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Development of zafirlukast analogues for improved anti-thrombotic activity through thiol isomerase inhibition
No full textBackground: Thiol isomerases play essential and non-redundant roles in platelet activation, aggregation, and thrombus formation. Thiol isomerase inhibitors have the potential to overcome the two major drawbacks of current antithrombotic therapies, as they target both arterial and venous thrombosis without enhancing bleeding risks. Recently, an FDA-approved drug, zafirlukast (ZAF), was shown to be a promising pan-thiol isomerase inhibitor. The objective of this study is to develop analogues of ZAF with optimized thiol isomerase inhibition and antithrombotic activity.
Methods: 35 ZAF analogues were tested in an insulin turbidometric assay for thiol isomerase inhibition. Analogues were tested for platelet activation, aggregation, P-selectin expression, and laser-induced thrombosis in mice and compared with the parent compound.
Results: Of the 35 analogues, 12 retained activity, with one, compound 21 that demonstrated a greater potency than that of ZAF, 5 had a similar potency to that of ZAF, and 6 had a weaker potency. Analogues demonstrated inhibition of platelet aggregation and P-selectin expression as compared to ZAF, consistent with their potencies. ZAF and compound 21 were shown to be reversible inhibitors of thiol isomerases, and not cytotoxic to cultured, lung, liver, and kidney cells. Finally, in an in vivo assessment of thrombus formation, compound 21 was able to significantly inhibit thrombus formation without affecting bleeding times.
Conclusions: A ZAF analogue, compound 21, with properties superior to those of ZAF was synthesized, demonstrating improved inhibition of platelet activation, aggregation, and thrombus formation as compared to the parent ZAF. This approach could yield a promising clinical candidate for treatment and prophylaxis of arterial and venous thrombosis
Impact of zinc on the gut bacterial microbiota and enterotoxigenic E. coli pathotypes causing post-weaning diarrhoea in porcine populations; an in vitro study
No full textZinc oxide provides a positive effect on the intestinal microflora of pigs in controlling
or preventing diarrhoea caused by both enterotoxigenic and Shiga-toxin-producing E. coli
pathotypes during weaning, but it remains unclear how zinc controls or prevents gut
pathogen infection. This study investigated the effects of both therapeutic and prophylactic
zinc levels on the gut microbiota of pre-weaned piglets to understand how zinc treatment
overcomes post-weaning diarrhoea (PWD) in pigs. An in vitro gut model approach was
employed where faecal specimens from piglets were inoculated into batch gut culture
vessels (n=36) in five runs. Moreover, cultivations were performed to determine the specific
effects of zinc on E. coli laboratory F4 and F18 strains – the most common causal agents of
postweaning diarrhoea in swine populations. For each inoculum in the case of a therapeutic
zinc trial, three conditions were maintained: the control, and zinc treatment (13.2 mM) using
piglet donors receiving dietary iron (FeSO4 at 150 mg/kg body weight) or piglet donors
receiving intramuscular iron regime (Iron Dextran® at 200 mg iron/piglet) in addition to
dietary iron. For each inoculum in the case a of sub-therapeutic zinc trial, four conditions
were employed: a non-treatment (control) and three zinc treatments (0.26, 0.52 and 0.78
mM) reflecting prophylactic zinc levels (piglet donors received identical iron regimes).
