Neutral and Cationic Rare Earth Metal Alkyl and Benzyl Compounds with the 1,4,6-Trimethyl-6-pyrrolidin-1-yl-1,4-diazepane Ligand and Their Performance in the Catalytic Hydroamination/Cyclization of Aminoalkenes

A new neutral tridentate 1,4,6-trimethyl-6-pyrrolidin-1-yl-1,4-diazepane (L) was prepared. Reacting L with trialkyls M(CH2SiMe3)3(THF)2 (M = Sc, Y) and tribenzyls M(CH2Ph)3(THF)3 (M = Sc, La) yielded trialkyl complexes (L)M(CH2SiMe3)3 (M = Sc, 1; M = Y, 2) and tribenzyl complexes (L)M(CH2Ph)3 (M = Sc, 3; M = La, 4). Complexes 1 and 2 can be converted to their corresponding ionic compounds [(L)M(CH2SiMe3)2(THF)][B(C6H5)4] (M = Sc, Y) by reaction with [PhNMe2H][B(C6H5)4] in THF. Complexes 3 and 4 can be converted to cationic species [(L)M(CH2Ph)2]+ by reaction with [PhNMe2H][B(C6F5)4] in C6D5Br in the absence of THF. The neutral complexes 1-4 and their cationic derivatives were studied as catalysts for the hydroamination/cyclization of 2,2-diphenylpent-4-en-1-amine and N-methylpent-4-en-1-amine reference substrates and compared with ligand-free Sc, Y, and La neutral and cationic catalysts. The most effective catalysts in the series were the cationic L-yttrium catalyst (for 2,2-diphenylpent-4-en-1-amine) and the cationic lanthanum systems (for N-methylpent-4-en-1-amine). For the La catalysts, evidence was obtained for release of L from the metal during catalysis.

Molecular Mechanisms of Paraptosis Induction: Implications for a Non-Genetically Modified Tumor Vaccine

Paraptosis is the programmed cell death pathway that leads to cellular necrosis. Previously, rodent and human monocytes/macrophages killed glioma cells bearing the membrane macrophage colony stimulating factor (mM-CSF) through paraptosis, but the molecular mechanism of this killing process was never identified. We have demonstrated that paraptosis of rat T9 glioma cells can be initiated through a large potassium channel (BK)-dependent process initiated by reactive oxygen species. Macrophage mediated cytotoxicity upon the mM-CSF expressing T9-C2 cells was not prevented by the addition of the caspase inhibitor, zVAD-fmk. By a combination of fluorescent confocal and electron microscopy, flow cytometry, electrophysiology, pharmacology, and genetic knock-down approaches, we demonstrated that these ion channels control cellular swelling and vacuolization of rat T9 glioma cells. Cell lysis is preceded by a depletion of intracellular ATP. Six-hour exposure to BK channel activation caused T9 cells to over express heat shock proteins (Hsp 60, 70, 90 and gp96). This same treatment forced HMGB1 translocation from the nuclear region to the periphery. These last molecules are “danger signals” that can stimulate immune responses. Similar inductions of mitochondrial swelling and increased Hsp70 and 90 expressions by BK channel activation were observed with the non-immunogenic F98 glioma cells. Rats injected with T9 cells which were killed by prolonged BK channel activation developed immunity against the T9 cells, while the injection of x-irradiated apoptotic T9 cells failed to produce the vaccinating effect. These results are the first to show that glioma cellular death induced by prolonged BK channel activation improves tumor immunogenicity; this treatment reproduces the vaccinating effects of mM-CSF transduced cells. Elucidation of strategies as described in this study may prove quite valuable in the development of clinical immunotherapy against cancer

A randomised controlled trial of cognitive behavioural treatment for obsessive compulsive disorder in children and adolescents

Cognitive behaviour therapy (CBT) for young people with obsessive compulsive disorder (OCD) has become the treatment of first choice. However, the literature is largely based on studies emphasising exposure and response prevention. In this study, we report on a randomised controlled trial of CBT for young people carried out in typical outpatient clinic conditions which focused on cognitions. A randomised controlled trial compares 10 sessions of manualised cognitive behavioural treatment with a 12-week waiting list for adolescents and children with OCD. Assessors were blind to treatment allocation. 21 consecutive patients with OCD aged between 9 and 18 years were recruited. The group who received treatment improved more than a comparison group who waited for 3 months. The second group was treated subsequently using the same protocol and made similar gains. In conclusion, CBT can be delivered effectively to young people with OCD in typical outpatient settings

