Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

阻止抬升盆地原油生物降解的深埋灭菌作用

微生物活动造成的原油生物降解作用发生地球中大多数的油藏中，人们认为生物降解作用大大降低油藏中原油的质量，为成功寻找工业油藏，理解地质建造中生物降解作用发生的条件与过程是十分重要的，尽管最近的研究推测微生物活动在温度在150℃仍能有效地发生，但是人们普遍认为在地质时代，有效的石油生物降解作用通常发生在温度低于80℃的储层中，然而奇怪的是在温度低于80℃的储层中，还可发现未降解的原油，本文收集了一些油藏中有关生物降解程度的数据，发现未降角原油局限于埋藏浅的冷盆地，这些盆地曾是地球中更深，更热的部位，后经抬升作用形成的，我们认为这石油储层在深埋过程中，在温度为80－90℃时经历了灭菌作用，使得深部生物圈中降解烃类的生物停止活动，尽管这些储层后期抬升到较冷的部位并再次发生石油充注，也不会发生生物降解作用，表明灭菌后的沉积物不再适合降解烃类的细菌生长。     

HLA-DR mismatching correlates with early cardiac allograft rejection, incidence, and graft survival when high-confidence-level serological DR typing is used

To determine if cardiac allograft outcome is improved among patients with fewer HLA-DR mismatches with their donors, we studied 132 recipients of a primary cardiac allograft who were transplanted between December 1985 and December 1991. These recipients and their donors all had high-confidence-level serological HLA-DR typing, previously shown to correlate highly with DNA DR typing. Patients were divided in two groups based on the HLA-DR mismatch with their donors. Group I consisted of 78 patients with 1 or zero DR mismatch and group II of 54 patients with 2 DR mismatches. Allograft outcome measurements included incidence of moderate rejection, incidence of allograft vasculopathy at 12 months, cardiac function measured as left ventricular ejection fraction (LVEF) and cardiac index (CI), and actuarial graft survival up to 7 years. Groups I and group II were not different with regard to recipient age, donor age, ischemia time, pulmonary vascular resistance, sex, or PRA greater than 0%. Group II had a higher incidence of moderate rejection on the first-week biopsy (47% vs. 25%, P = 0.019), and during the first month (84% vs. 58%, P = 0.006), but no difference was found in frequency of rejection from months 2 to 12. LVEF was not different in the groups at any point. CI was better in group I at 12 months (2.76 vs. 2.5, P = 0.03). No statistically significant difference was found in incidence of allograft vasculopathy (17% vs. 26%, P = 0.204). Actual graft survival at 1 year was better for group I (91% vs. 74%, P = 0.008), and actuarial graft survival at 6 years also favored group I (76% vs. 56%, P = 0.04). Using high-confidence-level serological HLA-DR typing assignments we demonstrated that HLA-DR mismatching correlates highly with cardiac allograft outcome. Implications are that heart transplant survival could be improved if prospective matching were feasible and prioritized or if immunosuppression were tailored to the HLA-DR match.     

Long-term static testing of an FRP prototype highway structure

In recent years it has become apparent that the labour and maintenance costs of highway structures fabricated from conventional constructional materials (i.e. steel and concrete) are rising, and therefore the whole life cost of these structures is being significantly affected. Highway structures manufactured from advanced composite materials provide a viable solution to reduce substantially both the labour and the maintenance costs, whilst providing structures that behave in accordance with the present British code of practice for highway structures.

The principle objectives of the investigations were to undertake experimentally and to verify, where applicable, numerically the suitability of advanced fibre-reinforced polymer (FRP) composite materials manufactured in the form of box beams for use as highway structures. It was also important to research into any unique behaviour exhibited by the FRP structures while under test and to develop relevant theoretical models and formulae to characterize completely this behaviour.

The composite box beam showed no signs of global deterioration and generally behaved as predicted; the short term stiffness of the beam measured at specific times during the test did not decrease to any extent. There was some local flexural cracking in the connectors at the position of the applied loads, but this can be eliminated by design. The creep and deflections of the beam at the end of the test were well within acceptable limits.     

Role of imidazoline receptors in the cardiovascular actions of moxonidine, rilmenidine and clonidine in conscious rabbits

The present study in conscious rabbits with intracisternal (i.c.) catheters sought to determine the relative contribution of the I1 subtype of imidazoline receptors (IR) and alpha 2 adrenoceptors to the hypotensive effects of rilmenidine, clonidine and moxonidine with an I1-IR/alpha 2 adrenoceptor antagonist efaroxan and a specific alpha 2 adrenoceptor antagonist 2-methoxyidazoxan (2-MI). The alpha 2 adrenoceptor antagonist effect of efaroxan was compared with 2-MI by performing cumulative dose-response curves in the presence of alpha-methyldopa (400 micrograms/kg i.c.). 2-MI was 5.6 times more potent than efaroxan at reversing 75% of the hypotension elicited by alpha-methyldopa (P < .025). This dose ratio was used to match doses of efaroxan and 2-MI for similar alpha 2 adrenoceptor blockade. The effects of efaroxan (4.1, 13, 41 micrograms/kg i.c.) and 2-MI (0.74, 2.3, 7.4 micrograms/kg i.c.) were investigated on a single i.c. dose of rilmenidine (12 micrograms/kg), clonidine (0.75 microgram/kg) and moxonidine (0.51 microgram/kg). These doses of the antihypertensive agents, which were determined from cumulative dose-response curves, produce 90% of the maximum hypotension. Efaroxan was more effective at reversing the hypotension induced by moxonidine and rilmenidine than was 2-MI (P < .01). These findings suggest that rilmenidine and moxonidine act predominantly via IR. By contrast, 2-MI was more effective at reversing the clonidine-induced hypotension than was efaroxan (P < .001), suggesting that clonidine acts mainly via alpha 2 adrenoceptors in conscious normotensive rabbits. Thus, a higher selectivity of the second generation agents moxonidine and rilmenidine for I1-IR over alpha 2 adrenoceptors, compared with the first generation agent clonidine, appears to be necessary for this effect to be manifested in their hypotensive actions.     

