areas prior to the implementation of these monitors into routine clinical practice.

Water insecurity among seasonal agriculture workers: perspectives from Spanish professionals.

BACKGROUND: Migrant seasonal agricultural workers face conditions of material vulnerability such as inadequate housing difficulties prevent access to running water supplies. The purpose of this study is to explore the perceptions of professionals involved in the care and support of seasonal migrant agricultural workers, as it relates to water access and water consumption and their impact on these workers' health, in a context of COVID-19 pandemic. METHODS: A qualitative exploratory and descriptive study was conducted in 2021 as part of a larger research project, based on 63 personal semi-structured interviews with professionals who provided support to seasonal migrant agricultural workers in three Spanish autonomous regions. COREQ checklist was used for reporting. The interviews were recorded, transcribed, and imported into ATLAS.ti-9 for an inductive thematic analysis. RESULTS: The results have been structured into two main themes: (1) Accessing and obtaining water; and (2) Health problems related to water consumption. Seasonal migrant agricultural workers experience barriers to obtaining safe water for hygiene, cleaning, food preparation and drinking. The implementation of regulations to reduce COVID-19 transmission resulted in improved hygiene levels in the migrants' quarters, including access to safe drinking water. CONCLUSION: This study suggests that water insecurity experienced by migrant seasonal agricultural workers in Spain results from their poor living conditions and causes health problems related to a lack of hygiene and the use of unsafe water. Sustainable solutions are needed beyond the pandemic in order to provide migrant workers with adequate living conditions and ensure their water needs are fulfilled.

Neonatal ventriculomegaly: Pathophysiology and management guided with cranial ultrasonography.

Neonatal ventriculomegaly often, but not always, follows intraventricular haemorrhage in infants born preterm. Serial cranial ultrasonography (CUS) is a very useful tool to evaluate the mechanism behind ventricular dilatation, to differentiate several types of cerebrospinal fluid retention, and to guide treatment. This review examines neonatal ventriculomegaly and its definition, pathophysiology, treatment, and prognosis from the perspective of CUS assessment. It also outlines the consensus statements formulated by the EurUS.Brain group, which are based on rounds of expert opinions on neonatal ventriculomegaly management, detailing the need and timing of ventricular access device placement, in the context of posthaemorrhagic ventricular dilation. The pathophysiology of neonatal ventriculomegaly is more complex than previously considered. CUS is a valuable, non-invasive tool to determine pathophysiology, intervention thresholds, and prognosis in neonates with ventriculomegaly. Given new insights into the existence of glymphatics and water circulation in the cerebrum, further research in that area may bring new treatment options. WHAT THIS PAPER ADDS: Cranial ultrasonography has a significant role in better understanding the complex pathophysiology of neonatal ventriculomegaly. The latest research suggests that treating posthaemorrhagic ventricular dilation in its early stages has several advantages. Proper definition, management, and a follow-up plan are essential because they can impact the infant and their family, health care providers, educational systems, and society.

State-of-the-art cranial ultrasound in clinical scenarios for infants born at term and near-term.

Neonates admitted to the intensive care unit are at risk of brain injury. Importantly, infants with signs of neurological impairment need prompt diagnosis to guide intervention. Cranial ultrasound (CUS) is the first-line imaging tool for infants born preterm. New developments in this technology, which now incorporates high-resolution equipment, have notably improved the performance of CUS in infants born at term and near-term. On the other hand, the potential of CUS as a diagnostic tool in older infants is less established. The lack of studies focusing on this topic, local protocol variability among clinical sites, and divergent opinions on CUS patterns of disease entities are the main constraints. This review provides an overview of state-of-the-art CUS as a decision-making tool under different clinical scenarios, such as neonatal encephalopathy, seizures, and suspected central nervous system infection. The CUS features that characterize several patterns supporting a diagnosis are detailed, focusing on haemorrhage and infection.

Soluble mutant huntingtin drives early human pathogenesis in Huntington's disease.