HUMAN MACHINE COOPERATIVE TELEROBOTICS

The remediation and deactivation and decommissioning (D&D) of nuclear waste storage tanks using telerobotics is one of the most challenging tasks faced in environmental cleanup. Since a number of tanks have reached the end of their design life and some of them have leaks, the unstructured, uncertain and radioactive environment makes the work inefficient and expensive. However, the execution time of teleoperation consumes ten to hundred times that of direct contact with an associated loss in quality. Thus, a considerable effort has been expended to improve the quality and efficiency of telerobotics by incorporating into teleoperation and robotic control functions such as planning, trajectory generation, vision, and 3-D modeling. One example is the Robot Task Space Analyzer (RTSA), which has been developed at the Robotics and Electromechanical Systems Laboratory (REMSL) at the University of Tennessee in support of the D&D robotic work at the Oak Ridge National Laboratory and the National Energy Technology Laboratory. This system builds 3-D models of the area of interest in task space through automatic image processing and/or human interactive manual modeling. The RTSA generates a task plan file, which describes the execution of a task including manipulator and tooling motions. The high level controller of the manipulator interprets the task plan file and executes the task automatically. Thus, if the environment is not highly unstructured, a tooling task, which interacts with environment, will be executed in the autonomous mode. Therefore, the RTSA not only increases the system efficiency, but also improves the system reliability because the operator will act as backstop for safe operation after the 3-D models and task plan files are generated. However, unstructured conditions of environment and tasks necessitate that the telerobot operates in the teleoperation mode for successful execution of task. The inefficiency in the teleoperation mode led to the research described as Human Machine Cooperative Telerobotics (HMCTR). The HMCTR combines the telerobot with robotic control techniques to improve the system efficiency and reliability in teleoperation mode. In this topical report, the control strategy, configuration and experimental results of Human Machines Cooperative Telerobotics (HMCTR), which modifies and limits the commands of human operator to follow the predefined constraints in the teleoperation mode, is described. The current implementation is a laboratory-scale system that will be incorporated into an engineering-scale system at the Oak Ridge National Laboratory in the future

Paediatric obsessive-compulsive disorder and depressive symptoms: clinical correlates and CBT treatment outcomes.

Depression frequently co-occurs with paediatric obsessive-compulsive disorder (OCD), yet the clinical correlates and impact of depression on CBT outcomes remain unclear. The prevalence and clinical correlates of depression were examined in a paediatric specialist OCD-clinic sample (N = 295; Mean = 15 [7 - 18] years, 42 % female), using both dimensional (Beck Depression Inventory-youth; n = 261) and diagnostic (Development and Wellbeing Assessment; n = 127) measures of depression. The impact of depressive symptoms and suspected disorders on post-treatment OCD severity was examined in a sub-sample who received CBT, with or without SSRI medication (N = 100). Fifty-one per-cent of patients reported moderately or extremely elevated depressive symptoms and 26 % (95 % CI: 18 - 34) met criteria for a suspected depressive disorder. Depressive symptoms and depressive disorders were associated with worse OCD symptom severity and global functioning prior to CBT. Individuals with depression were more likely to be female, have had a psychiatric inpatient admission and less likely to be attending school (ps < 0.01). OCD and depressive symptom severity significantly decreased after CBT. Depressive symptoms and depressive disorders predicted worse post-treatment OCD severity (βs = 0.19 and 0.26, ps < 0.05) but became non-significant when controlling for pre-treatment OCD severity (βs = 0.05 and 0.13, ns). Depression is common in paediatric OCD and is associated with more severe OCD and poorer functioning. However, depression severity decreases over the course of CBT for OCD and is not independently associated with worse outcomes, supporting the recommendation for treatment as usual in the presence of depressive symptoms

A shared frequency set between the historical mid-latitude aurora records and the global surface temperature

