Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.

In 2017 the Consultative Committee for Electricity and Magnetism (CCEM) commissioned a key comparison of electrical capacitance standards, the second time this quantity has been compared since the implementation of the Mutual Recognition Agreement by the Comité International des Poids et Mesures (CIPM—MRA) in 1999. This comparison—CCEM-K4.2017—was piloted by the Bureau International des Poids et Mesures (BIPM) and included seven National Metrology Institutes (NMI) belonging to four Regional Metrology Organizations. The measuring scheme adopted for the comparison was that of a star comparison consisting of a set of bilateral comparisons between the participating NMIs and the BIPM, whose capacitance reference base served as a common reference. For each of the bilateral comparisons, the measurands were the capacitance values of 10 pF travelling standard capacitors belonging to the NMIs and, optionally, the values of 100 pF standards. All the participants have been chosen from those able to realize and maintain a representation of the farad at the best known level of accuracy. Four of them, including the BIPM, were taking their traceability from dc or ac quantum Hall effect standards and, the four others, from a calculable capacitor. The comparison results analysis have evidenced an agreement within about ±5 parts in 108 for the mandatory 10 pF measurements and within about ±10 parts in 108 for the optional 100 pF measurements. Also, excepted for one of the participants, a good agreement has been found for the ratio 100 pF:10 pF (within ±5 parts in 108). In addition to the comparison, it has been possible to evaluate the difference between the value of R K (von Klitzing constant) measured by electrical means from calculable capacitors and its last CODATA recommended value (CODATA 2014 adjustment). A difference of (43 ± 23) parts in 109 (k = 1) has been found which is consistent with the difference that can be computed from the experimental data used in the CODATA 2014 adjustment of fundamental constants. This report presents the details of the measurements and analysis having led to these results. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCEM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

The impact of two different dialyzed styrene-acrylate polymer dispersions on the early hydration of OPC was studied. The polymer particles of both dispersions show a similar particle size distribution and high charge due to carboxylic groups on the surface of the particles. Both dispersions also show similar adsorption behavior. The hydration of the OPC was studied at a polymer concentration below the initial adsorption in order to evaluate possible reasons for the interaction of the polymer particles with cement hydration. It can be shown that the polymer particle with the lower glass transition temperature Tg shows a stronger impact on cement hydration, which cannot be explained by any influence on the pore solution composition or the initial dissolution of cement phases. Hence, the adsorption mechanism seems to be the most likely cause of the interaction of the polymers with hydrating cement.

Activation of ErbB4 by neuregulin 1 (NRG1) promotes cardiomyocyte hypertrophy and proliferation in neonatal and adult mice, whereas application of NRG1 following myocardial infarction reduces scar size and improves function. Less is known about ErbB4 participation in cardiac hypertrophy. We evaluated the role of cardiomyocyte ErbB4 in developmental-, exercise-, and angiotensin-induced hypertrophy. For adult studies, ErbB4 was deleted in αMHC-MerCreMer (cCre Tg+/−)/ErbB4 floxed (ErbB4ff) mice at ∼2 months of age with 10 injections of Tamoxifen (20 mg/kg/day). Mice were aged for up to 8 months, exposed to angiotensin II (1000 ng/kg/min, 14 days) or exercised (twice-daily swimming, 20 min/session increasing to 10 min/day to 90 min followed by 7 days at 90 min/session). Neonates (ErbB4ff or ErbB4ww) received temporal vein injections of AAV9-cTNT-eGFP-iCre (2.16 × 1011 viral particles) at p1 and were culled at p6. Three months after deletion of ErbB4 in adult hearts, contractile function was reduced in vivo (echocardiography, 16%) and ex vivo (isolated-perfused, 33%); however, deletion failed to modify heart size, survival for 8 months, or hypertrophy in response to angiotensin II or exercise. In neonates, the presence of iCre mRNA in hearts confirmed virus infection, and suppression of ErbB4 in ErbB4f/f mice was coincident with increased NRG1α, and reduced body and ventricular weights. Thus, ErbB4 is critical to cardiac hypertrophy and growth in neonatal mice, and maintains adult heart function (Figure 1).

