Controlled Clinical Trial of a Self-Help for Anxiety Intervention for Patients Waiting for Psychological Therapy

This study was a controlled clinical trial in which patients were offered a brief low cost, low intensity self-help intervention while waiting for psychological therapy. A CBT based self-help pack was given to patients with significant anxiety problems and no attempt was made to exclude patients on the basis of severity or co-morbidity. The treatment group received the intervention immediately following assessment and the control group after a delay of 8 weeks so comparisons between the two groups were made over 8 weeks. Although there was some support for the effectiveness of the self help intervention, with a significant time x group interaction for CORE-OM scores, this was not significant with the intention to treat analysis, nor for HADS anxiety and depression scores and the effect size was low. A follow up evaluation suggested some patients attributed significant goal attainment to the intervention. The findings suggest the routine use of self-help interventions in psychological therapies services should be considered although further more adequately powered research is required to identify the type of patients and problems that most benefit, possible adverse effects and the effect on subsequent uptake of and engagement in therapy

Improving estimates of alcohol-related crime with geographic and data science methods

Alcohol is considered by the UK Government as one of the six key drivers of crime. Many studies have recognised alcohol-related crime exists in some areas more than others, implying that certain area-level characteristics, known as geographic determinants, may be driving alcohol consumption and alcohol-related crime. The geographic determinants of alcohol-related crime include the availability of alcohol in an area and area-level deprivation amongst others. Previous studies have focused on finding the main geographic determinant of alcohol-related crime to find the most effective approaches needed for crime prevention. These studies have not always considered the role of local context and how different areas have different crime rates and characteristics, meaning that geographic determinants may have varying impacts depending on the local context. As space is expected to play a significant role in understanding these area-level drivers of alcohol-related crime, space needs to be integrated into any analysis. Moreover, in order to understand alcohol-related crime and its geographic determinants, we need access to data on alcohol-related crime. Although police data is the best source of detailed spatial data on alcohol-related crime, the measure of this crime type is inaccurate as they are known for being under-counted on the system. The overarching aim of this thesis is to determine if geographic and data science methods can improve estimates and our understanding of alcohol-related crime. The novelty of this work involved implementing these novel and maturing Geographic Data Science (GDS) and Data Science methods to consider these contextual issues and improve data on alcohol-related crime. The first empirical analysis implemented a GDS method called Geographically Weighted Regression to capture the spatially varying associations between geographic determinants and violent crime as a proxy measure of alcohol-related crime. GDS methods revealed how associations for each type of alcohol outlet varied in strength and direction spatially, demonstrating the importance of local context, which hasn’t always been considered in previous studies. High sales alcohol outlets had not previously been considered in the evidence base, and I found these outlets to increase alcohol-related crime in city centre night-time economies and less so elsewhere. In the second empirical analysis, I aimed to improve the identification of alcohol-related crimes in official police records of crime occurrences using text-based algorithms. A Support Vector Machine (SVM) algorithm classified police notes describing crimes investigated as whether they were alcohol-related or not. The SVM estimated a higher proportion of alcohol-related crime (31%) than current police estimates (13%). This helps to build on the wider literature as there are few sources of what figures one would expect to find in the wider evidence base. A final empirical analysis used spatial clustering methods to determine the value that SVM can bring to the police and the wider evidence base’s understanding of alcohol-related crime. The chapter used GDS methods which revealed how the SVM was detecting more harmful alcohol-related crimes types than the police in the most deprived areas. The thesis has demonstrated how GDS and Data Science methods can improve estimates and our understanding of alcohol-related crime, which has implications for the evidence base and police forces. GDS methods have highlighted how alcohol-related crime prevention efforts could be most effective if the local drivers of crime were targeted, rather than a catch all approach of targeting one specific issue. Data Science methods have also shown their potential for detecting alcohol-related crime in large datasets, saving police officers the manual task of recording this crime type, so police time can be spent on higher priority tasks. In combination, GDS and Data Science methods uncovered the spatial distribution of alcohol-related crime and its inequalities, some of which were not fully understood in the current police system. Doing so can assist the police in understanding and targeting this crime type as well as providing insight to the field’s overall understanding and prevalence of alcohol-related crime

A proteomic and phosphoproteomic analysis of Oryza sativa plasma membrane and vacuolar membrane

