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Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

The growing interest in the use of luminescence thermometry for noncontact temperature reading under very specific conditions imposes the need to develop an approach allowing modification of the luminescence parameters of a thermometer accordingly to requirements. Therefore, in response to these expectations, this manuscript reports an approach to modulate the spectral position and luminescence thermal quenching rate of Fe3+ ions by modifying the crystal field strength and the host material composition of nanocrystalline AB2O4 type nanocrystals (A = Mg, Ca; B = Al, Ga). It was proved that in a group of MgAl2O4, MgGa2O4, CaAl2O4, and CaGa2O4 nanocrystals doped with Fe3+ ions, the emission spectral range, as well as the relative thermal sensitivity (from 0.2%/°C for MAO to 2.07%/°C for CGO) and the operating temperature range, can be easily modified by the host material composition. For instance, a maximal relative thermal sensitivity of 2.58%/°C is obtained for Fe3+, Tb3+ co-doped CaAl2O4 nanocrystals. The proposed approach is a step toward the intentional designing of a highly sensitive luminescence thermometer.

Despite the numerous advantages of lanthanide based luminescent thermometers, a major limitation is the limited brightness associated with the low absorption cross section of the 4f–4f transitions. In this paper, co-doping with Cr3+/4+ is proposed as a strategy to enhance the near-infrared luminescence emission of Nd3+/Er3+-based luminescent thermometers, as well as to modulate the temperature sensitivity of the ratio of Nd3+ to Er3+ in YAG microcrystals. It was found that an increase in the Cr3+ concentration leads to the enhancement of the YAG:Nd3+,Er3+ emission intensity via the Cr3+ → Ln3+ sensitization process. The quantitative analysis of the absolute brightness indicates the 30-fold enhancement of their near infrared emission upon broad white light excitation for 20% Cr3+ with respect to the non co-doped with the Cr3+ counterpart. In addition, the phonon-assisted nature of the simultaneously occurring Cr3+ → Ln3+ and Nd3+ → Cr4+ → Er3+ energy transfers leads to a 7-fold increase of the relative temperature sensitivity of the ratio of Nd3+ to Er3+ emission. In conclusion, co-doping with transition metals can enhance simultaneously the luminescence brightness and the temperature sensitivity of NIR luminescent thermometers, holding promise for sensitive and robust remote temperature sensing at physiological temperatures.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C-H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp3)-H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)-H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C-H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

EUSO-Balloon is a pathfinder for JEM-EUSO, the mission concept of a spaceborne observatory which is designed to observe Ultra-High Energy Cosmic Ray (UHECR)-induced Extensive Air Showers (EAS) by detecting their UltraViolet (UV) light tracks “from above.” On August 25, 2014, EUSO-Balloon was launched from Timmins Stratospheric Balloon Base (Ontario, Canada) by the balloon division of the French Space Agency CNES. After reaching a floating altitude of 38 km, EUSO-Balloon imaged the UV light in the wavelength range ∼290–500 nm for more than 5 hours using the key technologies of JEM-EUSO. The flight allowed a good understanding of the performance of the detector to be developed, giving insights into possible improvements to be applied to future missions. A detailed measurement of the photoelectron counts in different atmospheric and ground conditions was achieved. By means of the simulation of the instrument response and by assuming atmospheric models, the absolute intensity of diffuse light was estimated. The instrument detected hundreds of laser tracks with similar characteristics to EASs shot by a helicopter flying underneath. These are the first recorded laser tracks measured from a fluorescence detector looking down on the atmosphere. The reconstruction of the direction of the laser tracks was performed. In this work, a review of the main results obtained by EUSO-Balloon is presented as well as implications for future space-based observations of UHECRs.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp3)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles., DNA-compatible C(sp3)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.

The synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor 3 is described. This complex structure contains a tetrazole modified by a chiral hemiaminal carbonate prodrug. A reg...

The present authors have put forward a quantum game theory based model of market prices movements. By using Fisher information, we present a construction of an equation of Schrodinger type for probability distributions for relationship between demand and supply. Various analogies between quantum physics and market phenomena can be found.

Non-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols by enantioselective acylation using an isothiourea-derived HyperBTM catalyst and racemization of slowly reacting alcohol by Backvall's ruthenium complex is reported. The DKR approach features high enantioselectivities (up to 99:1), employs easy-to-handle crystalline 4-nitrophenyl isobutyrate as the acylating reagent, and proceeds at room temperature and under an ambient atmosphere. The stereoinduction model featuring cation-π system interactions between the acylated HyperBTM catalyst and π electrons of an alcohol aryl subunit has been elaborated by DFT calculations.