À partir d’une étude transcriptomique différentielle de rein de rats hypertendus et néphrotiques, nous avons identifié et étudié, pour la première fois, l’Isthmine-1 (ISM-1), une molécule impliquée dans le syndrome néphrotique (SN). L’immunohistochimie montre que l’ISM-1 est exprimée physiologiquement dans le rein chez le rat, la souris et chez l’homme. Son expression est podocytaire en microscopie électronique, confirmée par une co-localisation avec la néphrine. Puisque ses deux récepteurs : l’intégrine alphaV beta5 et GRP78 (Bip) sont connus pour être impliqués respectivement dans la perméabilité vasculaire et dans des glomérulopathies, nous avons étudié l’ISM-1 au cours de 2 modèles expérimentaux de SN chez le rat par l’injection de puromycine d’aminonucléoside (PAN) et d’adriamycine (ADR). Dans ces 2 modèles, nous avons observé une augmentation du taux d’ARNm d’ISM-1 ainsi que de ses récepteurs dans les glomérules isolés, contrastant avec la diminution de l’expression de la néphrine. Afin de démontrer l’implication de l’ISM-1 dans le SN, nous avons inhibé son expression par l’administration d’antisens anti-ISM-1 à des rats néphrotiques PAN et ADR. Chez les rats PAN, l’inhibition de l’ISM-1 ne modifie pas l’évolution de la maladie probablement par une sévérité importante du modèle. Nous poursuivons l’investigation des rats ADR dont le développement de la maladie est plus progressif. En parallèle, nous avons incubé des podocytes humains en culture avec des doses croissantes d’ISM-1 recombinante et observé une diminution de la viabilité cellulaire. Cette baisse de la viabilité des podocytes s’accompagne d’une inhibition de l’autophagie visible par l’accumulation de la protéine P62 et d’une induction de la caspase 8 active, protéine impliquée dans l’apoptose. L’immuno-précipitation de GRP78 et de l’intégrine avb5 à partir des glomérules nous a permis de confirmer l’interaction de l’ISM-1 et avec ses récepteurs dans le rein. Nous développons actuellement des vecteurs viraux qui seront injectés à la souris pour induire une forte expression d’ISM-1. Nous attendons que ces souris développent une maladie glomérulaire. Nos résultats montrent pour la première fois que l’ISM-1 a une expression physiologique podocytaire. Son expression et celle de ses récepteurs sont augmentées au cours des syndromes néphrotiques expérimentaux. In vitro, L’ISM-1 semble avoir un rôle délétère sur les podocytes par inhibition de l’autophagie.

In-situ XRD, heat flow calorimetry, pore water analysis and 1H NMR were used in order to gain more detailed understanding for cement hydration within the first hours of hydration. All methods used show very satisfying accordance. All information gained from the different methods were used in order to calculate absolute mass balance for several ions in order to get an idea about ionic reservoirs adsorbed on surfaces during cement hydration. Sulfate and aluminum adsorption show impact on sulfate depletion, calcium does not.

A mixer-first receiver with high linearity and low noise is presented in this paper. Since there is no low noise amplifier (LNA) between the antenna and the mixer, the passive mixer reflecting the baseband impedance makes input impedance matching directly in the receiver. The choice of the operation amplifier (OTA) and the parasitic resistance of the passive mixer both decide the noise of the receiver, and the analysis and principle is shown in the paper. The mixer-first receiver here challenges a new structure of transimpedance amplifier (TIA), which consists of a gm stage and a TIA stage. This new structure achieves low noise and high linearity. However, this new structure has the risk of stability, and the analysis about the stability is discussed in this paper. With the core circuit consuming 135mW, the prototype receiver implemented in 180nm CMOS technology achieves >20dB conversion gain, <6dB in-band NF and >20dBm in-band IIP3 in 1.2GHz, with 1.8V supply.

The nonlinearity analysis of the full differential operational amplifier (op-amp) and Cascade System are introduced. A multistage op-amp with feedforward compensation (FFC) and linearity improvement technique circuit is designed. The proposed op-amp utilizes a current-reusing, split path technology. A 10MHz bandwidth 4th-order, Chebyshev-I, ladder active-RC LPF employing the op-amp in this paper is simulated and optimized with the guideline of the nonlinearity analysis. The optimized in-band IIP3 of the LPF can achieve 50.2dBm in a test two-tone input signal at 4.5MHz and 4.6MHz while consuming 14.76mW from a 1.8V supply in 180nm CMOS technology.

Proposed in this paper is a general parasitic-compatible LCR matching method suitable for N-path filter. Analysis of a conventional L-type matching is extended to accommodate the case of the N-path filter, where the different impedances of the band limited input matching network at multiple local oscillation (LO) harmonic frequencies have to be taken into consideration. Compared to the ideally wideband transformer matching technique, the proposed LCR method has advantages of smaller size and better harmonic folding rejection ratio, while keeping the same properties, such as impedance matching, in-band voltage gain, noise figure and ultimate rejection. Based on the derived equations, the procedure to determine the values of the matching components for given rejection specs has been described using design examples.

A 6th order Chebyshev active-RC complex filter for high linearity global navigation satellite (GNSS) receiver is proposed in this paper. The filter is synthesized from a 6th order leapfrog low pass filter where the frequency non-ideality compensation technique for integrator is used. High linearity demands a robust and stable IIP3 through the pass band. Meanwhile, the 35dB rejection spec at 1.5 times bandwidth requires at least 6th order which degrades the linearity performance. A gain enhanced, current-reusing, feedforward compensation (FFC) OTA is designed to improve the linearity performance. The complex filter is centered at 15.48MHz with a bandwidth of 20.46MHz. It has 0dB gain and less than 1dB ripple. It draws 21.7mA from 1.8V supply, meanwhile it achieve more than +32dBm IIP3 through the pass band and a maximum IIP3 of +39.1dBm which are relatively high performance in 0.18µm CMOS process compared to other papers.

