Quantitative and reliable in vitro method combining scanning electron microscopy and image analysis for the screening of osteotropic modulators

The increased generation and up-regulated activity of bone resorbing cells (osteoclasts) play a part in the impairment of bone remodeling in many bone diseases. Numerous drugs (bisphosphonates, calcitonin, selective estrogen receptor modulators) have been proposed to inhibit this increased osteoclastic activity. In this report, we describe a pit resorption assay quantified by scanning electron microscopy coupled with image analysis. Total rabbit bone cells with large numbers of osteoclasts were cultured on dentin slices. The whole surface of the dentin slice was scanned and both the number of resorption pits and the total resorbed surface area were measured. Resorption pits appeared at 48 h and increased gradually up to 96 h. Despite the observation of a strong correlation between the total resorption area and the number of pits, we suggest that area measurement is the most relevant marker for osteoclastic activity. Osteotropic factors stimulating or inhibiting osteoclastic activity were used to test the variations in resorption activity as measured with our method. This reproducible and sensitive quantitative method is a valuable tool for screening for osteoclastic inhibitors and, more generally, for investigating bone modulators.     

Identification of novel allosteric modulator binding sites in NMDA receptors: A molecular modeling study

The dysfunction of N-methyl-d-Aspartate receptors (NMDARs), a subtype of glutamate receptors, is correlated with schizophrenia, stroke, and many other neuropathological disorders. However, not all NMDAR subtypes equally contribute towards these disorders. Since NMDARs composed of different GluN2 subunits (GluN2A-D) confer varied physiological properties and have different distributions in the brain, pharmacological agents that target NMDARs with specific GluN2 subunits have significant potential for therapeutic applications. In our previous research, we have identified a family of novel allosteric modulators that differentially potentiate and/or inhibit NMDARs of differing GluN2 subunit composition. To further elucidate their molecular mechanisms, in the present study, we have identified four potential binding sites for novel allosteric modulators by performing molecular modeling, docking, and in silico mutations. The molecular determinants of the modulator binding sites (MBS), analysis of particular MBS electrostatics, and the specific loss or gain of binding after mutations have revealed modulators that have strong potential affinities for specific MBS on given subunits and the role of key amino acids in either promoting or obstructing modulator binding. These findings will help design higher affinity GluN2 subunit-selective pharmaceuticals, which are currently unavailable to treat psychiatric and neurological disorders.     

MASH ΣΔ modulators with a noise-shaped two-step ADC in the second stage

In this paper, a multi-stage noise-shaping (MASH) sigma-delta (ΣΔ) modulator is proposed to be used in low oversampling ratio (OSR) applications. It utilizes a noise-shaped two-step (NSTS) analog-to-digital converter (ADC) in the second stage and benefits its inter-stage gain to provide an extra attenuation of the quantization noise such that the same specifications of a traditional modulator are achieved but with a lower order of noise-shaping. Furthermore, large number of bits is resolved in the second stage while equal number of comparators is used. Compared to the single-loop NSTS ADC, in the proposed structure, the complexity problem of the feedback path and coefficient spreading are eliminated. As an example, a MASH 2-1 sigma-delta modulator has been designed and simulated in a 90 nm CMOS process using Spectre. The achieved resolution is 13.44 effective number of bits in 6.25 MHz signal bandwidth while consuming 19.6 mW power from a single 1 V supply. The sampling frequency is 100 MHz and the simulated figure of merit is 141 fJ/conv-step which shows the efficiency of the proposed modulator.     

The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed the lack of response to pharmacological treatment. Molecular characterization highlighted the presence of an additional amino acid substitution, L467F, in cis with the F508del variant, demonstrating that both patients were carriers of a complex allele. Functional and biochemical assays in heterologous expression systems demonstrated that the double mutant L467F-F508del has a severely reduced activity, with negligible rescue by CFTR modulators. While further studies are needed to investigate the actual prevalence of the L467F-F508del allele, our results suggest that this complex allele should be taken into consideration as plausible cause in CF patients not responding to CFTR modulators.     

基于TE/TM模式转换的偏振不敏感调制器

提出了一种能实现偏振不敏感调制的新方法：基于TE／TM偏振模式转换的聚合物电光调制。该器件的电极设计只使用了高（极化和调制）效率的微带线结构，与文献中报道的利用共面电极和微带线电极的组合实现偏振无关调制的器件相比，其半波电压的理论值更低。     

国际上光纤通信技术发展的新趋势

光纤通信技术具有广阔的应用前景。为扩大光纤通信技术的应用领域,必将对光纤通信技术的发展提出一系列的新要求。本文拟从光纤、连接技术、光源和探测器、光电子集成、光调制器和转换器等五个方面来具体阐述国际上光纤通信技术发展的新趋势。     

Chopper Modulators Using Current Conveyor Analogue Switches

The new CMOS Cowan, Ring, and Full-AM chopper modulators using current conveyor analogue switches are presented. The proposed chopper modulators use a square wave carrier current for controlling the transfer of a sine wave baseband voltage from nodes Y to nodes X, and the baseband currents from nodes X to nodes Z, of the current conveyors. The proposed chopper modulators are verified by simulating from the layout with a 0.5 μ m/level 49 MOSFET model of AMI obtained through MOSIS. With a supply voltage of ± 1.5 V, the operation range for the baseband voltage is between −300 mV and 300 mV. The operation range for the carrier current, bias currents for CCIIs, is ranged from ten to few hundred microamps. Using the carrier current of 20 μ A, the power consumption is not more than 0.8 mW in the operation range of the baseband voltage.     

Characterization of New PPARγ Agonists: Analysis of Telmisartan’s Structural Components

Telmisartan was originally designed as an AT₁ antagonist but was later also characterized as a selective PPARγ modulator. This study focused on the identification of the essential structural motifs of telmisartan for PPARγ activation activity, elucidating the individual SAR of each different component (shown).

     

10Gb/s EML Module Based on Identical Epitaxial Layer Scheme

A 10Gb/s transmitter module containing an electroabsorption modulator monolithically integrated with a distributed feedback (DFB) semiconductor laser is fabricated using the identical epitaxial layer scheme.Gain-coupling mechanism is employed to improve the single mode yield of the DFB laser,while inductively coupled plasma dry etching technique is utilized to reduce the modulator capacitance.The integrated device exhibits a threshold current as low as 12mA and an extinction ratio over 15dB at －2V bias.The small signal modulation bandwidth is measured to be over 10GHz.The transmission experiment at 10Gb/s indicates a power penalty less than 1dB at a bit-error-rate of 1e－12 after transmission through 35km single mode fiber.