STIM1 translocation to the nucleus protects cells from DNA damage.

DNA damage represents a challenge for cells, as this damage must be eliminated to preserve cell viability and the transmission of genetic information. To reduce or eliminate unscheduled chemical modifications in genomic DNA, an extensive signaling network, known as the DNA damage response (DDR) pathway, ensures this repair. In this work, and by means of a proteomic analysis aimed at studying the STIM1 protein interactome, we have found that STIM1 is closely related to the protection from endogenous DNA damage, replicative stress, as well as to the response to interstrand crosslinks (ICLs). Here we show that STIM1 has a nuclear localization signal that mediates its translocation to the nucleus, and that this translocation and the association of STIM1 to chromatin increases in response to mitomycin-C (MMC), an ICL-inducing agent. Consequently, STIM1-deficient cell lines show higher levels of basal DNA damage, replicative stress, and increased sensitivity to MMC. We show that STIM1 normalizes FANCD2 protein levels in the nucleus, which explains the increased sensitivity of STIM1-KO cells to MMC. This study not only unveils a previously unknown nuclear function for the endoplasmic reticulum protein STIM1 but also expands our understanding of the genes involved in DNA repair.

p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1.

During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.

A comprehensive study of source apportionment, spatial distribution, and health risks assessment of heavy metal(loid)s in the surface soils of a semi-arid mining region in Matehuala, Mexico.

BACKGROUND: This study investigates the contamination level, spatial distribution, pollution sources, potential ecological risks, and human health risks associated with heavy metal(loid)s (i.e., arsenic (As), copper (Cu), iron (Fe), manganese (Mn), lead (Pb), and zinc (Zn)) in surface soils within the mining region of Matehuala, located in central Mexico. OBJECTIVES: The primary objectives are to estimate the contamination level of heavy metal(loid)s, identify pollution sources, assess potential ecological risks, and evaluate human health risks associated with heavy metal(loid) contamination. METHODS: Soil samples from the study area were analysed using various indices including Igeo, Cf, PLI, mCd, EF, and PERI to evaluate contamination levels. Source apportionment of heavy metal(loid)s was conducted using the APCS-MLR and PMF receptor models. Spatial distribution patterns were determined using the most efficient interpolation technique among five different approaches. The total carcinogenic risk index (TCR) and total non-carcinogenic index (THI) were used in this study to assess the potential carcinogenic and non-carcinogenic hazards posed by heavy metal(loid)s in surface soil to human health. RESULTS: The study reveals a high contamination level of heavy metal(loid)s in the surface soil, posing considerable ecological risks. As was identified as a priority metal for regulatory control measures. Mining and smelting activities were identified as the primary factors influencing heavy metal(loid) distributions. Based on spatial distribution mapping, concentrations were higher in the northern, western, and central regions of the study area. As and Fe were found to pose considerable and moderate ecological risks, respectively. Health risk evaluation indicated significant levels of carcinogenic risks for both adults and children, with higher risks for children. CONCLUSION: This study highlights the urgent need for monitoring heavy metal(loid) contamination in Matehuala's soils, particularly in regions experiencing strong economic growth, to mitigate potential human health and ecological risks associated with heavy metal(loid) pollution.

PHIRI: lessons for an extensive reuse of sensitive data in federated health research.

BACKGROUND: The extensive and continuous reuse of sensitive health data could enhance the role of population health research on public decisions. This paper describes the design principles and the different building blocks that have supported the implementation and deployment of Population Health Information Research Infrastructure (PHIRI), the strengths and challenges of the approach and some future developments. METHODS: The design and implementation of PHIRI have been developed upon: (i) the data visiting principle-data does not move but code moves; (ii) the orchestration of the research question throughout a workflow that ensured legal, organizational, semantic and technological interoperability and (iii) a 'master-worker' federated computational architecture that supported the development of four uses cases. RESULTS: Nine participants nodes and 28 Euro-Peristat members completed the deployment of the infrastructure according to the expected outputs. As a consequence, each use case produced and published their own common data model, the analytical pipeline and the corresponding research outputs. All the digital objects were developed and published according to Open Science and FAIR principles. CONCLUSION: PHIRI has successfully supported the development of four use cases in a federated manner, overcoming limitations for the reuse of sensitive health data and providing a methodology to achieve interoperability in multiple research nodes.

