L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer

Abstract Recent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell\u2014endothelial cell interaction and thus angiogenesis without cytotoxic effects. Ovarian cancer cell lines and human microvascular endothelial cells (HMVEC) were exposed to L-ASP at physiologically attainable concentrations and subjected to analyses of endothelial tube formation, invasion, adhesion and the assessment of sialylated proteins involved in matrix-associated and heterotypic cell adhesion. Marked reduction in HMVEC tube formation in vitro, HMVEC and ovarian cancer cell invasion, and heterotypic cell-cell and cell-matrix adhesion was observed (P < 0.05\u20130.0001). These effects were associated with reduced binding to f1integrin, activation of FAK, and cell surface sialyl LewisX (sLex) expression. No reduction in HMVEC E-selectin expression was seen consistent with the unidirectional inhibitory actions observed. L-ASP concentrations were non-toxic to either ovarian cancer or HMVEC lines in the time frame of the assays. However, early changes of autophagy were observed in both cell types with induction of ATG12, beclin-1, and cleavage of LC-3, indicating cell injury did occur. These data and the known mechanism of action of L-ASP on glycosylation of nascent proteins suggest that L-ASP reduces of ovarian cancer dissemination and progression through modification of its microenvironment. The reduction of ovarian cancer cell surface sLex inhibits interaction with HMVEC and thus HMVEC differentiation into tubes, inhibits interactio

Gully cut- and- fill cycles as related to agromanagement : a historical curve number simulation in the Tigray Highlands

Gully cut-and-fill dynamics are often thought to be driven by climate and/or deforestation related to population pressure. However, in this case-study of nine representative catchments in the Northern Ethiopian Highlands, we find that neither climate changes nor deforestation can explain gully morphology changes over the twentieth century. Firstly, by using a Monte Carlo simulation to estimate historical catchment-wide curve numbers, we show that the landscape was already heavily degraded in the nineteenth and early twentieth century – a period with low population density. The mean catchment-wide curve number (> 80) one century ago was, under the regional climatic conditions, already resulting in considerable simulated historical runoff responses. Secondly, twentieth century land-cover and runoff coefficient changes were confronted with twentieth century changing gully morphologies. As the results show, large-scale land-cover changes and deforestation cannot explain the observed processes. The study therefore invokes interactions between authigenic factors, small-scale plot boundary changes, cropland management and sociopolitical forces to explain the gully cut processes. Finally, semi-structured interviews and sedistratigraphic analysis of three filled gullies confirm the dominant impact of (crop)land management (tillage, check dams in gullies and channel diversions) on gully cut-and-fill processes. Since agricultural land management – including land tenure and land distribution – has been commonly neglected in earlier related research, we argue therefore that it can be a very strong driver of twentieth century gully morphodynamics

Voluntary business engagement in climate change: A study of the ClimateWise Principles

There is an expectation that the insurance sector should be leading business efforts in responding to climate change due to their inherent exposure to increasing risks. However, insurance companies normally operate on a one year time horizon - underwriting risks through policies which change each year to reflect new knowledge of these risks. The ClimateWise principles is a voluntary initiative of the insurance sector that was launched in 2007 to provide a basis for insurance companies to engage with climate change risks. This paper introduces the ClimateWise initiative and explores progress made since its launch. The paper presents new knowledge on whether this voluntary initiative provides a useful structure for the insurance sector in responding to the challenge of climate change. It finds that while the insurance sector has engaged with climate change, there is much more to do and we welcome the recent changes to ClimateWise that more accurately reflect this. The paper concludes that ClimateWise has been a useful initiative for the insurance companies and as a potential benchmark for the sector it offers some value. However, ClimateWise has not provided a strong enough engagement across the sector to embed climate action into business decisions

As crises do século XIV. As origens duma economia contraída

(Primeiro Parágrafo do Artigo)Habitualmente se concorda em que, durante a maior parte do século XIV e pelo menos na primeira metade do século XV, a Europa Ocidental atravessou uma "crise" econômica de excepcional gravidade. Em compensação, não há nenhum acordo quanto às causas e às modalidades dessa contração

Understanding the role of adenosine A2AR heteroreceptor complexes in neurodegeneration and neuroinflammation

