RESUMEN

A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status.

RESUMEN

Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.

Asunto(s)

RESUMEN

BACKGROUND: Pregnant and postpartum women infected by COVID-19 are at increased risk of adverse outcomes, including negative effects on their mental health. Brazilian maternal mortality rate due to COVID-19 is 2.5 times higher than overall mortality rates. This study aimed to understand how pregnant/postpartum women experienced the COVID-19 suspicion/investigation or confirmed infection in different Brazilian cities, the pandemic's consequences to women and their families, and their needs to improve maternal health services during public health emergencies. METHODS: We conducted a qualitative study with 27 women with COVID-19 and 6 of their family members, as part of a multicenter study among 15 maternity hospitals in Brazil. We applied in-depth interviews through telephone calls when women received the diagnostic or had a suspect infection and after 60 days. Another semi-structured interview was applied to their close family members. The interviews were considered through thematic analysis. RESULTS: From the thematic content analysis three major themes emerged from the first and second interviews: (Cucinotta and Vanelli, 2020) assistance received by the woman and newborn in the medical services; (World Health Organization (WHO) 2021) stigma/fear of contamination from health workers and from family and friends reported by the women; (Allotey et al., 2020) the COVID-19 pandemic impact. CONCLUSION: Before the availability of the COVID-19 vaccine, pregnant women experienced fear of death, hospitalization, quarantine, loss of family members, and financial repercussions, resulting in physical, psychological, and socioeconomic impacts on these women's lives.

Asunto(s)

RESUMEN

The slow action of fungi is one of the biggest challenges in using entomopathogenic fungi. A promising alternative to reduce the time of action is to combine conidia with extracellular enzymes. This study aimed to characterize the production of Pr1 subtilisin protease and lipases by Beauveria bassiana and Metarhizium anisopliae in different culture media and to evaluate the efficiency of the enzymatic treatment against Aphis gossypii and Spodoptera frugiperda. The isolates were cultivated in five different liquid cultures, and, after 7 days, the culture was filtered and centrifuged, and the activity of the Pr1 and lipases was measured. The fungi cultured in a Luria-Bertani broth medium had the highest activity of proteases and lipases. The mortality of A. gossypii nymphs treated with conidia 7 days after the treatment was 39% (JEF-410), 76.5% (JEF-492), 74.8% (ERL-836), and 70.9% (JEF-214). The B. bassiana JEF-410 supernatant combined with conidia increased the fungal virulence at day 5 and day 6 after treatment. When S. frugiperda larvae were treated with B. bassiana JEF-492 conidia combined with its supernatant, the time of infection was shorter compared to the larvae treated with conidia only. Once the supernatant was incubated at 37 °C, the relative activity decreased from 100% to 80% after 2 h and to 45% after 24 h. The results suggest that the supernatant of entomopathogenic fungi may be formulated and used as a biopesticide in an efficient strategy for the biological control of pests.

RESUMEN

In this paper, we present a comprehensive computational framework aimed at suggesting genes whose transcriptional regulation is likely to be influenced by their chromosomal position. This framework provides a user-friendly web interface, enabling researchers to explore the positional properties of all human genes and their orthologs across species, with a focus on their relation to the telomeres. Our approach involves multiple scoring methods, each adjustable by users, representing different features of the genes' positional variation across species. The resulting rankings can be combined to identify candidate genes that may be subject to position effects. Furthermore, the ranking can be tailored to a specific set of reference genes. We evaluate the method within the context of TPE-OLD, a mechanism where telomeres can exert a direct influence on gene expression across considerable genomic distances, and empower researchers to delve deeper into genes of interest, analyzing their position across species and estimating their susceptibility to position effects like TPE-OLD. We also provide simple enrichment analyses of user-provided gene lists in relation to top-ranking candidate genes.

Asunto(s)

RESUMEN

Pressure-induced transformations in an archetypal chalcogenide glass (GeSe2) have been investigated up to 157 GPa by X-ray absorption spectroscopy (XAS) and molecular dynamics (MD) simulations. Ge and Se K-edge XAS data allowed simultaneous tracking of the correlated local structural and electronic changes at both Ge and Se sites. Thanks to the simultaneous analysis of extended X-ray absorption fine structure (EXAFS) signals of both edges, reliable quantitative information about the evolution of the first neighbor Ge-Se distribution could be obtained. It also allowed to account for contributions of the Ge-Ge and Se-Se bond distributions (chemical disorder). The low-density to high-density amorphous-amorphous transformation was found to occur within 10 to 30 GPa pressure range, but the conversion from tetrahedral to octahedral coordination of the Ge sites is completed above [Formula: see text] 80 GPa. No convincing evidence of another high-density amorphous state with coordination number larger than six was found within the investigated pressure range. The number of short Ge-Ge and Se-Se "wrong" bonds was found to increase upon pressurization. Experimental XAS results are confirmed by MD simulations, indicating the increase of chemical disorder under high pressure.