Delayed treatment in breast cancer patients during the COVID-19 pandemic: a population health information research infrastructure (PHIRI) case study.

BACKGROUND: The indirect impact of the coronavirus disease 2019 pandemic on healthcare services was studied by assessing changes in the trend of the time to first treatment for women 18 or older who were diagnosed and treated for breast cancer between 2017 and 2021. METHODS: An observational retrospective longitudinal study based on aggregated data from four European Union (EU) countries/regions investigating the time it took to receive breast cancer treatment. We compiled outputs from a federated analysis to detect structural breakpoints, confirming the empirical breakpoints by differences between the trends observed and forecasted after March 2020. Finally, we built several segmented regressions to explore the association of contextual factors with the observed changes in treatment delays. RESULTS: We observed empirical structural breakpoints on the monthly median time to surgery trend in Aragon (ranging from 9.20 to 17.38 days), Marche (from 37.17 to 42.04 days) and Wales (from 28.67 to 35.08 days). On the contrary, no empirical structural breakpoints were observed in Belgium (ranging from 21.25 to 23.95 days) after the pandemic's beginning. Furthermore, we confirmed statistically significant differences between the observed trend and the forecasts for Aragon and Wales. Finally, we found the interaction between the region and the pandemic's start (before/after March 2020) significantly associated with the trend of delayed breast cancer treatment at the population level. CONCLUSIONS: Although they were not clinically relevant, only Aragon and Wales showed significant differences with expected delays after March 2020. However, experiences differed between countries/regions, pointing to structural factors other than the pandemic.

Has the COVID-19 pandemic changed existing patterns of non-COVID-19 health care utilization? A retrospective analysis of six regions in Europe.

BACKGROUND: Resilience of national health systems in Europe remains a major concern in times of multiple crises and as more evidence is emerging relating to the indirect effects of the COVID-19 pandemic on health care utilization (HCU), resulting from de-prioritization of regular, non-pandemic healthcare services. Most extant studies focus on regional, disease specific or early pandemic HCU creating difficulties in comparing across multiple countries. We provide a comparatively broad definition of HCU across multiple countries, with potential to expand across regions and timeframes. METHODS: Using a cross-country federated research infrastructure (FRI), we examined HCU for acute cardiovascular events, elective surgeries and serious trauma. Aggregated data were used in forecast modelling to identify changes from predicted European age-standardized counts via fitted regressions (2017-19), compared against post-pandemic data. RESULTS: We found that elective surgeries were most affected, universally falling below predicted levels in 2020. For cardiovascular HCU, we found lower-than-expected cases in every region for heart attacks and displayed large sex differences. Serious trauma was the least impacted by the COVID-19 pandemic. CONCLUSION: The strength of this study comes from the use of the European Population Health Information Research Infrastructure's (PHIRI) FRI, allowing for rapid analysis of regional differences to assess indirect impacts of events such as pandemics. There are marked differences in the capacity of services to return to normal in terms of elective surgery; additionally, we found considerable differences between men and women which requires further research on potential sex or gender patterns of HCU during crises.

Role of Exosomal miR-205-5p Cargo in Angiogenesis and Cell Migration.

Exosomes or small extracellular vesicles (sEVs) represent a pivotal component in intercellular communication, carrying a diverse array of biomolecules. Several factors can affect sEVs release dynamics, as occurs in hyperglycemia or inflammation. In fact, sEVs release has been associated with the promotion of physio-pathological processes. Among the sEVs cargo, microRNAs play an essential role in cell-to-cell regulation. More concretely, miR-205-5p is related to angiogenesis and cell proliferation. The aim of this study is to understand the specific role of sEVs containing miR-205-5p under high glucose conditions. ARPE-19 cells were cultured with high glucose (HG) for 5 days. sEVs were isolated and characterized. sEVs from ARPE-19 were used for angiogenesis and cell proliferation. HG increased sEVs release but downregulated miR-205-5p cargo expression compared to the control. sEVs from HG-treated ARPE-19 cells promoted tube formation and migration processes. In contrast, miR-205-5p overexpression (by mimic transfection) decreased angiogenesis and cell migration. Our results demonstrate how ARPE-19 cells respond to HG challenge by increasing sEVs with weak miR-205-5p cargo. The absence of this miRNA in sEVs is enough to promote angiogenesis. In contrast, restoring sEVs-miR-205-5p levels decreased it. These findings open new possibilities in sEVs-based therapies containing miR-205-5p against angiogenesis.