Samples were harvested at 0, 8, 24 and 48 hours for analysis by flow-cytometry
fluorescence in situ hybridisation (Flow-FISH), short chain fatty acids (SCFAs) analysis,
elemental assay and microbiota community profiling. Interestingly, the Flow-FISH results
revealed that the therapeutic zinc level caused a minimum 100-fold reduction in gut bacterial
population levels with no significant difference between high and low iron treatment groups
at a 5% significance level. In contrast, the prophylactic zinc levels (0.52 and 0.78 mM), at 24
h, caused a significant reduction (~60-fold) in gut bacterial population levels without a
significant difference between 0.52 and 0.78 mM at a 5% significance level. However, 0.26
mM zinc resulted in only ~8-fold decline. The Flow-FISH results are supported by the
findings of SCFAs data revealing no production at 0.52-13 mM zinc. However, zinc addition
resulted in a 20-fold lower production of SCFAs than that noticed in the absence of added
Zn. The variations in total SCFA production induced by Zn treatment were highly significant
(Student’s t test, p = 0.001) at 24 h in the cases of both high and low iron regimes. The ICP-OES metal analysis indicated the likelihood of Zn-mediated interference with the distribution
of transition metals such as Fe, Cu, Ni, Co and Mn within the gut model between the pellet
and supernatant fractions, in the case of therapeutic zinc, while little effect was exerted by
the prophylactic zinc. Regarding application of therapeutic zinc, significant differences in Fe
levels (as compared to the corresponding 0 h) were found in pellets of the Zn-treated
cultures for the -Fe group at 24 and 48 h (increase from 5.1 to 7.7 µM, p <0.01),
supernatants of Zn-free cultures in the +Fe group at both 8 and 24 h (reductions of ~0.62
and ~0.59 fold, p <0.01 and <0.05, respectively) and pellets of the Zn-free cultures in the -Fe
group at 24 h (fall from 120 to 31.4 µM, p <0.05). Also, significant variations in Cu contents
(with respect to the corresponding 0 h) were noticed in supernatants of Zn-treated cultures in
the -Fe group at 48 h (2.5-fold rise; p <0.05), the supernatants of Zn-free cultures in the +Fe
group at the 24 h (1.7-fold fall, p <0.05), supernatants of Zn-free cultures in -Fe group at
both 8 h (decease of ~1.7-fold, p <0.05) and pellets of Zn-free cultures in -Fe group at 24 h
(elevation of ~1.8-fold, p <0.001). Again, significant differences in Ni contents (in regards to
the corresponding 0 h) were found in pellets of Zn-treated cultures of the +Fe group at 24 h
(~1.12-fold rise, p ≤0.05), supernatants of Zn-treated cultures for the +Fe group at 8 h (~60-
fold reduction, p =0.05) and supernatants of Zn-free cultures in the -Fe group at 24 h (~1.13-
fold increase, p =0.01). Further, significant differences of Co concentrations (with regards to
the corresponding 0 h) were found in pellets of Zn-treated cultures of the +Fe group at 24 h
(~1.06-fold e, p <0.05) and supernatants of Zn-treated cultures of the -Fe group at both 24
and 48 h (1.3- and 1.4-fold increases, p <0.05 and p ≤0.05, respectively). Furthermore, Mn
contents (as compared to the corresponding 0 h) showed significant differences in the
pellets and supernatants of Zn-free cultures in the +Fe group at 48 h (elevation of ~1.34-fold
at p <0.05 and reduction of ~1.6-fold at p =0.01) as well as pellets of Zn-free cultures in the -
Fe group at 24 h (increase of ~1.94-fold, p <0.05). From the next generation sequencing
(NGS) data analysis, it was evident that at 24 h, therapeutic Zn resulted in reduced
proportions of Bacteroidetes (~1.7-fold) and Firmicutes (~1.4-fold), while a raised level for
Proteobacteria (~3.3-fold). On the contrary, in the case of prophylactic Zn, 0.26 mM caused
a decrease in Bacteroidetes (~3-fold, FDR p <0.05) and Proteobacteria (~2.5-fold, FDR p
>0.05) but a significant (FDR p <0.01) increase in Firmicutes (~4.6-fold) at 24 h, whereas
0.52 mM causes a significantly (FDR p <0.001) lower level of Proteobacteria (~48.5-fold)
and insignificantly lower levels of Bacteroidetes (~1.15-fold) but insignificantly higher
Firmicutes (~6-fold) at the same time point; a similar trend was seen in the case of 0.78 mM
Zn. These results were reflected at the genus level. In laboratory pure cultures of the F4 and
F18 E. coli strains using either 96-well microtitre plates or shake flasks, almost complete
growth inhibition was observed for 0.52 and 0.78 mM zinc. In addition, it was endeavoured to
determine the effects of Zn on the ETEC pathogens of PPWD in an in vitro gut model co-culture. However, the designed Flow-FISH probes failed to detect the ETEC strains and
therefore, a Taqman qPCR approach was designed (but not executed due to time
constraints). To conclude, both therapeutic (13.2 mM) and prophylactic doses of zinc exert
major effects in reducing the total number of the gut bacterial microbiota of pre-weaned
piglets as well as F4 and F18 E. coli strains in laboratory cultivations which highlight the
antibacterial impact of zinc. Therefore, this PhD study has offered novel insights into
understanding the effects of Zn on the PPWD-causing ETEC pathogens and suggests that
the nutritional levels of Zn can be applied as prophylactic doses to prevent PWD in porcine
populations. Also, ZnCl2 appears to be more potent as an antibacterial, while ZnO seems to
be less potent, possibly because it is less soluble. This suggests that future experiments
