Controlling the Structure, Properties and Surface Reactivity of Clickable Azide-Functionalized Au25 (SR)18 Nanocluster Platforms Through Regioisomeric Ligand Modifications.

To fine-tune structure-property correlations of thiolate-protected gold nanoclusters through post-assembly surface modifications, we report the synthesis of the o, m, and p regioisomeric forms of the anionic azide-functionalized [Au25 (SCH2 CH2 -C6 H4 -N3 )18 ]1- platform. They can undergo cluster-surface strain-promoted alkyne-azide cycloaddition (CS-SPAAC) chemistry with complementary strained-alkynes. Although their optical properties are similar, the electrochemical properties appear to correlate with the position of the azido group. The ability to conduct CS-SPAAC chemistry without altering the parent nanocluster structure is different as the isomeric form of the surface ligand is changed, with the [Au25 (SCH2 CH2 -p-C6 H4 -N3 )18 ]1- isomer having the highest reaction rates, while the [Au25 (SCH2 CH2 -o-C6 H4 -N3 )18 ]1- isomer is not stable following CS-SPAAC. Single-crystal X-ray diffraction provide the molecular structure of the neutral forms of the three regioisomeric clusters, [Au25 (SCH2 CH2 -o/m/p-C6 H4 -N3 ]0 , which illustrates correlated structural features of the central core as the position of the azido moiety is changed.

Interrater reproducibility of the 2016 American society of echocardiography left ventricular diastolic function guidelines.

BACKGROUND: Little data exist regarding interreader variability of diastolic measurements and their application by the 2016 American Society of Echocardiography left ventricular (LV) diastolic function guidelines. METHODS: Volunteers (n = 49) were recruited from an outpatient cardiology practice. The presence and grade of diastology dysfunction (DD) was determined by the 2016 LV diastology guideline algorithm. We determined the mean, standard deviation, coefficient of variation, and intraclass correlation coefficient (ICC) for each measurement and Fleiss K-statistic to define differences in grading DD. We determined predictors associated with disagreement of DD grade using odds ratios. RESULTS: The mean LVEF was 56%, LAVI 32 ml/m2 , and peak TR velocity was 2.3 m/s. The ICC for mitral inflow and tissue Doppler velocities were >.90, for LV volumes were .80-.86, and for LA volume was .56. The Fleiss K-value for the agreement of the presence of DD was .68 and for DD grade was .59. Variables with increased odds of disagreement were (1) at least one reader considering a TR signal uninterpretable (OR 12.0; 95% CI 1.3-109.6), (2) at least one reader assessing both LVEF 50%-55% and LAVI 29-39 ml/m2 (OR 9.3; 95% CI 1.0-87), and (3) at least one reader assessing LVEF 50-55% (OR 3.8; 95% CI 1.1-13.4). CONCLUSIONS: Using the 2016 ASE/EACVI diastology guidelines, we found excellent interrater reliability of Doppler measurements, moderate-good interrater reliability of volumetric measurements, and moderate-good but not excellent agreement for diastology grade.

Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction.

There is substantial evidence that both N-methyl-D-aspartate receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains largely unknown. Although models using cell-type-specific genetic deletion of NMDARs have been informative, they display overly pronounced phenotypes extending beyond those of schizophrenia. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than complete receptor elimination, to examine the link between NMDAR hypofunction and decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction in the NMDAR coagonist d-serine, exhibit many of the neurochemical and behavioral abnormalities observed in schizophrenia. We found a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction increases the excitation/inhibition balance resulting in enhanced synaptically driven neuronal excitability without changes in intrinsic excitability. Consistently, significant reductions in inhibitory synapse density in CA1 were observed by immunohistochemistry. We further show, using a single-neuron genetic deletion approach, that the loss of GABAergic synapses onto pyramidal neurons observed in the SRKO mice is driven in a cell-autonomous manner following the deletion of SR in individual CA1 pyramidal cells. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapses leading to disrupted feedback inhibition and impaired neuronal synchrony.NEW & NOTEWORTHY Recently, disruption of excitation/inhibition (E/I) balance has become an area of considerable interest for psychiatric research. Here, we report a reduction in inhibition in the serine racemase knockout mouse model of schizophrenia that increases E/I balance and enhances synaptically driven neuronal excitability. This reduced inhibition was driven cell-autonomously in pyramidal cells lacking serine racemase, suggesting a novel mechanism for how chronic NMDA receptor hypofunction can disrupt information processing in schizophrenia.

