Search

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2- b ]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29 , an imidazo [1,2- b ]pyridazine with improved kinase selectivity with respect to closely related CLK kinases. [Display omitted] • Co-crystal structure of imidazo [1,2- b ]pyridazine 17 complexed with DYRK1A solved. • DYRK1A binding affinity increased by C-3 substitution under P-loop. • DYRK1A selectivity increased by C-2 substitution with a methyl group. • A series of potent, selective and cell-active inhibitors of DYRK1A are described. [ABSTRACT FROM AUTHOR]

Previous studies have found that repetitive transcranial magnetic stimulation (rTMS) to the left dorsal lateral prefrontal cortex (LDLPFC) transiently reduces smoking craving, decreases cigarette consumption, and increases abstinence rates. We investigated whether 10 daily MRI-guided rTMS sessions over two weeks to the LDLPFC paired with craving cues could reduce cigarette consumption and induce smoking cessation. We enrolled 42 treatment-seeking nicotine-dependent smokers (≥10 cigarettes per day) in a randomized, double-blind, sham-controlled trial. Participants received 10 daily sessions over 2 weeks of either active or sham MRI-guided rTMS (10Hz, 3000 pulses each session) to the LDLPFC concurrently with video smoking cues. The primary outcome was a reduction in biochemically confirmed cigarette consumption with a secondary outcome of abstinence on the target quit date. We also recorded cue-induced craving and withdrawal symptoms. Compared to sham (n = 17), participants receiving active rTMS (n = 21) smoked significantly fewer cigarettes per day during the 2-week treatment (mean [SD], 13.73[9.18] vs. 11.06[9.29], P <.005) and at 1-month follow-up (12.78[9.53] vs. 7.93[7.24], P <.001). Active rTMS participants were also more likely to quit by their target quit rate (23.81%vs. 0%, OR 11.67, 90% CL, 0.96–141.32, x2 = 4.66, P =.031). Furthermore, rTMS significantly reduced mean craving throughout the treatments and at follow-up (29.93[13.12] vs. 25.01[14.45], P <.001). Interestingly across the active treatment sample, more lateral coil location was associated with more success in quitting (−43.43[0.40] vs. −41.79[2.24], P <.013). Daily MRI-guided rTMS to the LDLPFC for 10 days reduces cigarette consumption and cued craving for up to one month and also increases the likelihood of smoking cessation. ClinicalTrials.gov identifier: NCT02401672. • A single session of rTMS over the left LDLPFC reduces cue-induced craving. • Two weeks of daily MRI-guided rTMS to the LDLPFC aids smoking cessation. • The more lateral stimulation, the better the rTMS efficiency for smoking cessation. [ABSTRACT FROM AUTHOR]

The appropriate communication and management of incidental findings on emergency department (ED) radiology studies is an important component of patient safety. Guidelines have been issued by the ACR and other medical associations that best define incidental findings across various modalities and imaging studies. However, there are few examples of health care facilities designing ways to manage incidental findings. Our institution aimed to improve communication and follow-up of incidental radiology findings in ED patients through the collaborative development and implementation of system-level process changes including a standardized loop-closure method. We assembled a multidisciplinary team to address the nature of these incidental findings and designed new workflows and operational pathways for both radiology and ED staff to properly communicate incidental findings. Our results are based on all incidental findings received and acknowledged between November 1, 2016, and May 30, 2017. The total number of incidental findings discovered was 1,409. Our systematic compliance fluctuated between 45% and 95% initially after implementation. However, after overcoming various challenges through optimization, our system reached a compliance rate of 93% to 95%. Through the implementation of our new, standardized communication system, a high degree of compliance with loop closure for ED incidental radiology findings was achieved at our institution. [ABSTRACT FROM AUTHOR]

Background: The complete removal of the cardiac sodium-calcium exchanger (NCX1) is associated with embryonic lethality, whereas its overexpression is linked to heart failure. To determine whether or not a reduced expression of NCX1 is compatible with normal heart structure and function, we studied 2 knockout (KO) mouse models with reduced levels of NCX1: a heterozygous global KO (HG-KO) with a 50% level of NCX1 expression in all myocytes, and a ventricular-specific KO (V-KO) with NCX1 expression in only 10% to 20% of the myocytes.Methods and Results: Both groups of mice were evaluated at baseline, after transaortic constriction (TAC), and after acute or chronic beta-adrenergic stimulation. At baseline, the HG-KO mice had smaller hearts and the V-KO mice had larger hearts than their wild-type (WT) controls (P < .05). The HG-KO and their control WT mice had normal responses to TAC and beta-adrenergic stimulation. However, the V-KO group was intolerant to TAC and had a significantly (P < .05) blunted response to beta-adrenergic stimulation as compared with the HG-KO mice and WT controls. Unlike the HG-KO mice, the V-KO mice did not tolerate chronic isoproterenol infusion. Telemetric analysis of the electrocardiogram, body temperature, and activity revealed a normal diurnal rhythm in all groups of mice, but confirmed shorter QT intervals along with increased arrhythmias and reduced R wave to P wave amplitude ratios in the V-KO mice.Conclusions: Though NCX1 can be reduced by half in all myocytes without significant functional alterations, it must be expressed in more than 20% of the myocytes to prevent severe remodeling and heart failure in mouse heart. [ABSTRACT FROM AUTHOR]

