Self-homodyne wavelength locking of a silicon microring resonator.

We propose and experimentally demonstrate a self-homodyne locking method for a silicon microring resonator (MRR). The device employs a self-homodyne detection structure and consists of a tunable MRR with two directional couplers along the ring for monitoring, two phase shifters to calibrate the phase difference between the two monitored optical signals, and a Y-branch to combine the two signals. A single photodetector is used to detect the output power of the Y-branch. If the MRR is on resonance, a destructive interference occurs in the Y-branch, therefore the monitored photocurrent is minimized. By using such a device structure and the homodyne detection scheme, the MRR with a Q factor of 1.9 × 104 can be accurately locked to the signal wavelength, and the locking process is insensitive to input power variation. The wavelength locking range is larger than one free spectral range (FSR) of 6 nm, and the locking errors are ≤0.015 nm.

Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor.

Diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor Pradigastat (1) was shown to be effective at decreasing postprandial triglyceride levels in a patient population with familial chylomicronemia syndrome (FCS). Although pradigastat does not cause photosensitization in humans at the high clinical dose of 40 mg, a positive signal was observed in preclinical models of phototoxicity. Herein, we describe a preclinical phototoxicity mitigation strategy for diarylamine containing molecules utilizing the introduction of an amide or suitable heterocyclic function. This strategy led to the development of two second-generation compounds with low risk of phototoxicity, disparate exposure profiles, and comparable efficacy to 1 in a rodent lipid bolus model for post-prandial plasma triglycerides.

Identification of Mutations in the mrdA Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of Escherichia coli Clinical Isolates with Mutations in ftsI (PBP3) and Which Carry blaNDM-1.

Penicillin-binding proteins (PBPs) are essential for bacterial cell wall biosynthesis, and several are clinically validated antibacterial targets of ß-lactam antibiotics. We identified mutations in the mrdA gene encoding the PBP2 protein in two Escherichia coliblaNDM-1 clinical isolates that reduce susceptibility to carbapenems and to the intrinsic antibacterial activity of a diazabicyclooctane (DBO) PBP2 and ß-lactamase inhibitor. These mutations coexisted with previously described mutations in ftsI (encoding PBP3) that reduce susceptibility to monobactams, penicillins, and cephalosporins. Clinical exposure to ß-lactams is driving the emergence of multifactorial resistance that may impact the therapeutic usefulness of existing antibacterials and novel compounds that target PBPs.IMPORTANCE Emerging antibacterial resistance is a consequence of the continued use of our current antibacterial therapies, and it is limiting their utility, especially for infections caused by multidrug-resistant isolates. ß-Lactams have enjoyed extensive clinical success, but their broad usage is linked to perhaps the most extensive and progressive example of resistance development for any antibacterial scaffold. In Gram-negative pathogens, this largely involves constant evolution of new ß-lactamases able to degrade successive generations of this scaffold. In addition, more recently, alterations in the targets of these compounds, penicillin-binding proteins (PBPs), are being described in clinical isolates, which often also have multiple ß-lactamases. This study underscores the multifactorial nature of ß-lactam resistance by uncovering alterations of PBP2 that reduce susceptibility to carbapenems in E. coli clinical isolates that also have alterations of PBP3 and express the NDM-1 ß-lactamase. The changes in PBP2 also reduced susceptibility to the intrinsic antibacterial activity of some diazabicyclooctane (DBO) compounds that can target PBP2. This may have implications for the development and use of the members of this relatively newer scaffold that are inhibitors of PBP2 in addition to their inhibition of serine-ß-lactamases.

112-Gb/s SSB 16-QAM signal transmission over 120-km SMF with direct detection using a MIMO-ANN nonlinear equalizer.

We propose and experimentally demonstrate a multiple input multiple output - artificial neural network (MIMO-ANN) nonlinear equalizer (NLE) to process the complex quadrature amplitude modulation (QAM) signal in a single-sideband (SSB) self-coherent detection (SCD) system. In the proposed scheme, a 2-by-2 MIMO structure with two ANNs is employed to effectively mitigate the signal distortions induced by in-phase and quadrature (IQ) imbalance and fiber nonlinear effects. By using the proposed MIMO-ANN NLE, we successfully transmit a 112-Gb/s SSB 16-QAM signal over a single-span 120-km single mode fiber (SMF) in a direct detection (DD) system with a bit error rate (BER) lower than 3.8 × 10-3. We also conduct a comparative study between the proposed MIMO-ANN NLE, a feedforward equalizer (FFE), a NLE consisting of two independent real-valued Volterra filters, and a MIMO-Volterra filter. The proposed MIMO-ANN NLE outperforms other equalizers with the longer fiber length and thus stronger nonlinearities, since it can easily approximate a complicated nonlinear function. To the best of our knowledge, this is the first experimental demonstration of an ANN-based equalizer in an SSB SCD system.

