Bursa-Derived cells show a distinct mechano-response to physiological and pathological loading in vitro

The mechano-response of highly loaded tissues such as bones or tendons is well investigated, but knowledge regarding the mechano-responsiveness of adjacent tissues such as the subacromial bursa is missing. For a better understanding of the physiological role of the bursa as a friction-reducing structure in the joint, the study aimed to analyze whether and how bursa-derived cells respond to physiological and pathological mechanical loading. This might help to overcome some of the controversies in the field regarding the role of the bursa in the development and healing of shoulder pathologies. Cells of six donors seeded on collagen-coated silicon dishes were stimulated over 3 days for 1 or 4 h with 1, 5, or 10% strain. Orientation of the actin cytoskeleton, YAP nuclear translocation, and activation of non-muscle myosin II (NMM-II) were evaluated for 4 h stimulations to get a deeper insight into mechano-transduction processes. To investigate the potential of bursa-derived cells to adapt their matrix formation and remodeling according to mechanical loading, outcome measures included cell viability, gene expression of extracellular matrix and remodeling markers, and protein secretions. The orientation angle of the actin cytoskeleton increased toward a more perpendicular direction with increased loading and lowest variations for the 5% loading group. With 10% tension load, cells were visibly stressed, indicated by loss in actin density and slightly reduced cell viability. A significantly increased YAP nuclear translocation occurred for the 1% loading group with a similar trend for the 5% group. NMM-II activation was weak for all stimulation conditions. On the gene expression level, only the expression of TIMP2 was down-regulated in the 1 h group compared to control. On the protein level, collagen type I and MMP2 increased with higher/longer straining, respectively, whereas TIMP1 secretion was reduced, resulting in an MMP/TIMP imbalance. In conclusion, this study documents for the first time a clear mechano-responsiveness in bursa-derived cells with activation of mechano-transduction pathways and thus hint to a physiological function of mechanical loading in bursa-derived cells. This study represents the basis for further investigations, which might lead to improved treatment options of subacromial bursa-related pathologies in the future

Understanding and tackling snakebite envenoming with transdisciplinary research

Snakebite envenoming (SBE) is a neglected tropical disease (NTD) of high global impact. The World Health Organization (WHO) estimates 4.5 to 5.4 million people are bitten by snakes annually, resulting in 1.8 to 2.7 million envenomings, 81,000 to 138,000 deaths, and at least 400,000 people suffering from physical or psychological sequelae. SBE mostly affects impoverished rural populations in sub-Saharan Africa, Asia, Latin America, and parts of Oceania, thus fueling a vicious cycle of poverty and illness. SBE not only affects humans, but also domestic animals, including livestock, with negative social and economic consequences. This requires a better understanding of the complex social, cultural, and ecological contexts where SBE occurs, within the conceptual frame of One Health, an integrated approach that recognizes the health of humans, animals, and the environment as closely linked and interdependent. Such complexity demands more integrative approaches for better understanding and confronting this disease. SBE has unique features that make its prevention and control challenging. Unlike many infectious diseases, SBE cannot be eradicated, but its incidence and impact can be reduced through effective programs aimed at better prevention and rapid access to treatment. This in turn demands the engagement of communities to improve the cohabitation of humans, domestic animals, and snakes in rural agroecosystems. In 2019, the WHO launched a strategy for the prevention and control of SBE, aimed at halving the deaths and disabilities caused by this NTD by the year 2030. This strategy is based on 4 pillars, i.e., empower and engage communities; ensure safe, effective treatment; strengthen health systems; and increase partnerships, coordination, and resources. Building on previous ideas and publications, this article discusses and advocates for transdisciplinary research on SBE and for promoting dialogue and collaboration between sectors, particularly by engaging communities affected by SBE at all levels of the research process

