On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan.

A Friedel-Crafts alkylation is described that efficiently transforms tryptophan-containing peptides into macrocycles of varying ring connectivity. Factors are surveyed that influence the distribution of regioisomers, with a focus on indole C3-alkylations leading to bridged endo-pyrroloindolines. We probe the stability and stereochemistry of these pyrroloindolines, study their rearrangement to C2-linked indolic macrocycles, and demonstrate a scalable, stereoselective synthesis of this compound class. Placing the macrocyclization in sequence with further template-initiated annulation leads to extraordinary polycyclic products and further demonstrates the potential for this chemistry to drive novel peptidomimetic lead discovery programs

Tides and Overtides in Long Island Sound

Using observations obtained by acoustic Doppler profilers and coastal water level recorders, we describe the vertical and horizontal structure of the currents and sea level due to the principal tidal constituents in Long Island Sound, a shallow estuary in southern New England. As expected, the observations reveal that M2 is the dominant constituent in both sea surface and velocity at all depths and sites. We also find evidence that the vertical structure of the M2 tidal current ellipse parameters vary with the seasonal evolution of vertical stratification at some sites. By comparing our estimates of the vertical structure of the M2 amplitudes to model predictions, we demonstrate that both uniform and vertically variable, time invariant eddy viscosities are not consistent with our measurements in the Sound. The current records from the western Sound contain significant overtides at the M4 and M6 frequencies with amplitudes and phases that are independent of depth. Though the M4 amplitude decreases to the west in proportion to M2, the M6 amplifies. Since the dynamics that generate overtides also produce tidal residuals, this provides a sensitive diagnostic of the performances of numerical circulation models. We demonstrate that the observed along-Sound structure of the amplitude of the M4 and M6 overtides is only qualitatively consistent with the predictions of a nonlinear, laterally averaged layer model forced by a mean flow and sea level at the boundaries. Since neither the vertical structure of the principal tidal constituent nor the pattern of horizontal variation of the largest overtides can be explained using well established models, we conclude that they are fundamentally inadequate and should no longer be used for more than a basic qualitative understanding, and even then should be used with caution. We provide comprehensive tables of the tidal current parameters to facilitate the critical evaluation of future models of the circulation in the Sound

Inverted binding of non-natural substrates in strictosidine synthase leads to a switch of stereochemical outcome in enzyme-catalyzed Pictet-Spengler reactions

The Pictet-Spengler reaction is a valuable route to 1,2,3,4-tetrahydro-Β-carboline (THBC) and isoquinoline scaffolds found in many important pharmaceuticals. Strictosidine synthase (STR), catalyzes the Pictet-Spengler condensation of tryptamine and the aldehyde secologanin to give (S)-strictosidine as a key intermediate in indole alkaloid biosynthesis. STRs also accept shortchain aliphatic aldehydes to give enantioenriched alkaloid products with up to 99% e.e. STRs are thus valuable asymmetric organocatalysts for applications in organic synthesis. The STR catalysis of reactions of small aldehydes gives an unexpected switch in stereopreference, leading to formation of the (R)-products. Here we report a rationale for the formation of the (R)-configured products by the STR enzyme from Ophiorrhiza pumila (OpSTR) using a combination of X-ray crystallography, mutational and molecular dynamics (MD) studies. We discovered that short chain aldehydes bind in an inverted fashion compared to secologanin leading to the inverted stereopreference for the observed (R)-product in those cases. The study demonstrates that the same catalyst can have two different productive binding modes for one substrate – but give different absolute configuration of the products by binding the aldehyde substrate differently. These results will guide future engineering of STRs and related enzymes for biocatalytic applications

Excitation-Dependent High-Lying Excitonic Exchange via Interlayer Energy Transfer from Lower-to-Higher Bandgap 2D Material

High light absorption (~15%) and strong photoluminescence (PL) emission in monolayer (1L) transition metal dichalcogenide (TMD) make it an ideal candidate for optoelectronic applications. Competing interlayer charge (CT) and energy transfer (ET) processes control the photocarrier relaxation pathways in TMD heterostructures (HSs). In TMDs, long-distance ET can survive up to several tens of nm, unlike the CT process. Our experiment shows that an efficient ET occurs from the 1Ls WSe2-to-MoS2 with an interlayer hBN, due to the resonant overlapping of the high-lying excitonic states between the two TMDs, resulting in enhanced HS MoS2 PL emission. This type of unconventional ET from the lower-to-higher optical bandgap material is not typical in the TMD HSs. With increasing temperature, the ET process becomes weaker due to the increased electron-phonon scattering, destroying the enhanced MoS2 emission. Our work provides new insight into the long-distance ET process and its effect on the photocarrier relaxation pathways.Comment: 5 figures and SI include

Adjuvant drugs for peripheral nerve blocks: The role of alpha-2 agonists, dexamethasone, midazolam, and non-steroidal anti-inflammatory drugs