Huntington's disease (HD) is an incurable inherited brain disorder characterised by massive degeneration of striatal neurons, which correlates with abnormal accumulation of misfolded mutant huntingtin (mHTT) protein. Research on HD has been hampered by the inability to study early dysfunction and progressive degeneration of human striatal neurons in vivo. To investigate human pathogenesis in a physiologically relevant context, we transplanted human pluripotent stem cell-derived neural progenitor cells (hNPCs) from control and HD patients into the striatum of new-born mice. Most hNPCs differentiated into striatal neurons that projected to their target areas and established synaptic connexions within the host basal ganglia circuitry. Remarkably, HD human striatal neurons first developed soluble forms of mHTT, which primarily targeted endoplasmic reticulum, mitochondria and nuclear membrane to cause structural alterations. Furthermore, HD human cells secreted extracellular vesicles containing mHTT monomers and oligomers, which were internalised by non-mutated mouse striatal neurons triggering cell death. We conclude that interaction of mHTT soluble forms with key cellular organelles initially drives disease progression in HD patients and their transmission through exosomes contributes to spread the disease in a non-cell autonomous manner.

Age-related hearing loss is not linked to cerebrospinal fluid levels of ß-amyloid or p-tau181.

INTRODUCTION: As Hearing loss and dementia affect people with the same profile, several epidemiological studies have evaluated their relationship. However, the link between age-related hearing loss and Alzheimer's disease is still unclear. METHODS: We selected subjects with no history of exposure to loud noises, blasts, head trauma with hearing loss, or sudden sensorineural hearing loss from a cohort intended to study preclinical phases of Alzheimer's disease. Participants are volunteers over 55 years without cognitive impairment. We correlated the results of an objective auditory evaluation with brain amyloid and p-tau181 levels and with the outcomes of a comprehensive neuropsychological assessment. RESULTS: Fifty-five subjects at different stages of the Alzheimer's disease continuum were evaluated. There were no statistically significant correlations between amyloid-ß and p-tau levels and any of the objective auditory measures. A weak but significant correlation was found between amyloid-ß values and the Hearing Handicap Inventory for the Elderly. The neuropsychological domains more correlated to hearing loss were executive function and processing speed. DISCUSSION: Age-related hearing loss is not linked to any pathological markers of Alzheimer's disease nor to neuropsychological domains typically affected in this disease. The Hearing Handicap Inventory for the Elderly has an important component of subjectivity and further studies are needed to explore its relationship with amyloid-ß levels.

Influence of Physiological Variables and Comorbidities on Plasma Aß40, Aß42, and p-tau181 Levels in Cognitively Unimpaired Individuals.

Plasma biomarkers for Alzheimer's disease (AD) are a promising tool that may help in early diagnosis. However, their levels may be influenced by physiological parameters and comorbidities that should be considered before they can be used at the population level. For this purpose, we assessed the influences of different comorbidities on AD plasma markers in 208 cognitively unimpaired subjects. We analyzed both plasma and cerebrospinal fluid levels of Aß40, Aß42, and p-tau181 using the fully automated Lumipulse platform. The relationships between the different plasma markers and physiological variables were studied using linear regression models. The mean differences in plasma markers according to comorbidity groups were also studied. The glomerular filtration rate showed an influence on plasma Aß40 and Aß42 levels but not on the Aß42/Aß40 ratio. The amyloid ratio was significantly lower in diabetic and hypertensive subjects, and the mean p-tau181 levels were higher in hypertensive subjects. The glomerular filtration rate may have an inverse relationship on plasma Aß40 and Aß42 levels but not on the amyloid ratio, suggesting that the latter is a more stable marker to use in the general population. Cardiovascular risk factors might have a long-term effect on the amyloid ratio and plasma levels of p-tau181.

Label-Free Identification of Carbonaceous Particles Using Nonlinear Optical Microscopy.

