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A bottleneck in the drug discovery process is target validation. Target validation is the process of demonstrating that engagement with a cellular target is linked to the desired therapeutic effect, confirming that the target has a key role in the disease phenotype. Incomplete or incorrect target validation can lead to costly failures at the later stages of drug development. Consequently, techniques that enable rapid and robust target validation are of great value to those seeking to discover new medicines. The advantage of using small molecule ligands over genetic knockdowns, in target validation, is the temporal control over the "knockdown". In this approach, reactive covalent fragments have been combined with a cysteine mutant of the target protein. It was hypothesised that covalent inhibition would circumvent the need to optimise ligand affinity, accelerating probe development, while also offering increased residency times that could potentially act as a functional knockdown, thus providing information on the function of the target. The BET bromodomain-containing protein, BRD4, was chosen for proof-of-concept studies. Bromodomains are epigenetic 'reader' modules that recognise and bind to acetylated lysines on histone tails, and signal for the recruitment of protein complexes responsible for gene regulation. Owing to the conserved nature of the BET bromodomains, the development of single-domain selective ligands has proved challenging. Consequently, development of ligands that enable the probing of single domain function are highly sought after. Herein, the application of a 'mutate & conjugate' approach to enable selective biological probing of BRD4(1) is reported. A structurally stable and functioning mutant, BRD4(1)L94C, was designed, expressed, and validated. Using a structure-guided, and a fragment-based approach, ~270 reactive fragments were screened for C94 labelling. Subsequent fragments were developed and exhibited selective inhibition of BRD4(1)L94C over BRD4(1)WT in an AlphaScreen™ assay. Clickable analogues were used to evaluate proteome-wide selectivity, leading to the discovery of a covalent fragment with exquisite in-cell selectivity for BRD4(1)L94C. Finally, a 'mutate & conjugate' strategy was applied to the development of selective protein degraders. This work shows that the combination of reactive fragments and site-directed-mutagenesis could be applied to rapidly develop chemical probes for target validation studies.

Primary total knee arthroplasty (TKA) for end-stage osteoarthritis (OA) is a surgical procedure with a long history of successful outcomes. However, one fifth of patients report dissatisfaction with the outcome of surgery which results from a combination of factors including poor functional improvement. This research examined the functional elements of recovery, with a focus on the role of skeletal muscle. The pain of OA normally limits activity; if the pain is relieved by TKA, any disuse atrophy associated with the OA has been reported in some patients to improve postoperatively with an eventual strengthening. Quadriceps muscle group strength is correlated with activities of daily living (ADLs). Myogenesis is complex but facilitated by muscle precursor stem cells; mainly muscle satellite cells. An individual’s skeletal muscle phenotype contributes to their physical recovery following surgery. Many factors have been reported as individually influencing skeletal muscle phenotype, but patient specific clinical data is lacking to evaluate these. In this study, these factors were examined in a primary TKA population to test the hypothesis that specific preoperative and perioperative muscle factors and patient background characteristics affect outcome, with the aim of indicating which patients might benefit from targeted treatment. Seventy-two patients listed for primary TKA were recruited to a single centre longitudinal observational cohort study. The participants underwent preoperative interview and assessment, provided a quadriceps skeletal muscle sample at time of surgery and completed a range of functional assessments and outcome reports during their recovery until 12 months following their operations. Muscle biopsies were analysed to determine morphometric and gene expression levels for each patient. Immunofluorescence histology identified muscle fibre type profiles, and quantitative real-time polymerase chain reaction (qPCR) determined relative translational profiles for myogenic, inflammatory, and senescent gene markers. GeNorm methodology identified 3 reference targets as optimal, and EIF4A2, UBC, and GAPDH were noted as the most stable (M=0.55) within the target superficial vastus medialis skeletal muscle tissue in the TKA cohort population. Patient functional performance was evaluated in outpatient hospital research clinics using a battery of functional tests in tandem with patient reported outcome measures (PROMs) tools. Patient function was also evaluated in a sub-cohort in the community setting using activity monitoring devices. Different temporal trends were observed between functional measurements. Substantial variation was observed in the response trajectory of functional metrics. Patients perceived that they meaningfully improved earlier than was observed through directly measured functional performance. Compared to preoperative values, by 12 weeks post-op, patients had achieved 82% of final (12 months post-op) PROM score, 63% of final leg power, 63% of final ADL performance, and 5% of final daily step count. The values further increased by 6 months post-op with PROM score increase at 92% of final score, leg power at 94% final, ADL at 116% final, and daily step count at 110% of final value. These findings highlighted the utility of using a combination of diverse metrics to evaluate patient functional outcome and showed that patient evaluated outcome alone may not fully represent early functional outcome. They also emphasise the critical nature of the follow up time points chosen for clinical trials. Patient background characteristics (demographic, health, and lifestyle factors) were contrasted with patient functional performance and skeletal muscle phenotype using univariate and exploratory multivariate regression modelling. Relationships were identified between patient preoperative baseline factors and post-surgical outcomes, with an observed R2 range of 0.14-0.31 (p≤0.05). Associations were found between background characteristics and physiological phenotypes at time of surgery (R2 0.11- 0.29, p≤0.06). Influences were identified from perioperative physiology on early or primary end-point surgical outcomes, with distinct contributions from certain molecular profiles and skeletal muscle fibre phenotypes (R2 0.09-0.24, p < 0.05). Models constructed using patient preoperative function combined with preoperative PROMs parameters provided the strongest prediction of surgical primary functional outcomes (R2 0.28-0.73, p≤0.006). The results provided new insights into the relationship between functional metrics during early recovery post-TKA. The study identified a variety of demographic and muscle related factors which significantly affect patient early surgical outcomes in primary TKA populations.