Adjuvant drugs for peripheral nerve blocks are a promising solution to acute postoperative pain and the transition to chronic pain treatment. Peripheral nerve blocks (PNB) are used in the brachial plexus, lumbar plexus, femoral nerve, sciatic nerve, and many other anatomic locations for site-specific pain relief. However, the duration of action of a PNB is limited without an adjuvant drug. The use of non-opioid adjuvant drugs for single-shot peripheral nerve blocks (sPNB), such as alpha-2 agonists, dexamethasone, midazolam, and non-steroidal anti-inflammatory drugs, can extend the duration of local anesthetics and reduce the dose-dependent adverse effects of local anesthetics. Tramadol is a weak opioid that acts as a central analgesic. It can block voltage-dependent sodium and potassium channels, cause serotonin release, and inhibit norepinephrine reuptake and can also be used as an adjuvant in PNBs. However, tramadol’s effectiveness and safety as an adjuvant to local anesthetic for PNB are inconsistent. The effects of the adjuvants on neurotoxicity must be further evaluated with further studies to delineate the safety in their use in PNB. Further research needs to be done. However, the use of adjuvants in PNB can be a way to help control postoperative pain

Evaluating the thermal vinylcyclopropane rearrangement (VCPR) as a practical method for the synthesis of difluorinated cyclopentenes : experimental and computational studies of rearrangement stereospecificity

Vinyl cyclopropane rearrangement (VCPR) has been utilised to synthesise a difluorinated cyclopentene stereospecifically and under mild thermal conditions. Difluorocyclopropanation chemistry afforded ethyl 3-(1'(2'2'-difluoro-3'-phenyl)cyclopropyl) propenoate as all four stereoisomers (18a, 18b, 22a, 22b) (all racemic). Trans-E isomer (18a), prepared in 70% yield over three steps, underwent near quantitative VCPR to difluorocyclopentene 23 (99%). Rearrangements were followed by 19F NMR (100-180 °C). While cis/trans cyclopropane stereoisomerisation was facile, favouring trans-isomers by a modest margin, no E/Z alkene isomerisation was observed even at higher temperatures. Neither cis nor trans Z-alkenoates underwent VCPR, even up to much higher temperatures (180 oC). Cis-cyclopropanes underwent [3,3]-rearrangement to afford benzocycloheptadiene species. The reaction stereospecificity was explored using electronic structure calculations and UB3LYP/6-31G* methodology allowed the energy barriers for cyclopropane stereoisomerisation, diastereoisomeric VCPR and [3,3]-rearrangement to be ranked in agreement with experiment

Modeling the Afferent Dynamics of the Baroreflex Control System

In this study we develop a modeling framework for predicting baroreceptor firing rate as a function of blood pressure. We test models within this framework both quantitatively and qualitatively using data from rats. The models describe three components: arterial wall deformation, stimulation of mechanoreceptors located in the BR nerve-endings, and modulation of the action potential frequency. The three sub-systems are modeled individually following well-established biological principles. The first submodel, predicting arterial wall deformation, uses blood pressure as an input and outputs circumferential strain. The mechanoreceptor stimulation model, uses circumferential strain as an input, predicting receptor deformation as an output. Finally, the neural model takes receptor deformation as an input predicting the BR firing rate as an output. Our results show that nonlinear dependence of firing rate on pressure can be accounted for by taking into account the nonlinear elastic properties of the artery wall. This was observed when testing the models using multiple experiments with a single set of parameters. We find that to model the response to a square pressure stimulus, giving rise to post-excitatory depression, it is necessary to include an integrate-and-fire model, which allows the firing rate to cease when the stimulus falls below a given threshold. We show that our modeling framework in combination with sensitivity analysis and parameter estimation can be used to test and compare models. Finally, we demonstrate that our preferred model can exhibit all known dynamics and that it is advantageous to combine qualitative and quantitative analysis methods

Microcat, Aquadopp, and ADCP, data from the eastern mid-Atlantic ridge mooring array as part of OSNAP (Overturning in the Subpolar North Atlantic Program) from 2014-2018

Data are saved in netCDF format, with individual files for each instrument time series. The structure and naming conventions of the netCDF file follows the OceanSITES data format described here: http://www.oceansites.org/docs/oceansites_data_format_reference_manual.pdfThe University of Miami's OSNAP (Overturning in the subpolar North Atlantic Program) is an NSF funded project that is part of the international OSNAP array put in place to measure the full depth, basin-wide overturning circulation and associated transport of heat and freshwater (www.o-snap.org). The UM array consists of a series of vertical sub-surface moorings deployed along the eastern slope of the Reykjanes Ridge and across the Iceland Basin near 58°N. This dataset contains data from the first four year-long deployments (2014 to 2018) of the Deep Western Boundary Current Array in the Iceland Basin. The data sets are time series of pressure, temperature, salinity and currents and have been fully processed, calibrated and quality controlled.National Science Foundatio