Adenosine is a nucleoside mainly formed by degradation of ATP, located intracellularly or extracellularly, and acts as a neuromodulator. It operates as a volume transmission signal through diffusion and flow in the extracellular space to modulate the activity of both glial cells and neurons. The effects of adenosine are mediated via four adenosine receptor subtypes: A1R, A2AR, A2BR, A3R. The A2AR has a wide-spread distribution but it is especially enriched in the ventral and dorsal striatum where it is mainly located in the striato-pallidal GABA neurons at a synaptic and extrasynaptic location. A number of A2AR heteroreceptor complexes exist in the striatum. The existence of A2AR-D2R heteroreceptor complexes with antagonistic A2AR-D2R interactions in the striato-pallidal GABA neurons is well-known with A2AR activation inhibiting Gi/o mediated signaling of D2Rs. A2AR-mGluR5 heteroreceptor complexes were also found in with synergistic receptor-receptor interactions enhancing the inhibition of the D2R protomer signaling. They are located mainly in extrasynaptic regions of the striato-pallidal GABA neurons. Results recently demonstrated the existence of brain A2AR-A2BR heteroreceptor complexes, in which A2BR protomer constitutively inhibited the function of the A2AR protomer. These adenosine A2AR heteroreceptor complexes may modulate alpha-synuclein aggregation and toxicity through postulated bidirectional direct interactions leading to marked increases in A2AR signaling both in nerve cells and microglia. It is of high interest that formation of A2AR-A2ABR heteroreceptor complexes provides a brake on A2AR recognition and signaling opening up a novel strategy for treatment of A2AR mediated neurodegeneration. KEYWORDS: G protein-coupled receptor; Parkinson's diseases; adenosine A2A receptor; adenosine receptor; heteroreceptor complexes; neurodegeneration; neuroinflammation; oligomerizatio

Développement physique et psychologique de gymnastes féminines prépubères

Les objectifs de cette étude prospective sur 4 ans étaient d’évaluer les effets de la pratique modérée de gymnastique sur la croissance, la masse grasse, l’âge pubertaire, les pratiques de contrôle de poids et les profils psychologiques de 27 gymnastes féminines prépubères, appariées par âge à des contrôles prépubères ne pratiquant que le sport récréationnel. G et C représentent les gymnastes et contrôles : première année (G1 ; C1) ; quatrième (G4 ; C4). Le taux d’abandon des gymnastes est élevé (63 %). Nous présentons les résultats des filles qui commencent et terminent l’étude : 10 gymnastes et 20 contrôles.Au temps T1, les jeunes filles ont 11,2 ± 0,9 ans. Les gymnastes font de la gymnastique à raison de 11,9 ± 4,4 heures par semaine. Les indices de masse corporelle (IMC) des 10 G1 et 20 C1 sont similaires (17,0 ± 1,3 kg/m2) mais le taux de masse grasse des 10 gymnastes est inférieur. Les apports nutritionnels des 2 groupes sont similaires (énergie = 1649 ± 310 kcal/j ; lipides = 38.8 % ; glucides = 46.2 %). Les apports protéiques sont élevés (1,9 ± 0,3 g/kg de poids). Les apports en calcium et fer sont insuffisants. L’insatisfaction envers le corps des gymnastes est faible ; leurs pratiques de contrôle de poids sont inexistantes. Leurs profils psychologiques sont identiques à ceux des témoins.Au temps T4, les IMC des 2 groupes sont similaires (19,8 ± 1,9 kg/m2), la masse grasse des gymnastes est inférieure (22.6 ± 3.1 vs 28.4 ± 5.7 % ; p = 0,008). Les apports alimentaires des gymnastes n’augmentent pas de T1 à T4. Les profils psychologiques des 2 groupes sont identiques, hormis de T1 à T4, la fatigabilité des gymnastes qui augmente et la timidité devant les étrangers des contrôles qui diminue. Les consultations pour rachis ou articulations et les arrêts pour blessures concernent, respectivement, 5/10 et 8/10 gymnastes.En conclusion, la pratique modérée de gymnastique ne semble pas altérer le développement physique et psychologique des gymnastes. Une attention doit être apportée pour améliorer l’alimentation des gymnastes et diminuer leurs taux de blessures.Our goals in this four-year study were to evaluate effects of moderate gymnastic practice on growth, fat mass, pubertal age, nutritionnal intakes, weight-control practice, psychological profiles, in matched-age 27 premenarche gymnasts and recreational sporting controls. G and C are gymnasts and controls, at the first year (G; C1) and at the fourth year (G4; C4). As most of gymnasts have dropped out (63%), we show the results of girls who have completed our study : 10 gymnasts and 20 controls.At the beginning of the study (T1), girls are 11,2 ± 0,9 years old. G1 training load is 11,9 ± 4,4 hours/week. Body mass index (BMI) of both groups are similar (17,0 ± 1,3 kg/m2) but G1 fat mass is lower. G1 and C1 nutritional intakes are similar (energy = 1649 ± 310 kcal/day; lipid = 38,8%; glucid = 46,2%). Protein intakes are high (1,9 ± 0,3 g/kg). Calcium and iron intakes are insufficient. G1 body dissatisfaction is low and weight-control practice is non-existent. Psychological profiles are the same in both groups.At time T4, BMI are the same (19,8 ± 1,9 kg/ m2) but G4 fat mass is lower (22,6 ± 3,1 vs 28,4 ± 5,7% ; p = 0,008). Both groups’ nutritionnal intakes do not increase from T1 to T4. Psychological profiles are the same, except that gymnasts’ asthenia increases and controls’ shyness with strangers decreases. Consultation for back and join complains concern 5/10 gymnasts; 8/10 stopped training because of injuries.In conclusion, moderate gymnastic practice does not seem to alter gymnasts physical and psychological development. It is necessary to be careful to improve gymnasts’nutrition and to decrease injuries