Bacillus cereus G9241 was originally isolated from a Louisiana welder suffering from an anthrax-like infection. A member of the Bacillus cereus sensu lato complex, strain G9241 is closely related to the mammalian pathogen Bacillus anthracis. It contains two plasmids pBCX01 and pBC218, which are homologous and analogous to pX01 and pX02 respectively, from Bacillus anthracis. In addition, it contains a phagemid, pBFH_1 encoding a putative prophage. The gene for PlcR, which is the pleiotropic quorum sensing regulator of secreted proteins, is truncated in all B. anthracis isolates. The current dogma suggests this truncation evolved to accommodate the acquisition of the anthrax toxin regulator, AtxA encoded on the pX01 plasmid. B. cereus G9241 appears to break this dogma as it encodes intact copies of both plcR and atxA. Work prior to this study showed when cultured at 25 °C, cell free B. cereus G9241 culture supernatant is cytotoxic to human macrophages, PMNs and T2 lymphocytes in addition to insect haemocytes from Manduca sexta. However, the cytotoxic activity of the culture supernatant is lost at 37 °C. B. cereus G9241 is also motile at 25 °C but immotile at 37 °C. This study proposes that BcG9241 is able to switch between B. cereus and B. anthracis –like phenotypes in a temperature-dependent manner. A combination of RNAseq, whole cell and secretome proteomics suggests that differential regulation of PlcR at a post transcriptional level is responsible for the temperature-dependent cytotoxic activity of the culture supernatant and temperature-dependent motility. Furthermore, expression from the extrachromosomal elements increases at 37 °C, particularly from the phagemid pBFH_1. This study shows that pBFH_1 encoded phage particles are expressed at 37 °C and this may be a link to a rapid sporulation phenotype also seen at this temperature.