The growing interest in the use of luminescence thermometry for noncontact temperature reading in very specific conditions imposes the need to develop an approach allowing modification of the luminescence parameters of the thermometer accordingly to the requirements. Therefore, in response to these expectations, this manuscript reports an approach to modulating the spectral position and the luminescence thermal quenching rate of Fe3+ ions by modifying the crystal field strength and the host material composition of nanocrystalline AB2O4 type nanocrystals (A= Mg, Ca; B=Al, Ga). It was proved that in a group of MgAl2O4, MgGa2O4, CaAl2O4, and CaGa2O4 nanocrystals doped with Fe3+ ions the emission spectral range, as well as the relative thermal sensitivity (from 0.2%/oC for MAO to 2.07%/oC for CGO) and the operating temperature range, can be easily modified by the host material composition. For instance, a maximal relative thermal sensitivity of 2.58%/oC is obtained for Fe3+, Tb3+ co-doped CaAl2O4 nanocrystals. The proposed approach is a step toward the intentional designing of the highly sensitive luminescent thermometer., Financial support from the NanoTBtech European Union's Horizon 2020 FET Open programme under grant agreement no. 801305

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health.One Sentence SummaryPF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.

Preparative reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, and polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Shown here are cobalt catalysts that react with alkenes under dilute, aqueous, buffered conditions and promote efficient cycloisomerization and formal Friedel-Crafts reactions. The constraining conditions of bioorthogonal chemistry are beneficial for reaction efficiency as superior conversion at low catalyst concentration is obtained and competent rates in dilute conditions are maintained. Efficiency at high dilution in the presence of buffer and nucleobases suggests that these reaction conditions may find broad application.

Preparative chemical reactions that occur efficiently under dilute, buffered, aqueous conditions in the presence of biomolecules find application in ligation, peptide synthesis, polynucleotide synthesis and sequencing. However, the identification of functional groups or reagents that are mutually reactive with one another, but unreactive with biopolymers and water, is challenging. Here we show that cobalt catalysts will react with the alkenes of unsaturated tertiary amines under dilute, aqueous, buffered conditions and promote efficient cycloisomerization, in many cases mediating a formal Friedel-Crafts reaction. We find the constraining conditions of biorthogonal chemistry to be beneficial for reaction efficiency as we obtain superior conversion at low catalyst concentration and maintain competent rates in dilute conditions. The efficiency at high dilution in the presence of buffer and nucleobases suggests that these conditions may find use on or in the presence of biomolecules.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a single experiment. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produces billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development DNA-encoded C(sp3)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of bifunctional building blocks, and facilitates access to certain setups for DELs. Furthermore, sequential C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

DNA Encoded Libraries have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently Reversible Adsorption to Solid Support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C–S, C–P and N–S linkages into DELs, which are underrepresented in the canonical methods.

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a single experiment. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produces billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development DNA-encoded C(sp3)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of bifunctional building blocks, and facilitates access to certain setups for DELs. Furthermore, sequential C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

Summary Objective This study aimed to explore the changes in vocal fold inferior surface hypertrophy (VFISH) on vocal fold vibration by aerodynamic and acoustic analysis. The present study allows us to gain new insights into the subglottal convergence angle (SCA), which will change with VFISH. Study Design The study is prospective, and designed for repeated measures with each excised canine larynx serving as own control. Subjects and Methods Three degrees of VFISH, initial, mild, and severe, were simulated by injecting different doses of fructose injections into the inferior surface of the vocal folds of 10 excised canine larynges. Computed tomographic images of the larynx were gathered, and three-dimensional models of the airway and vocal folds were reconstructed using the Mimics software. The SCA was measured from the reconstructed models. Phonation threshold flow (PTF), phonation threshold pressure (PTP), and mean flow rate (MFR) were recorded directly in the excised canine larynx phonation setup. Glottal resistance (GR), sound pressure level (SPL), fundamental frequency (F0), and formants 1–4 (F1–4) were measured when subglottal pressure (P sub ) was at 1.5 kPa or 2.5 kPa, separately. Using ordinary one-way analysis of variance, we compared the aerodynamic outcomes and voice quality among the three groups of hypertrophy. Results The SCA, PTP, and PTF increased with the degree of VFISH. When the P sub was controlled at 1.5 kPa or 2.5 kPa, F0 also increased significantly with the degree of VFISH of the excised canine larynges. The MFR, GR, SPL, and F1–4 had little change between the three groups and were not significantly different. Conclusion The VFISH makes onset phonation more difficult, increases the SCA, and increases the F0 in sustained phonation.

The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.