Social and temporal disorientation during the Covid-19 pandemic:An analysis of 3306 responses to a quantitative questionnaire

The societal hallmark of the Covid-19 pandemic was a set of mitigation measures such as lockdowns and curfews. The cognitive impact on the public of the resulting spatial, social and temporal constraints is still being investigated. While pandemic time has been extensively studied and mostly described as slowed down and elongated, opposite experimental patterns across national and social contexts leave open an important explanatory gap in order to understand which factor has been causally fundamental in determining the phenomenology of the crisis. In this paper, we use a quantitative questionnaire developed for measuring temporal and social disorientation on a sample of 3306 respondents during an acute phase of restrictions in France. We show that social disorientation greatly contributed to the temporal disruptions experienced during the pandemic. This result reinforces the importance for public authorities to address the compounding effect of feeling isolated during crises

Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function

Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor in mice. A high-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor-Ca(2+)channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms.Significance statementAgonists that bind to the same receptor can produce highly distinct signaling events and arrestins are a major mediator of this ligand bias. Here, we demonstrate that delta opioid receptor agonists differentially recruit arrestin isoforms. We found that the high-internalizing agonist SNC80 preferentially recruits arrestin 2 and knock-out (KO) of this protein results in increased efficacy of SNC80. In contrast, low-internalizing agonists (ARM390 and JNJ20788560) preferentially recruit arrestin 3 and, surprisingly, KO of arrestin 3 produces acute tolerance and impaired receptor resensitization to these agonists. Arrestin 3 is in pre-engaged complexes with the delta opioid receptor at the cell membrane and low-internalizing agonists promote this interaction. This study reveals a novel role for arrestin 3 as a facilitator of receptor resensitization

Distinct subsynaptic localization of type 1 metabotropic glutamate receptors at glutamatergic and GABAergic synapses in the rodent cerebellar cortex

Type 1 metabotropic glutamate (mGlu1) receptors play a pivotal role in different forms of synaptic plasticity in the cerebellar cortex, e.g. long-term depression at glutamatergic synapses and rebound potentiation at GABAergic synapses. These various forms of plasticity might depend on the subsynaptic arrangement of the receptor in Purkinje cells that can be regulated by protein-protein interactions. This study investigated, by means of the freeze-fracture replica immunogold labelling method, the subcellular localization of mGlu1 receptors in the rodent cerebellum and whether Homer proteins regulate their subsynaptic distribution. We observed a widespread extrasynaptic localization of mGlu1 receptors and confirmed their peri-synaptic enrichment at glutamatergic synapses. Conversely, we detected mGlu1 receptors within the main body of GABAergic synapses onto Purkinje cell dendrites. Although Homer proteins are known to interact with the mGlu1 receptor C-terminus, we could not detect Homer3, the most abundant Homer protein in the cerebellar cortex, at GABAergic synapses by pre-embedding and post-embedding immunoelectron microscopy. We then hypothesized a critical role for Homer proteins in the peri-junctional localization of mGlu1 receptors at glutamatergic synapses. To disrupt Homer-associated protein complexes, mice were tail-vein injected with the membrane-permeable dominant-negative TAT-Homer1a. Freeze-fracture replica immunogold labelling analysis showed no significant alteration in the mGlu1 receptor distribution pattern at parallel fibre-Purkinje cell synapses, suggesting that other scaffolding proteins are involved in the peri-synaptic confinement. The identification of interactors that regulate the subsynaptic localization of the mGlu1 receptor at neurochemically distinct synapses may offer new insight into its trafficking and intracellular signalling

Assessing barriers and solutions to financing adaptation projects in Africa : report

Except Southern Africa, funding requests for adaptation activities in all African regions far exceed funding received. Many of the Least Developed Countries (LDCs) in Africa have yet to submit national plans for adaptation activities, and are poorly positioned to access funding for adaptation. This paper details barriers to financial support for adaptation initiatives, with recommendations for improving access to funds. Among others: improve the use of existing data and analytical tools; establish national finance coordination committees; involve adaptation practitioners in project design; mainstream adaptation into national budgets; explore links with mitigation finance and other types of finance other than grants