Frailty and sarcopenia are geriatric conditions, becoming more prevalent with the United Kingdom's (UK) ageing population. More older patients are presenting for colorectal surgery, who may be frail or sarcopenic. Current literature suggests assessments for these conditions may have a predictive validity for adverse post-operative outcomes. There is confusion as to which measures are of true clinical value. Qualitative methodologies were employed to determine that whilst surgeons wish for frailty to be routinely identified at St James' hospital, Leeds, UK, pre-assessment staff would require an intervention to also be available before identification is implemented. Initial pilot studies investigate prevalence of frailty and sarcopenia, identifying that there is a substantial variance between prevalence rates of either condition, depending on the assessment methodology. Initial analyses indicate these measures may not be predictive of post-operative outcomes. Development of Frailty and Sarcopenia Trial (FAST) identified that whilst prevalence of frailty by different measures varied, predictive validity was poor. FAST also determined that sarcopenia, as measured by the European Working Group of Sarcopenia in Older People criteria, identifies patients who are more likely to require increased care in-hospital, post-operatively. This may support the identification of patients who may fare worse as a result of their operation, and interventions put into place to optimise patient's clinical conditions pre-operatively. An eccentric exercise program, lasting 4 weeks, can improve strength in older adults. It is hoped that developments from this study can inform physiotherapy interventions for frail or sarcopenic in-patients in the peri-operative window. This work highlights the possibility that there may be publication bias regarding frailty and sarcopenia, and that whilst these conditions may be prevalent in a clinical setting, caution is required when considering which assessment should be adopted to be clinically informative in a colorectal surgical pathway.

Let $G$ be a semisimple algebraic group over an algebraically closed field $K$, of characteristic $p \geq 0$. A closed subgroup of $G$ is said to be irreducible if it does not lie in any proper parabolic subgroup of $G$. In this thesis we address the following problem: classify the connected irreducible subgroups of $G$, up to conjugacy, where $G$ is of exceptional type. Work of Liebeck and Seitz classifies the conjugacy classes of simple, connected irreducible subgroups of rank at least 2, with a restriction on the characteristic of the underlying field ($p > 7$ is sufficient). When $G$ is of type $F_4$, Stewart has classified the conjugacy classes of simple, connected irreducible subgroups of rank at least 2 in all characteristics. We classify the conjugacy classes of simple, connected irreducible subgroups, of rank at least 2 for $E_6$, $E_7$ and $E_8$. Our approach works in all characteristics, rather than starting from the characteristics excluded in the result of Liebeck and Seitz. We use these classifications to prove corollaries concerning the representation theory of such irreducible subgroups. For example, with one exception, two simple irreducible connected subgroups of rank at least 2 are $G$-conjugate if and only if they have the same composition factors on the adjoint module of $G$. We also consider connected subgroups of rank 1. Work of Lawther and Testerman classifies conjugacy classes of rank 1 connected irreducible subgroups, with a restriction on $p$ ($p>7$ is sufficient). The connected irreducible subgroups of rank 1 were found, in arbitrary characteristic, by Amende for all but $E_8$. We give a new proof of this, finding a set of conjugacy class representatives without repetition. We prove corollaries on the overgroups of irreducible $A_1$ subgroups. For example, we prove that if $p=2$ or $3$ then any irreducible $A_1$ subgroup of $E_7$ is contained in $A_1 D_6$. Finally, consider the semisimple, non-simple connected irreducible subgroups. We classify these, up to conjugacy, for $G_2$, $F_4$ and $E_6$. So in conclusion, we classify conjugacy classes of connected irreducible subgroups of $G_2$, $F_4$ and $E_6$, all simple, connected irreducible subgroups of $E_7$ and all simple, connected irreducible subgroups of $E_8$ of rank at least 2.

