Search

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders with high rates of prevalence and mortality. MDD is pathophysiologically complex, and treatment options are limited. Blueberries are rich in polyphenols and have neuroprotective potential. The aim of this study was to investigate the effects of blueberry extract on neuroinflammatory and neuroplasticity parameters, as well as Na

This brief background highlights Brazil as a 'climate-health hotspot', i.e. a country where climate affects local populations negatively through multiple pathways (Di Napoli et al. BMC Public Health 22(1):1-8, 2022). Knowledge gaps still need to be filled concerning the various climaterelated dimensions of tourism, vector-borne diseases, mortality and morbidity in urban centers in the country (Krüger et al. Int J Biometeorol 66(7):1297-1315, 2022). Motivated by this, the first Brazilian Symposium on Human Biometeorology (Simpósio Brasileiro de Biometeorologia Humana 2022) was organized and held at the Federal University of Rio Grande do Norte (UFRN) in Natal, northeastern Brazil, between July 4 and 8, 2022. The symposium was organized as a hybrid event by a committee composed of researchers acting in different regions of the country, and who had an ongoing research collaboration on matters related to human biometeorology. The event was partly sponsored by the ISB and partly self-supported by the organizers and institutions involved. The symposium aimed to promote the development of the research area on human biometeorology in Brazil in facing challenges imposed by a globally and locally changing climate. To achieve this, the symposium focused on five main topics of discussion: a) climate-driven diseases; b) thermal comfort, urban and architectural biometeorology; c) atmospheric pollution and health; d) climate change; e) climate, health and climate change. This summary highlights the main findings, future research directions, and policy implications in each topic from the presentations and panel discussions.

This work aims to analyze the relationship between meteorological conditions and the occurrence of hospital admissions for pneumonia in children under 5 years of age in the Metropolitan Region of Porto Alegre, Brazil, from 1998 to 2017. To this end, data from hospital admissions obtained from the Unified Health System database (DATASUS) were used and classified into two groups: acute respiratory infections (ARI) and asthma, according to the international classification of diseases, tenth edition (ICD-10). Data regarding meteorological variables were also used: temperature, relative humidity, atmospheric pressure and wind speed, at 12Z and 18Z, as well as the Thermal Comfort Index (TCI), Effective Temperature as a function of the wind (ETw) and Windchill (W). From the data obtained, a descriptive analysis of the diseases and a statistical analysis with the analysis of correlation and main components were performed. Results showed that pneumonia (catalogued in the ICD-10 as J12 to J18) was the main cause of hospitalizations in children. The annual, monthly and daily hospitalization frequency distributions showed higher rates of admissions occurring in the months of May to September. The peaks of admissions and high admissions (HA) occurred mainly in the winter months (June, July and August), and in 1998. Meanwhile, the correlation and principal component analysis showed an increase in hospital admissions due to pneumonia related to a decrease in temperature and ETw and W indices (negative anomalies) and an increase in atmospheric pressure and relative humidity (positive anomalies).

The persistence of leukemic stem cells (LSCs) represents a problem in the therapy of chronic myeloid leukemia (CML). Hence, it is of utmost importance to explore the underlying mechanisms to develop new therapeutic approaches to cure CML. Using the genetically engineered ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML, we previously demonstrated that the loss of the docking protein GAB2 counteracts the infiltration of mast cells (MCs) in the bone marrow (BM) of BCR::ABL1 positive mice. Here, we show for the first time that BCR::ABL1 drives the cytokine independent expansion of BM derived MCs and sensitizes them for FcεRI triggered degranulation. Importantly, we demonstrate that genetic mast cell deficiency conferred by the Cpa3Cre allele prevents BCR::ABL1 induced splenomegaly and impairs the production of pro-inflammatory cytokines. Furthermore, we show in CML patients that splenomegaly is associated with high BM MC counts and that upregulation of pro-inflammatory cytokines in patient serum samples correlates with tryptase levels. Finally, MC-associated transcripts were elevated in human CML BM samples. Thus, our study identifies MCs as essential contributors to disease progression and suggests considering them as an additional target in CML therapy.

To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.

