A Cholecystokinin B Receptor-Specific Aptamer Does Not Activate Receptor Signaling

Targeted nanoparticles which deliver effective doses of chemotherapeutic drugs directly to pancreatic tumors could improve treatment efficacy without the toxicities associated with systemic drug administration. One protein on tumor cells that can be targeted by nanoparticles is a G-protein coupled cell surface receptor, the cholecystokinin B receptor (CCKBR). Previously, we had shown that attaching the CCKBR ligand gastrin to the surface of nanoparticles can enhance their up-take by tumors. The drawback of using gastrin is that it can also activate the receptor, causing tumor cell growth. This study shows that a DNA aptamer that binds to the CCKBR and enhances nanoparticle up-take by tumors does not activate this receptor. PANC-1 cells, a cultured human pancreatic cancer cell line, were treated for 24 h with CCKBR aptamer 1153. Cell lysates were run on Bis-Tris gels, transferred to membranes, blocked in 5% BSA and incubated overnight with primary antibodies, including antibodies directly against phosphorylated-Akt (Ser473), total Akt, and beta-actin, a protein loading control. Although the CCKBR aptamer 1153 is internalized by pancreatic cancer cells in a receptor-mediated fashion, it does not stimulate cell proliferation. Because of this, we anticipate that it will not activate CCKBR signaling. If aptamer 1153 does not activate downstream receptor signaling, our future work will test whether the aptamer could be used to specifically direct drug-containing nanoparticles to tumors, making chemotherapy treatments for pancreatic cancer patients more effective with fewer off-target effects and toxicity

Epidemiology and outcomes of patients admitted to hospital with a burn injury in Scotland

