Chronic Hypertension in Pregnancy and Placenta-Mediated Complications Regardless of Preeclampsia.

BACKGROUND: The prevalence of chronic hypertension in women of reproductive age is on the rise mainly due to delayed childbearing. Maternal chronic hypertension, prevailing prior to conception or manifesting within the early gestational period, poses a substantial risk for the development of preeclampsia with adverse maternal and fetal outcomes, specifically as a result of placental dysfunction. We aimed to investigate whether chronic hypertension is associated with placenta-mediated complications regardless of the development of preeclampsia in pregnancy. METHODS: This was a population-based, retrospective cohort study from 'Soroka' university medical center (SUMC) in Israel, of women who gave birth between 1991 and 2021, comparing placenta-mediated complications (including fetal growth restriction (FGR), placental abruption, preterm delivery, and perinatal mortality) in women with and without chronic hypertension. Generalized estimating equation (GEE) models were used for each outcome to control for possible confounding factors. RESULTS: A total of 356,356 deliveries met the study's inclusion criteria. Of them, 3949 (1.1%) deliveries were of mothers with chronic hypertension. Women with chronic hypertension had significantly higher rates of all placenta-mediated complications investigated in this study. The GEE models adjusting for preeclampsia and other confounding factors affirmed that chronic hypertension is independently associated with all the studied placental complications except placental abruption. CONCLUSIONS: Chronic hypertension in pregnancy is associated with placenta-mediated complications, regardless of preeclampsia. Therefore, early diagnosis of chronic hypertension is warranted in order to provide adequate pregnancy follow-up and close monitoring for placental complications, especially in an era of advanced maternal age.

Stereoselective Synthesis of Polysubstituted Spiropentanes.

A new approach to polysubstituted spiropentanes is developed through a regio- and diastereoselective carbometalation of sp2-disubstituted cyclopropenes. The control of selectivity originates from a combined syn-facial diastereoselective carbometalation with a regio-directed addition. The regio-controlling element subsequently serves as a leaving group in an intramolecular nucleophilic substitution. This method allows the preparation of various polysubstituted spiropentanes with up to five contiguous stereocenters.

Regio- and Diastereoselective Carbometalation Reaction of Cyclopropenes.

The various facets of the chemistry of cyclopropane derivatives, the smallest carbocycle, are amazingly diverse and continue to fascinate theoreticians, synthetic or structural chemists having interest in fundamental physical, medicinal chemistry, and natural product synthesis. The challenges generated by this intriguing cyclic arrangement of only three tetravalent carbons represent a wide area of the chemical spectrum. From fundamental aspects of bonding through the synthesis of highly strained molecules, the understanding of the mode of action in biological systems to the selective cleavage into acyclic substrates makes the chemistry of these small rings fascinating. Therefore, efficient routes to prepare differently polysubstituted cyclopropanes have always been of a primordial importance. In the past decade, we and others have expanded the scope of the carbometalation reaction of cyclopropenes as a broad and general method to the formation of stereodefined cyclopropane derivatives. Although cyclopropenes, with their even higher strain energy, easily undergo addition reactions of organometallic reagents, their carbometalation reactions generate new regio-, diastereo-, and enantioselectivity issues that needed to be addressed. These various stereochemical aspects accompanied our research from its origins to today, and we are proposing in this Account, a didactic overview of the different ways by which cyclopropenes can lead to the formation of polysubstituted cyclopropanes or open-products possessing several stereogenic centers as a single regio- and diastereomer.We initially launched our research campaign on the chemistry of these strained three-membered rings by the regio- and diastereoselective copper-catalyzed carbomagnesiation of enantiomerically enriched cyclopropenyl carbinols. The directing alcohol governed both the regio- and diastereoselectivity of the addition and also served as a good leaving group as it undergoes a selective 1,2-elimination reaction to provide enantioenriched alkylidenecyclopropanes in excellent yields and enantiomeric excesses. Then, we turned our attention to the regio- and stereoselective synthesis of stereodefined tri- and tetrasubstituted cyclopropanes through the diastereoselective addition to sp2- monosubstituted cyclopropenyl ester derivatives. With the aim to further expand this concept to the formation of penta- and hexa-substituted cyclopropanes as single isomer, we had first to design the preparation of the required 1,2-disubstituted cyclopropenes that would control the regioselective addition of the organometallic derivatives. The synthesis of penta- and hexa-substituted cyclopropanes was then reported for the first time as a single regio- and diastereomer. It should be noted that the in situ formed cyclopropyl-metal intermediate is configurationally stable and can be subsequently functionalized with pure retention of the configuration by addition of electrophiles. Then, the enantioselective-catalyzed carbometalation reaction of achiral cyclopropenes allowed the synthesis of several new classes of cyclopropane derivatives in high enantiomeric ratios. Finally, by combining the regio- and diastereoselective carbometalation reaction of a cyclopropene with a subsequent reaction of the resulting cyclopropylmetal species, a selective carbon-carbon bond cleavage was observed to lead to the preparation of acyclic substrates possessing several stereocenters including a quaternary carbon stereogenic center. Our original vision of using strain within an embedded double bond in a three-membered ring has provided new routes to the stereoselective synthesis of polysubstituted cyclopropanes and has been extremely successful, as it represents a current new tool for the synthesis of persubstituted cyclopropanes as a single diastereomer.

