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.     

安全信用评价在乌弄龙、里底水电工程建设中的应用

近年来澜沧江公司对安全生产工作采取了强有力手段,安全生产基础不断夯实。如何将安全工作推进更深的层次,如何把控"准入关",将信用评价纳入安全生产不失为一个行之有效的方式。安全信用评价是建立水电工程施工安全信用体系的重要手段,能够促进整体行业安全管理水平的提升。     

Prevention of violence

Primary care physicians can easily incorporate efforts toward the primary and secondary prevention of family violence into their practices. By designing a preventive effort using the phases of the family life cycle, a developmentally appropriate system of prevention is created. The anticipatory guidance at each (annual) visit acknowledges family transitions and assures the family that abuse is a health issue and that the physician is a resource for issues of violence prevention. Using the FLC, the first phase is Coupling, when there is a risk of partner violence that continues as long as there is a partnership. Pregnancy and childbirth bring concerns of child neglect and battery. Older children are at additional risk for child sexual abuse. As families age, risks develop for elder abuse, too. The regular discussion of these issues raises the awareness that the potential for family violence continues over the life span and allows the physician opportunities to assess the risk of violence in that family and make appropriate preventive referrals. Primary care physicians are optimally positioned to address violence and its prevention in the office: they know and care for family units over time. Physicians are respected and trusted advisors who can become effective in preventing violence.     

EVALUATING SOFTWARE OUTSOURCING OPTIONS Do Your Software Operations Add Value ?

If you don't know the current productivity rates, usage volumes, and other quantitative baseline data for your software operations, then software might not be a key component of the company's core business. The evaluation criteria in this article can help the IS executive determine the outsourcing options for software operations.     

The rationale for cementless total hip replacement

Current cementing techniques of distal plugging, pulsatile water cleaning of the canal, and retrograde filling with PMMA in a low-viscous state prepared using porosity reduction techniques and then pressurized have been shown to give excellent results at 10 or more years after operation. However, physical and aging characteristics of PMMA do not guarantee that those results will hold up in the 20- to 30-year time frame. Fifteen-year experience with bony ingrowth systems indicate the development of a durable interface without PMMA, although the interface does appear more vulnerable to attack by the biologic reaction to HMWPE debris. Bone remodeling appears more favorable around proximally fixed bone ingrowth prostheses than around distally fixed prostheses. Softening of the physical characteristics of the stem tip may reduce the incidence of thigh pain. Patients with high activity potential and a life expectancy of greater than 25 years should be strongly considered for a proximally fixed bone ingrowth or ongrowth prosthesis.     

Efficient computation of time-varying and adaptive filters

Two techniques for efficient computation of filters that support time-varying coefficients are developed. These methods are forms of distributed arithmetic that encode the data, rather than the filter coefficients. The first approach efficiently computes scalar-vector products, with which a digital filter is easily implemented in a transpose-form structure. This method, based on digital coding, supports time-varying coefficients with no additional overhead. Alternatively, distributed-arithmetic schemes that encode the data stream in sliding blocks support efficient direct-form filter computation with time-varying coefficients. A combination of both of these techniques greatly reduces the computation required to implement LMS adaptive filters