Molecular orientation echoes via concerted terahertz and near-IR excitations.

A new and efficient method for orientation echo spectroscopy is presented and realized experimentally. The excitation scheme utilizes concerted rotational excitations by both ultrashort terahertz and near-IR pulses and its all-optical detection is enabled by the molecular orientation-induced second harmonic method [J. Phys. Chem. A126, 3732 (2022)10.1021/acs.jpca.2c03237]. This method provides practical means for orientation echo spectroscopy of gas phase molecules and highlights the intriguing underlying physics of coherent rotational dynamics induced by judiciously-orchestrated interactions with both resonant (terahertz) and nonresonant (NIR) fields.

The effects of sample conductivity on the efficacy of dynamic nuclear polarization for sensitivity enhancement in solid state NMR spectroscopy.

In recent years dynamic nuclear polarization (DNP) has greatly expanded the range of materials systems that can be studied by solid state NMR spectroscopy. To date, the majority of systems studied by DNP were insulating materials including organic and inorganic solids. However, many technologically-relevant materials used in energy conversion and storage systems are electrically conductive to some extent or are employed as composites containing conductive additives. Such materials introduce challenges in their study by DNP-NMR which include microwave absorption and sample heating that were not thoroughly investigated so far. Here we examine several commercial carbon allotropes, commonly employed as electrodes or conductive additives, and consider their effect on the extent of solvent polarization achieved in DNP from nitroxide biradicals. We then address the effect of sample conductivity systematically by studying a series of carbons with increasing electrical conductivity prepared via glucose carbonization. THz spectroscopy measurements are used to determine the extent of µw absorption. Our results show that while the DNP performance significantly drops in samples containing the highly conductive carbons, sufficient signal enhancement can still be achieved with some compromise on conductivity. Furthermore, we show that the deleterious effect of conductive additives on DNP enhancements can be partially overcome through pulse-DNP experiments.

Echo Spectroscopy in Multilevel Quantum-Mechanical Rotors.

We study the dynamics of rotational echoes in gas phase molecular ensembles and their dependence on the delay and intensity of the excitation pulses. We explore the unique dynamics of alignment echoes that arise from the multilevel nature of the molecular rotors and impose severe difficulties in utilizing echo responses for rotational spectroscopy. We show experimentally and theoretically that judicious control of both the delay and intensity of the second pulse enables multilevel "rotational echo spectroscopy." The proposed methodology paves the way to rotational spectroscopy in high-density gas samples.

Asc-1 Transporter Regulation of Synaptic Activity via the Tonic Release of d-Serine in the Forebrain.

d-Serine is a co-agonist of NMDA receptors (NMDARs) whose activity is potentially regulated by Asc-1 (SLC7A10), a transporter that displays high affinity for d-serine and glycine. Asc-1 operates as a facilitative transporter and as an antiporter, though the preferred direction of d-serine transport is uncertain. We developed a selective Asc-1 blocker, Lu AE00527, that blocks d-serine release mediated by all the transport modes of Asc-1 in primary cultures and neocortical slices. Furthermore, d-serine release is reduced in slices from Asc-1 knockout (KO) mice, indicating that d-serine efflux is the preferred direction of Asc-1. The selectivity of Lu AE00527 is assured by the lack of effect on slices from Asc-1-KO mice, and the lack of interaction with the co-agonist site of NMDARs. Moreover, in vivo injection of Lu AE00527 in P-glycoprotein-deficient mice recapitulates a hyperekplexia-like phenotype similar to that in Asc-1-KO mice. In slices, Lu AE00527 decreases the long-term potentiation at the Schaffer collateral-CA1 synapses, but does not affect the long-term depression. Lu AE00527 blocks NMDAR synaptic potentials when typical Asc-1 extracellular substrates are present, but it does not affect AMPAR transmission. Our data demonstrate that Asc-1 mediates tonic co-agonist release, which is required for optimal NMDAR activation and synaptic plasticity.

