Green and Low Cost Mechanochemical Synthesis of 3,3’,5,5’-Azobenzene Tetracarboxylic Acid

Objective of this thesis is the development of a green, low cost, and scalable synthesis of 3,3’,5,5’-azobenzene tetracarboxylic acid, which is the organic building block for PCN-250. PCN-250(Fe3) is an important metal-organic framework that has excellent stability and gas adsorption properties and has been commercialized by Framergy, a start-up out of Texas A&M. All reported syntheses of 3,3’,5,5’-azobenzene tetracarboxylic acid are based on a one-step reductive coupling of commercially available 5-nitroisophtalic acid in alkaline aqueous or alcoholic solutions with either zinc or D-glucose as reducing agent. The first part of this thesis focuses on the optimization of the reported procedures in solution but the highest obtained yield of 45% remained well below the reported yields of 70%. In order to further reduce the amount of used solvent and potentially increase the yield, the reactions described above were subsequently conducted mechanochemically in a laboratory-scale ball milling unit. Optimization of the milling time, size and number of milling balls, amount and type of reducing agent, and solvent content improved the conversion to \u3e70% but the formation of hydrazo and N-oxide side-products could not be avoided. Unexpectedly, these mixtures of compounds were advantageous in the formation of the azo product under specific workup conditions. When the crude mixture was directly immersed in alkaline solution for a period of 48 hours under atmospheric conditions, the unreacted starting material and aniline, hydrazo and N-oxide side-products convert to 3,3’,5,5’-azobenzene tetracarboxylic acid, most likely by redox reactions between the side-products and with oxygen. These optimized conditions for the ball milling process and workup protocol furnish the desired 3,3’,5,5’-azobenzene tetracarboxylic acid in 90% yield and \u3e95% purity by using a green solvent assisted ball milling method and crystallization from aqueous solution as the sole purification step

Monitoring of alcohol consumption in primary care among adults with bipolar disorder:A cross-sectional and retrospective cohort study

BACKGROUND: Screening for alcohol use disorders is an important priority in the healthcare of people with bipolar disorder, incentivised in UK primary care since 2011, through the Quality and Outcomes Framework (QOF). The extent of alcohol monitoring in primary care, and impact of QOF, is unknown. The aim was to examine recording of alcohol consumption in primary care.  METHODS: Poisson regression of biennial alcohol recording rates between 2000 and 2013 among 14,051 adults with bipolar disorder and 90,023 adults without severe mental illness (SMI), from 484 general practices contributing to The Health Improvement Network UK-wide primary care database.  RESULTS: Alcohol recording rates among people with bipolar disorder increased from 88.6 records per 1000 person-years (95% confidence interval 81.2-96.6) in 2000/2002 to 837.4 records per 1000 person-years (817.4-858.0) in 2011/2013; a more than nine-fold increase, mainly occurring after the introduction of the QOF incentive in 2011. In 2000/2002 alcohol recording levels among people with bipolar disorder were not statistically significantly different from those without SMI (adjusted rate ratio 0.96, 0.88-1.05). By 2011/2013, people with bipolar disorder were over four times as likely to have an alcohol record: adjusted rate ratio 4.45 (4.15-4.77).  LIMITATIONS: The routinely collected data may be incomplete. Alcohol data entered as free-text was not captured.  CONCLUSIONS: The marked rise in alcohol consumption recording highlights what can be achieved. It is most likely attributable to QOF, suggesting that QOF, or similar schemes, can be powerful tools in promoting aspects of healthcare

Density-Dependence of Surface Transport in Tellurium-Enriched Nanograined Bulk Bi2Te3

Three-dimensional topological insulators (3D TI) exhibit conventional parabolic bulk bands and protected Dirac surface states. A thorough investigation of the different transport channels provided by the bulk and surface carriers using macroscopic samples may provide a path toward accessing superior surface transport properties. Bi2Te3 materials make promising 3D TI models; however, due to their complicated defect chemistry, these materials have a high number of charge carriers in the bulk that dominate the transport, even as nanograined structures. To partially control the bulk charge carrier density, herein the synthesis of Te-enriched Bi2Te3 nanoparticles is reported. The resulting nanoparticles are compacted into nanograined pellets of varying porosity to tailor the surface-to-volume ratio, thereby emphasizing the surface transport channels. The nanograined pellets are characterized by a combination of resistivity, Hall- and magneto-conductance measurements together with (THz) time-domain reflectivity measurements. Using the Hikami-Larkin-Nagaoka (HLN) model, a characteristic coherence length of ≈200 nm is reported that is considerably larger than the diameter of the nanograins. The different contributions from the bulk and surface carriers are disentangled by THz spectroscopy, thus emphasizing the dominant role of the surface carriers. The results strongly suggest that the surface transport carriers have overcome the hindrance imposed by nanoparticle boundaries

Parental experiences of supporting children with clinically significant post-traumatic distress: a qualitative study of families accessing psychological services

The aim of this study was to investigate the experiences of parents in providing support to their child following trauma exposure in cases where children are experiencing clinically significant levels of post-traumatic distress. Qualitative interviews were conducted with parents whose child was exposed to a trauma and referred for psychological treatment. Parents reported considerable anxiety in coping with their child’s post-traumatic distress. Avoidance of trauma-related discussions was encouraged due to concerns that non-avoidant approaches may worsen children’s post-trauma difficulties. Nonetheless, parents were often sensitive to their child’s distress and offered reassurance and other forms of support. Many barriers existed to accessing psychological treatment, and perceptions of inadequate guidance from therapists on supporting child adjustment contributed to parental distress. The results illustrate the strategies used by parents in supporting their child post-trauma and may assist mental health professionals in providing acceptable guidance to parents following child trauma