Burn injuries are a significant cause of both morbidity and mortality throughout the world. The prevalence of burn injuries and the demographics of those affected vary across the globe, especially between developed and developing countries. However, the risk of burn injury remains consistently higher in individuals from a background of socioeconomic deprivation. With advances in medical care in recent decades, the chances of survival following major burn injury have increased significantly. With individuals now surviving much more substantial injuries, there is an increasing appreciation of the long-lasting pathophysiological and psychological consequences that can occur following such an injury. Common sequelae include chronic pain, pruritus, depression or anxiety, post-traumatic stress disorder and an increase in the risk of cardiovascular disease, cancer and various infections. However, the exact aetiology and risk factors associated with being more likely to suffer such detrimental consequences are incompletely understood. Additionally, the deterioration in health conditions after injury may be explained by both the risk factors common to sustaining a burn injury and the physiological impact of the burn injury itself. The studies detailed in this thesis aim to explore the epidemiology of, and mortality from, burn injuries in Scotland; investigate the effectiveness of using neuropathic agents to manage the symptoms of burn-related pruritus; describe the prevalence and predictors of pruritus after burn injury; explore the use of a protocolised treatment regimen for pruritic symptoms; and use national administrative databases to explore the long-term consequences following survival of a burn injury including the use of drugs to manage pain and mental health conditions and the likelihood of death in the following years. This thesis includes a systematic review and meta-analysis to explore the effectiveness of drugs commonly used to treat neuropathic pain in the management of burn-related pruritus. Although there is a paucity of evidence that exists, gabapentinoids appear to be effective at reducing pruritus severity scores by 2.96 (95% CI 1.20, 4.73) on a zero to ten scale when compared to antihistamine or placebo. Using prospective data collected as part of a quality improvement project in a tertiary referral burn ward, this study explored the factors associated with pruritus severity in patients with a burn injury. Multivariable linear regression analysis demonstrated that increasing size of burn, as measured by surface area, flame burns, a history of smoking and history of alcohol use disorder were all associated with an increase in pruritus severity. Although low serum vitamin D levels were prevalent among this cohort of patients, with 83% of patients having serum vitamin D levels <50nmol/L, the presence or severity of this apparent deficiency did not correlate with the severity of pruritic symptoms. The use of a protocolised approach to pruritus management with various antihistamine drugs and gabapentin in the presence of neuropathic features was consistently effective at reducing pruritus severity scores. The remaining chapters of this thesis used large linked national datasets to describe the epidemiology and outcomes for patients that suffered a burn injury requiring hospital admission in Scotland. The results show that males are more likely to sustain a burn injury than females, accounting for 63% of admissions. Children were more likely to sustain a scald injury (63% of injuries) with flame burns being relatively rare in children (6%) but much more prevalent in adults (29%). Patients from areas of socioeconomic deprivation made up a greater proportion of both the adult and paediatric cohort. Children from an ethnic minority background were found to be at a higher proportion than would be expected for the general population in Scotland, a pattern not seen in the adult cohort. Of the adult population, 2.73% died within 30 days of their burn injury. Multivariable cox proportional hazards regression analysis demonstrated that, in keeping with multiple previous studies, increasing age (HR 1.08), increasing size of burn (HR 1.12) and the presence of smoke inhalation injury (HR 14.54) were all associated with an increased mortality. Additionally, a pre-existing history of depression or neurological disorder were also independently associated with mortality (HR 13.65 and 6.48 respectively). Pre-injury use of drugs such as opioids was significantly higher in this burn-injured cohort compared to the general population in Scotland (25.8% vs 18% respectively). Following burn injury, the use of opioids increased from 25.8% to 38.5% of patients. This increase was evident in prescriptions for both strong and weak opioids. An increase was also seen in the number of patients receiving recurrent (three or more) prescriptions. Factors associated with an increase in opioid use after injury included female gender, previous opioid use, increasing age, socioeconomic deprivation and increasing comorbidity burden. Compared with the general population of Scotland, the pre-injury use of various drugs for mental health conditions were all higher in this burn-injured cohort including antidepressants (15.2% vs 26.6% respectively), antipsychotics (1.5% vs 6%) and anxiolytics (6.8% vs 16.3%). This study did not demonstrate a higher proportion of patients using these drugs post-injury, however, following a burn, there was a higher burden of drug utilisation, with more patients receiving multiple drugs for mental health conditions, and a higher frequency of prescriptions. Factors associated with this increase in the use of these drugs were found to be similar to that seen with opioids, namely female gender, history of alcohol excess, depression and previous opioid use. Gabapentinoid use was also higher in the burn cohort pre-injury (6%) compared to the general population (4.1%), with their use increasing further after burn injury to 9.5%. Lastly, for patients that survived to 30 days following burn injury, one in twenty died in the follow-up period to a maximum of four years. Multivariable Cox proportional hazards analysis demonstrated that increasing age and increasing comorbidity burden were associated with increased hazards ratios (1.06 and 3.51 respectively). As were the presence of airway burn or smoke inhalation (HR 2.8) and the pre-injury use of anxiolytic drugs (2.13). The work presented in this thesis systematically reviews the existing evidence for neuropathic agents in managing burn-related pruritus; assesses a protocolised approach to managing such pruritus; outlines the epidemiology of burns in Scotland; describes the mortality from burns and the associated risk factors; describes the burden of pain and mental health conditions using drug prescription data as a surrogate measure of these conditions; and describes the factors associated with death in the years after surviving a burn injury. This information may be used by clinicians to inform decisions regarding management of burn-related pruritus. This work also provides a deeper understanding of the complex interplay between mental health conditions, drug use, comorbidity burden and socioeconomic deprivation that often affect those that suffer a burn injury. It also highlights some of the important outcomes following survival of a burn injury with an increased risk of chronic opioid use, especially among those with certain characteristics. Future research should focus on exploring the influence of the pathological effects of the burn injury compared to the high prevalence of pre-existing conditions that can similarly contribute to morbidity and mortality

Can I Count on You? Social support, Depression and Suicide Risk

Objectives: Interpersonal factors play an important role in the etiology and treatment of depression. Social support derives from compassionate words and helpful actions provided by family, friends or a significant other. The present study was designed to examine various sources of social support as they relate to the severity of depressive symptoms, hopelessness and suicide risk in adult psychiatric outpatients. Method: Participants were recruited through mental health clinics at a veteran\u27s affairs medical centre. A total of 96 depressed patients were assessed using a diagnostic interview and self-report measures of depression severity, hopelessness and social support. Among these depressed adults, 45.8% had attempted suicide at least once. Social support variables were compared between suicide attempters and non-attempters to better understand the relationship between social support and suicidal behaviour. Results: Depression severity and hopelessness were both significantly associated with lower levels of social support in multiple areas. Individuals with a history of suicide attempt reported lower levels of available support as compared to those who have never attempted suicide. Conclusion: Deficient social relationships increase the risk of suicide in depressed patients, exceeding the impact of depression alone on suicide risk. The lack of social support may play a vital role in feelings of hopelessness and isolation that contribute to a suicidal crisis. Psychosocial treatment should be considered to reduce the risk of suicide and severity of depression by strengthening social support and bolstering interpersonal relationships