Political regimes, income and health: Evidence from sub-national comparative method.

This paper investigates the effect of political regimes on healthcare outcomes with a novel approach. Instead of focusing on cross-country comparisons, like most studies do, we utilize the within-country variation of political regimes across individual regions. We use the case of the Russian Federation, where large sub-national differences exist in both health outcomes and political regimes in different provinces. General differences in sub-national politics in Russia have been subject of investigation of a large literature our paper adds to. The paper shows that the effect of political regimes on health is heterogeneous and depends on the type of health problems more salient for the region. More pluralist and competitive regimes are able to produce better results than the less competitive ones in rich regions, while in poor regions political pluralism and competition have an adverse impact on health.

Coherent Radiative Decay of Molecular Rotations: A Comparative Study of Terahertz-Oriented versus Optically Aligned Molecular Ensembles.

The decay of field-free rotational dynamics is experimentally studied by two complementary methods: laser-induced molecular alignment and terahertz-field-induced molecular orientation. A comparison between the decay rates of different molecular species at various gas pressures reveals that oriented molecular ensembles decay faster than aligned ensembles. The discrepancy in decay rates is attributed to the coherent radiation emitted by the transiently oriented ensembles and is absent from aligned molecules. The experimental results reveal the dramatic contribution of coherent radiative emission to the observed decay of rotational dynamics and underline a general phenomenon expected whenever field-free coherent dipole oscillations are induced.

The alanine-serine-cysteine-1 (Asc-1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission.

Asc-1 (SLC7A10) is an amino acid transporter whose deletion causes neurological abnormalities and early postnatal death in mice. Using metabolomics and behavioral and electrophysiological methods, we demonstrate that Asc-1 knockout mice display a marked decrease in glycine levels in the brain and spinal cord along with impairment of glycinergic inhibitory transmission, and a hyperekplexia-like phenotype that is rescued by replenishing brain glycine. Asc-1 works as a glycine and L-serine transporter, and its transport activity is required for the subsequent conversion of L-serine into glycine in vivo. Asc-1 is a novel regulator of glycine metabolism and a candidate for hyperekplexia disorders.

Nuclear Compartmentalization of Serine Racemase Regulates D-Serine Production: IMPLICATIONS FOR N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ACTIVATION.

D-Serine is a physiological co-agonist that activates N-methyl D-aspartate receptors (NMDARs) and is essential for neurotransmission, synaptic plasticity, and behavior. D-Serine may also trigger NMDAR-mediated neurotoxicity, and its dysregulation may play a role in neurodegeneration. D-Serine is synthesized by the enzyme serine racemase (SR), which directly converts L-serine to D-serine. However, many aspects concerning the regulation of D-serine production under physiological and pathological conditions remain to be elucidated. Here, we investigate possible mechanisms regulating the synthesis of D-serine by SR in paradigms relevant to neurotoxicity. We report that SR undergoes nucleocytoplasmic shuttling and that this process is dysregulated by several insults leading to neuronal death, typically by apoptotic stimuli. Cell death induction promotes nuclear accumulation of SR, in parallel with the nuclear translocation of GAPDH and Siah proteins at an early stage of the cell death process. Mutations in putative SR nuclear export signals (NESs) elicit SR nuclear accumulation and its depletion from the cytosol. Following apoptotic insult, SR associates with nuclear GAPDH along with other nuclear components, and this is accompanied by complete inactivation of the enzyme. As a result, extracellular D-serine concentration is reduced, even though extracellular glutamate concentration increases severalfold. Our observations imply that nuclear translocation of SR provides a fail-safe mechanism to prevent or limit secondary NMDAR-mediated toxicity in nearby synapses.

Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity.

D-Serine and glycine are coagonists of NMDA receptors (NMDARs), but their relative contributions for several NMDAR-dependent processes are unclear. We now report that the alanine-serine-cysteine transporter-1 (Asc-1) mediates release of both D-serine and glycine from neurons, and, in turn, this modulates NMDAR synaptic activity. Asc-1 antiporter activity is enhanced by D-isoleucine (D-Ile), which releases D-serine and glycine from Asc-1-transfected cells, primary neuronal cultures, and hippocampal slices. D-Ile has no effect on astrocytes, which do not express Asc-1. We show that D-Ile enhances the long-term potentiation (LTP) in rat and mouse hippocampal CA1 by stimulating Asc-1-mediated endogenous D-serine release. D-Ile effects on synaptic plasticity are abolished by enzymatically depleting D-serine or by using serine racemase knock-out (SR-KO) mice, confirming its specificity and supporting the notion that LTP depends mostly on D-serine release. Conversely, our data also disclose a role of glycine in activating synaptic NMDARs. Although acute enzymatic depletion of D-serine also drastically decreases the isolated NMDAR synaptic potentials, these responses are still enhanced by D-Ile. Furthermore, NMDAR synaptic potentials are preserved in SR-KO mice and are also enhanced by D-Ile, indicating that glycine overlaps with D-serine binding at synaptic NMDARs. Altogether, our results disclose a novel role of Asc-1 in regulating NMDAR-dependent synaptic activity by mediating concurrent non-vesicular release of D-serine and glycine. Our data also highlight an important role of neuron-derived D-serine and glycine, indicating that astrocytic D-serine is not solely responsible for activating synaptic NMDARs.

D-serine in glia and neurons derives from 3-phosphoglycerate dehydrogenase.

d-Serine is an endogenous ligand for NMDARs generated from l-serine by the enzyme serine racemase (Srr). Both neuronal and glial localizations have been reported for d-serine and Srr. 3-Phosphoglycerate dehydrogenase is an exclusively astrocytic enzyme that catalyzes the first committed step of l-serine biosynthesis. Using transgenic mice expressing enhanced green fluorescent protein under the Srr promoter and mice with targeted deletion of Srr or 3-Phosphoglycerate dehydrogenase, we demonstrate predominantly neuronal sources of d-serine dependent on astrocytic supply of l-serine. These findings clarify the cellular basis for the regulation of NMDAR neurotransmission by d-serine.

Ergodicity breaking in rapidly rotating C60 fullerenes.

Ergodicity, the central tenet of statistical mechanics, requires an isolated system to explore all available phase space constrained by energy and symmetry. Mechanisms for violating ergodicity are of interest for probing nonequilibrium matter and protecting quantum coherence in complex systems. Polyatomic molecules have long served as a platform for probing ergodicity breaking in vibrational energy transport. Here, we report the observation of rotational ergodicity breaking in an unprecedentedly large molecule, 12C60, determined from its icosahedral rovibrational fine structure. The ergodicity breaking occurs well below the vibrational ergodicity threshold and exhibits multiple transitions between ergodic and nonergodic regimes with increasing angular momentum. These peculiar dynamics result from the molecule's distinctive combination of symmetry, size, and rigidity, highlighting its relevance to emergent phenomena in mesoscopic quantum systems.

Protective Policy Index (PPI) global dataset of origins and stringency of COVID 19 mitigation policies.

We have developed and made accessible for multidisciplinary audience a unique global dataset of the behavior of political actors during the COVID-19 pandemic as measured by their policy-making efforts to protect their publics. The dataset presents consistently coded cross-national data at subnational and national levels on the daily level of stringency of public health policies by level of government overall and within specific policy categories, and reports branches of government that adopted these policies. The data on these public mandates of protective behaviors is collected from media announcements and government publications. The dataset allows comparisons of governments' policy efforts and timing across the world and can serve as a source of information on policy determinants of pandemic outcomes-both societal and possibly medical.

Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration.