Proteomic and phosphoproteomic analyses of rice shoot and root tonoplast-enriched and plasma membrane-enriched membrane fractions were carried out to look at tissue-specific expression, and to identify putative regulatory sites of membrane transport proteins. Around 90 unique membrane proteins were identified, which included primary and secondary transporters, ion channels and aquaporins. Primary H+ pumps from the AHA family showed little isoform specificity in their tissue expression pattern, whereas specific isoforms of the Ca2+ pump ECA/ACA family were expressed in root and shoot tissues. Several ABC transporters were detected, particularly from the MDR and PDR subfamilies, which often showed expression in either roots or shoots. Ammonium transporters were expressed in root, but not shoot, tissue. Large numbers of sugar transporters were expressed, particularly in green tissue. The occurrence of phosphorylation sites in rice transporters such as AMT1;1 and PIP2;6 agrees with those previously described in other species, pointing to conserved regulatory mechanisms. New phosphosites were found in many transporters, including H+ pumps and H+:cation antiporters, often at residues that are well conserved across gene families. Comparison of root and shoot tissue showed that phosphorylation of AMT1;1 and several further transporters may be tissue dependent

Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

Nutrient iron sequestration is the most significant form of nutritional immunity and causes bacterial pathogens to evolve strategies of host iron scavenging. Cigarette smoking contains iron particulates altering lung and systemic iron homeostasis, which may enhance colonization in the lungs of patients suffering chronic obstructive pulmonary disease (COPD) by opportunistic pathogens such as nontypeable. NTHi is a heme auxotroph, and the NTHi genome contains multiple heme acquisition systems whose role in pulmonary infection requires a global understanding. In this study, we determined the relative contribution to NTHi airway infection of the four heme-acquisition systems HxuCBA, PE, SapABCDFZ, and HbpA-DppBCDF that are located at the bacterial outer membrane or the periplasm. Our computational studies provided plausible 3D models for HbpA, SapA, PE, and HxuA interactions with heme. Generation and characterization of single mutants in the hxuCBA, hpe, sapA, and hbpA genes provided evidence for participation in heme binding-storage and inter-bacterial donation. The hxuA, sapA, hbpA, and hpe genes showed differential expression and responded to heme. Moreover, HxuCBA, PE, SapABCDFZ, and HbpA-DppBCDF presented moonlighting properties related to resistance to antimicrobial peptides or glutathione import, together likely contributing to the NTHi-host airway interplay, as observed upon cultured airway epithelia and in vivo lung infection. The observed multi-functionality was shown to be system-specific, thus limiting redundancy. Together, we provide evidence for heme uptake systems as bacterial factors that act in a coordinated and multi-functional manner to subvert nutritional- and other sources of host innate immunity during NTHi airway infection

Barley plasma membrane intrinsic proteins (PIP aquaporins) as water and CO2 transporters

We identified barley aquaporins and demonstrated that one, HvPIP2;1, transports water and CO2. Regarding water homeostasis in plants, regulations of aquaporin expression were observed in many plants under several environmental stresses. Under salt stress, a number of plasma membrane-type aquaporins were down-regulated, which can prevent continuous dehydration resulting in cell death. The leaves of transgenic rice plants that expressed the largest amount of HvPIP2;1 showed a 40% increase in internal CO2 conductance compared with leaves of wild-type rice plants. The rate of CO2 assimilation also increased in the transgenic plants. The goal of our plant aquaporin research is to determine the key aquaporin species responsible for water and CO2 transport, and to improve plant water relations, stress tolerance, CO2 uptake or assimilation, and plant productivity via molecular breeding of aquaporins.</p

Dose-dependent selection drives lineage replacement during the experimental evolution of SDHI fungicide resistance in Zymoseptoria tritici

Fungicide resistance is a constant threat to agricultural production worldwide. Molecular mechanisms of fungicide resistance have been studied extensively in the wheat pathogen Zymoseptoria tritici. However, less is known about the evolutionary processes driving resistance development. In vitro evolutionary studies give the opportunity to investigate this. Here, we examine the adaptation of Z. tritici to fluxapyroxad, a succinate dehydrogenase (Sdh) inhibitor. Replicate populations of Z. tritici derived from the sensitive isolate IPO323 were exposed to increasing concentrations of fluxapyroxad with or without UV mutagenesis. After ten increases in fungicide concentration, sensitivity had decreased dramatically, with replicate populations showing similar phenotypic trajectories. Sequencing the Sdh subunit B, C and D encoding genes identified seven mutations associated with resistance to fluxapyroxad. Mutation frequency over time was measured with a pyrosequencing assay, revealing sequential lineage replacement in the UV mutagenized populations but not in the untreated populations. Repeating selection from set timepoints with different fungicide concentrations revealed that haplotype replacement of Sdh variants was driven by dose-dependent selection as fungicide concentration changed, and was not mutation limited. These findings suggest that fungicide field applications may select for highly insensitive Sdh variants with higher resistance factors if the fungicide concentration is increased to achieve a better disease control. However, in the absence or presence of lower fungicide concentrations, the spread of these strains might be restricted if the underlying Sdh mutations carry fitness penalties

Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema

Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies