Migration’s Alienations: Bertolt Brecht’s Mother Courage

Brecht’s so-called anti-war drama Mother Courage and her Children (1939) will be read as a migration drama that demystifies rhetorical cynicism as a coping device for the traumatic torments of migration. By placing Brecht’s work in the context of Peter Sloterdijk’s theory of cynicism, our reading demonstrates how this work adds further perspectives to Thomas Nail’s recent theory of migration and to the discussion of the play’s theatrical production

Migration’s Alienations: Bertolt Brecht’s Mother Courage

23 pagesBrecht’s so-called anti-war drama Mother Courage and her Children (1939) will be read as a migration drama that demystifies rhetorical cynicism as a coping device for the traumatic torments of migration. By placing Brecht’s work in the context of Peter Sloterdijk’s theory of cynicism, our reading demonstrates how this work adds further perspectives to Thomas Nail’s recent theory of migration and to the discussion of the play’s theatrical production

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

SummaryRIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-α) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective “hybrid” RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Variation in postoperative outcomes of patients with intracranial tumors: insights from a prospective international cohort study during the COVID-19 pandemic

Background: This study assessed the international variation in surgical neuro-oncology practice and 30-day outcomes of patients who had surgery for an intracranial tumor during the COVID-19 pandemic. Methods: We prospectively included adults aged ≥18 years who underwent surgery for a malignant or benign intracranial tumor across 55 international hospitals from 26 countries. Each participating hospital recorded cases for 3 consecutive months from the start of the pandemic. We categorized patients’ location by World Bank income groups (high [HIC], upper-middle [UMIC], and low- and lower-middle [LLMIC]). Main outcomes were a change from routine management, SARS-CoV-2 infection, and 30-day mortality. We used a Bayesian multilevel logistic regression stratified by hospitals and adjusted for key confounders to estimate the association between income groups and mortality. Results: Among 1016 patients, the number of patients in each income group was 765 (75.3%) in HIC, 142 (14.0%) in UMIC, and 109 (10.7%) in LLMIC. The management of 200 (19.8%) patients changed from usual care, most commonly delayed surgery. Within 30 days after surgery, 14 (1.4%) patients had a COVID-19 diagnosis and 39 (3.8%) patients died. In the multivariable model, LLMIC was associated with increased mortality (odds ratio 2.83, 95% credible interval 1.37–5.74) compared to HIC. Conclusions: The first wave of the pandemic had a significant impact on surgical decision-making. While the incidence of SARS-CoV-2 infection within 30 days after surgery was low, there was a disparity in mortality between countries and this warrants further examination to identify any modifiable factors

High refractive index and low-birefringence polyamides containing thiazole and naphthalene units

Highly refractive and solution processable polyamides (PAs) were synthesized by the introduction of thiazole rings, naphthalene groups, and thioether linkages. These PAs were synthesized by the polycondensation of a new diamine monomer, 5,5'-thiobis(2-amino-4-(2-naphthyl)thiazole) (DA), with various aromatic diacids. The bulky pendant naphthyl units endowed the resulting PAs with non-coplanar structures and excellent solubilities in organic solvents. The obtained PAs showed high thermal stability, with 10% weight loss temperatures exceeding 478°C under nitrogen and 431°C in air atmosphere, while their glass transition temperatures were in the range of 194-229°C. The synergic effects of the thiazole groups, naphthyl substituents, and thioether linkages provided PAs with very high refractive indices of up to 1.7701 at 632.8 nm, along with small birefringences (<0.0076) and high Abbe's numbers. The structure-property relationships of these PAs due to the presence of naphthyl substituents were also studied in detail by comparing the results with the previously reported analogous PA

Evidence for autophagy attenuation during post-mortem maturation of hypertrophied muscle in myostatin deficient mice

