Abstract
Microcatheters have enabled diverse minimally invasive endovascular operations and notable health benefits compared with open surgeries. However, with tortuous routes far from the arterial ...puncture site, the distal vascular regions remain challenging for safe catheter access. Therefore, we propose a wireless stent-shaped magnetic soft robot to be deployed, actively navigated, used for medical functions, and retrieved in the example M4 segment of the middle cerebral artery. We investigate shape-adaptively controlled locomotion in phantoms emulating the physiological conditions here, where the lumen diameter shrinks from 1.5 mm to 1 mm, the radius of curvature of the tortuous lumen gets as small as 3 mm, the lumen bifurcation angle goes up to 120
°
, and the pulsatile flow speed reaches up to 26 cm/s. The robot can also withstand the flow when the magnetic actuation is turned off. These locomotion capabilities are confirmed in porcine arteries ex vivo. Furthermore, variants of the robot could release the tissue plasminogen activator on-demand locally for thrombolysis and function as flow diverters, initiating promising therapies towards acute ischemic stroke, aneurysm, arteriovenous malformation, dural arteriovenous fistulas, and brain tumors. These functions should facilitate the robot’s usage in new distal endovascular operations.
The Bicoid (Bcd) protein gradient is generally believed to be established in pre-blastoderm Drosophila embryos by the diffusion of Bcd protein after translation of maternal mRNA, which serves as a ...strictly localized source of Bcd at the anterior pole. However, we previously published evidence that the Bcd gradient is preceded by a bcd mRNA gradient. Here, we have revisited and extended this observation by showing that the bcd mRNA and Bcd protein gradient profiles are virtually identical at all times. This confirms our previous conclusion that the Bcd gradient is produced by a bcd mRNA gradient rather than by diffusion. Based on our observation that bcd mRNA colocalizes with Staufen (Stau), we propose that the bcd mRNA gradient forms by a novel mechanism involving quasi-random active transport of a Stau-bcd mRNA complex through a nonpolar microtubular network, which confines the bcd mRNA to the cortex of the embryo.
IntroductionThe combination of checkpoint inhibition and cisplatin-based chemotherapy is investigated in muscle invasive bladder cancer (MIBC) and results from phase 2 trials have been presented. ...Intravesical BCG has been used for non-MIBC (NMIBC) in patients with carcinoma in situ and high-grade Ta/T1 tumours. BCG induces innate and adapted immune response and upregulation of PD-L1 in preclinical models. The proposed trial is intended to implement a new immuno-immuno-chemotherapy induction therapy for MIBC. The combination of BCG and checkpoint inhibition with chemotherapy aims at higher intravesical responses and better local and systemic control of disease.Methods and analysisSAKK 06/19 is an open-label single-arm phase II trial for patients with resectable MIBC T2-T4a cN0-1. Intravesical recombinant BCG (rBCG: VPM1002BC) is applied weekly for three instillations followed by four cycles of neoadjuvant cisplatin/gemcitabine every 3 weeks. Atezolizumab 1200 mg every 3 weeks is started together with rBCG and given for four cycles. All patients then undergo restaging and radical cystectomy and pelvic lymphadenectomy. Atezolizumab is continued as maintenance therapy after surgery every 3 weeks for 13 cycles. Pathological complete remission is the primary endpoint. Secondary endpoints include pathological response rate (<ypT2 N0), event-free survival, recurrence-free survival, overall survival, feasibility and toxicity. An interim safety analysis will be performed after the first 12 patients have completed neoadjuvant treatment specifically assessing toxicity possibly associated with intravesical rBCG application.The study has received approval by ethical committee Zurich, Switzerland, BASEC-No. 2021–01872. Results will be made available by publication.Trial registration numberNCT04630730.
Summary
Syngas fermentation with acetogens is known to produce mainly acetate and ethanol efficiently. Co‐cultures with chain elongating bacteria making use of these products are a promising approach ...to produce longer‐chain alcohols. Synthetic co‐cultures with identical initial cell concentrations of Clostridium carboxidivorans and Clostridium kluyveri were studied in batch‐operated stirred‐tank bioreactors with continuous CO/CO2‐gassing and monitoring of the cell counts of both clostridia by flow cytometry after fluorescence in situ hybridization (FISH‐FC). At 800 mbar CO, chain elongation activity was observed at pH 6.0, although growth of C. kluyveri was restricted. Organic acids produced by C. kluyveri were reduced by C. carboxidivorans to the corresponding alcohols butanol and hexanol. This resulted in a threefold increase in final butanol concentration and enabled hexanol production compared with a mono‐culture of C. carboxidivorans. At 100 mbar CO, growth of C. kluyveri was improved; however, the capacity of C. carboxidivorans to form alcohols was reduced. Because of the accumulation of organic acids, a constant decay of C. carboxidivorans was observed. The measurement of individual cell concentrations in co‐culture established in this study may serve as an effective tool for knowledge‐based identification of optimum process conditions for enhanced formation of longer‐chain alcohols by clostridial co‐cultures.
