Catalysts for Suzuki-Miyaura coupling processes: scope and studies of the effect of ligand structure

Suzuki-Miyaura coupling reactions of aryl and heteroaryl halides with aryl-, heteroaryl- and vinylboronic acids proceed in very good to excellent yield with the use of 2-(2',6'-dimethoxybiphenyl)dicyclohexylphosphine, SPhos (1). This ligand confers unprecedented activity for these processes, allowing reactions to be performed at low catalyst levels, to prepare extremely hindered biaryls and to be carried out, in general, for reactions of aryl chlorides at room temperature. Additionally, structural studies of various 1.Pd complexes are presented along with computational data that help elucidate the efficacy that 1 imparts on Suzuki-Miyaura coupling processes. Moreover, a comparison of the reactions with 1 and with 2-(2',4',6'-triisopropylbiphenyl)diphenylphosphine (2) is presented that is informative in determining the relative importance of ligand bulk and electron-donating ability in the high activity of catalysts derived from ligands of this type. Further, when the aryl bromide becomes too hindered, an interesting C-H bond functionalization-cross-coupling sequence intervenes to provide product in high yield.     

Some limit results for longest common subsequences

The length l_n of a longest common subsequence before time n sequences (B₁₁, B₁₂, …) (B₂₁, B₂₂, …) is the cardinality of the largest increasing set of pairs of integers {(j_1α, j_2α)}

$\text{l?}\text{j}{}_{11}\text{<}\text{j}{}_{12}\text{<·<}\text{j}{}_{11}{}_{\mathrm{n}}\text{?}\text{n}\text{l?}\text{j}{}_{21}\text{<}\text{j}{}_{22}\text{<·<}\text{j}{}_{21}{}_{\mathrm{n}}\text{?}\text{n}$

such that ?1?α?l_n, (B_1j1α=B_2j2α). If B₁ and B₂ are independent random sequences with co-ordinates i.i.d. uniform on {1, 2, …, k}, it follows from Kingman's subadditive ergodic theorem that the ratio l_n/n converges to a constant c_k a.s. A method of deriving lower bounds for the constants c_k is given, the bounds obtained improving known lower bounds, for k>2. The rate of decrease of c_k with k is shown to be no faster than 1/√k, contrasting with P{B_1i?B_2i}=1/k. Finally, an alternative method of deriving lower bounds is given and used to improve the lower bound for c₂.     

Recovery in multilayer optical networks

The integration of different network technologies into a multilayer network, as in Internet-based networks carried by optical transport networks (OTNs), creates new opportunities but also challenges with respect to network survivability. In different network layers, recovery mechanisms that are active can be exploited jointly to reach a more efficient or faster recovery from failures. This interworking is also indispensable in order to overcome the variety of failure scenarios that can occur in the multilayer-network environment. A well-considered coordination between the different layers and their recovery mechanisms is crucial in order to attain high performance recovery. This paper provides an overview of multilayer recovery issues and solutions in an Internet protocol (IP)-over-optical-network environment, which is illustrated by quantitative case studies.     

Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases

Voltage-gated Na⁺ (Na_V) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel Na_V channel ligands. With the objective of discovering new blockers of Na_V channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of Na_V channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC₅₀. These five alkaloids were then assayed using the Na⁺ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNa_V1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na⁺ currents elicited by the hNa_V1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na⁺ currents elicited by the hNav1.2 and hNav1.6 channels, with IC₅₀ values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block Na_V channels, with promising therapeutical applications.     

Application of Cleavable Linkers to Improve Therapeutic Index of Radioligand Therapies

Radioligand therapy (RLT) is an emergent drug class for cancer treatment. The dose administered to cancer patients is constrained by the radiation exposure to normal tissues to maintain an appropriate therapeutic index. When a radiopharmaceutical or its radiometabolite is retained in the kidneys, radiation dose deposition in the kidneys can become a dose-limiting factor. A good exemplar is [¹⁷⁷Lu]Lu-DOTATATE, where patients receive a co-infusion of basic amino acids for nephroprotection. Besides peptides, there are other classes of targeting vectors like antibody fragments, antibody mimetics, peptidomimetics, and small molecules that clear through the renal pathway. In this review, we will review established and emerging strategies that can be used to mitigate radiation-induced nephrotoxicity, with a focus on the development and incorporation of cleavable linkers for radiopharmaceutical designs. Finally, we offer our perspectives on cleavable linkers for RLT, highlighting future areas of research that will help advance the technology.     