Automotive and engine technology (2022). doi:10.1007/s41104-022-00106-8, Published by Springer International Publishing, [Cham, Switzerland]

This systematic review aims to give an overview of the diversity of research areas related to human biometeorology in Brazil. The main focus of this paper addresses research trends, represented by published papers with national and international authorship, main contributions and shortcomings, as well as challenges and prospects of research in this area of study. An extensive literature search was conducted in the Scopus, Web of Science, and Science Direct databases so as to identify relevant publication output up to July 2021 related to the research area. The screening resulted in 96 studies chosen for full-text reading. Overall, results indicated a reduced amount of articles on the subject matter published internationally, with noticeable gaps in research in some regions of the country, such as the Amazon region and in the Brazilian Midwest region. Research gaps in relevant areas have been identified with limited output in the climate dimensions of tourism, vector-borne diseases, mortality and morbidity in urban centers. Such gaps should further encourage researchers to engage in research focused on those areas.

We study the relation between board gender diversity and goodwill (GW). GW on the balance sheet is connected to both the firm’s risk-taking and its accounting conservatism which are two popular topics in how gender diversity affects the governance of firms. GW captures the firm’s decision to acquire another business for a price exceeding the received identifiable net assets and the subsequent valuation of the purchase. We propose that board decisions affecting GW could depict information about board gender diversity and its potential effects. Specifically, we examine Nordic listed firms in the period 2009–2018, to determine whether and how female representation on the board of directors is linked to the GW change. Big GW increases are associated with risk-taking and GW write-downs are signs of conservative accounting. Thus, we hypothesize and evidence that firms with substantial GW increases (decreases) are associated with fewer (more) women on the board. These results provide insight on board composition and potentially also on good governance and their consequences for strategic decision-making. Our findings contribute to the board diversity literature in accounting and corporate governance.

This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1 mg/kg), scopolamine plus inosine (50 mg/kg), and scopolamine plus inosine (100 mg/kg). Inosine was pre-administered for 7 days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24 hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer’s disease.

This study aimed to evaluate the effect of three hydrofluoric acid (HF) etching periods on the micro-tensile bond strength between two CAD–CAM ceramic systems [Vita Suprinity (VS) and feldspathic CEREC blocs (CB)] and a composite resin. The ceramics were categorized into six groups based on the surface conditioning protocol used, as follows: G1: CB-HF 5% for 20 s; G2: CB-HF 5% for 40 s; G3: CB-HF 5% for 60 s; G4: VS-HF 5% for 20 s; G5: VS-HF 5% for 40 s; G6: VS-HF 5% for 60 s. Scotchbond Universal was applied onto the pretreated ceramic surfaces and covered with Filtek Z350 XT composite resin. After 24 h, the specimens were cut into microbars (n = 16) and a micro-tensile bond strength test (μTBS) was carried out. An optical microscope was used to examine the fractured microbars. The results showed statistically significant differences between the factors tested (p

Bipolar disorder (BD) is a complex psychiatric disease characterized by mood swings that include episodes of mania and depression. Given its cyclical nature, BD is especially hard to model; however, the standard practice has been to mimic manic episodes in animal models. Despite scientific advances, the pathophysiology of BD is not fully understood, and treatment remains limited. In the last years, natural products have emerged as potential neuroprotective agents for the treatment of psychiatric diseases. Thus, the aim of this review was to explore the therapeutic potential of natural compounds and derivatives against BD, taking into account preclinical and clinical studies. Reliable articles indexed in databases such as PubMed, Web of Science and Science Direct were used. In clinical studies, treatment with herbal plants extracts, omega-3, inositol, n-acetylcysteine and vitamin D has been associated with a clinical improvement in symptoms of mania and depression in BD patients. In animal models, it has been shown that red fruits extracts, curcumin, quercetin, gallic acid, alpha-lipoic acid and carvone can modulate many neurochemical pathways involved in the pathophysiology of manic episodes. Thus, this review appointed the advances in the consumption of natural compounds and derivatives as an important therapeutic strategy to mitigate the symptoms of BD.

Neuroinflammation is an event that occurs in several pathologies of brain. Rubus sp. (blackberry) is a powerful antioxidant fruit, and its extract has neuroprotective activity. The aim of this study was to investigate the blackberry extract properties on lipopolysaccharide (LPS)-induced neuroinflammation, in relation to oxidative parameters and acetylcholinesterase activity in the brain structures of mice. We also investigated interleukin-10 levels in serum. Mice were submitted to Rubus sp. extract treatment once daily for 14 days. On the fifteenth day, LPS was injected in a single dose. LPS induced oxidative brain damage and the blackberry extract demonstrated preventive effects in LPS-challenged mice. LPS administration increased reactive oxygen species levels in the cerebral cortex and striatum, as well as lipid peroxidation in the cerebral cortex. However, the blackberry extract prevented all these parameters. Furthermore, LPS decreased thiol content in the striatum and hippocampus, while a neuroprotective effect of blackberry extract treatment was observed in relation to this parameter. The blackberry extract also prevented a decrease in catalase activity in all the brain structures and of superoxide dismutase in the striatum. An increase in acetylcholinesterase activity was detected in the cerebral cortex in the LPS group, but this activity was decreased in the Rubus sp. extract group. Serum IL-10 levels were reduced by LPS, and the extract was not able to prevent this change. Finally, we observed an antioxidant effect of blackberry extract in LPS-challenged mice suggesting that this anthocyanin-rich extract could be considered as a potential nutritional therapeutic agent for preventive damage associated with neuroinflammation.