Abstract: Photoconversion, the method by which a fluorescent dye is transformed into a stable, osmiophilic product that can be visualized by transmission electron microscopy, is the most widely used method to enable the ultrastructural analysis of fluorescently labeled cellular structures. Nevertheless, the conventional method of photoconversion using widefield fluorescence microscopy requires long reaction times and results in low resolution cell targeting which limit its utility. Accordingly, we developed a photoconversion method that ameliorates these limitations by adapting confocal laser scanning microscopy to the procedure. We confirmed that photoconversion times were dramatically reduced when using a confocal laser scanning microscope in the photoconversion process. We also demonstrated that the region of interest scanning capabilities of a confocal laser scanning microscope equipped with an acousto-optical tunable filter represented a unique tool to facilitate the targeting of the photoconversion process to individual cellular or subcellular elements within a fluorescent field. Moreover, region of interest scanning greatly reduced the area of the cell exposed to light energy, ameliorating the ultrastructural damage common to this process when widefield microscopes are employed. The potential of this new methodology extends beyond the neurosciences to any scientific modality which requires ultrastructural analysis of fluorescently labeled specimens, especially those where discrete photoconversion on a cellular or subcellular basis could be beneficial. [Copyright &y& Elsevier]

Abstract: Background: The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with d-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. Methods: Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. Results: Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. Conclusions: Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples. [Copyright &y& Elsevier]

Background: The ability to predict potential for relapse to substance use following treatment could be very useful in targeting aftercare strategies. Recently, a number of investigators have focused on using neural activity measured by fMRI to predict relapse propensity. The purpose of the present study was to use fMRI to investigate prospective associations between brain reactivity to cocaine and response inhibition cues and relapse to cocaine use. Methods: Thirty cocaine-dependent participants with clean cocaine urine drug screens (UDS) completed a baseline fMRI scan, including a cocaine-cue reactivity task and a go no-go response inhibition task. After participating in a brief clinical trial of c-cycloserine for the facilitation of cocaine-cue extinction, they returned for a one-week follow-up UDS. Associations between baseline activation to cocaine and inhibition cues and relapse to cocaine use were explored. Results: Positive cocaine UDS was significantly associated with cocaine-cue activation in the right putamen and insula, as well as bilateral occipital regions. Associations between positive cocaine UDS and activation to no-go cues were concentrated in the postcentral gyri, a region involved in response execution. Conclusions: Although preliminary, these results suggest that brain imaging may be a useful tool for predicting risk for relapse in cocaine-dependent individuals. Further, larger-scale naturalistic studies are needed to corroborate and extend these findings. [ABSTRACT FROM AUTHOR]

Abstract: We describe the use of the fast Fourier transform (FFT) in the measurement of anisotropy in electrospun scaffolds of gelatin as a function of the starting conditions. In electrospinning, fiber alignment and overall scaffold anisotropy can be manipulated by controlling the motion of the collecting mandrel with respect to the source electrospinning solution. By using FFT to assign relative alignment values to an electrospun matrix it is possible to systematically evaluate how different processing variables impact the structure and material properties of a scaffold. Gelatin was suspended at varying concentrations (80, 100, 130, 150mg/ml) and electrospun from 2,2,2 trifluoroethanol onto rotating mandrels (200–7000 RPM). At each starting concentration, fiber diameter remained constant over a wide range of mandrel RPM. Scaffold anisotropy developed as a function of fiber diameter and mandrel RPM. The induction of varying degrees of anisotropy imparted distinctive material properties to the electrospun scaffolds. The FFT is a rapid method for evaluating fiber alignment in tissue-engineering materials. [Copyright &y& Elsevier]