Uniform binding and negative catalysis at the origin of enzymes.

Enzymes are well known for their catalytic abilities, some even reaching "catalytic perfection" in the sense that the reaction they catalyze has reached the physical bound of the diffusion rate. However, our growing understanding of enzyme superfamilies has revealed that only some share a catalytic chemistry while others share a substrate-handle binding motif, for example, for a particular phosphate group. This suggests that some families emerged through a "substrate-handle-binding-first" mechanism ("binding-first" for brevity) instead of "chemistry-first" and we are, therefore, left to wonder what the role of non-catalytic binders might have been during enzyme evolution. In the last of their eight seminal, back-to-back articles from 1976, John Albery and Jeremy Knowles addressed the question of enzyme evolution by arguing that the simplest mode of enzyme evolution is what they defined as "uniform binding" (parallel stabilization of all enzyme-bound states to the same degree). Indeed, we show that a uniform-binding proto-catalyst can accelerate a reaction, but only when catalysis is already present, that is, when the transition state is already stabilized to some degree. Thus, we sought an alternative explanation for the cases where substrate-handle-binding preceded any involvement of a catalyst. We find that evolutionary starting points that exhibit negative catalysis can redirect the reaction's course to a preferred product without need for rate acceleration or product release; that is, if they do not stabilize, or even destabilize, the transition state corresponding to an undesired product. Such a mechanism might explain the emergence of "binding-first" enzyme families like the aldolase superfamily.

Elucidating the Effect of Aliphatic Molecular Plugs on Ion-Rejecting Properties of Polyamide Membranes.

Polyamide RO membranes are widely used for seawater desalination owing to their high salt rejection and water permeability; however, improved selectivity-permeability trade-off is still desired. "Molecular plugs," small molecules immobilized within the polyamide structure, offer an attractive approach; however, their overall effect on polyamide physicochemical properties poses many questions. Here, we analyze the effect of decylamine, a promising plug, and a few charged and uncharged mimics on polyamide films using several in situ techniques. Electrochemical impedance spectroscopy (EIS) reveals a complex pH-dependent response, whereby, upon exposure to amine solution, conductivity first rapidly drops; however, under alkaline conditions, when amine is uncharged, the trend subsequently slowly reverses, and conductivity increases. This slow reversal was observed for noncharged alcohols of similar size as well, but not for larger surfactant molecules. The reversal was assigned to the uptake of plug molecules within polyamide, as opposed to the fast initial drop assigned to surface adsorption. EIS and quartz-crystal microbalance (QCM) results showed that exposure to decylamine under alkaline conditions ultimately led to an irreversible decrease in conductivity, that is, stronger ion rejection, remaining after re-exposure of polyamide to amine-free buffer. This suggests that plug uptake within polyamide resulted in polymer stress, indeed observed in surface stress measurements, and subsequent relaxation. The results indicate that the moderate size of decylamine and conditions minimizing its charge were optimal for irreversible change; however, charge interactions helped maximize its binding within polymer and induce the desired sustained change in selectivity. The results have many potential implications for improving current membrane desalination technology and increasing inherent membrane selectivity toward hard-to-remove species.

Directed Regioselective Carbometallation of 1,2-Dialkyl-Substituted Cyclopropenes.

A regio- and diastereoselective copper-catalyzed carbomagnesiation of 1,2-dialkylated cyclopropenes is reported. The regioselectivity is controlled by a subtle tethered Lewis basic moiety. The chelating moieties allow the differentiation between two electronically tantamount organometallic intermediates. Further functionalization grants access to polysubstituted stereodefined cyclopropanes bearing up to five alkyl groups.