Regular aerobic exercise has a wide range of positive effects on health and cognition. Exercise has been demonstrated to provide a particularly powerful and replicable method of triggering a wide range of structural changes within both human and animal brains. However, the details and mechanisms of these changes remain poorly understood. This thesis undertakes a comprehensive examination of the relationship between brain plasticity and aerobic exercise. A large, longitudinal experiment was conducted in which healthy but sedentary participants were scanned before and after six-weeks of monitored aerobic exercise. Increases in the volume of the anterior hippocampus were observed, as previously reported in an older cohort after a longer exercise intervention. Multimodal imaging methods allowed an in-depth exploration of the mechanisms underlying this volume change, which proved to be dominated by white matter changes rather than the vascular changes that have been previously reported. A surprising global change in the balance of CSF, blood, and brain tissue within the cranial cavity was also observed. Cross-sectional differences in memory and brain structure associated with fitness were also observed. The volume of the anterior hippocampus was shown to correlate with a measure of working memory. Higher cerebral blood volume throughout the brain was found to correlate with greater fitness and better working memory. Focal associations between fitness and magnetic susceptibility, a measure of iron content, were also observed in the basal ganglia. These findings demonstrate that aerobic fitness is associated with improved cognition and brain structure throughout the lifespan rather than simply acting to mitigate age related brain atrophy or accelerate brain development. Finally, a new pipeline was developed for analysing hippocampal morphometry using high-resolution, 7 Tesla scans. Striking variability in the convolution of the hippocampal surface is reported. This technique shows promise for imaging the precise nature of the change in hippocampal volume associated with aerobic exercise. This thesis adds to the evidence that aerobic exercise is a potent catalyst for behavioural and brain plasticity while also demonstrating that the mechanisms for those plastic changes are likely different than previously supposed. Future work will refine these measurement techniques, perhaps to a point where brain changes can be monitored on a single subject level. This work will provide an important tool to understand how best to utilize aerobic exercise to facilitate adaptive behavioural changes, mitigate the negative effects of ageing and disease on the brain, and maximize the benefits of active lifestyles.

Shedding new light on the relationship between Black Power and mainstream American politics and society, this thesis explores the ways in which white politicians, institutions, and organizations engaged with, and responded to, African Americans‘ demands for economic and political empowerment during the mid-to-late 1960s through the mid-1970s. At the same time, it considers how these demands themselves reflected urban African American communities‘ own responses to, and engagement with, Black Power ideology. The final and broadest concern of this study is how these two processes – along with the political and economic pressures created by white mainstream resistance to demands for racial and socio-economic change – affected urban African American society and politics during the Black Power era and beyond. This story is traced by exploring the nexus of public policies, black community organizations, white and black elected officials, liberal foundations, and Black Power activists in New York, Atlanta, and Los Angeles during the mid-to-late 1960s through the 1970s. By considering throughout how African American community activists in the three cities fought to capitalize on, and create, new opportunities through public policies, this project details the impact that Black Power had upon existing grassroots community activism, illuminating Black Power‘s development at the local level. Finally, focusing on the evolution and longer term trajectory of public policies intended to negotiate and control the meaning of Black Power, this thesis explains how and why those policies sought to cultivate a mainstream, middle-class interest oriented brand of Black Power politics that aimed to reinforce the nation‘s existing political and social order. Highlighting the relationship between these policies and black middle-class progress of the period, this thesis underscores the enduring capacity of mainstream whites to successfully defend and assert their interests and resist transformative socio-economic and racial change, and ultimately, to dictate the scope and direction of black progress.

Genetic toxicology assesses the genotoxic potential of chemicals in consumer products, pharmaceuticals and from agricultural and industrial processes. Such assessment is integral in hazard identification and risk assessment to prevent unnecessary human exposure and limit cancer risk. Human risk assessments for genotoxic alkylating agents were based upon linear dose-response models where genotoxicity accrues proportionally with dose. Evidence is accumulating to support a non-linear dose-response at low doses of ethyl methanesulfonate (EMS), a model alkylating agent. For acceptance of non-linear dose responses, a strong explanatory mechanism of action needs to be elucidated. In the following work, low dose mutagenic effects of methyl nitorosurea (MNU), the most potent alkylating agent, have been examined in AHH-1 human lymphoblastoid cells using the HPRT assay. An increase in mutant frequency was not observed until 0.01pg/ml MNU (LOGEL, Lowest Observed Genotoxic Effect Level) with a No-Observed Genotoxic Effect Level (NOGEL) at 0.0075pg/ml MNU. Of interest, is the apparent hormesis induced at 0.0025pg/ml MNU. The principle adduct responsible for MNU mutagenesis is 0 6Methylguanine (06MeG) that miscodes during replication and becomes fixed as GC→AT transitions. Accordingly, the non-linear increase in mutant frequency is accompanied by a non-linear increase in GC→AT transitions. Furthermore, evidence is provided that implicates methlyguanine methyltransferase (MGMT) in protecting DNA from MNU induced mutagenesis by repairing 0 6MeG at low doses, thereby creating the NOGEL. AHH-1 cells treated with 0 6Benzylguanine (06BG), to inactivate MGMT, were hypersensitive to low dose MNU mutagenesis. At 0.0075pg/ml MNU, there was a three-fold increase in mutant frequency and an increase in proportion of GC-^AT transitions, from 28% to 48% in MGMT inactivated cells. This thesis presents a non-linear dose-response for MNU with a strong biological mechanism of action involving DNA repair.