Asunto(s)

RESUMEN

OBJECTIVES: To compare maternal and perinatal outcomes among women with obesity, overweight, and normal body mass index, associated with COVID-19 infection during pregnancy and postpartum. METHOD: Prospective Cohort Study, within the REBRACO (Brazilian Network of COVID-19 in Pregnancy) multicenter initiative. Confirmed positive cases of SARS-CoV-2 were included, and women categorized into three groups according to their pre-pregnancy BMI: obesity (BMI ≥ 30), overweight (BMI <30 but >25), and normal BMI. Sociodemographic, clinical, and obstetric characteristics and different maternal and perinatal outcomes were compared, and a multiple regression analysis was performed to investigate factors independently associated with adverse maternal and perinatal outcomes. RESULTS: Two hundred eighty-nine women positive for SARS-CoV-2 infection were considered, and 202 had available data on maternal BMI for the current analysis. Overall, 72 (35.6%)obese, 68 (33.6%) overweight, and 60 (29.7%) normal BMI. Obesity was associated with increased adverse clinical outcomes including sepsis (P = 0.02), acute respiratory distress syndrome (P = 0.002), and the need for mechanical ventilation (P = 0.044). Considering perinatal outcomes, a multiple regression model confirmed obesity as an independent factor associated with adverse results (adjusted odds ratio 3.73, 95% CI 1.54-9.08). CONCLUSION: Obesity and overweight were associated with worse clinical outcomes, severe/critical COVID-19, and adverse perinatal outcomes.

Asunto(s)

RESUMEN

The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n=5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE-ε4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE-ε4 genotype adjustment, a finding which we replicate in an external cohort (n=719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE-ε4. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.

RESUMEN

The deformation of hemispherical sessile bubbles made of ferrofluid soap under vertical uniform magnetic fields was studied using Helmholtz coils. The deformation and the shape of the bubbles were monitored according to the amplitude of the magnetic field, the initial volume of the bubbles and the ferrofluid volume used to create them. The meniscus was found to bear most of the deformation, reshaping into a cylinder, with the remainder of the bubble forming a spherical cap, mainly adapting to the meniscus transformation. The growth of the meniscus height was rationalised using a simple model. More precisely, the meniscus shape depends on the competition between capillary, gravity and magnetic effects. These three ingredients can be rewritten to highlight two characteristic lengths of the system: the capillary and the magnetic lengths. Depending on the magnetic field intensity, the shape of the meniscus is described by one of the two lengths, thus revealing the existence of two distinct regimes.

RESUMEN

Despite the great success of hybrid CH3NH3PbI3 perovskite in photovoltaics, ascribed to its excellent optical absorption properties, its instability toward moisture is still an insurmountable drawback. All-inorganic perovskites are much less sensitive to humidity and have potential interest for solar cell applications. Alternative strategies have been developed to design novel materials with appealing properties, which include different topologies for the octahedral arrangements from three-dimensional (3D, e.g., CsPbBr3 perovskite) or two-dimensional (2D, e.g., CsPb2Br5) to zero-dimensional (0D, i.e., without connection between octahedra), as the case of Cs4PbX6 (X = Br, I) halides. The crystal structure of these materials is complex, and their thermal evolution is unexplored. In this work, we describe the synthesis of Cs4PbBr6-xIx (x = 0, 2, 4, 6) halides by mechanochemical procedures with green credentials; these specimens display excellent crystallinity enabling a detailed structural investigation from synchrotron X-ray powder diffraction (SXRD) data, essential to revisit some features in the temperature range of 90-298 K. In all this regime, the structure is defined in the trigonal R3̅c space group (#167). The presence of Cs and X vacancies suggests some ionic mobility into the crystal structure of these 0D halides. Bond valence maps (BVMs) are useful in determining isovalent surfaces for both Cs4PbBr6 and Cs4PbI6 phases, unveiling the likely ionic pathways for cesium and bromide ions and showing a full 3D connection in the bromide phase, in contrast to the iodide one. On the other hand, the evolution of the anisotropic displacement parameters is useful to evaluate the Debye temperatures, confirming that Cs atoms have more freedom to move, while Pb is more confined at its site, likely due to a higher covalency degree in Pb-X bonds than that in Cs-X bonds. Diffuse reflectance ultraviolet-visible (UV-vis) spectroscopy shows that the optical band gap can be tuned depending on iodine content (x) in the range of 3.6-3.06 eV. From density functional theory (DFT) simulations, the general trend of reducing the band gap when Br is replaced by I is well reproduced.