International audienceThe conversion of skeletal muscle into meat, i.e. maturation, is a complex process where muscle undergoes different biochemical and physiological changes. In agronomic field, the study of these events is of particular interest, in order to improve the quality of the final product put on the market. If the characterization of the proteolytic mechanisms involved in skeletal muscle maturation is still ongoing, the participation of autophagy in this process is still under debate.In order to decipher the involvement of autophagy during skeletal muscle maturation, the expression and activation of keys proteins regulating this process have been followed within a 48h postmortem (PM) time frame in mice. The interaction between autophagy and myostatin, a negative regulator of skeletal muscle mass, was also analyzed during this post-mortem interval.Using 6 month-old wild-type (WT) and myostatin knocked-out (Mstn KO) mice, we measured the proteolysis of myofibrillar proteins (filamin and troponin T), as well as the activation and expression of proteins involved in autophagic pathway (AMPK, FOXO, ULK, LC3 and p62).Our results showed a progressive degradation of myofibrillar proteins over the 48h PM period. Moreover, it was more pronounced in gastrocnemius muscle of Mstn KO mice when compared to WT mice. AMPK activation was more marked in WT mice, with a maximal induction between 2 and 4h PM, suggestive of an energetic stress. Inhibition of Foxo1 phosphorylation (Thr24) was relieved in the late PM interval (8h PM) in both genotypes, indicating the activation of proteolytic pathways. Concerning autophagy, the phosphorylation profile of ULK1 (Ser757 vs Ser555) suggests an early activation (1h PM) of autophagy in Mstn KO mice. To estimate the autophagic flux, LC3 and p62 protein expression were measured after autophagy blockade with colchicine at 0h, 4h, 8h and 24h postmortem. Our results showed a higher flux in the WT mice compared to Mstn KO mice, whatever the PM time.In conclusion, our data showed that autophagy is maintained during skeletal muscle PM maturation, but to a lower extent in Mstn-deficient mice, suggesting a relationship between myostatin and autophagy

Control of the proteolytic events by the Myostatin in the post-mortem skeletal muscle

International audienceThe conversion of skeletal muscle into meat, i.e. maturation, is a complex process where muscle undergoes different biochemical and physiological changes. In agronomic field, the study of these events is of particular interest, in order to improve the quality of meat.It is well established that the proteolytic events generated by the enzymes such as cathepsins, calpains and ubiquitine proteasome system are involved in skeletal muscle maturation. Recent data suggest that other mechanisms, such as apoptosis and autophagy, may also contribute to the post-mortem maturation. However, their intervention is not clearly described. We designed a pilot study using mice to evaluate the proteolytic mechanisms within a 48h post-mortem time frame and their interaction with myostatin, a negative regulator of skeletal muscle mass. We measured the proteolysis of myofibrillar proteins (filamin, desmin, troponin T), as well as the activation and the expression of proteins involved in autophagic pathways. Our data showed a significant progressive degradation of myofibrillar proteins over the 48h PM period. Moreover, it was more pronounced in the muscle of Mstn KO mice. AMPK activation was attenuated in Mstn KO mice and was associated to a lower activation of the protein kinase ULK (inducer of autophagy) which suggests a reduced autophagy in Mstn KO mice. Using colchicine (an inhibitor of autophagy), we showed in Mstn KO muscle a reduced basal autophagic flux that remained low within the postmortem time frame. In conclusion, our results showed a difference in the proteolytic profile between the two genotypes during the post-mortem maturation of skeletal muscle. The absence of myostatin promotes a faster degradation of myofibrillar proteins associated to a reduced level of autophagy. The mechanisms responsible for this difference between the two genotypes remain to be elucidated

Contribution de l’apoptose et de l’autophagie aux mécanismes de transformation post-mortem du muscle

International audienced’une cinétique de temps (0 à 48h PM) des indicateurs de la maturation post-mortem du muscle (pH, dégradation des protéines myofibrillaires) et mesuré l’expression protéique et/ou l’activité de marqueurs et régulateurs de la protéolyse musculaire, de l’apoptose et de l’autophagie.Nos résultats préliminaires montrent une protéolyse significativement plus importante dans le muscle KO Myostatine (représentatif d'un muscle plus tendre par analogie avec les muscles de bovins culards). L'apoptose est présente dans les deux génotypes mais rapidement atténuée dans le muscle KO Myostatine. L'autophagie basale est réduite dans le muscle KO Myostatine. Cependant, tout en restant inférieur au niveau basal d'autophagie du muscle contrôle, le flux autophagique est induit lors du processus de maturation dans le muscle KO Myostatine. Ainsi la contribution relative de l'autophagie et de l'apoptose dans la maturation post-mortem du muscle est dépendante du génotype. restent à confirmer dans des échantillons de viande de bovins culards (ayant des mutations de myostatine) vs. bovins contrôles présentant des potentiels de tendreté différents