George Onslows Opus 81 und das Bläserquintett um die Mitte des 19. Jahrhunderts

Der Beitrag versucht, die wenig bekannte Entstehung des Werks zu beleuchten, gibt aber auch Einblick in seine musikalische Faktur

Entretien avec Pascale Kramer

Artiste invitée de la Chaire de littérature et culture française de l’École polytechnique fédérale de Zurich, Pascale Kramer a donné à l’automne 2019 un cours intitulé « Cheminement autodidacte en écriture ». Celui-ci aura été l’occasion de revenir sur les textes, les films et les expériences de vie qui ont nourri son travail de romancière. C’est dans ce cadre qu’elle a souhaité partager avec son amie, l’auteure Ghislaine Dunant, une soirée consacrée à l’écriture de la sexualité. L’entretien qu’on lira ici y fait allusion. Réalisé le 26 novembre 2019 dans les bureaux de l’École polytechnique, cet entretien a été revu par Pascale Kramer. Si elle a procédé aux coupes jugées indispensables pour supprimer certaines répétitions et alléger l’ensemble, sa relecture a principalement visé à prolonger la réflexion initiale, à en préciser les lignes et les enjeux. L’ensemble garde cependant quelque chose de sa parole, de son rythme et de sa force. Que Pascale Kramer soit chaleureusement remerciée d’avoir accepté de poursuivre un dialogue amical initié il y a quelques années déjà lors de rencontres au Romanisches Seminar de l’Université de Zurich. Un grand merci à Sophie Hochuli qui a assuré la transcription. Keywords : Pascale Kramer, roman contemporain, littérature francophone, écriture et technique romanesques, éthique, réception critique, monde de l’éditio

Heterogeneous kinetics of AKT signaling in individual cells are accounted for by variable protein concentration

In most solid cancers, cells harboring oncogenic mutations represent only a sub-fraction of the entire population. Within this sub-fraction the expression level of mutated proteins can vary significantly due to cellular variability limiting the efficiency of targeted therapy. To address the causes of the heterogeneity, we performed a systematic analysis of one of the most frequently mutated pathways in cancer cells, the phosphatidylinositol 3 kinase (PI3K) signaling pathway. Among others PI3K signaling is activated by the hepatocyte growth factor (HGF) that regulates proliferation of hepatocytes during liver regeneration but also fosters tumor cell proliferation. HGF mediated responses of PI3K signaling were monitored both at the single cell and cell population level in primary mouse hepatocytes and in the hepatoma cell line Hepa1_6. Interestingly, we observed that the HGF mediated AKT responses at the level of individual cells is rather heterogeneous. However, the overall average behavior of the single cells strongly resembled the dynamics of AKT activation determined at the cell population level. To gain insights into the molecular cause for the observed heterogeneous behavior of individual cells, we employed dynamic mathematical modeling in a stochastic framework. Our analysis demonstrated that intrinsic noise was not sufficient to explain the observed kinetic behavior, but rather the importance of extrinsic noise has to be considered. Thus, distinct from gene expression in the examined signaling pathway fluctuations of the reaction rates has only a minor impact whereas variability in the concentration of the various signaling components even in a clonal cell population is a key determinant for the kinetic behavior

Wharton's Jelly Mesenchymal Stem Cells Protect the Immature Brain in Rats and Modulate Cell Fate.

The development of a mammalian brain is a complex and long-lasting process. Not surprisingly, preterm birth is the leading cause of death in newborns and children. Advances in perinatal care reduced mortality, but morbidity still represents a major burden. New therapeutic approaches are thus desperately needed. Given that mesenchymal stem/stromal cells (MSCs) emerged as a promising candidate for cell therapy, we transplanted MSCs derived from the Wharton's Jelly (WJ-MSCs) to reduce the burden of immature brain injury in a murine animal model. WJ-MSCs transplantation resulted in protective activity characterized by reduced myelin loss and astroglial activation. WJ-MSCs improved locomotor behavior as well. To address the underlying mechanisms, we tested the key regulators of responses to DNA-damaging agents, such as cyclic AMP-dependent protein kinase/calcium-dependent protein kinase (PKA/PKC), cyclin-dependent kinase (CDK), ataxia-telangiectasia-mutated/ATM- and Rad3-related (ATM/ATR) substrates, protein kinase B (Akt), and 14-3-3 binding protein partners. We characterized WJ-MSCs using a specific profiler polymerase chain reaction array. We provide evidence that WJ-MSCs target pivotal regulators of the cell fate such as CDK/14-3-3/Akt signaling. We identified leukemia inhibitory factor as a potential candidate of WJ-MSCs' induced modifications as well. We hypothesize that WJ-MSCs may exert adaptive responses depending on the type of injury they are facing, making them prominent candidates for cell therapy in perinatal injuries

Early Switch from Intravenous to Oral Antibiotics in Skin- and Soft-tissue Infections: An Algorithm-based Prospective Multicentre Pilot Trial.