This thesis examines the ecology, parasites and pathogens of three insectivorous bat species in Wytham Woods, Oxfordshire; Myotis nattereri (Natterer’s bat), M. daubentonii (Daubenton’s bat) and Plecotus auritus (Brown long-eared bat). The population structure was assessed by monitoring associations between ringed individuals, utilising recent advances in social network analysis. Populations of both M. daubentonii and M. nattereri were found to subdivide into tight-knit social groups roosting within small areas of a continuous woodland (average minimum roost home range of 0.23km2 and 0.17km2 respectively). If this population structure is a general attribute of these species it may make them more sensitive to small scale habitat change than previously thought and has implications for how diseases may spread through the population. M. daubentonii had a strong preference for roosts close to water, away from woodland edge and in areas with an easterly aspect. The factors driving roost choice in M. nattereri and P. auritus remain elusive. The segregation of M. daubentonii into bachelor and nursery colonies was not a result of the exclusion of males from roosts close to water by females, or variation in microclimate preferences between the sexes, as was predicted. Body condition (weight/forearm length) was correlated with host characteristics including age and reproductive status, and weather variables. Astroviruses and Coronaviruses, which have characteristics typical of zoonotic viruses, were identified in UK bat species for the first time. Coronaviruses identified formed species-specific clades while Astroviruses were highly diverse. Though not closely related to human viruses these are potential zoonotic diseases of the future. Models of Coronavirus and ectoparasite distribution suggest individual attributes (e.g. sex and age) and population structure (e.g. the formation of nursery and bachelor colonies) are important predictors of parasite and pathogen prevalence. This study characterises a system that offers many opportunities for future research including studies of sociality, disease modelling and conservation management.

The condition known as tick-borne fever (TBF),which occurs in sheep and cattle, is due to a tick-transmitted rickettsia called Cytoecetes phagocytophila , and has frequently been suggested to have an immunosuppressive effect, predisposing animals to other disease conditions. The work in this thesis was directed towards examining c. phagocytophila as a pathogen per se and its role in other diseases of sheep such as tick pyaemia, louping-ill and pneumonic pasteurellosis. The mechanism whereby the immunosuppressive effect occurred was investigated and methods for the oontrol or prevention of 'lBF and tick pyaemia explored.