Improvement of the engineering properties of asphalt pavements using a ‘soft’ compaction technique (AMIR-Compaction)

In most countries of the world asphalt pavement of road networks represents the biggest single investment in the transportation system. In Canada, asphalt pavement built over the past decade is worth more than 70 billion dollars (in 1984 dollars). In order to maintain the current road network at the present level of service and prevent it from further deterioration, over 6 billion dollars is needed anually.

Traditionally, asphalt overlays are widely used to rehabilitate existing deteriorated pavements. Unfortunately the new overlays have been observed to fail in a relatively short time. Thus the investment in overlays is lost.

Recent research based on the concept of relative rigidity has indicated that the rapid deterioration of new asphalt overlays is directly related to current construction equipment. It has been shown analytically and experimentally that steel rollers used in compacting the asphalt layer will result in surface cracks during construction. Traffic and environmental influences will accelerate the failure of the new layer.

This paper presents the results of a testing programme evaluating the engineering properties of asphalt slabs compacted by a new method using a compactor termed AMIR. The results showed that the AMIR compactor will prevent the formation of constitution cracks resulting in an increase of indirect tensile strength of 10% and an increase of direct tensile strength of up to 60% when compared to steel roller compacted asphalt slabs.     

压力容器用封头制造质量控制和专业化生产发展方向

中国法规首次对压力容器等特种设备用封头实施制造资格许可和强制的监督检验制度。本文根据法规标准的规定,对压力容器封头制造质量控制和专业化生产发展方向的要求作一系统的综述,以提高压力容器产品的整体质量,确保特种设备安全万无一失。     

Perceived interactivity leading to e-loyalty: Development of a model for cognitive–affective user responses

Novel applications of website interactivity are important to attract and retain online users. In this empirical study five designs for interactivity are examined using different web-poll interfaces. The goal of the investigation is to examine perceived interactivity in a model which includes most commonly tested cognitive elements such as efficiency and effectiveness, but augments this model with the inclusion of a cognitive–affective element for trust, and an affective element of enjoyment. More specifically, a model is created to validate the relationship of perceived interactivity (comprised of user control, user connectedness, and responsiveness of the web-poll application) to efficiency, effectiveness, trust and enjoyment, of the website. In turn, efficiency, effectiveness, trust, and enjoyment are tested for their influence on user behavioral intentions for e-loyalty. All relationships in the model are supported. In addition, exploratory evaluation of qualitative comments is conducted to investigate additional insights between the five web-poll treatments in this investigation. The research confirms the complexity of a model in which cognitive, cognitive–affective and affective elements are present, and advances knowledge on the consequences of perceived interactivity. In additional to theoretical advancements, the research has merit for web designers and online marketers regarding how to enhance interactive online web applications.     

Hybrid simulation and optimization-based design and operation of integrated photovoltaic generation,storage units,and grid

Unlike fossil-fueled generation, solar energy resources are geographically distributed and highly intermittent, which makes their direct control extremely difficult and requires storage units as an additional concern. The goal of this research is to design and develop a flexible tool, which will allow us to obtain (1) an optimal capacity of an integrated photovoltaic (PV) system and storage units and (2) an optimal operational decision policy considering the current and future market prices of the electricity. The proposed tool is based on hybrid (system dynamics model and agent-based model) simulation and meta-heuristic optimization. In particular, this tool has been developed for three different scenarios (involving different geographical scales), where PV-based solar generators, storage units (compressed-air-energy-storage (CAES) and super-capacitors), and grid are used in an integrated manner to supply energy demands. Required data has been gathered from various sources, including NASA and TEP (utility company), US Energy Information Administration, National Renewable Energy Laboratory, commercial PV panel manufacturers, and publicly available reports. The constructed tool has been demonstrated to (1) test impacts of several factors (e.g. demand growth, efficiencies in PV panel and CAES system) on the total cost of the integrated generation and storage system and an optimal mixture of PV generation and storage capacity, and to (2) demonstrate an optimal operational policy.     

减少离散大系统两级镇定控制的保守性

The aim of this paper is to propose a new algorithm for multilevel stabilization of large scale systems. In two-level stabilization method, a set of local stabilizers for the individual subsystems in a completely decentralized environment is designed. The solution of the control problem involves designing of a global controller on a higher hierarchical level that provides corrective signals to account for interconnections effect. The principle feature of this paper is to reduce conservativeness in global controller design. Here, the key point is to reduce the effect of interactions instead of neutralizing them. In fact, unlike prior methods, our idea does not ignore the possible beneficial aspects of the interactions and does not try to neutralize them.