A novel series of morpholine-based nonsteroidal mineralocorticoid receptor antagonists is reported. Starting from a pyrrolidine HTS hit 9 that possessed modest potency but excellect selectivity versus related nuclear hormone receptors, a series of libraries led to identification of morpholine lead 10. After further optimization, cis disubstituted morpholine 22 was discovered, which showed a 45-fold boost in binding affinity and corresponding functional potency compared to 13. While 22 had high clearance in rat, it provided sufficient exposure at high doses to favorably assess in vivo efficacy (increased urinary Na

One of the most important parameters that affect the thermal resolution in the luminescent thermometry is the relative sensitivity of phosphor to temperature changes. Therefore various approaches to enhance its value are intensively investigated. The strategy of the relative sensitivity enhancement of the ratiometric lanthanide ions based luminescent thermometer by the sensitization with the transition metal ions is proposed in this work. It was found that by taking advantage of the temperature dependent energy transfer from transition metal ion (Mn4+-, Cr3+- and Ti3+/4+-) to the Tb3+ and Eu3+ ions in the YAG powder, the thermal variation of the Tb3+ to Eu3+ luminescence intensity ratio increases leading to the improvement of its thermometric properties even by 300%. Therefore, the maximal relative sensitivity increases from SR = 0.09%/°C for unco-doped powder up to SR = 0.15, 0.28, 0.30%/°C, for powders co-doped with Cr3+, Mn4+ and Ti3+/4+, respectively. The beneficial influence of the transition metal to lanthanides energy transfer was investigated in a function of the transition metal ion concentration.

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F-isotopologue validated our liver-targeting approach.

We consider properties of the measurement intensity ρ of a random variable for which the probability density function represented by the corresponding Wigner function attains negative values on a part of the domain. We consider a simple economic interpretation of this problem. This model is used to present the applicability of the method to the analysis of the negative probability on markets where there are anomalies in the law of supply and demand (e.g. Giffen’s goods). It turns out that the new conditions to optimize the intensity ρ require a new strategy. We propose a strategy (so-called a rebours strategy) based on the fixed point method and explore its effectiveness.

A new catalyst for the dynamic kinetic resolution of azole hemiaminals has been developed using late-stage structural modifications of the tert-leucinol-derived chiral subunit of DMAP species.

DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of unprecedented size and diversity, the idiosyncratic and hydrophilic nature of the DNA tag severely limits the scope of applicable chemistries. It is known that biomacromolecules can be reversibly, non-covalently adsorbed and eluted from solid supports, and this phenomenon has been utilized to perform synthetic modification of biomolecules in a strategy we have described as reversible adsorption to solid support (RASS). Herein, we present the adaptation of RASS for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp(2))-C(sp(3)) decarboxylative cross-couplings with broad substrate scope, an electrochemical amination (the first electrochemical synthetic transformation performed in a DEL context), and improved reductive amination conditions. The utility of these reactions was demonstrated through a DEL-rehearsal in which all newly developed chemistries were orchestrated to afford a compound rich in diverse skeletal linkages. We believe that RASS will offer expedient access to new DEL reactivities, expanded chemical space, and ultimately more drug-like libraries.

Herein, we present the adaptation of reversible adsorption to solid support (RASS) for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp2)-C(sp3) decarboxylative cross-couplings with broad substrate scope, an electrochemical amination (the first electrochemical synthetic transformation performed in a DEL context), and improved reductive amination conditions. We believe that RASS will offer expedient access to new DEL reactivities, expanded chemical space, and ultimately more drug-like libraries.

A series of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1-carboxamides were identified as small molecule PCSK9 mRNA translation inhibitors. Analogues from this new chemical series, such as 4d and 4g, exhibited improved PCSK9 potency, ADME properties, and in vitro safety profiles when compared to earlier lead structures.

C–X–C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure–activity-relationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 Ki = 13 nM, adrenergic α 1a Kb > 10 000 nM, and adrenergic β 2 Kb > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor 1α (SDF-1α) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a st...

Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR and CD spectra revealed an N-terminal β-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of the GLP-1 receptor to treat type 2 diabetes.

LIF (laser-induced fluorescence) LIDAR (light detection and ranging) is one of the very few promising methods in terms of long-range stand-off detection of air-borne biological particles. A limited classification of the detected material also appears as a feasible asset. We present the design details and hardware setup of the developed range-resolved multichannel LIF-LIDAR system. The device is based on two pulsed UV laser sources operating at 355 nm and 266 nm wavelength (3rd and 4th harmonic of Nd:YAG, Q-switched solid-state laser, respectively). Range-resolved fluorescence signals are collected in 28 channels of compound PMT sensor coupled with Czerny–Turner spectrograph. The calculated theoretical sensitivities are confronted with the results obtained during measurement field campaign. Classification efforts based on 28-digit fluorescence spectral signatures linear processing are also presented.