Mesenchymal Stromal Cells as Potential Antimicrobial for Veterinary Use-A Comprehensive Review.

The emergence of "superbugs" resistant to antimicrobial medications threatens populations both veterinary and human. The current crisis has come about from the widespread use of the limited number of antimicrobials available in the treatment of livestock, companion animal, and human patients. A different approach must be sought to find alternatives to or enhancements of present conventional antimicrobials. Mesenchymal stromal cells (MSC) have antimicrobial properties that may help solve this problem. In the first part of the review, we explore the various mechanisms at work across species that help explain how MSCs influence microbial survival. We then discuss the findings of recent equine, canine, and bovine studies examining MSC antimicrobial properties in which MSCs are found to have significant effects on a variety of bacterial species either alone or in combination with antibiotics. Finally, information on the influence that various antimicrobials may have on MSC function is reviewed. MSCs exert their effect directly through the secretion of various bioactive factors or indirectly through the recruitment and activation of host immune cells. MSCs may soon become a valuable tool for veterinarians treating antimicrobial resistant infections. However, a great deal of work remains for the development of optimal MSC production conditions and testing for efficacy on different indications and species.

Postsynaptic Serine Racemase Regulates NMDA Receptor Function.

d-serine is the primary NMDAR coagonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-serine remains limited. Though early studies suggested d-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional KO mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-serine action.SIGNIFICANCE STATEMENT NMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which is d-serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-serine availability remains limited. d-serine is synthesized in the brain by the neuronal enzyme serine racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-serine action at synapses.

Electrogenerated Chemiluminescence and Electroluminescence of N-Doped Graphene Quantum Dots Fabricated from an Electrochemical Exfoliation Process in Nitrogen-Containing Electrolytes.

Artificial lighting sources are one of the most important technological developments for our modern lives; the search for cost-effective and efficient luminophores is therefore crucial to a sustainable future. Graphene quantum dots (GQDs) are carbon-based nanomaterials that exhibit exceptional optical and electronic properties, making them a prime candidate for a luminophore in a light-emitting device. Nitrogen-doped GQDs fabricated from a facile top-down electrochemical exfoliation process with a nitrogen-containing electrolyte in this report showed strong photoluminescent emission at 450 nm, and electrogenerated chemiluminescence at 660 nm in the presence of benzoyl peroxide as a coreactant. When introduced into solid-state light-emitting electrochemical cells, for the first time, the GQDs displayed a broad white emission centered at 610 nm, corresponding to Commision Internationale de l'eclairage (CIE) colour coordinates of (0.38, 0.36).

Benzosiloles with Crystallization-Induced Emission Enhancement of Electrochemiluminescence: Synthesis, Electrochemistry, and Crystallography.

Crystallization-induced emission enhancement (CIEE) was demonstrated for the first time for electrochemilunimescence (ECL) with two new benzosiloles. Compared with their solution, the films of the two benzosiloles gave CIEE of 24 and 16 times. The mechanism of the CIEE-ECL was examined by spooling ECL spectroscopy, X-ray crystal structure analysis, photoluminescence, and DFT calculations. This CIEE-ECL system is a complement to the well-established aggregation-induced emission enhancement (AIEE) systems. Unique intermolecular interactions are noted in the crystalline chromophore. The first heterogeneous ECL system is established for organic compounds with highly hydrophobic properties.

Revealing Crystallization-Induced Blue-Shift Emission of a Di-Boron Complex by Enhanced Photoluminescence and Electrochemiluminescence.