Multiwavelength InGaAs/InGaAsP strained-layer MQW-laser array usingshadow-masked growth

A simple technique for fabricating multiwavelength laser arrays is presented. The lateral variations in bandgap (or emission wavelength) between the different lasers are obtained by the use of shadow-masked growth. The shadow masked growth results in variations in thickness (and to a lesser extent, in composition) over the substrate. In combination with a multiquantum well (MQW) active region, this gives the required bandgap variations. By varying the window width in the shadow mask between 10 μm and >500 μm it was possible to obtain a wavelength span of 130 nm centered around 1.55 μm. The strained-layer-ridge MQW Fabry-Perot lasers showed a constant threshold current (around 70 mA for an 11-μm×500-μm stripe)     

Performance of cellular packet CDMA in an integrated voice/data network

This paper presents a simulation-based study of cellular packet CDMA systems operating in an integrated voice/data traffic scenario. Spread-spectrum CDMA provides a suitable framework for resource-shared packet transport capable of combining isochronous (voice, ISDN) and bursty data services. In this work, a general network model for cellular packet CDMA with mixed voice/data traffic is described and used to evaluate the capacity/performance impact of several key system parameters. First, the effect of spreading factor (N) and forward error correction (FEC) rate are studied, confirming earlier work indicating a weak dependence onN and a well-defined optimum code rate in the range of 0.5–0.7 (with BCH coding). Next, the effect of propagation loss coefficient () on network capacity is investigated over a range of possible assumptions for, including both constant and distance-dependent models. The results show that system capacity depends strongly on, varying by as much as a factor of 2 over the range of parameters considered. For a given distance-dependent assumption, performance results are also obtained for different cell sizes in order to understand the overall spatial reuse efficiency achievable in different cellular and microcellular scenarios. This is followed by an investigation of traffic source model effects: first the capacity improvement from voice activity detection VAD) is presented, showing the expected 21 gains. Results for varying proportions of voice and data traffic intensities indicate that the operating efficiency does not change significantly as the proportion of bursty data relative to voice is varied.     

Reduced Endocannabinoid Tone in Saliva of Chronic Orofacial Pain Patients

Background: the endocannabinoid system (ECS) participates in many physiological and pathological processes including pain generation, modulation, and sensation. Its involvement in chronic orofacial pain (OFP) in general, and the reflection of its involvement in OFP in salivary endocannabinoid (eCBs) levels in particular, has not been examined. Objectives: to evaluate the association between salivary (eCBs) levels and chronic OFP. Methods: salivary levels of 2 eCBs, anandamide (AEA), 2-arachidonoylglycerol (2-AG), 2 endocannabinoid-like compoundsN-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed using liquid chromatography/tandem mass spectrometry in 83 chronic OFP patients and 43 pain-free controls. The chronic OFP patients were divided according to diagnosis into musculoskeletal, neurovascular/migraine, and neuropathic pain types. Results: chronic OFP patients had lower levels of OEA (p = 0.02) and 2-AG (p = 0.01). Analyzing specific pain types revealed lower levels of AEA and OEA in the neurovascular group (p = 0.04, 0.02, respectively), and 2-AG in the neuropathic group compared to controls (p = 0.05). No significant differences were found between the musculoskeletal pain group and controls. Higher pain intensity was accompanied by lower levels of AA (p = 0.028), in neuropathic group. Conclusions: lower levels of eCBs were found in the saliva of chronic OFP patients compared to controls, specifically those with neurovascular/migraine, and neuropathic pain. The detection of changes in salivary endocannabinoids levels related to OFP adds a new dimension to our understanding of OFP mechanisms, and may have diagnostic as well as therapeutic implications for pain.     

From Passive Inorganic Oxides to Active Matters of Micro/Nanomotors

Controllable actuation and coordinating motion of artificial self‐propelled micro/nanomotors to mimic the motile natural microorganism systems are of great significance for constructing intelligent nanoscale machines. In particular, inorganic oxide particles have shown considerable promise in implementation of synthetic micro/nanomotors, due to their unique features and active response to environmental stimuli. This work critically reviews the recent progress in inorganic oxide‐based micro/nanomotors and focuses on their propulsion response to chemical and physical stimuli, especially emphasizing and discussing operating principles in the single engine, adaptive navigation under composite‐driven powers, and intriguing collective behaviors. The impact of oxide structure, multiple fields in motion controllability, and interaction between grouped micro/nanomotors are explored. Practical applications of individual and assembled micro/nanomotors in environmental and biomedical fields are demonstrated, including the removal of pollutants, drug delivery, cancer therapy, and in vivo imaging. Finally, current challenges for the development of novel micro/nanomotors and possible constraints toward the defined structure and accumulated toxicity are discussed along with future opportunities and directions. Owing to their facile synthesis, impressive physicochemical performances, high biocompatibility, and versatile actuations, it is expected that the association of inorganic oxides with micro/nanomotors will bring new and unique capabilities to the field of active matter.     

Oxygen-sensitive 19F NMR imaging of the vascular system in vivo

The fluorine nuclear magnetic resonance spin-lattice relaxation rate (1/T1) of the perfluorochemical blood substitute perfluorotripropylamine (FTPA) is very sensitive to oxygen tension. This presents the possibility of measuring blood oxygen tension by 19F MR imaging. We obtained oxygen-sensitive 19F NMR images of the circulatory system of rats infused with emulsified FTPA. Blood oxygenation was assessed under conditions of both air- and 100% O2-breathing. T1 relaxation times were derived from MR images using a partial saturation pulse sequence. The T1 times were compared with a phantom calibration curve to calculate average blood pO2 values in the lung, liver, and spleen. The results showed marked, organ-specific increases in blood oxygen tension when the rat breathed 100% O2 instead of air.