This article discusses web collection of interest group statements on bills as a data source. Written statements allow the identification of actors active in policy-making as well as those actors’ positions, lobbying coalitions and issue saliency. These data also can contribute to the measurement of interest groups’ influence on legislation. Taking web collection from the German parliament’s and ministries’ web pages as an example, we demonstrate the collection process and the merits and limitations of employing written statements as identificatory data. Our analysis of statements submitted by interest groups, private firms and policy experts to four federal ministries and the respective parliamentary committees in the years 2015 and 2016 reveals differences between parliamentary and ministerial consultations. Although ministries have invited written statements for fewer draft laws than parliamentary committees, they received far more statements from interest groups. The reason is that German ministries often issue open calls, in which all actors are given the opportunity to comment on legislation, whereas the German parliament invites selected interest group representatives and other experts. As a further result, ministries are mostly contacted by business groups, whereas parliamentary committees use their gatekeeper function to balance interests.

Depression is an emotional disorder that causes mental and physical changes, and has limited pharmacotherapy. Tannic acid (TA) is a polyphenol with previously described antioxidant and neuroprotective properties. The aim of this study was to evaluate the effects of TA on lipopolysaccharide (LPS)-induced depressive-like behavior, as well as oxidative stress parameters and TNF-α levels in the brains of mice. Animals were pretreated once daily, with TA (30 or 60 mg/kg), fluoxetine (20 mg/kg) or vehicle for 7 days. On the 7th day, the animals received a single injection of LPS (830 μg/kg). After 24 h, open field, forced swimming, tail suspension, and splash tests were conducted. The endotoxin induced depressive-like behavior in these mice and this was attenuated by TA. In the cerebral cortex, hippocampus, and striatum, LPS increased lipid peroxidation and reactive oxygen species production, and this was also prevented by TA administration. TA treatment also prevented a decrease in catalase activity within the striatum. Further, LPS administration caused increased levels of TNF-α in all brain structures, and this was prevented in the cortex by TA treatment. In conclusion, TA shows many neuroprotective properties, with demonstrated antioxidant, anti-inflammatory and antidepressant effects in this animal model of acute depressive-like behavior. Therefore, this compound could provide an alternative therapeutic approach for the treatment of depression.

Glioblastoma (GBM) is the most common adult primary tumor of the CNS characterized by rapid growth and diffuse invasiveness into the brain parenchyma. The GBM resistance to chemotherapeutic drugs may be due to the presence of cancer stem cells (CSCs). The CSCs activate the same molecular pathways as healthy stem cells such as WNT, Sonic hedgehog (SHH), and Notch. Mutations or deregulations of those pathways play a key role in the proliferation and differentiation of their surrounding environment, leading to tumorigenesis. Here we investigated the effect of SHH signaling pathway inhibition in human GBM cells by using GANT-61, considering stem cell phenotype, cell proliferation, and cell death. Our results demonstrated that GANT-61 induces apoptosis and autophagy in GBM cells, by increasing the expression of LC3 II and cleaved caspase 3 and 9. Moreover, we observed that SHH signaling plays a crucial role in CSC phenotype maintenance, being also involved in the epithelial-mesenchymal transition (EMT) phenotype. We also noted that SHH pathway modulation can regulate cell proliferation as revealed through the analysis of Ki-67 and c-MYC expressions. We concluded that SHH signaling pathway inhibition may be a promising therapeutic approach to treat patients suffering from GBM refractory to traditional treatments.