Confronted with DNA damage, cells can undergo cell cycle arrest and DNA repair, or cell death. However, communal DNA damage response (DDR) proteins involved in each of these cell fates, has confounded attempts to unravel the molecular nuances that drive cell fate determinations. Aim: This study sought to identify whether distinct molecular signatures in the form of DDR protein and miRNA expression exist to underpin cell fate decisions. Methods: Human lymphoblastoid (TK6) cells were exposed to a temozolomide (TMZ) dose range to identify sub-lethal and lethal doses. These doses (30 μM and 900 μM, respectively) were used for all subsequent experiments. TMZ-induced effects were determined based on DDR protein levels (immunoblotting), DNA damage accumulation (immunofluorescence), cell fate (flow cytometry), and miRNA expression (RNA sequencing and qRT-PCR). Mimics of identified miRNAs were over-expressed in TK6 cells and functional analysis performed with flow cytometry and immunoblotting. Results: TK6 cells exposed to 30 μM TMZ (30TMZ) preferentially underwent G2 arrest whereas 900 μM (900TMZ) caused apoptosis, identifying these as sub-lethal and lethal doses respectively. ATR-γH2Ax-Chk1-p53 pathway was significantly upregulated among 900TMZ-treated cells when compared to 30TMZ. Collectively, 31 miRNAs were differentially expressed when comparing 30TMZ-, and 900TMZ-treated cells to control-treated cells. Among these, miR-29b-3p, miR-363-5p, and miR-485-3p were determined to be significantly downregulated in response to 900TMZ-treated cells when compared to 30TMZ-treated cells. Moreover, p53 and miRNAs (miR-29b-3p, miR-363-5p, and miR-485-3p) were regulated in opposing directions following TMZ exposure, alluding to a possible miRNA-regulatory role for p53 in this context. Over-expression of miR-29b-3p or miR-363-5p individually or in combination did not affect cell fate. Conclusion: TK6 cells exposed to a lethal dose of TMZ expresses a unique molecular profile in the form of significantly upregulated ATR-γH2Ax-Chk1-p53 signalling, along with significant downregulation of miR-29b-3p, miR-363-5p, and miR-485-3p when compared to sub-lethally-treated TK6 cells. This suggests these miRNAs to be DDR-responsive and thus, provides a link between DDR proteins and miRNA regulation. This is the first time these miRNAs have been reported in TK6 cells in the context of the DDR and these, along with the other differentially expressed miRNAs identified here, may prove useful as diagnostic biomarkers, druggable targets in future therapies, or become therapies in itself.

In my dissertation I seek to contribute to the revival of interest in Augustine’s political thought by attempting to uncover his doctrine of eternal law. While absent from his mature writings, including the City of God, this doctrine is central to the investigation of justice in Augustine’s early writings. After considering Augustine’s summary of this early investigation in the Confessions, the most surprising feature of which is Augustine’s insistence on the importance of specifically political questions to his mature understanding of justice, I take up the two treatments of eternal law. In the dialogue On Free Choice, the eternal law is contrasted with the temporal law and is understood in terms of the fundamental command to “order,” which means in the first place wisdom, but also “right and honorable” action. In the anti-Manichean polemic Contra Faustum, the eternal law is presented as the will of God that commands the preservation of the natural order, which means that actions are truly just insofar as they conduce to “mortal health.” I argue that these two discussions of eternal law indicate the limitations of any kind of “higher law” doctrine. On Free Choice demonstrates the difficulty of breaking free of the guidance of temporal law and its harmonization of the demands of eternal and temporal law depends on an understanding of moral virtue whose independence is rather assumed than proven. Contra Faustum shows that the natural ends of self-preservation, procreation, and civic peace are only the beginning points of moral reasoning, since the pursuit of those ends is governed by further moral criteria that cannot easily be understood in terms of nature. In the end, then, I argue that the doctrine of eternal law, while illuminating a great deal about the problems of politics and morality as Augustine encountered them, points to the crucial importance of the question of human virtue and of acquiring the prudence that provides for this virtue in light of the necessary limitations of political life. It is probably for this reason that Augustine does not return to the doctrine in his later writings and does not rely on it in his reconciliation of the two cities in the City of God.