Synthetic co‐cultures with identical initial cell concentrations of Clostridium carboxidivorans and Clostridium kluyveri were studied in batch operated stirred‐tank bioreactors with continuous CO/CO2‐gassing and monitoring of the cell counts of both clostridia by flow cytometry after fluorescence in situ hybridization (FISH‐FC). At 800 mbar CO, chain elongation activity was observed at pH 6.0, although growth of C. kluyveri was restricted. At 100 mbar CO, growth of C. kluyveri was improved; however, the capacity of C. carboxidivorans to form alcohols was reduced.
Although cellular uptake of vitamin E was initially described as a passive process, recent studies in the liver and brain have shown that SR-BI (scavenger receptor class B type I) is involved in this ...phenomenon. As SR-BI is expressed at high levels in the intestine, the present study addressed the involvement of SR-BI in vitamin E trafficking across enterocytes. Apical uptake and efflux of the main dietary forms of vitamin E were examined using Caco-2 TC-7 cell monolayers as a model of human intestinal epithelium. (R,R,R)-γ-tocopherol bioavailability was compared between wild-type mice and mice overexpressing SR-BI in the intestine. The effect of vitamin E on enterocyte SR-BI mRNA levels was measured by real-time quantitative reverse transcription-PCR. Concentration-dependent curves for vitamin E uptake were similar for (R,R,R)-α-, (R,R,R)-γ-, and dl-α-tocopherol. (R,R,R)-α-tocopherol transport was dependent on incubation temperature, with a 60% reduction in absorption at 4 °C compared with 37 °C (p < 0.05). Vitamin E flux in enterocytes was directed from the apical to the basal side, with a relative 10-fold reduction in the transfer process when measured in the opposite direction (p < 0.05). Co-incubation with cholesterol, γ-tocopherol, or lutein significantly impaired α-tocopherol absorption. Anti-human SR-BI antibodies and BLT1 (a chemical inhibitor of lipid transport via SR-BI) blocked up to 80% of vitamin E uptake and up to 30% of apical vitamin E efflux (p < 0.05), and similar results were obtained for (R,R,R)-γ-tocopherol. SR-BI mRNA levels were not significantly modified after a 24-h incubation of Caco-2 cells with vitamin E. Finally, (R,R,R)-γ-tocopherol bioavailability was 2.7-fold higher in mice overexpressing SR-BI than in wild-type mice (p < 0.05). The present data show for the first time that vitamin E intestinal absorption is, at least in part, mediated by SR-BI.
More than 20 years ago, an oxytocin/vasopressin-like peptide, CLITNCPRGamide, was isolated from the locust, Locusta migratoria Proux JP, et al. (1987) Identification of an arginine vasopressin-like ...diuretic hormone from Locusta migratoria. Biochem Biophys Res Commun 149:180-186. However, no similar peptide could be identified in other insects, nor could its prohormone be cloned, or its physiological actions be established. Here, we report that the recently sequenced genome from the red flour beetle Tribolium castaneum contains a gene coding for an oxytocin/vasopressin-like peptide, identical to the locust peptide, which we named inotocin (for insect oxytocin/vasopressin-like peptide) and a gene coding for an inotocin G protein-coupled receptor (GPCR). We cloned the Tribolium inotocin preprohormone and the inotocin GPCR and expressed the GPCR in CHO cells. This GPCR is strongly activated by low concentrations of inotocin (EC₅₀, 5 x 10⁻⁹ M), demonstrating that it is the inotocin receptor. Quantitative RT-PCR (qPCR) showed that in adult Tribolium, the receptor is mainly expressed in the head and much less in the hindgut and Malpighian tubules, suggesting that the inotocin/receptor couple does not play a role in water homeostasis. Surprisingly, qPCR also showed that the receptor is 30x more expressed in the first larval stages than in adult animals. The inotocin/receptor couple can also be found in the recently sequenced genome from the parasitic wasp Nasonia vitripennis but not in any other holometabolous insect with a completely sequenced genome (12 Drosophila species, the malaria mosquito Anopheles gambiae, the yellow fever mosquito Aedes aegypti, the silk worm Bombyx mori, and the honey bee Apis mellifera), suggesting that this neuropeptide system is confined to basal holometabolous insects. Furthermore, we identified an oxytocin/vasopressin-like peptide and receptor in the recently sequenced genome from the water flea Daphnia pulex (Crustacea). To our knowledge, this is the first report on the molecular cloning of an oxytocin/vasopressin-like receptor and its ligand from arthropods.