This paper proposes a process variation sensor for monitoring random variations in the threshold voltage. The proposed circuit monitors the pmos and nmos process variabilities independently by using two types of the inverter-based ring oscillators (RO). The nmos (pmos) type ring oscillator is designed to improve its sensitivity to the process variation of nmos (pmos) transistors. In addition, a modified iterative estimation method is used to reduce the nonlinearity of the estimated parameter and enhance the reliability of the detection. All work is in TSMC-180nm process.

A LNTA with robust improvement of IIP3 over temperature and process is proposed. Four auxiliary transistors are employed to achieve 3rd nonlinearity compensation using DS (derivative superposition) method. In order to maintain the high IIP3 over process and temperature (PT) variation, transistor's nonlinearity under PT is explored and corresponding bias circuit is built to keep enhancement in IIP3. The LNTA is designed under TSMC 0.18um process and achieves 23mS gain while drawing 3.1mA from 1.8V supply voltage at 1.2GHz. Simulation shows the auxiliary transistors offer over 10dB improvement of IIP3 regardless of process and temperature variation while consuming nearly no extra power and noise.

A low-cost low-power area-efficient receiver front-end prototype for X-band applications is presented. The front-end primarily consists of 3 blocks: a single ended input differential-output Low noise amplifier (LNA), a double balanced down-converter, and Inter-frequency (IF) buffers providing single-ended output. Including are also Low dropout regulators (LDO) and Electrostatic discharge (ESD) protection circuits coinciding with the forgoing blocks. Local oscillator (LO) frequency is chosen such that output signal locates in L/S-band for extending subsequent applications. Experimentally exhibiting a conversion gain of around 44dB with 7.5-dB Single-sideband (SSB) Noise figure (NF), the front-end totally draws 24mA from an external 3.3-V supply. Fabricated in a 65-nm CMOS technology, this compact receiver occupies an area of only 0.22mm(2).

The invention provides a DC variable low-frequency envelope digital detector. The DC variable low-frequency envelope digital detector at least comprises a disperse adjustable band-gap reference voltage generator, a comparator for comparing input signals with band-gap reference voltage, a digital calibration detector for detecting the output of the comparator and calibrating the band-gap reference voltage. According to the low-frequency characteristics of input voltage, the DC variable low-frequency envelope digital detector can greatly simplify the complexity of a circuit scheme, achieve degree of freedom and avoid influence of process and temperature change on signal processing performance to the maximum degree; a calibration tracing scheme can solves the problem of DC drift, which cannot be handled by traditional methods, and save on-chip large capacitors; due to the fact that most signal processing tasks are undertaken in a digital circuit part, so that the circuit power consumption can be greatly reduced.

A new architecture of ring oscillator for ultra high frequency is presented in this paper. Both coupling and frequency multiplication techniques are used to generate high frequency signals while optimizing the phase noise performance. A ring oscillator with wide tuning range using the proposed method is designed in 40nm CMOS process. The proposed oscillator operates from 5.91 GHz to 13.91 GHz with 80.72% tuning range. The phase noise of the proposed oscillator is -111.37dBc/Hz@1 MHz at 5.91 GHz and -102.72dBc/Hz@1MHz at 13.91 GHz respectively. The power consumption is simulated only 2.66 mW and 12.1 mW at 5.91GHz and 13.91GHz, respectively.

A novel edge voltage (EV) quantizer with digital-intensive implementation is proposed to detect DC voltage, peak-to-peak magnitude, and frequency of low-frequency simple waveforms (e.g. sinusoidal). The proposed EV quantizer does not need the area-consuming low pass filter. It can be implemented using digital-intensive circuits with little computing complexity, thanks to the simple detection algorithm. A successive approximation register (SAR) version of the EV quantizer was integrated in a monolithic satellite low noise block (LNB) IC in a 65 nm CMOS process to detect low-frequency control signals. And the measurement results validate that the EV quantizer enables low-cost operation for detection of lowfrequency simple waveforms.

As the demand for multi-mode and multi-band RF receiver blooms, traditional off-chip bulky and non-tunable filters such as SAW and BAW filter are no longer suitable for receiver chips. The newly appeared on-chip N-path filter becomes appealing due to its large-scale frequency tuning range, high Q and progress-scalable feature. However, conventional N-path filter is limited by its normally narrow passband and inevitable center-frequency offset. To overcome these two shortcomings, gm-C stages are proposed to compensate center frequency offset and obtain high out of band (OOB) rejection. This paper presented a 4th-order N-path filter with eliminated center-frequency offset and configurable bandwidth by 40nm CMOS technology.