Prescribed fire, thinning, and mastication are common forest management practices implemented in southern pine forests. These practices affect ecosystem properties differently depending upon the intensity at which they are implemented. One ecosystem property of interest is the chemical composition of forest detritus, commonly referred to as the litter and duff. This material is largely responsible for the replenishment of organic resources into soils. It may also be a primary contributor to surface water quality. In this study we were given an opportunity to evaluate two long-term forest management strategies at two sites along the South Carolina coastal plain to determine their effects on forest detrital chemical composition and potential water quality: 1) frequent prescribed fire (annual and biennial) and 2) a combination of periodic prescribed fire (every 3-4 years) and singular implementations of tree thinning and understory mastication. Based upon our analyses, we confirmed that the prescribed fires implemented on these sites display the characteristics of low intensity, low severity surface fires. As such, fuel quantities decreased as a result of forest management at both sites. At one of our sites, the Tom Yawkey Wildlife Center in Georgetown, South Carolina, the chemical functional groups of forest detritus were not greatly altered by fire. Specific compounds within these groups may have been affected by fire, but returned to or fell below long-term unburned levels within one-year post-fire. On our other site, the Santee Experimental Forest, it appears that long-term forest management has altered overstory species composition and subsequently detrital chemical composition. At both sites, potential organic pollutants were reduced by the forest management practices. This reduction may be beneficial in terms of water treatment and human health. These results add to the long list of benefits noted in the literature for active forest management, particularly the benefits of prescribed fire.

This dissertation asks how the end of slavery affected ideas of community belonging and social authority. It illuminates the tension created between societal perceptions of a subject’s race based on physical appearance and contradictory perceptions based on behavior and allegiance. These conflicts engendered exclusion of those said to have “black skin and white hearts” or seen as “white niggers,” undermining radical and liberal visions of emancipation. Tracing transnational circulations of people and ideologies, the dissertation shows that similar notions of racial authenticity operated in the Caribbean (c.1823-1866) and US (c.1861-1900), challenging exceptionalist narratives of American racial history. Though many reformers believed emancipation would eradicate racial difference, subjects in every instance grounded authority to enact their vision of emancipation in claims of purity. While research on the relationship between race and slavery tends to focus on origins, it is only by examining the formal end of bondage that we can understand how race survived slavery’s nominal demise to continue as a source of social division today.

While the design of mechanisms is a well-studied field, current optimization techniques generally focus on the kinematics and dynamics and relegate other aspects of the analysis to separate stages of the overall design process, resulting in a loss of optimality when the entire multi-domain system is considered. This thesis presents a general method by which a mechanism optimization problem may be efficiently formulated and solved, considering multiple competing design objectives across multiple analysis domains. Two case studies illustrate the practical application of this general method. The first is the kinematic-structural optimization of a hydraulic rescue spreader ("jaws of life"). The second is the kinematic-dynamic-thermodynamic optimization of a novel six-bar linkage for an internal combustion engine. A variety of powerful general-purpose multi-objective algorithms are available from the literature. In particular, genetic algorithms are well-suited to multi-objective problems, and the NSGA-II algorithm from this category is employed here. Three strategies are presented to formulate multi-domain mechanism optimizations in a way that can be solved efficiently by a multi-objective genetic algorithm and is free of explicit constraint functions even for complex problems. First, it is shown that the use of non-traditional design variables, such as angles and adaptive interpolations, can result in smaller design spaces to be searched and can guarantee that all optima lie within the selected range of a given design variable. It is also shown that traditional precision-position synthesis techniques can in some cases be employed in a preliminary analysis to reduce the dimension of the design space. Finally, a nested optimization structure is proposed in which kinematic design variables and objectives are optimized in an outer loop, with the non-kinematic problem being optimized in an inner loop at every outer loop iteration, improving the efficiency and stability of the optimization process. These techniques were applied to the hydraulic rescue spreader problem in order to design a six-bar mechanism that could exert a 10,000 pound force through a pair of jaws over a 24 inch spreading distance while maintaining performance-critical kinematic behavior and remaining light and compact enough to be a handheld tool. The structural stresses in each part of the linkage were modeled, using a combination of analytical methods and finite element analysis. The final optimization result was superior to a similar commercially available model with respect to all four kinematic and structural objectives. Having successfully optimized a low-speed mechanism with a structural motivation, the method was also applied to a high-speed mechanism with a thermodynamic motivation. A Stephenson-III six-bar linkage was developed in order to optimize the motion of the piston in an internal combustion engine and achieve a cylinder volume as a function of time most conducive to efficient combustion. A number of mechanical objectives relating to balancing and mechanism size were used in order to find a solution capable of practical implementation. A slight increase in thermal efficiency over a purely sinusoidal piston motion was obtained, along with satisfactory values of the mechanical objectives.