Elucidating the effects of crystallization-induced blue-shift emission of a newly synthesized di-boron complex (DBC) by enhanced photoluminescence (PL) and electrochemiluminescence (ECL) in the annihilation pathway was realized for the first time. The 57 nm blue-shift and great enhancement in the crystalline lattice relative to the DBC solution were attributed to the restriction of intramolecular rotation (RIR) and confirmed by PL imaging, X-ray diffraction, as well as DFT calculations. It was discovered that ECL at crystalline film/solution interfaces can be further enhanced by means of both co-reactant route and RIR. The RIR contributions with co-reactant increased ECL up to 5 times more. Very interestingly, the co-reactant system was found to give off a red-shifted light emission. Mechanistic studies reveal that a difference between location of the ECL in the co-reactant route and that in the annihilation pathway leads to an alternative emission wavelength.

Comparing Major Bleeding Risk in Outpatients With Atrial Fibrillation or Flutter by Oral Anticoagulant Type (from the National Cardiovascular Disease Registry's Practice Innovation and Clinical Excellence Registry).

Direct oral anticoagulants (DOACs) have a favorable bleeding risk profile in patients with atrial fibrillation (AF). However, the safety of individual DOACs relative to warfarin for specific bleeding outcomes is less certain. We identified 423,450 patients with AF between 2013 to 2015 in the NCDR PINNACLE national ambulatory registry matched to the Centers for Medicare and Medicaid Services database. Outcomes included time to first major bleed, intracranial hemorrhage (ICH), major gastrointestinal bleed (GIB), or other major bleed. We estimated the association of OAC with bleeding using Cox proportional hazard models. The median duration of follow-up was 1.4 years. OACs were used in 64% of AF patients (66% warfarin, 15% rivaroxaban, 12% dabigatran, and 7% apixaban). A major bleeding event occurred in 6.9% of patients. Compared with warfarin users, fewer patients experienced ICH with the use of rivaroxaban (HR 0.73; 95% CI 0.64 to 0.84), dabigatran (HR 0.56; 95% CI 0.48 to 0.65), and apixaban (HR 0.70; 95% CI 0.55 to 0.90). The risk of major GIB was higher in rivaroxaban users (HR 1.20; 95% CI 1.12 to 1.27), and lower in dabigatran (HR 0.88; 95% CI 0.82 to 0.95) and apixaban (HR 0.84; 95% CI 0.74 to 0.95) users. For any DOAC versus warfarin, age (≥75 or <75 years) interacted with major bleeding (HR 0.93 vs 0.78; p <0.001), GIB (HR 1.10 vs 0.82; p <0.001), and other major bleeding (HR 0.93 vs 0.80; p <0.001). In conclusion, our results suggest that the safety of DOACs is superior to warfarin in AF patients, except with rivaroxaban and GIB. Age ≥75 years attenuated the relative safety benefits of DOACs.

Incomplete block of NMDA receptors by intracellular MK-801.

NMDA receptors (NMDARs) are essential components in glutamatergic synaptic signaling. The NMDAR antagonist MK-801 has been a valuable pharmacological tool in evaluating NMDAR function because it binds with high affinity to the NMDAR ion channel pore and is non-competitive with ligand binding. MK-801 has also been used to selectively inhibit NMDAR current in only the cell being recorded by including the drug in the intracellular recording solution. Here, we report that intracellular MK-801 (iMK-801) only partially inhibits synaptic NMDAR currents at +40 mV at both cortical layer 4 to layer 2/3 and hippocampal Schaffer collateral to CA1 synapses. Furthermore, iMK-801 incompletely inhibits heterologously expressed NMDAR currents at -60 mV, consistent with a model of iMK-801 having a very slow binding rate and consequently ∼30,000 times lower affinity than MK-801 applied to the extracellular side of the receptor. While iMK-801 can be used as a qualitative tool to study reduced postsynaptic NMDAR function, it cannot be assumed to completely block NMDARs at concentrations typically used in experiments.

Psychedelics Promote Structural and Functional Neural Plasticity.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

Long-Term Depression Is Independent of GluN2 Subunit Composition.