Single-resonance silicon nanobeam filter with an ultra-high thermo-optic tuning efficiency over a wide continuous tuning range.

Energy-efficient tunability is highly desired for silicon photonic devices. We demonstrate a thermo-optic tunable filter with an ultra-high tuning efficiency based on a suspended photonic crystal nanobeam cavity. Attributed to the ultra-small mode volume and free-standing waveguide structure, a tuning efficiency of 21 nm/mW is achieved over a wide single-resonance tuning range of ∼43.9 nm. The 10%-90% switching times are 67.0 µs and 68.8 µs for the rising edge and the falling edge, respectively. The demonstrated energy-efficient tunable device can find applications in reconfigurable photonic integrated circuits.

Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228.

Metallo-ß-lactamases (MBLs), such as New Delhi metallo-ß-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of ß-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine ß-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of ß-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).

Ultra-compact tunable silicon nanobeam cavity with an energy-efficient graphene micro-heater.

We propose and experimentally demonstrate an ultra-compact silicon photonic crystal nanobeam (PCN) cavity with an energy-efficient graphene micro-heater. Owing to the PCN cavity with an ultra-small optical mode volume of 0.145 µm3, the light-matter interaction is greatly enhanced and the thermo-optic (TO) tuning efficiency is increased. The TO tuning efficiency is measured to be as high as 1.5 nm/mW, which can be further increased to 3.75 nm/mW based on numerical simulations with an optimized structure. The time constants with a rise time constant of τrise = 1.11 µs and a fall time constant of τfall = 1.47 µs are obtained in the experiment.

Phylogenetic and biological significance of evolutionary elements from metazoan mitochondrial genomes.

The evolutionary history of living species is usually inferred through the phylogenetic analysis of molecular and morphological information using various mathematical models. New challenges in phylogenetic analysis are centered mostly on the search for accurate and efficient methods to handle the huge amounts of sequence data generated from newer genome sequencing. The next major challenge is the determination of relationships between the evolution of structural elements and their functional implementation, which is largely ignored in previous analyses. Here, we described the discovery of structural elements in metazoan mitochondrial genomes, termed key K-strings, that can serve as a basis for phylogenetic tree construction. Although comprising only a small fraction (0.73%) of all K-strings, these key K-strings are pivotal to the tree construction because they allow for a significant reduction in the computational time required to construct phylogenetic trees, and more importantly, they make significant improvement to the results of phylogenetic inference. The trees constructed from the key K-strings were consistent overall to our current view of metazoan phylogeny and exhibited a more rational topology than the trees constructed by using other conventional methods. Surprisingly, the key K-strings tended to accumulate in the conserved regions of the original sequences, which were most likely due to strong selection pressure. Furthermore, the special structural features of the key K-strings should have some potential applications in the study of the structures and functions relationship of proteins and in the determination of evolutionary trajectory of species. The novelty and potential importance of key K-strings lead us to believe that they are essential evolutionary elements. As such, they may play important roles in the process of species evolution and their physical existence. Further studies could lead to discoveries regarding the relationship between evolution and processes of speciation.

Discovery of LFF571: an investigational agent for Clostridium difficile infection.

Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.

3,5-diarylazoles as novel and selective inhibitors of protein kinase D.

The synthesis and preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, optimized compounds in this class have been found to be active in cellular assays of phosphorylation-dependant HDAC5 nuclear export, orally bioavailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases. Therefore these compounds could provide attractive tools for the further study of PKD/HDAC5 signaling.

Identification of potent and selective amidobipyridyl inhibitors of protein kinase D.

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.

Solvent-free fluids based on rhombohedral nanoparticles of calcium carbonate.

Calcium carbonate nanoparticles are one of the most economical nanomaterials. However, the ease of agglomeration and lack of functionalities are obstacles to their widespread application. Here we report the preparation and characterization of the solvent-free fluids based on rhombohedral nanoparticles of calcium carbonate, with a soft organic shell on the inorganic particle surface. For the first time, solvent-free fluids based on an inorganic salt are demonstrated. The fluidity of this nanosystem derived from the soft shell will be of great value for processability, manipulation, and ease of dispersion. Moreover, the solvent-free fluids are intrinsically conductive, which is a new functionality for calcium carbonate nanoparticles. The core/shell structure is clearly revealed by the high-resolution transmission electron microscopy images, and this verifies the presumed structure of this family of functionalized nanostructures.

Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors.

A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities.

[Identification of Aaron's beard with clustering analysis by attenuation reflection-Fourier transform infrared spectrometry].

OBJECTIVE: To establish a new method to discriminate Aaron's beard by Fourier transformation infrared spectrometry. METHODS: Attenuation Reflection-Fourier transformation infrared spectrometry with clustering analysis was used to the identification of Aaron's beard. RESULTS: There were obvious differences in Aaron's beard. The results are consistent with that of morphologic study. CONCLUSION: This method is rapid, simple and economical, and can be used to the quality control.