The influence of memory on the perceptual integration of speech sounds over time is poorly understood. The current study examined the influence of different linguistic properties on the sequential integration of speech using a novel methodology. Cues to lateralization were varied in order to produce perceptual segregation of an /s/ onset from the following speech sounds within words and nonwords (e.g. “slaz”). In Experiment 1, different sources of contextual (lexical, phonological) information elicited different amounts of perceptual segregation, indicated by a subjective measure of streaming. Experiment 2 used gap detection, a task showing impairment in segregated relative to integrated percepts (Woods, Sorkin, & Boggs, 1979). This experiment strengthened interpretations of the results of Experiment 1 as being due to changes in sequential integration. Gap detection worsened for items reported as streamed, validating the results of Experiment 1. The results of the current study provide evidence for a schematic grouping process in speech perception and provide the groundwork for further investigation, both for the contribution of schemas to the perceptual grouping of speech and their relevance to higher-level processes of spoken word recognition.

Alfalfa (Medicago sativa L.) is the most important forage crop in the United States and consistently produces high yields and quality, but harvest frequency is the most significant factor for maximizing forage yield and quality. The objective of this research was to determine forage yield, quality, and regrowth rate among new alfalfa cultivars under four different harvest frequencies. Some of these cultivars have been marketed as having rapid rates of regrowth after cutting to maximize the number of harvests per year. Five cultivars were placed under four harvest frequencies of 25, 30, 35, and 40 days in a split-plot design. There was a significant yield and regrowth rate effect across cultivars and harvest frequencies, but little forage quality effect during the two years of this research. These results confirm previous findings that a 35-d harvest frequency is optimal for forage yield, quality, and stand persistence.

The importance of soybeans to producers, processors, exporters and ultimately consumers has been increasing rapidly, pushing soy beans from a botanical curiosity in the 1920's to the second most important cash crop produced in the United States. Prices play an important role in the industry. Producers, exporters, processors and other businesses related to soybeans and soybean products require accurate and timely information on soybean prices to promote efficient business flow and to allow for long-term planning. This benefits the consumer by providing a steady supply of products at stable prices. The objectives of this study were: 1. to determine if recent price changes from close to close of November soybean futures can be used to indicate a weak market in the short run and, if so, 2. to determine if the indication of a weak market in the short run also indicates a good time to forward contract for harvest delivery. Three models with different cutoff criteria of -$1.00, -$.90 . and -$.80 were developed on 1973/1974 through 1981/1982 data. Contract years 1982/1983 and 1983/1984 were preserved to test the models. The independent variables were the changes in the 20 previous daily closes. If the closes decreased in price greater than the cutoff criteria over the next 30 days, then that observation was classified as a sell signal. To avoid placing a hedge on an observation misclassified as a sell signal, a hedge was not placed until five sell signals occurred in a row. Once a hedge had been placed, the success of the three models was analyzed based upon the resulting profit (or loss) per bushel from the time the hedge was placed until the date the hedge was lifted. For comparative purposes, two possible dates were used for lifting the hedge. The first date was at the time of harvest (assumed to be October 15) and the second was the last day of the contract. Thus it was found, that if the producer hedged using the -$.80 criterion and placed a hedge after five predicted sell signals occurred in succession and lifted the hedge on the last day of the contract's life, his profits per bushel could increase by 53.33^ per bushel over lifting the hedge at the time of harvest (72.33¢- 19¢). Furthermore, if the producer hedged after five predicted sell signals occurred in succession and lifted the hedge on the last day of the contract's life, his profits per bushel could increase 3.16¢ per bushel over the same trading procedure, but using the -$1.00 criterion.