The adverse health effects of ambient carbonaceous particles (CPs) such as carbon black (CB), black carbon (BC), and brown carbon (BrC) are becoming more evident and depend on their composition and emission source. Therefore, identifying and quantifying these particles in biological samples are important to better understand their toxicity. Here, we report the development of a nonlinear optical approach for the identification of CPs such as CB and BrC using imaging conditions compatible with biomedical samples. The unique visible light fingerprint of CB and BrC nanoparticles (NPs) upon illumination with a femtosecond (fs) pulsed laser at 1300 nm excitation wavelength is an effective approach for their identification in their biological context. The emission from spectral features of these CPs was investigated with time-domain fluorescence lifetime imaging (FLIM) to further support their identification. This study is performed for different types of CPs embedded in agarose gel as well as in in vitro mammalian cells. The unique nonlinear emissive behavior of CP NPs used for their label-free identification is further complementary with fluorophores typically used for specific staining of biological samples thus providing the relevant bio-context.

Immunomodulatory effects of inactivated Ligilactobacillus salivarius CECT 9609 on respiratory epithelial cells.

The microbiota in humans and animals play crucial roles in defense against pathogens and offer a promising natural source for immunomodulatory products. However, the development of physiologically relevant model systems and protocols for testing such products remains challenging. In this study, we present an experimental condition where various natural products derived from the registered lactic acid bacteria Ligilactobacillus salivarius CECT 9609, known for their immunomodulatory activity, were tested. These products included live and inactivated bacteria, as well as fermentation products at different concentrations and culture times. Using our established model system, we observed no morphological changes in the airway epithelium upon exposure to Pasteurella multocida, a common respiratory pathogen. However, early molecular changes associated with the innate immune response were detected through transcript analysis. By employing diverse methodologies ranging from microscopy to next-generation sequencing (NGS), we characterized the interaction of these natural products with the airway epithelium and their potential beneficial effects in the presence of P. multocida infection. In particular, our discovery highlights that among all Ligilactobacillus salivarius CECT 9609 products tested, only inactivated cells preserve the conformation and morphology of respiratory epithelial cells, while also reversing or altering the natural immune responses triggered by Pasteurella multocida. These findings lay the groundwork for further exploration into the protective role of these bacteria and their derivatives.

Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC-induced cholestatic injury by promoting a pro-restorative inflammatory response.

Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1-2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland.

Primary neonatal and pediatric ECMO transport: First experience in Spain.

INTRODUCTION: The organization of primary Extracorporeal membrane oxygenation (ECMO) transport is highly variable. METHODS: To present the experience of the first mobile pediatric ECMO program in Spain, we designed a prospective descriptive study of all primary neonatal and pediatric (0-16 years) ECMO transports carried out over 10 years. The main variables recorded include demographic information, patient background, clinical data, ECMO indications, adverse events, and main outcomes. RESULTS: 39 primary ECMO transports were carried out with a 66.7% survival to hospital discharge. The median age was 1.24 months[IQR: 0.09-96]. Cannulation was mostly peripheral venoarterial (33/39). The mean response time from the call from the sending center to the departure of the ECMO team was 4 h[2.2-8]. The median inotropic score at the time of cannulation was 70[17.2-206.5], with a median oxygenation index of 40.5[29-65]. In 10% of the cases, ECMO-CPR was performed. Adverse events occurred in 56.4%, mostly related to the means of transport (40% overall). On arrival at the ECMO center, 44% of the patients underwent interventions. The median PICU stay was 20.5 days[11-32]. 5 patients developed neurological sequels. Statistically significant differences between survivors and deceased patients were not found. CONCLUSIONS: A good survival rate, with a low prevalence of serious adverse events, suggests a clear benefit of primary ECMO transport when conventional therapeutic measures are exhausted and the patient is too unstable to undergo conventional transport. A nationwide primary ECMO-transport program must therefore be offered to all patients regardless of their location.

From students to nurses under pressure: Nursing students' entry into employment during the first COVID-19 wave.