Understanding and tackling snakebite envenoming with transdisciplinary research

Snakebite envenoming (SBE) is a neglected tropical disease (NTD) of high global impact. The World Health Organization (WHO) estimates 4.5 to 5.4 million people are bitten by snakes annually, resulting in 1.8 to 2.7 million envenomings, 81,000 to 138,000 deaths, and at least 400,000 people suffering from physical or psychological sequelae. SBE mostly affects impoverished rural populations in sub-Saharan Africa, Asia, Latin America, and parts of Oceania, thus fueling a vicious cycle of poverty and illness. SBE not only affects humans, but also domestic animals, including livestock, with negative social and economic consequences. This requires a better understanding of the complex social, cultural, and ecological contexts where SBE occurs, within the conceptual frame of One Health, an integrated approach that recognizes the health of humans, animals, and the environment as closely linked and interdependent. Such complexity demands more integrative approaches for better understanding and confronting this disease. SBE has unique features that make its prevention and control challenging. Unlike many infectious diseases, SBE cannot be eradicated, but its incidence and impact can be reduced through effective programs aimed at better prevention and rapid access to treatment. This in turn demands the engagement of communities to improve the cohabitation of humans, domestic animals, and snakes in rural agroecosystems. In 2019, the WHO launched a strategy for the prevention and control of SBE, aimed at halving the deaths and disabilities caused by this NTD by the year 2030. This strategy is based on 4 pillars, i.e., empower and engage communities; ensure safe, effective treatment; strengthen health systems; and increase partnerships, coordination, and resources. Building on previous ideas and publications, this article discusses and advocates for transdisciplinary research on SBE and for promoting dialogue and collaboration between sectors, particularly by engaging communities affected by SBE at all levels of the research process

Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers

Introduction Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents. Methods Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed. Results By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator. Conclusions These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC

Tauopathic Changes in the Striatum of A53T α-Synuclein Mutant Mouse Model of Parkinson's Disease

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated levels of α-Syn were observed in striatum of the adult A53T α-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3β, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of α-Syn suggesting that α-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3β and pSer396/404 were also found associated with aggregated α-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, α-Syn remained tightly bound to the cytoskeleton, while p-GSK-3β was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that α-Syn, pSer396/404 Tau and p-GSK-3β co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T α-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Adaptation of prisoners to prison conditions: the impact of repeated imprisonment on the demonstrated model of adaptation

Osoby skazane podczas odbywania kary pozbawienia wolności muszą przystosować siędo specyficznych warunków panujących w Zakładzie Karnym. Erving Goffman w swojej teoriiwyróżnił pięć modeli adaptacji: wycofanie, bunt, zadomowienie, konwersja, zimnakalkulacja.  W badaniach wykorzystano Kwestionariusz Modeli Adaptacji autorstwa DorotyKanarek-Lizik. Przedstawiono różnicę w częstości wykazywania modelu adaptacji przez osobyskazane odbywające karę pozbawienia wolności po raz pierwszy, a recydywistamipenitencjarnymi. W badaniu wzięło udział 142 skazanych mężczyzn w wieku 18-66 lat w tym 69osób odbywających karę po raz pierwszy i 73 recydywistów penitencjarnych. W wyniku badańwłasnych stwierdzono różnicę w częstości wykazywania modeli adaptacji: bunt, zadomowienieoraz brak różnic w przypadku modeli: wycofanie, konwersja i zimna kalkulacja. Uzyskanewyniki mogą wpłynąć na postrzeganie procesu resocjalizacji i pomóc dostrzec problem brakuindywidualnego podejścia do osób skazanych.People who are sentenced while serving a sentence of imprisonment must adapt to thespecific conditions in the prison. In his theory Erving Goffman distinguished five models ofadaptation such as: withdrawal, rebellion, settling down, conversion and cold calculation. In myown research presented in this paper, the Questionnaire of Adaptation Models by DorotaKanarek-Lizik was used. The difference has been shown in the frequency of demonstrating themodel of adaptation by convicts serving a sentence of imprisonment for the first time andpenitentiary recidivists. 142 convicted men aged 18 – 66 took part in the research including 69people serving their sentencje for the first time and 73 penitentiary recidivists. As a result of theresearch a difference was found in the frequency of demonstrating the models: rebellion, settlingdown and there were no differences for models such as: withdrawal, conversion and coldcalculation. The obtained results may affect the perception of the resocialization process andhelp to notice the problem of the Lack of an individual approach to convicts