Fusion proteins involving the BRAF serine/threonine kinase occur in many cancers. The oncogenic potential of BRAF fusions has been attributed to the loss of critical N-terminal domains that mediate BRAF autoinhibition. We used whole-exome and RNA sequencing in a patient with glioblastoma multiforme to identify a rearrangement between TTYH3, encoding a membrane-resident, calcium-activated chloride channel, and BRAF intron 1, resulting in a TTYH3–BRAF fusion protein that retained all features essential for BRAF autoinhibition. Accordingly, the BRAF moiety of the fusion protein alone, which represents full-length BRAF without the amino acids encoded by exon 1 (BRAFΔE1), did not induce MEK/ERK phosphorylation or transformation. Likewise, neither the TTYH3 moiety of the fusion protein nor full-length TTYH3 provoked ERK pathway activity or transformation. In contrast, TTYH3–BRAF displayed increased MEK phosphorylation potential and transforming activity, which were caused by TTYH3-mediated tethering of near-full-length BRAF to the (endo)membrane system. Consistent with this mechanism, a synthetic approach, in which BRAFΔE1 was tethered to the membrane by fusing it to the cytoplasmic tail of CD8 also induced transformation. Furthermore, we demonstrate that TTYH3–BRAF signals largely independent of a functional RAS binding domain, but requires an intact BRAF dimer interface and activation loop phosphorylation sites. Cells expressing TTYH3–BRAF exhibited increased MEK/ERK signaling, which was blocked by clinically achievable concentrations of sorafenib, trametinib, and the paradox breaker PLX8394. These data provide the first example of a fully autoinhibited BRAF protein whose oncogenic potential is dictated by a distinct fusion partner and not by a structural change in BRAF itself.

Copy number gains, point mutations and epigenetic silencing events are increasingly observed in genes encoding elements of the Ras/Raf/MEK/ERK signaling axis in human breast cancer. The three Raf kinases A-Raf, B-Raf, and Raf-1 have an important role as gatekeepers in ERK pathway activation and are often dysregulated by somatic alterations of their genes or by the aberrant activity of receptor tyrosine kinases (RTKs) and Ras-GTPases. B-Raf represents the most potent Raf isoform and a critical effector downstream of RTKs and RAS proteins. Aberrant RTK signaling is mimicked by the polyoma middle T antigen (PyMT), which activates various oncogenic signaling pathways, incl. the RAS/ERK axis, in a similar manner as RTKs in human breast cancer. Mammary epithelial cell directed expression of PyMT in mice by the MMTV-PyMT transgene induces mammary hyperplasia progressing over adenoma to metastatic breast cancer with an almost complete penetrance. To understand the functional role of B-Raf in this model for luminal type B breast cancer, we crossed MMTV-PyMT mice with animals that either lack B-Raf expression in the mammary gland or express the signaling impaired B-RafAVKA mutant. The AVKA mutation prevents phosphorylation of T599 and S602 in the B-Raf activation loop and thereby activation of the kinase by upstream signals. We demonstrate for the first time that B-Raf expression and activation is important for tumor initiation in vivo as well as for lung metastasis. Isogenic tumor cell lines generated from conditional Braf knock-out or knock-in mice displayed a reduction in EGF-induced ERK pathway activity as well as in proliferation and invasive growth in three-dimensional matrigel cultures. Our results suggest that B-Raf, which has been hardly studied in the context of breast cancer, represents a critical effector of the PyMT oncoprotein and invite for an assessment of its functional role in human breast cancer.

Glioblastoma is an extremely aggressive and deadly brain tumor known for its striking cellular heterogeneity and capability to communicate with microenvironment components, such as microglia. Microglia-glioblastoma interaction contributes to an increase in tumor invasiveness, and Wnt signaling pathway is one of the main cascades related to tumor progression through changes in cell migration and invasion. However, very little is known about the role of canonical Wnt signaling during microglia-glioblastoma crosstalk. Here, we show for the first time that Wnt3a is one of the factors that regulate interactions between microglia and glioblastoma cells. Wnt3a activates the Wnt/β-catenin signaling of both glioblastoma and microglial cells. Glioblastoma-conditioned medium not only induces nuclear translocation of microglial β-catenin but also increases microglia viability and proliferation as well as Wnt3a, cyclin-D1, and c-myc expression. Moreover, glioblastoma-derived Wnt3a increases microglial ARG-1 and STI1 expression, followed by an upregulation of IL-10 mRNA levels, and a decrease in IL1β gene expression. The presence of Wnt3a in microglia-glioblastoma co-cultures increases the formation of membrane nanotubes accompanied by changes in migration capability. In vivo, tumors formed from Wnt3a-stimulated glioblastoma cells presented greater microglial infiltration and more aggressive characteristics such as growth rate than untreated tumors. Thus, we propose that Wnt3a belongs to the arsenal of factors capable of stimulating the induction of M2-like phenotype on microglial cells, which contributes to the poor prognostic of glioblastoma, reinforcing that Wnt/β-catenin pathway can be a potential therapeutic target to attenuate glioblastoma progression.