Engineering the Fab fragment of the anti-IgE omalizumab to prevent Fab crystallization and permit IgE-Fc complex crystallization

Immunoglobulin E (IgE) plays a central role in the allergic response, in which cross-linking of allergen by Fc[epsilon]RI-bound IgE triggers mast cell and basophil degranulation and the release of inflammatory mediators. The high-affinity interaction between IgE and Fc[epsilon]RI is a long-standing target for therapeutic intervention in allergic disease. Omalizumab is a clinically approved anti-IgE monoclonal antibody that binds to free IgE, also with high affinity, preventing its interaction with Fc[epsilon]RI. All attempts to crystallize the pre-formed complex between the omalizumab Fab and the Fc region of IgE (IgE-Fc), to understand the structural basis for its mechanism of action, surprisingly failed. Instead, the Fab alone selectively crystallized in different crystal forms, but their structures revealed intermolecular Fab/Fab interactions that were clearly strong enough to disrupt the Fab/IgE-Fc complexes. Some of these interactions were common to other Fab crystal structures. Mutations were therefore designed to disrupt two recurring packing interactions observed in the omalizumab Fab crystal structures without interfering with the ability of the omalizumab Fab to recognize IgE-Fc; this led to the successful crystallization and subsequent structure determination of the Fab/IgE-Fc complex. The mutagenesis strategy adopted to achieve this result is applicable to other intractable Fab/antigen complexes or systems in which Fabs are used as crystallization chaperones

Projective simulation for artificial intelligence

We propose a model of a learning agent whose interaction with the environment is governed by a simulation-based projection, which allows the agent to project itself into future situations before it takes real action. Projective simulation is based on a random walk through a network of clips, which are elementary patches of episodic memory. The network of clips changes dynamically, both due to new perceptual input and due to certain compositional principles of the simulation process. During simulation, the clips are screened for specific features which trigger factual action of the agent. The scheme is different from other, computational, notions of simulation, and it provides a new element in an embodied cognitive science approach to intelligent action and learning. Our model provides a natural route for generalization to quantum-mechanical operation and connects the fields of reinforcement learning and quantum computation.Comment: 22 pages, 18 figures. Close to published version, with footnotes retaine

Lyapunov-Based Reinforcement Learning for Decentralized Multi-Agent Control

Decentralized multi-agent control has broad applications, ranging from multi-robot cooperation to distributed sensor networks. In decentralized multi-agent control, systems are complex with unknown or highly uncertain dynamics, where traditional model-based control methods can hardly be applied. Compared with model-based control in control theory, deep reinforcement learning (DRL) is promising to learn the controller/policy from data without the knowing system dynamics. However, to directly apply DRL to decentralized multi-agent control is challenging, as interactions among agents make the learning environment non-stationary. More importantly, the existing multi-agent reinforcement learning (MARL) algorithms cannot ensure the closed-loop stability of a multi-agent system from a control-theoretic perspective, so the learned control polices are highly possible to generate abnormal or dangerous behaviors in real applications. Hence, without stability guarantee, the application of the existing MARL algorithms to real multi-agent systems is of great concern, e.g., UAVs, robots, and power systems, etc. In this paper, we aim to propose a new MARL algorithm for decentralized multi-agent control with a stability guarantee. The new MARL algorithm, termed as a multi-agent soft-actor critic (MASAC), is proposed under the well-known framework of "centralized-training-with-decentralized-execution". The closed-loop stability is guaranteed by the introduction of a stability constraint during the policy improvement in our MASAC algorithm. The stability constraint is designed based on Lyapunov's method in control theory. To demonstrate the effectiveness, we present a multi-agent navigation example to show the efficiency of the proposed MASAC algorithm.Comment: Accepted to The 2nd International Conference on Distributed Artificial Intelligenc

Phase II trial of docetaxel in advanced or metastatic endometrial cancer: a Japanese Cooperative Study

The purpose of this study was to determine whether docetaxel has antitumour activity in patients with advanced or recurrent endometrial carcinoma. Chemotherapy-naïve or previously treated patients (one regimen) with histopathologically documented endometrial carcinoma and Eastern Cooperative Oncology Group performance status ⩽2 entered the study. Docetaxel 70 mg m−2 was administered intravenously on day 1 of a 3-week cycle up to a maximum of six cycles. If patients responded well to docetaxel, additional cycles were administered until progressive disease or unacceptable toxicity occurred. Of 33 patients with a median age of 59 years (range, 39–74 years) who entered the study, 14 patients (42%) had received one prior chemotherapy regimen. In all, 32 patients were evaluable for efficacy, yielding an overall response rate of 31% (95% confidence interval, 16.1–50.0%); complete response and partial response (PR) were 3 and 28%, respectively. Of 13 pretreated patients, three (23%) had a PR. The median duration of response was 1.8 months. The median time to progression was 3.9 months. The predominant toxicity was grade 3–4 neutropenia, occurring in 94% of the patients, although febrile neutropenia arose in 9% of the patients. Oedema was mild and infrequent. Docetaxel has antitumour activity in patients with advanced or recurrent endometrial carcinoma, including those previously treated with chemotherapy; however, the effect was transient and accompanied by pronounced neutropenia in most patients

Regional differences in HIV prevalence among drug users in China: potential for future spread of HIV?

