Activity

eded to confirm those results. Farnesyl pyrophosphate synthase (FPPS) is a crucial enzyme for the synthesis of isoprenoids and the key target of nitrogen-containing bisphosphonates (N-BPs). N-BPs are potent and selective FPPS inhibitors that are used in the treatment of bone-related diseases, but have poor pharmacokinetic properties. Given the key role played by FPPS in many cancer-related pathways and the pharmacokinetic limits of N-BPs, hundreds of molecules have been screened to identify new FPPS inhibitors characterized by improved drug-like properties that are useful for broader therapeutic applications in solid, non-skeletal tumours. We have previously shown that N6-isopentenyladenosine (i6A) and its related compound N6-benzyladenosine (2) exert anti-glioma activity by interfering with the mevalonate pathway and inhibiting FPPS. Here, we report the design and synthesis of a panel of N6-benzyladenosine derivatives (compounds 2a-m) incorporating different chemical moieties on the benzyl ring. Compounds 2a-m show in vitro antiproliferative activity in U87MG glioma cells and, analogous to the bisphosphonate FPPS inhibitors, exhibit immunogenic properties in ex vivo γδ T cells from stimulated peripheral blood mononuclear cells (PBMCs). Using saturation transfer difference (STD) and quantitative 1H nuclear magnetic resonance (NMR) experiments, we found that 2f, the N6-benzyladenosine analogue that includes a tertbutyl moiety in the para position of the benzyl ring, is endowed with increased FPPS binding and inhibition compared to the parent compounds i6A and 2. N6-benzyladenosine derivatives, characterized by structural features that are significantly different from those of N-BPs, have been confirmed to be promising chemical scaffolds for the development of non N-BP FPPS inhibitors, exerting combined cytotoxic and immunostimulatory activities. The scope of this paper is the analysis of open-loop and L2/D controlled closed-loop behavior of the Cholette’s bioreactor under different operating conditions. The open-loop behavior is studied by means of the steady-state multiplicity areas formed by substrate feed concentration and substrate concentration in the output using the nonlinear model of the bioreactor. SR1 antagonist in vitro The stability of each steady-state inside areas is determined by a polynomial representation. The nonlinear dynamic and steady-state multiplicity areas of the Cholette’s bioreactor are shown to depend on the operating conditions and concentration required. The closed-loop behavior is studied by the tuning of a set of Pareto-optimal L2/D linear controllers at a stable operating point. Numerical simulations and phase portraits are used to evaluate the control system. This paper could be a guide for theoretical and practical applications in the fields of biotechnology and automatic control. Given the strong cyber-physical interactions in today’s smart grid, false data injection (FDI) attack can readily mislead the state estimation and influence the system operation by manipulating meter measurements. In this paper, a new FDI attack strategy is considered where multiple attackers cooperatively launch an unobservable attack. Firstly, the entire transmission system is partitioned into several subsystems, with each attacker only acquiring and manipulating the measurements in its local area. With limited communications among neighboring attackers, all of them can successfully modify the estimated states without being detected. In addition, by taking practical constraints into account, a least-effort attack problem is formulated and subsequently solved by a distributed alternating direction method of multipliers (ADMM)-based approach. Several case studies implemented on a 4-bus and IEEE 118-bus power systems have finally demonstrated the effectiveness of the proposed approach in the scenario of multiple attackers. For permanent magnet synchronous motor drives, the difficulty of parameter tuning of nonlinear active disturbance rejection control (ADRC) current controller is the bottleneck for its application. This paper proposes a measurement delay compensated linear ADRC (LADRC), and a simple tuning method for LADRC’s parameters is presented. Firstly, an ideal model without resistance is acquired, because the current coupling terms, dead-time effects, and motor parameter variations are estimated and canceled out by an linear extended state observer. Secondly, an improved LADRC considering time delay of current measurement is developed. It eliminates unmatched disturbance compensation caused by measurement delay. And frequency responses of current closed-loop gain and disturbance suppression are evaluated. Then, based upon the frequency characteristics of the LADRC controller, a simple tuning method founded on desired frequency bandwidth is presented. It is convenient to be implemented. Finally, experimental results demonstrate that the proposed method is effective. This paper introduces this Special Issue of the Journal of Human Evolution entitled “Kanapoi Paleobiology of a Pliocene site in Kenya.” Kanapoi, West Turkana, Kenya, is part of the Omo-Turkana Basin and is the type site of the earliest known genus of Australopithecus, A. anamensis. Kanapoi preserves among the earliest earliest evidence of Australopithecus in deposits dated between 4.195 to 4.108 million years old. Explored by several teams since the 1960s, the Kanapoi sediments have yielded a rich and abundant fauna, providing important information about the paleoenvironments and the context surrounding the earliest evolution of the genus Australopithecus, as well as about the evolution and biogeography of African Pliocene vertebrate faunas. Mucinous and medullary breast cancers (BCs) have different histological substrates that manifest as different imaging features on mammography, ultrasound, and MRI. The aim of the present review is to demonstrate the differences between these two rare BC subtypes and to describe the microscopic features, review the imaging methods for detection of both cancer subtypes, illustrate the imaging findings and present useful pearls and pitfalls. Out of a total of 30 patients with mucinous BC and nine with medullary BC, we have selected typical and also unusual imaging features that best represent these cancers. The patients underwent a mammography and breast ultrasound followed by magnetic resonance imaging. We briefly exhibit histological characteristics for a better understanding of the imaging aspects.