Monitoring Macroalgae in the Great Bay Estuary for 2016

In 2016, five of the eight locations with fixed intertidal transects were sampled as part of a long-term effort to monitor changes in the abundance of macroalgae in the Great Bay Estuary. Since 2013, the abundance and taxa of intertidal macroalgae have been assessed at fixed locations to serve as an indicator of ecological changes in the Estuary. Changes in the algae may reflect changes associated with excess nutrient loading, termed eutrophication, and may be especially informative of algal impacts to eelgrass meadows in the Estuary. Macroalgae collections over the past four years have resulted in the accumulation of two years of data for six locations, three years of data for a seventh location and four years of data for an eighth location. Based upon this short-term data set we found significant cover and biomass of nuisance algae, some of these are recognized as introduced, invasive species. Monitoring results from 2016 show high levels of cover of nuisance algae, either green or red (Ulva and Gracilaria, respectively) at all sites sampled, but especially at the lowest elevations, nearest to the subtidal habitats. Visual examination of our intertidal transect data along with anecdotal observations suggest that algal populations are changing, but long-term collections will be needed to determine whether significant differences in intertidal macroalgal populations are occurring over time

Discovery of a Very Young Field L Dwarf, 2MASS J01415823-4633574

While following up L dwarf candidates selected photometrically from the Two Micron All Sky Survey, we uncovered an unusual object designated 2MASS J01415823-4633574. Its optical spectrum exhibits very strong bands of vanadium oxide but abnormally weak absorptions by titanium oxide, potassium, and sodium. Morphologically such spectroscopic characteristics fall intermediate between old, field early-L dwarfs (log(g)~5) and very late M giants (log(g)~0), leading us to favor low gravity as the explanation for the unique spectral signatures of this L dwarf. Such a low gravity can be explained only if this L dwarf is much lower in mass than a typical old field L dwarf of similar temperature and is still contracting to its final radius. These conditions imply a very young age. Further evidence of youth is found in the near-infrared spectrum, including a triangular-shaped H-band continuum reminiscent of young brown dwarf candidates discovered in the Orion Nebula Cluster. Using the above information along with comparisons to brown dwarf atmospheric and interior models, our current best estimate is that this L dwarf has an age of 1-50 Myr and a mass of 6-25 M_Jupiter. The location of 2MASS 0141-4633 on the sky coupled with a distance estimate of ~35 pc and the above age estimate suggests that this object may be a brown dwarf member of either the 30-Myr-old Tucana/Horologium Association or the ~12-Myr-old beta Pic Moving Group.Comment: Accepted for publication in the 10 March 2006 issue (volume 639) of the Astrophysical Journa

CLIMB: Curriculum Learning for Infant-inspired Model Building

We describe our team's contribution to the STRICT-SMALL track of the BabyLM Challenge. The challenge requires training a language model from scratch using only a relatively small training dataset of ten million words. We experiment with three variants of cognitively-motivated curriculum learning and analyze their effect on the performance of the model on linguistic evaluation tasks. In the vocabulary curriculum, we analyze methods for constraining the vocabulary in the early stages of training to simulate cognitively more plausible learning curves. In the data curriculum experiments, we vary the order of the training instances based on i) infant-inspired expectations and ii) the learning behavior of the model. In the objective curriculum, we explore different variations of combining the conventional masked language modeling task with a more coarse-grained word class prediction task to reinforce linguistic generalization capabilities. Our results did not yield consistent improvements over our own non-curriculum learning baseline across a range of linguistic benchmarks; however, we do find marginal gains on select tasks. Our analysis highlights key takeaways for specific combinations of tasks and settings which benefit from our proposed curricula. We moreover determine that careful selection of model architecture, and training hyper-parameters yield substantial improvements over the default baselines provided by the BabyLM challenge