Small Extracellular Vesicles and Oxidative Pathophysiological Mechanisms in Retinal Degenerative Diseases.

This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related to or modulated by the oxidative burden of retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment, and in some instances, they might also be mediated by autophagy. The fate of these vesicles is diverse: they could end up in circulation being used as markers, or target neighbor cells modulating gene and protein expression, or eventually, in angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles' cargo or free circulating, in the regulation of retinal angiogenesis is also discussed.

Impact of telenurse-led intervention in clinical trials on health literacy, empowerment, and health outcomes in patients with solid tumours: a pilot quasi-experimental study.

BACKGROUND: During the COVID-19 pandemic, decentralised clinical trials incorporated self-monitoring, self-reporting, and telenursing tools to address health literacy and health empowerment of patients enrolled in clinical trials. We aimed to determine the impact of an educational intervention using telenursing consultations on health literacy, health empowerment, and health-related quality of life in cancer patients enrolled in clinical trials by measuring the level of satisfaction with the care received and assessing the views of healthcare professionals concerning the advanced practice nurse (APN) role in oncology clinical trials. METHODS: In this pilot analytical, descriptive, longitudinal, quasi-experimental, and pre-post test study, an educational intervention was conducted by 5 visits with an APN using synchronous teleconsultation in patients starting cancer treatment for the first time in a clinical trial (n = 60), and health professionals working with the APN (n = 31). A descriptive analysis of the samples and questionnaires were utilised along with statistical comparisons. RESULTS: After the intervention, patients' health literacy (31.7%), health empowerment (18.3%), and health-related quality of life (33.3%) increased (p < 0.05), with a decrease and trend towards resolution of care needs (p < 0.05). Satisfaction with the quality and care received in terms of perceived convenience, transition, and continuity of care showed positive results in 64.9 ± 20.7, 77.6 ± 19.5, and 72.1 ± 20.4 of respondents, respectively. On the overall assessment of the APN role, healthcare professionals expressed a high level of agreement with the statements related to their work performance. CONCLUSIONS: The data indicates that a clinical trial APN-led telenursing educational intervention results in an overall increase in health literacy, an improvement in health empowerment and health-related quality of life, and a decrease in care needs of oncology clinical trials patients. Patients stated that they received a high quality of care and health professionals indicated high levels of acceptance with APNs. Based on these results, we suggest that the APN role should gain more recognition in the Spanish healthcare system and their professional competencies should be aligned with those of other countries.

Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation. APPROACH AND RESULTS: The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA. CONCLUSIONS: Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.

How to study a highly toxic protein to bacteria: A case of voltage sensor domain of mouse sperm-specific sodium/proton exchanger.

Heterologous expression systems have been used as a powerful experimental strategy to study the function of many proteins, particularly ion transporters. For this experiment, it is fundamental to prepare an expression vector encoding a protein of interest. However, we encountered problems in vector preparation of the voltage sensor domain (VSD) of murine sperm-specific Na+/H+ exchanger (sNHE) due to its severe toxicity to bacteria. We overcame the problems by insertion of an amber stop codon or a synthetic intron into the coding sequence of the VSD in the expression vectors. Both methods allowed us to express the protein of interest in HEK293 cells (combined with a stop codon suppression system for amber codon). The VSD of mouse sNHE generates voltage-dependent outward ionic currents, which is a probable cause of toxicity to bacteria. We propose these two strategies as practical solutions to study the function of any protein toxic to bacteria.

Federated causal inference based on real-world observational data sources: application to a SARS-CoV-2 vaccine effectiveness assessment.