Chronic inflammation promotes atherosclerosis in cardiovascular disease and is a major prognostic factor for patients undergoing percutaneous coronary intervention (PCI). Macrophage migration ...inhibitory factor (MIF) is involved in the progress of atherosclerosis and plaque destabilization and plays a pivotal role in the development of acute coronary syndromes (ACS). Little is known to date about the clinical impact of MIF in patients with symptomatic coronary artery disease (CAD).
In a pilot study, 286 patients with symptomatic CAD (n = 119 ACS, n = 167 stable CAD) undergoing PCI were consecutively evaluated. 25 healthy volunteers served as control. Expression of MIF was consecutively measured in patients at the time of PCI. Baseline levels of interleukin 6 (IL-6), "regulated upon activation, normal T-cell expressed, and secreted" (RANTES) and monocyte chemoattractant protein-1 (MCP-1) were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Patients with ACS showed higher plasma levels of MIF compared to patients with stable CAD and control subjects (median 2.85 ng/mL, interquartile range (IQR) 3.52 versus median 1.22 ng/mL, IQR 2.99, versus median 0.1, IQR 0.09, p<0.001). Increased MIF levels were associated with CRP and IL-6 levels and correlated with troponin I (TnI) release (spearman rank coefficient: 0.31, p<0.001). Patients with ACS due to plaque rupture showed significantly higher plasma levels of MIF than patients with flow limiting stenotic lesions (p = 0.002).
To our knowledge this is the first study, demonstrating enhanced expression of MIF in ACS. It is associated with established inflammatory markers, correlates with the extent of cardiac necrosis marker release after PCI and is significantly increased in ACS patients with "culprit" lesions. Further attempts should be undertaken to characterize the role of MIF for risk assessment in the setting of ACS.
RESUMO: A partir de questões suscitadas pela clínica da recepção em um ambulatório público de saúde mental, investigamos o manejo clínico da urgência subjetiva. Tendo em vista a recorrência do ...sofrimento psíquico relacionado à angústia e a manifestações ligadas ao ato, revisamos o lugar da angústia em psicanálise e sua relação com o acting out e a passagem ao ato. Verificamos como o psicanalista pode acolher a urgência subjetiva, permitindo que este momento de crise dê lugar ao trabalho psíquico e possibilite uma subjetivação do sofrimento.
Abstract: From issues raised by the reception clinic in a public mental health clinic, we investigated the clinical management of subjective urgency. In view of the recurrence of psychic suffering related to the anguish and manifestations associated with the act, we review the place of anguish in psychoanalysis and its relation to the acting out and the passage to the act. We verify how the psychoanalyst can take on the subjective urgency, allowing this moment of crisis to give way to psychic work and enable a subjectivation of suffering.
Syngas fermentation with clostridial co-cultures is promising for the conversion of CO to alcohols. A CO sensitivity study with
monocultures in batch operated stirred-tank bioreactors revealed total ...growth inhibition of
already at 100 mbar CO, but stable biomass concentrations and ongoing chain elongation at 800 mbar CO. On/off-gassing with CO indicated a reversible inhibition of
. A continuous supply of sulfide led to increased autotrophic growth and ethanol formation by
even at unfavorable low CO concentrations. Based on these results, a continuously operated cascade of two stirred-tank reactors was established with a synthetic co-culture of both
An amount of 100 mbar CO and additional sulfide supply enabled growth and chain elongation in the first bioreactor, whereas 800 mbar CO resulted in an efficient reduction of organic acids and de-novo synthesis of C2-C6 alcohols in the second reactor. High alcohol/acid ratios of 4.5-9.1 (
/
) were achieved in the steady state of the cascade process, and the space-time yields of the alcohols produced were improved by factors of 1.9-5.3 compared to a batch process. Further improvement of continuous production of medium chain alcohols from CO may be possible by applying less CO-sensitive chain-elongating bacteria in co-cultures.
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