Macrocyclic peptides were designed and synthesized for secondary structural analysis. A PyBroP-based cyclization protocol was employed and was facilitated by solid-phase synthesis. After systematic NMR analyses of each macrocycle, multiple structures were found to exist as 3 10 -helices.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts., Author summary Many disease-mediating proteins have proven difficult to target with traditional small-molecule pharmaceuticals. In this paper, we report that a small molecule, PF-06446846, directly inhibits translation of one such protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), by acting on the translating human ribosome. PF-06446846 causes the translating ribosome to stall soon after translating the PCSK9 signal sequence. We further show that PF-06446846 activity is dependent on the amino acid sequence of the nascent chain inside the ribosome exit tunnel. In a rat safety study, we observe decreases in plasma PCSK9, total cholesterol, and low-density lipoprotein (LDL) cholesterol. Using mass spectrometry in cell culture and ribosome profiling, we demonstrate that despite acting on the ribosome, which synthesizes every protein in the cell, PF-06446846 displays a high level of selectivity for PCSK9. This unexpected potential for small molecules to selectively inhibit the human ribosome opens the possibility for future development of small molecules targeting disease-mediating proteins that were previously thought to be undruggable.

The authors briefly review quantum game theory and its application in economics. This review is addressed at newcomers and some basic ideas of quantum theory are necessary to follow the text—the short introduction in chapter “A Brief Introduction to Quantum Formalism” will be sufficient. Due to the lack of space only the flagship issues will be discussed. Quantum game theory, whatever opinions may be held due to its abstract physical formalism, have already found various applications even outside the orthodox physics domain. We are aware that the implementation of genuine quantum models is not an easy task. Nevertheless, such models are already an interesting although sophisticated theoretical tool.

Measurement of vehicles speed by means of displacement measurement with "time of flight" lidar requires gathering of accurate information about distance to the vehicle in a set time interval. As with any pulsed laser lidar, its maximum range is limited by available incoming signal to noise ratio. That ratio determines not only maximum range, but also accuracy of measurement. For fast and precise measurements of speed of the vehicles their displacement should bee measured with centimeter accuracy. However that demand is hard to reach on long distances and poor quality of the echo signal. Improving accuracy beyond given by a single pulse probing requires emission of several probing pulses. Total displacement error will than fall with the square root of the number of executed measurements. Yet this method will not extend available distance beyond the limit set by threshold detection systems. Acquisition of the full waveform of received signals is a method that allows extension of maximum range through synchronic addition of subsequent waveforms. Doing so improves SNR by a well-known factor of square root of the number of carried additions. Disadvantage of this method is that it requires use of fast analog to digital converters for data acquisition, and simple distance calculation algorithms may not give the adequate accuracy due to relatively long sampling period of reasonable priced ADC’s. In this article more advanced algorithms of distance calculations that base on ADC raw data are presented and analyzed. Practical implementation of algorithm in prototype design of laser speed gun is shown along with real life test results.