Regio- and Diastereoselective Copper-Catalyzed Carbomagnesiation for the Synthesis of Penta- and Hexa-Substituted Cyclopropanes.

Despite the highly strained nature of cyclopropanes possessing three vicinal quaternary carbon stereocenters, the regio- and diastereoselective copper-catalyzed carbomagnesiation reaction of cyclopropenes provides an easy and efficient access to these novel persubstituted cyclopropyl cores with a complete regio- and diastereoselectivity.

Creating Stereocenters within Acyclic Systems by C-C Bond Cleavage of Cyclopropanes.

Recent developments in the stereoselective synthesis of polysubstituted cyclopropanes nowadays allow chemists to easily access these strained rings with high diastereo- and enantiomeric ratios. In turn, this development has created a paradigm shift for the synthesis of stereodefined acyclic molecules though selective carbon-carbon bond cleavage. Through chosen illustrative examples, we aim to show in this review that the cleavage of cyclopropane is a powerful approach to reveal sp3 stereocenters in acyclic systems. The application of these concepts was illustrated by the total syntheses of several natural products and other important molecules, further showing the power of these strategies as a powerful tool in organic synthesis.

Unified Entrainment and Detrainment Closures for Extended Eddy-Diffusivity Mass-Flux Schemes.

We demonstrate that an extended eddy-diffusivity mass-flux (EDMF) scheme can be used as a unified parameterization of subgrid-scale turbulence and convection across a range of dynamical regimes, from dry convective boundary layers, through shallow convection, to deep convection. Central to achieving this unified representation of subgrid-scale motions are entrainment and detrainment closures. We model entrainment and detrainment rates as a combination of turbulent and dynamical processes. Turbulent entrainment/detrainment is represented as downgradient diffusion between plumes and their environment. Dynamical entrainment/detrainment is proportional to a ratio of a relative buoyancy of a plume and a vertical velocity scale, that is modulated by heuristic nondimensional functions which represent their relative magnitudes and the enhanced detrainment due to evaporation from clouds in drier environment. We first evaluate the closures off-line against entrainment and detrainment rates diagnosed from large eddy simulations (LESs) in which tracers are used to identify plumes, their turbulent environment, and mass and tracer exchanges between them. The LES are of canonical test cases of a dry convective boundary layer, shallow convection, and deep convection, thus spanning a broad rangeof regimes. We then compare the LES with the full EDMF scheme, including the new closures, in a single-column model (SCM). The results show good agreement between the SCM and LES in quantities that are key for climate models, including thermodynamic profiles, cloud liquid water profiles, and profiles of higher moments of turbulent statistics. The SCM also captures well the diurnal cycle of convection and the onset of precipitation.

Regio- and Diastereoselective Copper-Catalyzed Carbometalation of Cyclopropenylsilanes.

We therein report a regio- and diastereoselective copper-catalyzed carbometalation of enantioenriched readily available cyclopropenylsilanes as a synthetic tool to access a large family of stereodefined fully-(hexa)-substituted cyclopropanes.

Tuning Chemical and Physical Properties of Phosphorus Corroles for Advanced Applications.

Although the affinity of metallocorroles to axial ligands is quite low, this is not the case when the chelated element is phosphorus. This work is hence focused on the mechanism of ligand exchange of six-coordinate phosphorus corroles as a tool for affecting their chemical and physical properties. These fundamental investigations allowed for the development of facile methodologies for the synthesis of a large series of complexes and the establishment of several new structure/activity profiles that may be used to understand and predict spectroscopic features and for tailor-made modification of photophysical and electrochemical properties. This is exemplified by the facile access to complexes with terminal groups that are of large potential for practical applications based on click chemistry, optical imaging, and surface science.

Measuring the water content in freshly-deposited fingermarks.

The literature view regarding the composition of deposited fingermarks has long been that the average water content is in the range of 98-99wt.%. This value has recently been challenged by Kent, claiming that it should be 20wt.% at most. Herein we have measured the weight percentage of water content in freshly-deposited fingermarks, with and without hand pre-washing. Two complementary techniques were utilized for the measurements, namely quartz crystal microbalance (QCM) for determining the relative mass-loss and its rate at ca. 37°C, and temperature-programmed desorption-mass spectrometry (TPD-MS) for establishing that the mass loss arises solely from the complete evaporation of all the water content in the fingermarks (done with hand pre-washing only). Unlike the traditional narrow-range values of 98-99% and the limiting value of 20wt.% suggested by Kent, our measurements indicate the occurrence of a broad 20-70% water content. Higher contents of water in fingermarks were found post hand pre-washing, most probably due to removal of the sebum from the fingertips, but none of the results exceeded 90%.