INTRODUCTION: Causal inference helps researchers and policy-makers to evaluate public health interventions. When comparing interventions or public health programs by leveraging observational sensitive individual-level data from populations crossing jurisdictional borders, a federated approach (as opposed to a pooling data approach) can be used. Approaching causal inference by re-using routinely collected observational data across different regions in a federated manner, is challenging and guidance is currently lacking. With the aim of filling this gap and allowing a rapid response in the case of a next pandemic, a methodological framework to develop studies attempting causal inference using federated cross-national sensitive observational data, is described and showcased within the European BeYond-COVID project. METHODS: A framework for approaching federated causal inference by re-using routinely collected observational data across different regions, based on principles of legal, organizational, semantic and technical interoperability, is proposed. The framework includes step-by-step guidance, from defining a research question, to establishing a causal model, identifying and specifying data requirements in a common data model, generating synthetic data, and developing an interoperable and reproducible analytical pipeline for distributed deployment. The conceptual and instrumental phase of the framework was demonstrated and an analytical pipeline implementing federated causal inference was prototyped using open-source software in preparation for the assessment of real-world effectiveness of SARS-CoV-2 primary vaccination in preventing infection in populations spanning different countries, integrating a data quality assessment, imputation of missing values, matching of exposed to unexposed individuals based on confounders identified in the causal model and a survival analysis within the matched population. RESULTS: The conceptual and instrumental phase of the proposed methodological framework was successfully demonstrated within the BY-COVID project. Different Findable, Accessible, Interoperable and Reusable (FAIR) research objects were produced, such as a study protocol, a data management plan, a common data model, a synthetic dataset and an interoperable analytical pipeline. CONCLUSIONS: The framework provides a systematic approach to address federated cross-national policy-relevant causal research questions based on sensitive population, health and care data in a privacy-preserving and interoperable way. The methodology and derived research objects can be re-used and contribute to pandemic preparedness.

The importance of CXCR4 expression in tumor stroma as a potential biomarker in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the main causes of cancer mortality in the world. A characteristic feature of this cancer is that a large part of the tumor volume is composed of a stroma with different cells and factors. Among these, we can highlight the cytokines, which perform their function through binding to their receptors. Given the impact of the CXCR4 receptor in the interactions between tumor cells and their microenvironment and its involvement in important signaling pathways in cancer, it is proposed as a very promising prognostic biomarker and as a goal for new targeted therapies. Numerous studies analyze the expression of CXCR4 but we suggest focusing on the expression of CXCR4 in the stroma. METHODS: Expression of CXCR4 in specimens from 33 patients with PDAC was evaluated by immunohistochemistry techniques and matched with clinicopathological parameters, overall and disease-free survival rates. RESULTS: The percentage of stroma was lower in non-tumor tissue (32.4 ± 5.2) than in tumor pancreatic tissue (67.4 ± 4.8), P-value = 0.001. The level of CXCR4 expression in stromal cells was diminished in non-tumor tissue (8.7 ± 4.6) and higher in tumor pancreatic tissue (23.5 ± 6.1), P-value = 0.022. No significant differences were identified in total cell count and inflammatory cells between non-tumor tissue and pancreatic tumor tissue. No association was observed between CXCR4 expression and any of the clinical or pathological data, overall and disease-free survival rates. Analyzing exclusively the stroma of tumor samples, the CXCR4 expression was associated with tumor differentiation, P-value = 0.05. CONCLUSIONS: In this study, we reflect the importance of CXCR4 expression in the stroma of patients diagnosed with PDAC. Our results revealed a high CXCR4 expression in the tumor stroma, which is related to a poor tumor differentiation. On the contrary, we could not find an association between CXCR4 expression and survival and the rest of the clinicopathological variables. Focusing the study on the CXCR4 expression in the tumor stroma could generate more robust results. Therefore, we consider it key to develop more studies to enlighten the role of this receptor in PDAC and its implication as a possible biomarker.

Sinorhizobium meliloti DnaJ Is Required for Surface Motility, Stress Tolerance, and for Efficient Nodulation and Symbiotic Nitrogen Fixation.