D-serine is thought to be a glia-derived transmitter that activates N-methyl D-aspartate receptors (NMDARs) in the brain. Here, we investigate the pathways for D-serine release using primary cultures, brain slices, and in vivo microdialysis. In contrast with the notion that D-serine is exclusively released from astrocytes, we found that D-serine is released by neuronal depolarization both in vitro and in vivo. Veratridine (50 microM) or depolarization by 40 mM KCl elicits a significant release of endogenous D-serine from primary neuronal cultures. Controls with astrocyte cultures indicate that glial cells are insensitive to veratridine, but release D-serine mainly by the opening of volume-regulated anion channels. In cortical slices perfused with veratridine, endogenous D-serine release is 10-fold higher than glutamate receptor-evoked release. Release of D-serine from slices does not require internal or external Ca(2+), suggesting a nonvesicular release mechanism. To confirm the neuronal origin of D-serine, we selectively loaded neurons in cortical slices with D-[(3)H]serine or applied D-alanine, which specifically releases D-serine from neurons. Depolarization with veratridine promotes D-serine release in vivo monitored by high temporal resolution microdialysis of the striatum. Our data indicate that the neuronal pool of D-serine plays a major role in D-serine dynamics, with implications for the regulation of NMDAR transmission.

ERK Activity in Immature Leukemic Cells Drives Clonal Selection during Induction Therapy for Acute Myeloid Leukemia.

Selection of resistant clones following intensive chemotherapy is a common obstacle for cure in many cancers, particularly in acute myeloid leukemia (AML). In AML, clone-specific sensitivity to chemotherapy varies even within the same patient. Multiple mutations and genetic aberrations are associated with clones surviving chemotherapy. The current study explored the role of activated signaling pathways in chemoresistance as a function of cell maturation, reflected by CD34 expression. In-vitro, Kasumi-1 leukemic cell line, sorted by CD34 expression, showed increased apoptosis only in the CD34- subpopulation after exposure to cytosine arabinoside (Ara-C) or daunorubicin. The resistant CD34+ subset demonstrated higher expression of ERK1/2 and BCL-2 proteins than CD34- cells. MEK1/2 inhibition elevated Ara-C ability to induce apoptosis in CD34+ cells, suggesting that MEK1/2-ERK1/2 is surviving signaling, which correlates to cell maturation levels and plays a role in chemoresistance. Deep sequencing of sorted CD34+/- populations, both derived from the same patient samples, demonstrated various subclonal distribution of NPM1, DNMT3A and FLT3-ITD mutations. Interestingly, in these samples, p-ERK levels and apoptosis rates following chemotherapy exposure significantly differed between CD34+/- populations. Hence, clones may be selected due to their ability to escape apoptosis rather than a direct effect of chemotherapy on a specific mutated clone.

Political Economy of Infant Mortality Rate: Role of Democracy Versus Good Governance.

Despite numerous studies on whether democracy reduces the infant mortality rate (IMR), the empirical results remain mixed at best. In this article, I perform several theoretical and empirical exercises that help explain why and under what conditions we should expect politics to matter most for a decrease in IMR. First, I capitalize on the epidemiological view that IMR - the most commonly used indicator of health in social sciences - is better suited to reflect public health micromanagement than overall social development. Second, I theorize that autocrats have incentives to invest in health up to a certain point, which could lead to a reduction in IMR. Third, I introduce an omitted variable - good governance - that trumps the importance of a political regime for IMR: (1) it directly affects public health micromanagement, and (2) many autocrats made inroads in achieving good governance. Finally, for the first time in such research, I use a disaggregated IMR approach to corroborate my hypotheses.

Rotational Echoes: Rephasing of Centrifugal Distortion in Laser-Induced Molecular Alignment.

We study and demonstrate the rephasing property of the echo response in a multilevel rotational system of iodomethane via long time-resolved optical birefringence measurements. The strong centrifugal distortion of iodomethane is utilized as a dephasing mechanism imprinted on the echo signal and is shown to rephase throughout its evolution. The dependence of the echo signal amplitude on the driving pulses' intensities is theoretically and experimentally explored. The analogy to Hahn's spin echoes is discussed, and a quantum-mechanical version of Hahn's track runners is provided for the case of multilevel rotational system.