An Extended Eddy-Diffusivity Mass-Flux Scheme for Unified Representation of Subgrid-Scale Turbulence and Convection.

Large-scale weather forecasting and climate models are beginning to reach horizontal resolutions of kilometers, at which common assumptions made in existing parameterization schemes of subgrid-scale turbulence and convection-such as that they adjust instantaneously to changes in resolved-scale dynamics-cease to be justifiable. Additionally, the common practice of representing boundary-layer turbulence, shallow convection, and deep convection by discontinuously different parameterizations schemes, each with its own set of parameters, has contributed to the proliferation of adjustable parameters in large-scale models. Here we lay the theoretical foundations for an extended eddy-diffusivity mass-flux (EDMF) scheme that has explicit time-dependence and memory of subgrid-scale variables and is designed to represent all subgrid-scale turbulence and convection, from boundary layer dynamics to deep convection, in a unified manner. Coherent up and downdrafts in the scheme are represented as prognostic plumes that interact with their environment and potentially with each other through entrainment and detrainment. The more isotropic turbulence in their environment is represented through diffusive fluxes, with diffusivities obtained from a turbulence kinetic energy budget that consistently partitions turbulence kinetic energy between plumes and environment. The cross-sectional area of up and downdrafts satisfies a prognostic continuity equation, which allows the plumes to cover variable and arbitrarily large fractions of a large-scale grid box and to have life cycles governed by their own internal dynamics. Relatively simple preliminary proposals for closure parameters are presented and are shown to lead to a successful simulation of shallow convection, including a time-dependent life cycle.

Systemic inflammatory response syndrome-related lymphopenia is associated with adenosine A1 receptor dysfunction.

SIRS is associated with lymphopenia, and prolonged lymphopenia of septic patients has been associated with increased mortality risk. We hypothesize that elevated adenosine during SIRS down-regulates Gi-coupled A1R, which signals an effect that sensitizes a cAMP-dependent lymphotoxic response. In this study, we evaluate the role of adenosine in SIRS-mediated lymphopenia and impaired IL-15 production. Cecal ligation and puncture was used to induce sepsis-associated SIRS in mice. BMDCs were cultured and used to measure the effect of adenosine on IL-15. We found that A1R mRNA levels were significantly down-regulated and A1R-dependent Gi activity was abolished in T cells of septic mice. In accordance, cAMP was elevated in isolated T cells from cecal ligation and puncture compared with sham-treated mice. Similar to septic mice, leukopenia was evident in sham A1R-KO mice, after treatment with the A1R antagonist (8-cyclopentyl-1,3-dipropylxanthine), or after A1R desensitization. In contrast, A2AR-KO mice were protected from leukopenia. In addition, we observed that septic A1R-KO mice exhibited low IL-15 levels. Cultured BMDC agonists of A2AR and A2BR inhibited IL-15 production and adenosine blocked IL-15-dependent proliferation of cytotoxic T cells that were cocultured with stimulated BMDCs. To conclude, we suggest that SIRS-associated lymphopenia is initiated by A1R desensitization and adenosine-mediated inhibition of IL-15 production is part of the mechanism that accounts for the delay in leukopenia recovery in patients with severe sepsis. Interference with adenosine signaling may thus be potentially beneficial for septic patients with leukopenia.

In situ electrochemical stress measurements examining the oxygen evolution reaction in basic electrolytes.

In situ electrochemical stress measurements are used to interrogate changes in oxide structure before and during the oxygen evolution reaction (OER) from Ir, Ni, Co, Au, and Pt electrodes in alkaline electrolyte. Stress evolution during potential cycling reports on changes in oxidation state and oxide forms. Hysteresis observed in the potential-dependent stress from Ir, Au, and Pt electrodes is associated with chemical irreversibility in electrode composition and roughness. Alternatively, Ni and Co exhibit reversible conversion between hydroxide and oxyhydroxide forms during cycling. From the experimentally determined stress, charge passed during electrode oxidation, and Young's modulus, the change in strain exhibited by Ni and Co electrodes during hydroxide-oxyhydroxide conversion is calculated to be 7.0% and 8.4%, respectively. We also show that the magnitude of change in stress is proportional to the amount of material that is further oxidized.