CLIMB: Curriculum Learning for Infant-inspired Model Building

We describe our team's contribution to the STRICT-SMALL track of the BabyLM Challenge. The challenge requires training a language model from scratch using only a relatively small training dataset of ten million words. We experiment with three variants of cognitively-motivated curriculum learning and analyze their effect on the performance of the model on linguistic evaluation tasks. In the vocabulary curriculum, we analyze methods for constraining the vocabulary in the early stages of training to simulate cognitively more plausible learning curves. In the data curriculum experiments, we vary the order of the training instances based on i) infant-inspired expectations and ii) the learning behavior of the model. In the objective curriculum, we explore different variations of combining the conventional masked language modeling task with a more coarse-grained word class prediction task to reinforce linguistic generalization capabilities. Our results did not yield consistent improvements over our own non-curriculum learning baseline across a range of linguistic benchmarks; however, we do find marginal gains on select tasks. Our analysis highlights key takeaways for specific combinations of tasks and settings which benefit from our proposed curricula. We moreover determine that careful selection of model architecture, and training hyper-parameters yield substantial improvements over the default baselines provided by the BabyLM challenge

Open Data Meets Digital Curation: An Investigation of Practices and Needs

In the United States, research funded by the government produces a significant portion of data. US law mandates that these data should be freely available to the public through ‘public access’, which is defined as fully discoverable and usable by the public. The U.S. government executive branch supported the public access requirements by issuing an Executive Directive titled ‘Increasing Access to the Results of Federally Funded Scientific Research’ that required federal agencies with annual research and development expenditures of more than $100 million to create public access plans by 22 August 2013. The directive applied to 19 federal agencies, some with multiple divisions. Additional direction for this initiative was provided by the Executive Order ‘Making Open and Machine Readable the New Default for Government Information’ which was accompanied by a memorandum with specific guidelines for information management and instructions to find ways to reduce compliance costs through interagency cooperation. In late 2013, the Institute of Museum and Library Services (IMLS) funded the Council on Library and Information Resources (CLIR) to conduct a project to help IMLS and its constituents understand the implications of the US federal public access mandate and how needs and gaps in digital curation can best be addressed. Our project has three research components: (1) a structured content analysis of federal agency plans supporting public access to data and publications, identifying both commonalities and differences among plans; (2) case studies (interviews and analysis of project deliverables) of seven projects previously funded by IMLS to identify lessons about skills, capabilities and institutional arrangements that can facilitate data curation activities; and (3) a gap analysis of continuing education and readiness assessment of the workforce. Research and cultural institutions urgently need to rethink the professional identities of those responsible for collecting, organizing, and preserving data for future use. This paper reports on a project to help inform further investments.

Denial at the top table: status attributions and implications for marketing

Senior marketing management is seldom represented on the Board of Directors nowadays, reflecting a deteriorating status of the marketing profession. We examine some of the key reasons for marketing’s demise, and discuss how the status of marketing may be restored by demonstrating the value of marketing to the business community. We attribute marketing’s demise to several related key factors: narrow typecasting, marginalisation and limited involvement in product development, questionable marketing curricula, insensitivity toward environmental change, questionable professional standards and roles, and marketing’s apparent lack of accountability to CEOs. Each of these leads to failure to communicate, create, or deliver value within marketing. We argue that a continued inability to deal with marketing’s crisis of representation will further erode the status of the discipline both academically and professionally

Magneto-optical trapping in a near-suface borehole

Borehole gravity sensing can be used in a number of applications to measure features around a well, including rock-type change mapping and determination of reservoir porosity. Quantum technology gravity sensors, based on atom interferometry, have the ability to offer increased survey speeds and reduced need for calibration. While surface sensors have been demonstrated in real world environments, significant improvements in robustness and reductions to radial size, weight, and power consumption are required for such devices to be deployed in boreholes. To realise the first step towards the deployment of cold atom-based sensors down boreholes, we demonstrate a borehole-deployable magneto-optical trap, the core package of many cold atom-based systems. The enclosure containing the magneto-optical trap itself had an outer radius of (60 ± 0.1) mm at its widest point and a length of (890 ± 5) mm. This system was used to generate atom clouds at 1 m intervals in a 14 cm wide, 50 m deep borehole, to simulate how in-borehole gravity surveys are performed. During the survey, the system generated, on average, clouds of (3.0 ± 0.1) × 105 87Rb atoms with the standard deviation in atom number across the survey observed to be as low as 8.9 × 104