AIMS AND OBJECTIVE: To describe the experiences of nursing students and their mental health as they entered employment during the first wave of the COVID-19 pandemic (May-June 2020). BACKGROUND: As other healthcare professionals, nursing students who worked during the first COVID-19 wave suffered from dysfunctional mental health symptoms. DESIGN: Sequential, mixed-method, multicentre study. METHODS: The study population comprised 92 students in the third and fourth year of the Nursing degree at three Spanish universities, who entered employment during the pandemic. Data were collected between May and June 2020. In the quantitative phase, data were collected using an online questionnaire containing both validated anxiety and stress scales. In the qualitative phase, semi-structured interviews were conducted with 18 participants. A descriptive analysis of the quantitative data and a reflexive thematic analysis of the qualitative data were carried out, and analyses were combined. COREQ checklist was used for reporting. RESULTS: The combined quantitative and qualitative results were organised into five thematic areas: (1) Interruption of clinical placements, (2) Entering employment on a healthcare assistant contract, (3) Preventing contagion, (4) Adapting to the situation and managing emotions, and (5) Lessons learned. CONCLUSION: The students had a positive overall experience of entering employment, as they were able to develop their nursing skills. However, they had an emotional impact in form of stress caused by excessive responsibility, academic uncertainty, lack of personal protective equipment and training in its use, and the possibility of spreading disease to their family members. RELEVANCE TO CLINICAL PRACTICE: In the current context, changes must be made in study programmes to instruct nursing students to be able to cope with extreme clinical situations, such as pandemics. The programmes should include a more extensive coverage of epidemics and pandemics and management of emotional aspects such as resilience.

Phospho-RNA-Seq Highlights Specific Small RNA Profiles in Plasma Extracellular Vesicles.

Small RNAs (sRNAs) are bioactive molecules that can be detected in biofluids, reflecting physiological and pathological states. In plasma, sRNAs are found within extracellular vesicles (EVs) and in extravesicular compartments, offering potential sources of highly sensitive biomarkers. Deep sequencing strategies to profile sRNAs favor the detection of microRNAs (miRNAs), the best-known class of sRNAs. Phospho-RNA-seq, through the enzymatic treatment of sRNAs with T4 polynucleotide kinase (T4-PNK), has been recently developed to increase the detection of thousands of previously inaccessible RNAs. In this study, we investigated the value of phospho-RNA-seq on both the EVs and extravesicular plasma subfractions. Phospho-RNA-seq increased the proportion of sRNAs used for alignment and highlighted the diversity of the sRNA transcriptome. Unsupervised clustering analysis using sRNA counts matrices correctly classified the EVs and extravesicular samples only in the T4-PNK treated samples, indicating that phospho-RNA-seq stresses the features of sRNAs in each plasma subfraction. Furthermore, T4-PNK treatment emphasized specific miRNA variants differing in the 5'-end (5'-isomiRs) and certain types of tRNA fragments in each plasma fraction. Phospho-RNA-seq increased the number of tissue-specific messenger RNA (mRNA) fragments in the EVs compared with the extravesicular fraction, suggesting that phospho-RNA-seq favors the discovery of tissue-specific sRNAs in EVs. Overall, the present data emphasizes the value of phospho-RNA-seq in uncovering RNA-based biomarkers in EVs.

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer's Disease.

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aß1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

Ultrafine Kaolinite Removal in Recycled Water from the Overflow of Thickener Using Electroflotation: A Novel Application of Saline Water Splitting in Mineral Processing.

The presence of ultrafine clay particles that are difficult to remove by conventional filtration creates many operational problems in mining processing systems. In this work, the removal of clay suspensions has been investigated using an electroflotation (EF) process with titanium electrodes. The results show that EF is a viable and novel alternative for removing ultrafine particles of kaolinite-type clay present in sedimentation tank overflows with low salt concentrations (<0.1 mol/L) in copper mining facilities based on the saline water splitting concept. Maximum suspended solid removal values of 91.4 and 83.2% in NaCl and KCl solutions, respectively, were obtained under the experimental conditions of the constant applied potential of 20 V/SHE, salinity concentration of 0.1 mol/L, and electroflotation time of 10 and 20 min in NaCl and KCl solutions, respectively. Furthermore, the visual evidence of particle aggregation by flocculation during the experiments indicates a synergy between EF and electrocoagulation (EC) that enhances the removal of ultrafine particles of kaolinite.