Autoradiography of diffusible substances : localization of steroids in the testis

The testis contains two cell compartments respectively having an endocrine and an exocrine function. The seminiferous tubules contain a cell renewal system concerned with the production of spermatozoa, and are the exocrine part of the organ. In the other compartment, the interstitial tissue, Leydig cells are found having an endocrine function in the biosynthesis of androgenic steroids. The studies presented in this thesis are mainly concerned with two questions regarding the role of steroids in the testis: -Firstly, which (sub) cellular structures are involved in the synthesis and secretion of androgen in the Leydig cells. -Secondly, which testicular cells or cell organelles are targets for androgen and estrogen action and what" is the route by which these steroids reach their targets. To answer these questions tritiated steroids have been administered to the rat testis under various experimental conditions. The incorporated radioactivity was subsequently localized in tissue sections by autoradiography both at the level of the light and of the electron microscope. Before discussing the merits and the technical problems of this experimental approach an outline of the role of steroids (among other factors) in testis in general and for spermatogenesis in particular will be given

Transmembrane gradient driven phase transitions within vesicles: lessons for drug delivery

AbstractPhase transitions in closed vesicles, i.e., microenvironments defined by the size of the vesicle, its contents, and permeability of its membrane are becoming increasingly important in several scientific disciplines including catalysis, growth of small crystals, cell function studies, and drug delivery. The membrane composed from lipid bilayer is in general impermeable to ions and larger hydrophilic ions. Ion transport can be regulated by ionophores while permeation of neutral and weakly hydrophobic molecules can be controlled by concentration gradients. Some weak acids or bases, however, can be transported through the membrane due to various gradients, such as electrical, ionic (pH) or specific salt (chemical potential) gradients. Upon permeation of appropriate species and reaction with the encapsulated species precipitation may occur in the vesicle interior. Alternatively, these molecules can also associate with the leaflets of the bilayer according to the transmembrane potential. Efficient liposomal therapeutics require high drug to lipid ratios and drug molecules should have, especially when associated with long circulating liposomes, low leakage rates. In this article we present very efficient encapsulation of two drugs via their intraliposomal precipitation, characterize the state of encapsulated drug within the liposome and try to fit the experimental data with a recently developed theoretical model. Nice agreement between a model which is based on chemical potential equilibration of membrane permeable species with experimental data was observed. The high loading efficiencies, however, are only necessary but not sufficient condition for effective therapies. If adequate drug retention within liposomes, especially in the case of long-circulating ones, is not achieved, the therapeutic index decreases substantially. Anticancer drug doxorubicin precipitates in the liposome interior in a form of gel with low solubility product and practically does not leak out in blood circulation in the scale of days. With an antibiotic, ciprofloxacin, the high loading efficacy and test tube stability is not reproduced in in vitro plasma leakage assays and in vivo. We believe that the reasons are higher solubility product of precipitated drug in the liposome, larger fraction of neutral molecules due closer pK values of the drug with the pH conditions in the solutions and high membrane permeability of this molecule. High resolution cryoEM shows that encapsulated anticancer agent doxorubicin is precipitated in the form of bundles of parallel fibers while antibiotic ciprofloxacin shows globular precipitate. Doxorubicin gelation also causes the change of vesicle shape

New Vesicle-polymer Hybrids: the parachute architecture

The influence of organized media on polymerization reactions results in many cases in interesting morphologies of the polymeric material. In the present study, vesicle bilayers were used as ordered medium for the free radical polymerization of styrene. Cryo-electron microscopy gives evidence that the polymerization induces phase-separation phenomena leading to parachute-like morphologies. On the basis of general knowledge about vesicles and polymerizations in heterogeneous media, explanations for the observed phenomena are given. Bearing in mind that vesicles are outstanding models for membrane mimetic chemistry, it becomes evident that these findings can be relevant to the investigation of, for example, membrane−protein interactions

Distributions of flux vacua

We give results for the distribution and number of flux vacua of various types, supersymmetric and nonsupersymmetric, in IIb string theory compactified on Calabi-Yau manifolds. We compare this with related problems such as counting attractor points.Comment: 43 pages, 7 figures. v2: improved discussion of finding vacua with discrete flux, references adde

Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis

Objective: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. Methods: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. Results: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. Conclusion: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations

Addressing climate change with behavioral science:A global intervention tournament in 63 countries

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions' effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior-several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people's initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors.</p

Addressing climate change with behavioral science: a global intervention tournament in 63 countries

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions’ effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior—several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people’s initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors

Addressing climate change with behavioral science:A global intervention tournament in 63 countries

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions' effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior-several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people's initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors.</p