The role of parenting behaviors in childhood post-traumatic stress disorder: a meta-analytic review

Studies that have examined the association between parenting behaviors and childhood post-traumatic stress disorder (PTSD) have yielded mixed findings. To clarify the role of parenting in childhood PTSD we conducted a systematic review and meta-analysis of 14 studies that investigated the association between parenting and youth PTSD symptoms (total n = 4010). Negative parenting behaviors (e.g. overprotection, hostility) accounted for 5.3% of the variance in childhood PTSD symptoms. Positive parenting behaviors (e.g. warmth, support) account for 2.0% of variance. The negative and positive parenting and child PTSD symptom associations did not statistically differ in magnitude. Moderator analyses indicated that methodological factors and trauma variables may affect the association between parenting and child PTSD. Most studies relied upon questionnaire measures of general parenting style, and studies were predominantly cross-sectional with weaker evidence found in longitudinal studies. Given the small number of high quality studies available, only provisional recommendations about the role of parenting in childhood PTSD are made

Rab18 and a Rab18 GEF complex are required for normal ER structure

The ancestral Rab GTPase Rab18 and both subunits of the Rab3GAP complex are mutated in the human neurological and developmental disorder Warburg Micro syndrome. Here, we demonstrate that the Rab3GAP complex is a specific Rab18 guanine nucleotide exchange factor (GEF). The Rab3GAP complex localizes to the endoplasmic reticulum (ER) and is necessary for ER targeting of Rab18. It is also sufficient to promote membrane recruitment of Rab18. Disease-associated point mutations of conserved residues in either the Rab3GAP1 (T18P and E24V) or Rab3GAP2 (R426C) subunits result in loss of the Rab18 GEF and membrane-targeting activities. Supporting the view that Rab18 activity is important for ER structure, in the absence of either Rab3GAP subunit or Rab18 function, ER tubular networks marked by reticulon 4 were disrupted, and ER sheets defined by CLIMP-63 spread out into the cell periphery. Micro syndrome is therefore a disease characterized by direct loss of Rab18 function or loss of Rab18 activation at the ER by its GEF Rab3GAP

Development and Implementation of a Transdiagnostic, Stepped-Care Approach to Treating Emotional Disorders in Children via Telehealth

Stepped-care interventions may increase the accessibility of evidence-based treatments but remain relatively underexplored in the child mental health literature. Further, while the feasibility and efficacy of stepped-care interventions have been examined for specific diagnoses or classes or disorders, transdiagnostic stepped-care interventions have not yet been developed. We discuss the development and initial implementation of a transdiagnostic approach to emotional disorders using the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Children (UP-C; Ehrenreich-May et al., 2018). A case series is presented to illustrate the delivery of UP-C stepped care (UPC-SC) via telehealth, using a collaborative decision-making process to inform step-up/step-down decisions. Lessons learned are discussed to guide refinements of UPC-SC and inform a larger trial. •Reviewed the rationale for transdiagnostic, stepped-care approaches to treatment•Discussed development of a stepped-care Unified Protocol for Children (UPC-SC)•Illustrated the implementation of UPC-SC through presentation of three case examples•Discussed preliminary results, implementation challenges, and future direction

Abnormal Lysosomal Positioning and Small Extracellular Vesicle Secretion in Arterial Stiffening and Calcification of Mice Lacking Mucolipin 1 Gene

Recent studies have shown that arterial medial calcification is mediated by abnormal release of exosomes/small extracellular vesicles from vascular smooth muscle cells (VSMCs) and that small extracellular vesicle (sEV) secretion from cells is associated with lysosome activity. The present study was designed to investigate whether lysosomal expression of mucolipin-1, a product of the mouse Mcoln1 gene, contributes to lysosomal positioning and sEV secretion, thereby leading to arterial medial calcification (AMC) and stiffening. In Mcoln1−/− mice, we found that a high dose of vitamin D (Vit D; 500,000 IU/kg/day) resulted in increased AMC compared to their wild-type littermates, which was accompanied by significant downregulation of SM22-α and upregulation of RUNX2 and osteopontin in the arterial media, indicating a phenotypic switch to osteogenic. It was also shown that significantly decreased co-localization of lysosome marker (Lamp-1) with lysosome coupling marker (Rab 7 and ALG-2) in the aortic wall of Mcoln1−/− mice as compared to their wild-type littermates. Besides, Mcoln1−/− mice showed significant increase in the expression of exosome/ sEV markers, CD63, and annexin-II (AnX2) in the arterial medial wall, accompanied by significantly reduced co-localization of lysosome marker (Lamp-1) with multivesicular body (MVB) marker (VPS16), suggesting a reduction of the lysosome-MVB interactions. In the plasma of Mcoln1−/− mice, the number of sEVs significantly increased as compared to the wild-type littermates. Functionally, pulse wave velocity (PWV), an arterial stiffening indicator, was found significantly increased in Mcoln1−/− mice, and Vit D treatment further enhanced such stiffening. All these data indicate that the Mcoln1 gene deletion in mice leads to abnormal lysosome positioning and increased sEV secretion, which may contribute to the arterial stiffness during the development of AMC

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep

Abstract People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short‐ and long‐term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2) and 40% carbon dioxide (CO2) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V.E.), tidal volume (V.T.), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short‐term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long‐term facilitation following AIH in either group