Bacterial surface motility is a complex microbial trait that contributes to host colonization. However, the knowledge about regulatory mechanisms that control surface translocation in rhizobia and their role in the establishment of symbiosis with legumes is still limited. Recently, 2-tridecanone (2-TDC) was identified as an infochemical in bacteria that hampers microbial colonization of plants. In the alfalfa symbiont Sinorhizobium meliloti, 2-TDC promotes a mode of surface motility that is mostly independent of flagella. To understand the mechanism of action of 2-TDC in S. meliloti and unveil genes putatively involved in plant colonization, Tn5 transposants derived from a flagellaless strain that were impaired in 2-TDC-induced surface spreading were isolated and genetically characterized. In one of the mutants, the gene coding for the chaperone DnaJ was inactivated. Characterization of this transposant and newly obtained flagella-minus and flagella-plus dnaJ deletion mutants revealed that DnaJ is essential for surface translocation, while it plays a minor role in swimming motility. DnaJ loss-of-function reduces salt and oxidative stress tolerance in S. meliloti and hinders the establishment of efficient symbiosis by affecting nodule formation efficiency, cellular infection, and nitrogen fixation. Intriguingly, the lack of DnaJ causes more severe defects in a flagellaless background. This work highlights the role of DnaJ in the free-living and symbiotic lifestyles of S. meliloti.

Gastrointestinal symptoms and complications in patients hospitalized due to COVID-19, an international multicentre prospective cohort study (TIVURON project).

BACKGROUND: Retrospective studies suggest that coronavirus disease (COVID-19) commonly involves gastrointestinal (GI) symptoms and complications. Our aim was to prospectively evaluate GI manifestations in patients hospitalized for COVID-19. METHODS: This international multicentre prospective cohort study recruited COVID-19 patients hospitalized at 31 centres in Spain, Mexico, Chile, and Poland, between May and September 2020. Patients were followed-up until 15 days post-discharge and completed comprehensive questionnaires assessing GI symptoms and complications. A descriptive analysis as well as a bivariate and multivariate analysis were performer using binary logistic regression. p<0.05 was considered significant. RESULTS: Eight hundred twenty-nine patients were enrolled; 129 (15.6%) had severe COVID-19, 113 (13.7%) required ICU admission, and 43 (5.2%) died. Upon admission, the most prevalent GI symptoms were anorexia (n=413; 49.8%), diarrhoea (n=327; 39.4%), nausea/vomiting (n=227; 27.4%), and abdominal pain (n=172; 20.7%), which were mild/moderate throughout the disease and resolved during follow-up. One-third of patients exhibited liver injury. Non-severe COVID-19 was associated with ≥2 GI symptoms upon admission (OR 0.679; 95% CI 0.464-0.995; p=0.046) or diarrhoea during hospitalization (OR 0.531; 95% CI 0.328-0.860; p=0.009). Multivariate analysis revealed that worse hospital outcomes were not independently associated with liver injury or GI symptoms. CONCLUSION: GI symptoms were more common than previously documented, and were mild, rapidly resolved, and not independently associated with COVID-19 severity. Liver injury was a frequent complication in hospitalized patients not independently associated with COVID-19 severity.

TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation.

BACKGROUND & AIMS: Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis. METHODS: TREM-2 expression was analyzed in the livers of patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Primary cultured Kupffer cells were incubated with lipopolysaccharide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed. RESULTS: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/- mice. This was characterized by enhanced necroptotic cell death, inflammatory responses and biliary expansion. Antibiotic treatment partially abrogated the effects observed in Trem-2-/- mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and dampened inflammatory gene transcription via a TREM-2-dependent mechanism. CONCLUSIONS: TREM-2 acts as a negative regulator of inflammation during cholestasis, representing a novel potential therapeutic target. LAY SUMMARY: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (specifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.

Aprotinin treatment against SARS-CoV-2: A randomized phase III study to evaluate the safety and efficacy of a pan-protease inhibitor for moderate COVID-19.