NMDA receptors (NMDARs) mediate both long-term potentiation and long-term depression (LTD) and understanding how a single receptor can initiate both phenomena remains a major question in neuroscience. A prominent hypothesis implicates the NMDAR subunit composition, specifically GluN2A and GluN2B, in dictating the rules of synaptic plasticity. However, studies testing this hypothesis have yielded inconsistent and often contradictory results, especially for LTD. These inconsistent results may be due to challenges in the interpretation of subunit-selective pharmacology and in dissecting out the contributions of differential channel properties versus the interacting proteins unique to GluN2A or GluN2B. In this study, we address the pharmacological and biochemical challenges by using a single-neuron genetic approach to delete NMDAR subunits in conditional knock-out mice. In addition, the recently discovered non-ionotropic nature of NMDAR-dependent LTD allowed the rigorous assessment of unique subunit contributions to NMDAR-dependent LTD while eliminating the variable of differential charge transfer. Here we find that neither the GluN2A nor the GluN2B subunit is strictly necessary for either non-ionotropic or ionotropic LTD.SIGNIFICANCE STATEMENT NMDA receptors are key regulators of bidirectional synaptic plasticity. Understanding the mechanisms regulating bidirectional plasticity will guide development of therapeutic strategies to treat the dysfunctional synaptic plasticity in multiple neuropsychiatric disorders. Because of the unique properties of the NMDA receptor GluN2 subunits, they have been postulated to differentially affect synaptic plasticity. However, there has been significant controversy regarding the roles of the GluN2 subunits in synaptic long term depression (LTD). Using single-neuron knock-out of the GluN2 subunits, we show that LTD requires neither GluN2A nor GluN2B.

The effects of long duration chronic exposure to hexavalent chromium on single live cells interrogated by scanning electrochemical microscopy.

Chromium is a useful heavy metal which has been employed in numerous industry and house applications. However, there are several known health risks associated with its uses. Cr (VI) is a toxic heavy metal format which serves no essential biological role in humans. It has been associated with oxidative stress, cytotoxicity, and carcinogenicity. Contamination of groundwater or soil due to improper handling lead to long term environmental damage. This study explores the effects of long duration chronic exposure to Cr (VI) on live human cells. Herein, scanning electrochemical microscopy (SECM) depth scan imaging was employed to monitor the membrane permeability of single live human bladder cancer (T24) cells following incubation with various Cr (VI) concentration stimuli. SECM was used to provide insights into the long duration effects on membrane homeostasis of individual cells exposed to constant levels of Cr (VI). Further investigation of total population viability was performed by MTT assay. Dependent on the exposure time, transition between three distinct trends was observed. At short incubation times (≤1-3 h) with low concentrations of Cr (VI) (0-10 µM), membrane permeability was largely unaffected. As time increased a decrease in membrane permeability coefficient was observed, reaching a minimum at 3-6 h. Following this a dramatic increase in membrane permeability was observed as cell viability decreased. Higher concentrations were also found to accelerate the timeframe at which these trends occurred. These findings further demonstrate the strength of SECM as a bioanalytical technique for monitoring cellular homeostasis.

The potential role of the left atrial septal pouch in cryptogenic stroke.

The left atrial septal pouch (LASP) is an anatomic variant of the atrial septum that forms a blind-ending pouch, communicating exclusively with the left atrium (LA). Case reports have demonstrated thrombus within LASP and in the setting of cryptogenic stroke. Initial epidemiologic results are mixed, one study showing and others not showing an association between LASP and cryptogenic stroke. Additional investigation should take place to determine the clinical significance of LASP and what interventions are required to prevent ischemic stroke in at-risk individuals.

Left atrial septal pouch in cryptogenic stroke.