BACKGROUND: In hospitalized patients with skin and soft tissue infections (SSTIs), intravenous (IV) empiric antibiotic treatment is initiated. The best time point for switching from IV to oral treatment is unknown. We used an algorithm-based decision tree for the switch from IV to oral antibiotics within 48 hours and aimed to investigate the treatment outcome of this concept. METHODS: In a nonrandomized trial, we prospectively enrolled 128 patients hospitalized with SSTI from July 2019 to May 2021 at 3 institutions. Clinical and biochemical response data during the first week and at follow-up after 30 days were analyzed. Patients fulfilling criteria for the switch from IV to oral antibiotics were assigned to the intervention group. The primary outcome was a composite definition consisting of the proportion of patients with clinical failure or death of any cause. RESULTS: Ninety-seven (75.8%) patients were assigned to the intervention group. All of them showed signs of clinical improvement (ie, absence of fever or reduction of pain) within 48 hours of IV treatment, irrespective of erythema finding or biochemical response. The median total antibiotic treatment duration was 11 (interquartile range [IQR], 9–13) days in the invention group and 15 (IQR, 11–24) days in the nonintervention group (P < .001). The median duration of hospitalization was 5 (IQR, 4–6) days in the intervention group and 8 (IQR, 6–12) days in the nonintervention group (P < .001). There were 5 (5.2%) failures in the intervention group and 1 (3.2%) in the nonintervention group after a median follow-up of 37 days. CONCLUSIONS: In this pilot trial, the proposed decision algorithm for early switch from IV to oral antibiotics for SSTI treatment was successful in 95% of cases. Clinical Trials Registration. ISRCTN1524549

Prenatal and Postnatal Tobacco Exposure and Behavioral Problems in 10-Year-Old Children: Results from the GINI-plus Prospective Birth Cohort Study

BACKGROUND: Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear. OBJECTIVE: We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally. METHODS: We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as &quot;normal,&quot; &quot;borderline,&quot; or &quot;abnormal&quot; according to the subscales &quot;emotional symptoms,&quot; &quot;conduct problems,&quot; &quot;hyperactivity/inattention,&quot; &quot;peer-relationship problems,&quot; and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires. RESULTS: Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4-3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9-4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9-1.9). These results could not be explained by confounding by parental education, father&#39;s employment, child&#39;s time spent in front of computer or television screen, being a single father or mother, or mother&#39;s age. CONCLUSIONS: Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important

Extracerebral metastases determine the outcome of patients with brain metastases from renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>In the era of cytokines, patients with brain metastases (BM) from renal cell carcinoma had a significantly shorter survival than patients without. Targeted agents (TA) have improved the outcome of patients with metastatic renal cell carcinoma (mRCC) however, their impact on patients with BM is less clear. The aim of this analysis was to compare the outcome of patients with and without BM in the era of targeted agents.</p> <p>Methods</p> <p>Data from 114 consecutive patients who had access to targeted agent were analyzed for response rates (ORR), progression free survival (PFS) and overall survival (OS). All patients diagnosed with BM underwent local, BM-specific treatment before initiation of medical treatment.</p> <p>Results</p> <p>Data of 114 consecutive patients who had access to at least one type of targeted agents were analyzed. Twelve out of 114 renal cell carcinoma (RCC) patients (10.5%) were diagnosed with BM. Systemic treatment consisted of sunitinib, sorafenib, temsirolimus or bevacizumab. The median PFS was 8.7 months (95% CI 5.1 - 12.3) and 11.4 months (95% CI 8.7 - 14.1) for BM-patients and non-BM-patients, respectively (p = 0.232). The median overall survival for patients with and without BM was 13.4 (95% CI 1- 43.9) and 33.3 months (95% CI 18.6 - 47.0) (p = 0.358), respectively. No patient died from cerebral disease progression. ECOG Performance status and the time from primary tumor to metastases (TDM) were independent risk factors for short survival (HR 2.74, p = 0.001; HR: 0.552, p = 0.034).</p> <p>Conclusions</p> <p>Although extracerebral metastases determine the outcome of patients with BM, the benefit from targeted agents still appears to be limited when compared to patients without BM.</p