Sickle cell disease (SCD) is a severe genetic disorder caused by a single point mutation on the β-chain of adult hemoglobin (Hb A), β6 Glu→Val (Hb S). In the deoxygenated state Hb S polymerizes, leading to RBC sickling and precipitating all downstream consequences, including vaso-occlusion (pain crisis), hemolytic anemia, and stroke. Over time, these features cause significant organ damage and eventual organ failure, dramatically impacting both quality of life and expected lifespan. Numerous small molecules which covalently bind to Hb S have been evaluated clinically, however, the molecules that have demonstrated clinical efficacy all carry a reactive aldehyde group. The reactive aldehyde, a moiety that has the potential to react with any free amine, forms a covalent Schiff base with the N-terminal amine of the α1-Val. At least one member of this class of molecules, Tucaresol, showed a significant safety signal attributed to off-target Schiff base formation. An early investigation of covalent hemoglobin modification, extracorporeal carbamylation, both improved anemia and decreased the frequency of vaso-occlusive events by 80%, when there was a sufficiently high level of modification (30-50%). These results suggest that a molecule that binds Hb S and stabilizes the oxygenated state can impact both hemolytic anemia and vaso-occlusive crisis, if the molecule can achieve the necessary degree of hemoglobin modification. PFE-001 is a non-covalent molecule which binds selectively to Hb S and stabilizes the oxygenated state. Biochemical and biophysical studies show that PFE-001 binds specifically to Hb with double digit nanomolar potency and exhibits strong in vivo partitioning into RBCs. In a two-week multiple dose study using Townes SCD model animals (200 mg/kg, twice daily), PFE-001 significantly improved markers of hemolytic anemia, increased oxygen affinity, and reduced RBC sickling. Following 15 days of treatment blood drawn from PFE-001 treated animals and exposed to intense hypoxic conditions (4% O2, 4 hr) showed a 37.8% reduction in sickling compared to vehicle treated mice. Oxygen affinity was increased, demonstrated by a 53.7% reduction in p50 and an 84.4% reduction in p20 in the PFE-001 treated group. Hemoglobin levels in mice treated with PFE-001 increased by 42%, a mean increase of 5 g/dL. Hematocrit in the PFE-001 treated group increased to 42%, in contrast to 29% in the vehicle group. Reticulocyte percentages were reduced from 53% in vehicle treated animals to 24% in PFE-001 treated animals. In addition to the significant impact PFE-001 had on hemolytic anemia, a 10% reduction in sVCAM-1 levels in the PFE-001 treated group indicates a small but statistically significant improvement in vasculopathy following 15 days of treatment. This improvement in vasculopathy suggests that PFE-001 has the potential to address vaso-occlusive crisis in addition to anemia. In total, the in vitro and in vivo data suggest that PFE-001 is a potent, selective, and effective inhibitor of Hb S polymerization and RBC sickling. PFE-001 can reduce hemolytic anemia, improve vasculopathy, increase oxygen affinity, and reduce RBC sickling under hypoxic conditions. Plans for advancement of PFE-001 to clinical trials are in progress. Disclosures Knee: Pfizer Inc: Employment. Jasuja:Pfizer Inc.: Employment. Barakat:Pfizer Inc.: Employment. Rao:Pfizer Inc.: Employment. Wenzel:Pfizer Inc.: Employment. Sahasrabudhe:Pfizer Inc.: Employment. Narula:Pfizer Inc.: Employment. Jasti:Pfizer Inc.: Employment. Chang:Pfizer Inc.: Employment. Beaumont:Pfizer Inc.: Employment. Piotrowski:Pfizer Inc.: Employment. Janz:Pfizer Inc.: Employment.

Summary Objective This study aimed to investigate the duration of straw phonation effects using aerodynamic, electroglottographic, and acoustic metrics. Methods Twenty-four participants were recruited to perform both a 5-minute and a 10-minute straw phonation exercise. Upon completion of the exercises, phonation threshold pressure (PTP), mean airflow, contact quotient, fundamental frequency, jitter, shimmer, and noise-to-harmonics ratio were measured over a 20-minute time frame. Parameters were measured before the intervention (baseline), immediately after the intervention (m0), 5 minutes (m5), 10 minutes (m10), 15 minutes (m15), and 20 minutes (m20) after the intervention. Results PTP significantly decreased immediately after 5 minutes of straw phonation and returned to initial state within 5 minutes. PTP remained decreased over 5 minutes after 10 minutes of straw phonation. Mean airflow increased immediately after both 5 minutes and 10 minutes of straw phonations and remained improved for 20 minutes. No significant changes were obtained for contact quotient and acoustic parameters over the intervention period. Conclusions The results extended our knowledge of proper clinical application of straw phonation regarding the duration of exercise. This study confirmed that 10 minutes of straw phonation lead to optimal and relatively continuous effects in PTP and mean airflow. Although straw phonation did show lingering effects in aerodynamics, repeated practices were recommended to obtain optimum and therapeutic effects.

Pyridine-N-oxides are often used as reactive precursors in the syntheses of substituted pyridines. Isolation and subsequent reduction of the associated pyridine-N-oxide intermediates can be challenging. We have discovered that tetrahydroxydiboron functions as a mild, versatile, and remarkably selective reducing agent for pyridine-N-oxides and may be used in an in situ fashion, thus ­obviating the isolation of N-oxide-containing intermediates

Two regioselective and complementary hydroarylation reactions of an unsymmetrical cyclic olefin have been developed. The products can be transformed in one step into constrained γ-amino acids. Regioselective arylation of Vince lactam is controlled by the choice of phosphine ligand enantiomer and the substituent on the amide nitrogen atom. The method was extended to a general regiodivergent parallel kinetic resolution of the racemic lactam.

We report novel syntheses of 12-membered macrocyclic templates and a library of 4000 macrocyclic analogs. The key macrocyclization step was performed at up to 100 g scale without resorting to syringe pumps, flow reactors or large volumes of solvent. An interesting observation of considerably different permeability properties was made on diastereomeric analogs due to differences in intramolecular hydrogen bond interactions.