RESUMEN

Pressure-induced transformations in glassy GeSe2have been studied using the x-ray absorption spectroscopy. Experiments have been carried out at the scanning-energy beamline BM23 (European Synchrotron Radiation Facility) providing a micrometric x-ray focal spot up to pressures of about 45 GPa in a diamond anvil cell. Both Se and Ge K-edge experiments were performed under different hydrostatic conditions identifying the metallization onsets by accurate determinations of the edge shifts. The semiconductor-metal transition was observed to be completed around 20 GPa when neon was used as a pressure transmitting medium (PTM), while this transition was slightly shifted to lower pressures when no PTM was used. Accurate double-edge extended x-ray absorption fine structure (EXAFS) refinements were carried out using advanced data-analysis methods. EXAFS data-analysis confirmed the trend shown by the edge shifts for this disordered material, showing that the transition from tetrahedral to octahedral coordination for Ge sites is not fully achieved at 45 GPa. Results of present high pressure EXAFS experiments have shown the absence of significant neon incorporation into the glass within the pressure range up to 45 GPa.

RESUMEN

The aim of this technical note is to describe a protocol for three-dimensional virtual simulation of orthognathic surgery that has been designed to be easily implemented, without the need for any special clinical apparatus, software brand, or computed tomography sequence. The protocol comprises innovative concepts and simplified steps for image segmentation, creation of a composite skull, control of the condylar position, and sequencing of bimaxillary surgery. This protocol was applied by the developers in about 2000 cases performed between 2015 and 2022, and has become quite popular among local surgeons. Previous preliminary studies have shown that it meets the accuracy standards for clinical use, although further studies with larger numbers of patients are desirable for additional validation.

Asunto(s)

RESUMEN

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables. METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

Asunto(s)

RESUMEN

BACKGROUND: The objective of our study was to evaluate a single blood collection tube with a novel antithrombotic formulation to measure both hematological, biochemical, and d-dimer analytes. METHODS: Paired samples of gold standard blood tubes (EDTA, lithium heparin, sodium citrate) and a new antithrombotic formulation blood tube were collected from 187 patients. The new antithrombotic tube is a lithium heparin tube preloaded with a liquid form of prostacyclin analog. The novel tube was tested on seventeen hematological parameters and smears against EDTA, on fourteen biochemical parameters against lithium heparin and on d-dimer against sodium citrate. RESULTS: All correlation coefficients were close to 0.99. The Bland-Altman analyses presented a satisfactory correspondence for all analytes. All the hematological examinations demonstrated comparable results between EDTA and the novel formulation, except for platelet counts analyzed by impedance method, but not by fluorescence. We detected lower mean platelet volume with/without outliers (5.06%)/(5.13%) in the novel formulation and increased mean corpuscular hemoglobin concentration (2.55%). All the biochemistry analytes demonstrated comparable results between lithium heparin and the novel tube. d-dimer showed comparable results between citrated blood and the novel formulation after dilution correction. CONCLUSIONS: We describe a novel antithrombotic formulation tube with the potential to be introduced into clinical laboratories for simultaneous analysis of thirty-two blood analytes.

Asunto(s)

RESUMEN

Brazil presented a very high number of maternal deaths and evident delays in healthcare. We aimed at evaluating the characteristics of SARS-CoV-2 infection and associated outcomes in the obstetric population. We conducted a prospective cohort study in 15 Brazilian centers including symptomatic pregnant or postpartum women with suspected COVID-19 from Feb/2020 to Feb/2021. Women were followed from suspected infection until the end of pregnancy. We analyzed maternal characteristics and pregnancy outcomes associated with confirmed COVID-19 infection and SARS, determining unadjusted risk ratios. In total, 729 symptomatic women with suspected COVID-19 were initially included. Among those investigated for COVID-19, 51.3% (n = 289) were confirmed COVID-19 and 48% (n = 270) were negative. Initially (before May 15th), only 52.9% of the suspected cases were tested and it was the period with the highest proportion of ICU admission and maternal deaths. Non-white ethnicity (RR 1.78 [1.04-3.04]), primary schooling or less (RR 2.16 [1.21-3.87]), being overweight (RR 4.34 [1.04-19.01]) or obese (RR 6.55 [1.57-27.37]), having public prenatal care (RR 2.16 [1.01-4.68]), planned pregnancies (RR 2.09 [1.15-3.78]), onset of infection in postpartum period (RR 6.00 [1.37-26.26]), chronic hypertension (RR 2.15 [1.37-4.10]), pre-existing diabetes (RR 3.20 [1.37-7.46]), asthma (RR 2.22 [1.14-4.34]), and anaemia (RR 3.15 [1.14-8.71]) were associated with higher risk for SARS. The availability of tests and maternal outcomes varied throughout the pandemic period of the study; the beginning was the most challenging period, with worse outcomes. Socially vulnerable, postpartum and previously ill women were more likely to present SARS related to COVID-19.

Asunto(s)

RESUMEN

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.

Asunto(s)