BACKGROUND: The left atrial septal pouch (LASP), an anatomic variant of the interatrial septum, has uncertain clinical significance. We examined the association between LASP and ischemic stroke subtypes in patients undergoing transesophageal echocardiography (TEE). METHODS: We determined the prevalence of LASP among consecutive patients who underwent TEE at our institution. Patients identified with ischemic strokes were further evaluated for stroke subtype using standard and modified criteria from the Trial of Org 10172 in Acute Stroke Treatment (TOAST). We compared the prevalence of LASP in ischemic stroke, cryptogenic stroke, and non-stroke patients using prevalence ratios (PR). RESULTS: The mean age of all 212 patients (including stroke and non-stroke patients) was 57 years. The overall prevalence of LASP was 17% (n = 35). Of the 75 patients who were worked-up for stroke at our institution during study period, we classified 31 as cryptogenic using standard TOAST criteria. The prevalence of LASP among cryptogenic stroke patients (using standard and modified TOAST criteria) was increased compared to the prevalence among other ischemic stroke patients (26 vs. 9%, p = 0.06; PR = 1.8, 95% CI = 1.1-3.1, and 30 vs. 10%, p = 0.04; PR = 2.2, 95% CI = 1.2-4.1, respectively). CONCLUSION: In this population of relatively young patients, prevalence of LASP was increased in cryptogenic stroke compared to stroke patients of other subtypes. These findings suggest LASP is associated with cryptogenic stroke, which should be verified by future large-scale studies.

A comparison of cook-medley hostility subscales and mortality in patients with coronary heart disease: data from the heart and soul study.

OBJECTIVE: Hostility is associated with adverse outcomes in patients with coronary heart disease (CHD). However, assessment tools used to evaluate hostility in epidemiological studies vary widely. METHODS: We administered nine subscales of the Cook-Medley Hostility Scale (CMHS) to 656 outpatients with stable CHD between 2005 and 2007. We used Cox proportional hazards models to determine the association between each hostility subscales and all-cause mortality. We also performed an item analysis using logistic regression to determine the association between each CMHS item and all-cause mortality. RESULTS: There were 136 deaths during 1364 person-years of follow-up. Four of nine CMHS subscales were predictive of mortality in age-adjusted analyses, but only one subscale (the seven-item Williams subscale) was predictive of mortality in multivariable analyses. After adjustment for age, sex, education, smoking, history of heart failure, diabetes, and high-density lipoprotein, each standard deviation increase in the Williams subscale was associated with a 20% increased mortality rate (hazard ratio = 1.20, 95% confidence interval = 1.00-1.43, p = .046), and participants with hostility scores in the highest quartile were twice as likely to die as those in the lowest quartile (hazard ratio = 2.00, 95% confidence interval = 1.10-3.65, p = .023). CONCLUSIONS: Among nine variations of the CMHS that we evaluated, a seven-item version of the Williams subscale was the most strongly associated with mortality. Standardizing the assessment of hostility in future epidemiological studies may improve our understanding of the relationship between hostility and mortality in patients with CHD.

Relation of left atrial dysfunction to ischemic stroke in patients with coronary heart disease (from the heart and soul study).

This study sought to determine whether left atrial (LA) dysfunction independently predicts ischemic stroke. Atrial fibrillation (AF) impairs LA function and is associated with ischemic stroke. However, ischemic stroke frequently occurs in patients without known AF. The direct relation between LA function and risk of ischemic stroke is unknown. We performed transthoracic echocardiography at rest in 983 subjects with stable coronary heart disease. To quantify LA dysfunction, we used the left atrial function index (LAFI), a validated formula incorporating LA volumes at end-atrial systole and diastole. Cox proportional hazards models were used to evaluate the association between LAFI and ischemic stroke or transient ischemic attack (TIA). Over a mean follow-up of 7.1 years, 58 study participants (5.9%) experienced an ischemic stroke or TIA. In patients without known baseline AF or warfarin therapy (n = 893), participants in the lowest quintile of LAFI had >3 times the risk of ischemic stroke or TIA (hazard ratio 3.3, 95% confidence interval 1.1 to 9.7, p = 0.03) compared with those in the highest quintile. For each standard deviation (18.8 U) decrease in LAFI, the hazard of ischemic stroke or TIA increased by 50% (hazard ratio 1.5, 95% confidence interval 1.0 to 2.1, p = 0.04). Among measured echocardiographic indexes of LA function, including LA volume, LAFI was the strongest predictor of ischemic stroke or TIA. In conclusion, LA dysfunction is an independent risk factor for stroke or TIA, even in patients without baseline AF.