Herein we show that the historical records of mid-latitude auroras from 1700 to 1966 present oscillations with periods of about 9, 10-11, 20-21, 30 and 60 years. The same frequencies are found in proxy and instrumental global surface temperature records since 1650 and 1850, respectively and in several planetary and solar records. Thus, the aurora records reveal a physical link between climate change and astronomical oscillations. Likely, there exists a modulation of the cosmic ray flux reaching the Earth and/or of the electric properties of the ionosphere. The latter, in turn, have the potentiality of modulating the global cloud cover that ultimately drives the climate oscillations through albedo oscillations. In particular, a quasi 60-year large cycle is quite evident since 1650 in all climate and astronomical records herein studied, which also include an historical record of meteorite fall in China from 619 to 1943. These findings support the thesis that climate oscillations have an astronomical origin. We show that a harmonic constituent model based on the major astronomical frequencies revealed in the aurora records is able to forecast with a reasonable accuracy the decadal and multidecadal temperature oscillations from 1950 to 2010 using the temperature data before 1950, and vice versa. The existence of a natural 60-year modulation of the global surface temperature induced by astronomical mechanisms, by alone, would imply that at least 60-70% of the warming observed since 1970 has been naturally induced. Moreover, the climate may stay approximately stable during the next decades because the 60-year cycle has entered in its cooling phase.Comment: 18 pages, 11 figure

Perception and practice of Kangaroo Mother Care after discharge from hospital in Kumasi, Ghana: A longitudinal study

BACKGROUND: The practice of Kangaroo Mother Care (KMC) is life saving in babies weighing less than 2000 g. Little is known about mothers' continued unsupervised practice after discharge from hospitals. This study aimed to evaluate its in-hospital and continued practice in the community among mothers of low birth weight (LBW) infants discharged from two hospitals in Kumasi, Ghana. METHODS: A longitudinal study of 202 mothers and their inpatient LBW neonates was conducted from November 2009 to May 2010. Mothers were interviewed at recruitment to ascertain their knowledge of KMC, and then oriented on its practice. After discharge, the mothers reported at weekly intervals for four follow up visits where data about their perceptions, attitudes and practices of KMC were recorded. A repeated measure logistic regression analysis was done to assess variability in the binary responses at the various reviews visits. RESULTS: At recruitment 23 (11.4%, 95%CI: 7.4 to 16.6%) mothers knew about KMC. At discharge 95.5% were willing to continue KMC at home with 93.1% willing to practice at night. 95.5% thought KMC was beneficial to them and 96.0% beneficial to their babies. 98.0% would recommend KMC to other mothers with 71.8% willing to practice KMC outdoors.At first follow up visit 99.5% (181) were still practicing either intermittent or continuous KMC. This proportion did not change significantly over the four weeks (OR: 1.4, 95%CI: 0.6 to 3.3, p-value: 0.333). Over the four weeks, increasingly more mothers practiced KMC at night (OR: 1.7, 95%CI: 1.2 to 2.6, p = 0.005), outside their homes (OR: 2.4, 95%CI: 1.7 to 3.3, p < 0.001) and received spousal help (OR: 1.6, 95%CI: 1.1 to 2.4, p = 0.007). Household chores and potentially negative community perceptions of KMC did not affect its practice with odds of 0.8 (95%CI: 0.5 to 1.2, p = 0.282) and 1.0 (95%CI: 0.6 to 1.7, p = 0.934) respectively. During the follow-up period the neonates gained 23.7 sg (95%CI: 22.6 g to 24.7 g) per day. CONCLUSION: Maternal knowledge of KMC was low at outset. Once initiated mothers continued practicing KMC in hospital and at home with their infants gaining optimal weight. Continued KMC practice was not affected by perceived community attitudes

Structural basis of PROTAC cooperative recognition for selective protein degradation

Inducing macromolecular interactions with small molecules to activate cellular signaling is a challenging goal. PROTACs (proteolysis-targeting chimeras) are bifunctional molecules that recruit a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. Structural elucidation of the key ternary ligase-PROTAC-target species and its impact on target degradation selectivity remain elusive. We solved the crystal structure of Brd4 degrader MZ1 in complex with human VHL and the Brd4 bromodomain (Brd4BD2). The ligand folds into itself to allow formation of specific intermolecular interactions in the ternary complex. Isothermal titration calorimetry studies, supported by surface mutagenesis and proximity assays, are consistent with pronounced cooperative formation of ternary complexes with Brd4BD2. Structure-based-designed compound AT1 exhibits highly selective depletion of Brd4 in cells. Our results elucidate how PROTAC-induced de novo contacts dictate preferential recruitment of a target protein into a stable and cooperative complex with an E3 ligase for selective degradation

High-Resolution Melting Analysis for the Rapid Detection of Fluoroquinolone and Streptomycin Resistance in Mycobacterium tuberculosis

published_or_final_versio