BACKGROUND: SARS-CoV-2 virus requires host proteases to cleave its spike protein to bind to its ACE2 target through a two-step furin-mediated entry mechanism. Aprotinin is a broad-spectrum protease inhibitor that has been employed as antiviral drug for other human respiratory viruses. Also, it has important anti-inflammatory properties for inhibiting the innate immunity contact system. METHODS: This was a multicentre, double-blind, randomized trial performed in four Spanish hospitals comparing standard treatment versus standard treatment + aprotinin for patients with COVID-19 between 20 May 2020 and 20 October 2021. The primary efficacy outcomes were length of hospital stay and ICU admission. The secondary endpoints were each of the primary efficacy outcomes and a composite of oxygen therapy, analytical parameters and death. Safety outcomes included adverse reactions to treatment during a 30-day follow-up period. Treatment was given for 11 days or till discharge. RESULTS: With almost identical analytical profiles, significant differences were observed in treatment time, which was 2 days lower in the aprotinin group (p = .002), and length of hospital admission, which was 5 days shorter in the aprotinin group (p = .003). The incidence of discharge was 2.19 times higher (HR: 2.188 [1.182-4.047]) in the aprotinin group than in the placebo group (p = .013). In addition, the aprotinin-treated group required less oxygen therapy and had no adverse reactions or side effects. CONCLUSION: Inhaled aprotinin may improve standard treatment and clinical outcomes in hospitalized patients with COVID-19, resulting in a shorter treatment time and hospitalization compared with the placebo group. The administration of aprotinin was safe.

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

Smartphone-Based Localization for Passengers Commuting in Traffic Hubs.

Passengers commute between different modes of transportation in traffic hubs, and passenger localization is a key component for the effective functioning of these spaces. The smartphone-based localization system presented in this work is based on the 3D step and heading approach, which is adapted depending on the position of the smartphone, i.e., held in the hand or in the front pocket of the trousers. We use the accelerometer, gyroscope and barometer embedded in the smartphone to detect the steps and the direction of movement of the passenger. To correct the accumulated error, we detect landmarks, particularly staircases and elevators. To test our localization algorithm, we have recorded real-world mobility data in a test station in Munich city center where we have ground truth points. We achieve a 3D position accuracy of 12 m for a smartphone held in the hand and 10 m when the phone is placed in the front pocket of the trousers.

Internalized Amyloid-ß (1-42) Peptide Inhibits the Store-Operated Calcium Entry in HT-22 Cells.

Dysregulation in calcium signaling pathways plays a major role in the initiation of Alzheimer's disease (AD) pathogenesis. Accumulative experimental evidence obtained with cellular and animal models, as well as with AD brain samples, points out the high cytotoxicity of soluble small oligomeric forms of amyloid-ß peptides (Aß) in AD. In recent works, we have proposed that Aß-calmodulin (CaM) complexation may play a major role in neuronal Ca2+ signaling, mediated by CaM-binding proteins (CaMBPs). STIM1, a recognized CaMBP, plays a key role in store-operated calcium entry (SOCE), and it has been shown that the SOCE function is diminished in AD, resulting in the instability of dendric spines and enhanced amyloidogenesis. In this work, we show that 2 and 5 h of incubation with 2 µM Aß(1-42) oligomers of the immortalized mouse hippocampal cell line HT-22 leads to the internalization of 62 ± 11 nM and 135 ± 15 nM of Aß(1-42), respectively. Internalized Aß(1-42) oligomers colocalize with the endoplasmic reticulum (ER) and co-immunoprecipitated with STIM1, unveiling that this protein is a novel target of Aß. Fluorescence resonance energy transfer measurements between STIM1 tagged with a green fluorescent protein (GFP) and Aß(1-42)-HiLyte™-Fluor555 show that STIM1 can bind nanomolar concentrations of Aß(1-42) oligomers at a site located close to the CaM-binding site in STIM1. Internalized Aß(1-42) produced dysregulation of the SOCE in the HT-22 cells before a sustained alteration of cytosolic Ca2+ homeostasis can be detected, and is elicited by only 2 h of incubation with 2 µM Aß(1-42) oligomers. We conclude that Aß(1-42)-induced SOCE dysregulation in HT-22 cells is caused by the inhibitory modulation of STIM1, and the partial activation of ER Ca2+-leak channels.