should be performed to compare ZnO and ZnCl2, with/without gastric predigestion
Comparing eating and mealtime experiences in families of children with autism, attention deficit hyperactivity disorder and dual diagnosis
Get PDFShared family meals are associated with family functioning and thought to protect against disordered eating in families with neurotypical children. Limited research, however, has examined the mealtime structure or experience in families with children with autism (Autism spectrum condition) and/or attention deficit hyperactivity disorder, despite eating behaviour differences in these populations. This study sought to compare children’s eating behaviours and caregivers’ mealtime experiences between families with neurotypical children and those with Autism spectrum condition, attention deficit hyperactivity disorder and dual diagnosis (Autism spectrum condition + attention deficit hyperactivity disorder). Think-Aloud methods established validity for the Children’s Eating Behaviour Questionnaire, Meals in our Household and Perceived Stress Scale measures (N = 9), prior to administering these to caregivers of children aged 3–15 (N = 351). Neurodevelopmental condition groups (Autism spectrum condition, n = 80; Attention deficit hyperactivity disorder, n = 88; Autism spectrum condition + attention deficit hyperactivity disorder, n = 65) reported higher food fussiness, emotional undereating, problematic child mealtime behaviours, dietary concerns, caregiver and spousal stress, and less conventionally structured mealtimes than neurotypical families (n = 118). Attention deficit hyperactivity disorder and Autism spectrum condition + attention deficit hyperactivity disorder groups reported higher food responsiveness, problematic behaviour and caregiver stress than the Autism spectrum condition group. Conversely, Autism spectrum condition and Autism spectrum condition + attention deficit hyperactivity disorder groups reported lower food enjoyment and mealtime structure than the attention deficit hyperactivity disorder group. Distinct eating and mealtime patterns in neurodevelopmental condition families may adversely impact family functioning, emphasising the need for bio-psychosocial approaches and transdiagnostic mealtime support
Training human super-recognizers’ detection and discrimination of AI-generated faces
Get PDFGenerative adversarial networks (GANs) can create realistic synthetic faces, which have the potential to be used for nefarious purposes. The synthetic faces produced by GANs are difficult to detect and are often judged to be more realistic than real faces. Training programmes have been developed to improve human synthetic face detection accuracy, with mixed results. Here, we investigate synthetic face detection and discrimination in super-recognizers (SRs; who have exceptional face recognition skills), and typical-ability control participants. We also devised a training procedure which sought to highlight rendering artefacts. In two different experimental designs, we found that SRs (total N = 283) were better at detecting and discriminating synthetic faces than controls (total N = 381), where control participants were below chance without training. Trained SRs and controls had significantly better performance than those without training, and the magnitude of the training effect was similar in both groups. Our results suggest that SRs are using cues unrelated to rendering artefacts to detect and discriminate synthetic faces, and that an easily implementable training procedure increases their performance to above chance levels. These results have implications for real-world scenarios, where trained SRs' performance could be harnessed for synthetic face detection
From Loops to caps: discriminating peptide binding to distinct G-quadruplex tetrads using 5-furyl-2′-deoxyuridine fluorescent probes
Get PDFWe report the use of 5-furyl-2′-deoxyuridine (5FU) as a fluorescent probe to distinguish ligand binding to distinct G-quadruplex tetrads. Site-specific incorporation of 5FU into T95-2T at the capping regions enabled discrimination of peptide-binding events via fluorescence turn-on, providing insights into tetrad preference and binding affinities using the 5FU-G4/RHAU peptide system
Eco-evolutionary modelling of global vegetation dynamics and the impact of CO2 during the late Quaternary: insights from contrasting periods
Get PDFChanges in climate have had major impacts on global vegetation during the Quaternary. However, variations in CO2 levels also play a role in shaping vegetation dynamics by influencing plant productivity and water-use efficiency and consequently the relative competitive success of the C3 and C4 photosynthetic pathways. We use an eco-evolutionary optimality (EEO)-based modelling approach to examine the impacts of climate fluctuations and CO2-induced alterations on gross primary production (GPP). We considered two contrasting periods, the Last Glacial Maximum (LGM; 21 000 years before present) and the mid-Holocene (MH; 6000 years before present) and compared both to pre-industrial (PI) conditions. The LGM, characterized by generally colder and drier climate, had a CO2 level close to the minimum for effective C3 plant operation. In contrast, the MH had warmer summers and increased monsoonal rainfall in the Northern Hemisphere, although with a CO2 level still below the PI. We simulated vegetation primary production at the LGM and the MH compared to the PI baseline using a light-use efficiency model that simulates GPP coupled to an EEO model that simulates leaf area index (LAI) and C3 / C4 competition. We found that low CO2 at the LGM was nearly as important as climate in reducing tree cover, increasing the abundance of C4 plants and lowering GPP. Global GPP in the MH was similar to the PI (although greater than the LGM), also reflecting CO2 constraints on plant growth despite the positive impacts of warmer and/or wetter climates experienced in the Northern Hemisphere and tropical regions. These results emphasize the importance of taking account of impacts of changing CO2 levels on plant growth to model ecosystem changes