Anticonvulsant agents show promise in the treatment of the acute symptoms of alcohol withdrawal and may also treat some symptoms associated with the protracted abstinence syndrome. Impulsivity, hostility and irritability are common characteristics of alcohol-dependent individuals, and there is some evidence that anticonvulsant agents decrease these traits in individuals with a number of different psychiatric disorders. This pilot study is a 12-week, double-blind, placebo-controlled trial of an anticonvulsant agent, divalproex (DVPX), in alcohol-dependent individuals. Alcohol use (Timeline Follow Back), impulsivity (Barratt Impulsivity Scale), irritability and aggression (Buss-Durkee Hostility Index; and Anger, Irritability, Aggression Scale) were measured at baseline and throughout the 12-week treatment period. Drinking decreased significantly in both the placebo and the DVPX-treated groups. In the DVPX group, a significantly smaller percentage of individuals relapsed to heavy drinking, but there were no significant differences in other alcohol-related outcomes. There were significantly greater decreases in irritability in the DVPX-treated group and a trend towards greater decreases on measures of lability and verbal assault. There were no significant between-group differences on measures of impulsivity. While DVPX did not have a robust effect on alcohol-related outcomes, it did have modest impact on a measure of irritability. This is consistent with the findings of other investigators exploring the use of DVPX in schizophrenia, personality disorder and a number of other psychiatric disorders. [Copyright &y& Elsevier]

Graphical abstract Abstract H460 non-small cell lung, HCT116 colon and 4T1 breast tumor cell lines induced into senescence by exposure to either etoposide or doxorubicin were able to recover proliferative capacity both in mass culture and when enriched for the senescence-like phenotype by flow cytometry (based on β-galactosidase staining and cell size, and a senescence-associated reporter, BTG1-RFP). Recovery was further established using both real-time microscopy and High-Speed Live-Cell Interferometry (HSLCI) and was shown to be accompanied by the attenuation of the Senescence-Associated Secretory Phenotype (SASP). Cells enriched for the senescence-like phenotype were also capable of forming tumors when implanted in both immunodeficient and immunocompetent mice. As chemotherapy-induced senescence has been identified in patient tumors, our results suggest that certain senescence-like phenotypes may not reflect a terminal state of growth arrest, as cells that recover with self-renewal capacity may ultimately contribute to disease recurrence. [ABSTRACT FROM AUTHOR]

Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation. [ABSTRACT FROM AUTHOR]

A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5 h post-injury. Injured-hemisphere brain water content ( n =6 animals/group) and astrocytic area ( n =3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm 2 ) versus sham groups (78.3±0.1%; 9.5±0.9 µm 2 ), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8 µm 2 ). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation ( n =6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03±0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 ( n =3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema. [ABSTRACT FROM AUTHOR]

Background: The degree of KCNQ1/KCNE1 (IKs components) colocalization in cardiomyocytes is unclear. Results: In ventricular myocytes, KCNE1 is mainly on the cell surface, whereas KCNQ1 is mainly in the intracellular compartment. [Ca2+]i elevation or oxidative stress triggers KCNQ1 trafficking to the cell surface. Conclusion: Stress-induced KCNQ1 trafficking influences IKs amplitude. Significance: This is a novel mechanism for IKs function as a "ventricular repolarization reserve." [ABSTRACT FROM AUTHOR]

Abstract: Paranodal axo-glial junctional complexes anchor the myelin sheath to the axon and breakdown of these complexes presumably facilitates demyelination. Myelin deterioration is also prominent in the aging central nervous system (CNS); however, the stability of the paranodal complexes in the aged CNS has not been examined. Here, we show that transverse bands, prominent components of paranodal junctions, are significantly reduced in the aged CNS; however, the number of paired clusters of both myelin and axonal paranodal proteins is not altered. Ultrastructural analyses also reveal that thicker myelin sheaths display a “piling” of paranodal loops, the cytoplasm-containing sacs that demarcate the paranode. Loops involved in piling are observed throughout the paranode and are not limited to loops positioned in either the nodal- or juxtanodal-most regions. Here, we propose that as myelination continues, previously anchored loops lose their transverse bands and recede away from the axolemma. Newly juxtaposed loops then lose their transverse bands, move laterally to fill in the gap left by the receded loops and finally reform their transverse bands. This paranodal reorganization results in conservation of paranodal length, which may be important in maintaining ion channel spacing and axonal function. Furthermore, we propose that transverse band reformation is less efficient in the aged CNS, resulting in the significant reduction of these junctional components. Although demyelination was not observed, we propose that loss of transverse bands facilitates myelin degeneration and may predispose the aged CNS to a poorer prognosis following a secondary insult. [Copyright &y& Elsevier]