Kretzschmar M, Zhang W, Mikolajczyk RT, et al. Regional differences in HIV prevalence among drug users in China: potential for future spread of HIV? BMC Infectious Diseases. 2008;8(1):108.Background: Drug use and in particular injecting drug use has been at the forefront of the explosive spread of HIV in general populations in many countries in Asia. There is concern that also in China increased HIV incidence in drug users might spark off a generalized epidemic in the wider population. Close monitoring of HIV incidence and risk factors in drug users is therefore important to be able to target interventions effectively. Second generation surveillance was launched to assess HIV prevalence and risk behaviours jointly with the purpose of describing trends and predicting future developments. To assess whether these goals were fulfilled among drug users in China we provide an analysis of risk factors for HIV infection and of regional differences in HIV prevalence. Methods: We analysed data collected in 2005 in 21 drug user second generation surveillance sentinel sites from 14 provinces in China. We used random effects logistic regression to test for risk factors for HIV infection and regional differences. Results: The overall HIV-1 antibody prevalence was 5.4% (279/5128); 4.9% among injecting drug users (IDU) not sharing needles and 3.7% among non-injecting drug users. We found substantial heterogeneity among the surveillance sites with prevalence rates ranging between 0% and 54%. HIV status was strongly affected by the regional prevalence of HIV. Risk behaviours were highly prevalent in regions where HIV prevalence is still low. The distribution of duration of drug use in different sites indicated different stages of the drug use epidemics. Conclusion: ]Regional differences in HIV prevalence in China reflect different stages of the drug use and HIV epidemics rather than differences in risk behaviours. Therefore, outbreaks of HIV among drug users in regions where prevalence is still low can be expected in the future. However, methodological limitations of surveillance embedded into routine systems limit the usability of existing data. More standardized approaches to data collection in secondary generation HIV surveillance are necessary to better understand regional differences in risk behaviour and prevalence and to design targeted intervention for those regions at risk of experiencing outbreaks

A chronology of global air quality

Air pollution has been recognized as a threat to human health since the time of Hippocrates, ca 400 BC. Successive written accounts of air pollution occur in different countries through the following two millennia until measurements, from the eighteenth century onwards, show the growing scale of poor air quality in urban centres and close to industry, and the chemical characteristics of the gases and particulate matter. The industrial revolution accelerated both the magnitude of emissions of the primary pollutants and the geographical spread of contributing countries as highly polluted cities became the defining issue, culminating with the great smog of London in 1952. Europe and North America dominated emissions and suffered the majority of adverse effects until the latter decades of the twentieth century, by which time the transboundary issues of acid rain, forest decline and ground-level ozone became the main environmental and political air quality issues. As controls on emissions of sulfur and nitrogen oxides (SO2 and NOx) began to take effect in Europe and North America, emissions in East and South Asia grew strongly and dominated global emissions by the early years of the twenty-first century. The effects of air quality on human health had also returned to the top of the priorities by 2000 as new epidemiological evidence emerged. By this time, extensive networks of surface measurements and satellite remote sensing provided global measurements of both primary and secondary pollutants. Global emissions of SO2 and NOx peaked, respectively, in ca 1990 and 2018 and have since declined to 2020 as a result of widespread emission controls. By contrast, with a lack of actions to abate ammonia, global emissions have continued to grow

Probing charge transfer characteristics in a donor–acceptor metal-organic framework by Raman spectroelectrochemistry and pressure-dependence studies

The stimuli responsive behaviour of charge transfer donor-acceptor metal-organic frameworks (MOFs) remains an understudied phenomenon which may have applications in tuneable electronic materials. We now report the modification of donor-acceptor charge transfer characteristics in a tetrathiafulvalene-naphthalene diimide-based MOF under applied electrochemical bias and pressure. We employ a facile solid state in situ Raman spectroelectrochemical technique, applied for the first time in the characterisation of electroactive MOFs, to monitor the formation of a new complex TTFTC•+–DPNI from a largely neutral system, upon electrochemical oxidation of the framework. In situ pressure-dependent Raman spectroscopy and powder X-ray diffraction experiments performed in a diamond anvil cell revealed blue shifts in the donor and acceptor vibrational modes in addition to contractions in the unit cell which are indicative of bond shortening. This study demonstrates the utility of in situ Raman spectroscopic techniques in the characterisation of redox-active MOFs and the elucidation of their electronic behaviours

Plastisol Foaming Process. Decomposition of the Foaming Agent, Polymer Behavior in the Corresponding Temperature Range and Resulting Foam Properties

The decomposition of azodicarbonamide, used as foaming agent in PVC - plasticizer (1/1) plastisols was studied by DSC. Nineteen different plasticizers, all belonging to the ester family, two being polymeric (polyadipates), were compared. The temperature of maximum decomposition rate (in anisothermal regime at 5 K min-1 scanning rate), ranges between 434 and 452 K. The heat of decomposition ranges between 8.7 and 12.5 J g -1. Some trends of variation of these parameters appear significant and are discussed in terms of solvent (matrix) and viscosity effects on the decomposition reactions. The shear modulus at 1 Hz frequency was determined at the temperature of maximum rate of foaming agent decomposition, and differs significantly from a sample to another. The foam density was determined at ambient temperature and the volume fraction of bubbles was used as criterion to judge the efficiency of the foaming process. The results reveal the existence of an optimal shear modulus of the order of 2 kPa that corresponds roughly to plasticizer molar masses of the order of 450 ± 50 g mol-1. Heavier plasticizers, especially polymeric ones are too difficult to deform. Lighter plasticizers such as diethyl phthalate (DEP) deform too easily and presumably facilitate bubble collapse