An osteobiography of a celebrity chimpanzee reflects the changing roles of modern zoos
Get PDFThe role of zoos has shifted markedly from their origins in the nineteenth century to the present day. Long-lived and charismatic individual animals have been central to zoological collections, as priorities have changed from a primary focus on entertainment to a greater emphasis on education, conservation, research and welfare. Here, we construct the osteobiography of a celebrity chimpanzee to highlight the changing practices of modern zoos over a near half-century timescale. We applied archival, biogeochemical, pathological, and morphometric analyses to the skeleton and tissues of Choppers, a captive female western chimpanzee (Pan troglodytes verus), who featured in the PG Tips television advertisements in the United Kingdom in the 1970s. We show the efficacy of the osteobiographical method in revealing Choppers’ life events, including her capture from the wild, dietary transitions over decadal timescales, and her declining health in old age. These direct analytical techniques applied to her physical remains allow for a more in-depth understanding of her life history than from archival material alone. By using a mixed-method, in-depth assessment of a single captive chimpanzee, we provide a rich context for analysing the impact of the changing roles of zoos on captive animals during the late 20th and 21st centuries
Teaching citation to university students
No full textA frequent comment by academic writing tutors is ‘use more citation’, yet this may not be helpful. University students may have difficulty with citation practices for several reasons. Prior to university, students may be encouraged to develop arguments based on personal opinions. At university, the risks of plagiarism are emphasised. Finally, students may be uncertain about challenging ‘expert’ views and how to assert their own voices critically and in ways that are acceptable in the disciplines and genres they are producing. This paper integrates findings from research that reveals the complexity of citation practices which could be presented as an intricate system network that might be practical for research purposes or for teacher education, but is more complicated than most students need. Three sample lessons are presented to show how research findings have been simplified for teaching students about citation. We are therefore able to compare theory that presents many logical possibilities, with research that presents probabilities and findings from specific contexts, with pedagogical practice in sample lessons that condense and often simplify theory and research in order to influence student writing
Prosecuting piracy in peacetime: crime, empire, and the High Court of Admiralty, 1603-1620
No full textThis thesis focuses on the records of the High Court of Admiralty to reconstruct the history
of Jacobean piracy from 1603 to 1620. By emphasising the role of the court in shaping historical
evidence, it offers fresh analysis of piracy and its role in the expanding maritime world of early
modern England. It takes an explicitly social approach to piracy, using elements of history ‘from
below’ and social network analysis to uncover how rovers and their supporters came together to
successfully plunder the seventeenth-century Atlantic.
Chapter 1 focuses on the High Court of Admiralty itself, offering a new understanding of its
criminal jurisdiction and process. Chapters 2 to 7 then provides a chronological approach to the rise
and fall of Jacobean piracy. I identify several four clear stages in the development of Jacobean
roving, and trace social genealogy that connected them to plot the coalescence and dissolution of
organised roving. I show that pirates were intimately connected to the wider maritime world, as
successful, sustained piracy relied on access to support and supplies, facilitated through key social
links and brokers. As a result, connections emerge between piracy and wider patterns of mercantile
growth and colonialism.
This thesis’ closer attention to the legal records used to historicise piracy enables a more
critical view of maritime depredation. I highlight the legal strategies used by pirates, their
accessories, and their victims in court, and consider how these affect the historical information
available to historians. Chapter 8 also applies these elements of legal history to the cultural history
of piracy, re-centring law as culture and comparing portrayals of piracy in court as well as on stage
and in print. Overall, Jacobean roving emerges as a vital chapter not only in the history of piracy, but
in the greater history of the maritime world