Thomas McCrie: churchman and historian

To have deserved the title, the "Discoverer of John Knox," would seem to he certain assurance of undying fame and regard, at least in Scotland, if not among all Protestants; and yet, the man who earned that title is little known in his native land and practically unknown in his native town of Duns. Not that his name has disappeared entirely, for "Thomas McCrie" may still be discovered in the footnotes of even recent historical works concerned with the Scottish Church, and his "Life of Knox," which was responsible for restoring the great Reformer to his rightful place among the greatly honoured and highly regarded of Scotia's sons, will, probably, always be recognised as a standard which later historians have only embellished. However, McCrie accomplished much more in life than the composition of his biography of Knox, and this thesis is an attempt to recover Dr. McCrie's works from the oblivion for which they seemed to be destined and to assess his Importance and determine his place among the Scottish Historians. At the same time, an effort has been made to sketch enough of his life so that his character and background may be understood, and also to make a study of his main contribution to Scottish Churchmanship, which was in the field of Church and State relations, an area which, more than any other, has been the field of conflict in the Scottish Church.Although a detailed review of any single work has not been presented, a study of all McCrie's works has been made in the course of the preparation of this thesis. It should be mentioned , too, that not one of them proved to be dull or uninteresting and their style was found to be unexpectedly modern. In fact, his historical works are as easily read as a good novel which one scarcely wishes to lay aside until one has finished reading it all. His support of the Presbyterian Church of Scotland, the Reformers, and the Covenanters, and his intense pride in and love of his native land, gratifying to anyone of Scottish descent and of Presbyterian conviction but his outspoken criticism of prelacy and his undisguised preference for Scotland and Scottish life above any other, may be aggravating to the Episcopalians, particularly to those "south of the Border," as it evidently was when his works were first penned.Besides McCrie's own works and other general works on Scottish Church History and on the development of the science of Historiography, a study has been made of the periodicals and reviews contemporary with McCrle, and the conclusion seems to be Justified that, though McCrie was, in some respects, a late historian of the "Enlightenment," he was much more, for Scotland at least, a precursor of the age of scientific Historiography which has always been recognised to have commenced with Ranke

An investigation into lipid exchange in the maintenance of lipid asymmetry pathway

The Maintenance of Lipid Asymmetry (Mla) pathway is a 6 component system implicated in the transport of phospholipids between the Gram-negative bacterial membranes, specifically in the transport of ectopic phospholipids from the outer leaflet of the outer membrane to the inner membrane. However, papers from 2019 proposed a potential role in phospholipid export. As phospholipid export to the outer membrane currently represents the last unexplored frontier of outer membrane biogenesis, the prospect of identifying a pathway responsible presents an attractive topic for further investigation. Moreover, deficiencies in Mla activity have been shown to reduce virulence and increase susceptibility to membrane destabilising agents, cementing Mla as a topic of significant interest to the field of antimicrobial research. As such, the original objective of this project was to investigate lipid transport between the inner membrane component of the Mla pathway and the periplasmic chaperone with the intent of understanding the discrepancies between the findings in the 2019 papers and the original categorisation of Mla function. However, subsequent publications have provided clear evidence that Mla plays no role in lipid export. Thus we chose to shift the main objective of the project to understanding the mechanism by which ATPase activity in MlaFE results in lipid exchange between MlaC and MlaD. We present structural data of a stalled intermediate complex of MlaC and MlaD, showing the binding interface, from which we have identified several residues with significant effects on lipid exchange between the two proteins. Based on these results, and existing understanding of MlaFEDB conformational changes we propose a mechanism by which ATPase induced conformational changes in MlaD might result in the expulsion of lipid from the MlaC binding pocket

Optimal scales to observe habitat dynamics: A coral reef example

A new technique to estimate the characteristic length scales (CLSs) of real ecological systems provides an objective means to identify the optimal scale(s) of observation to best detect underlying dynamical trends. Application of the technique to natural systems has focused on identifying appropriate scales to measure the dynamics of species as descriptors of community and ecosystem dynamics. However, ecosystem monitoring is often based not on assessing single species, but on species assemblages, functional groups, or habitat types. We asked whether the concept of CLSs based on dynamic interactions among species could be extended to examine interactions among habitat types and thus to identify optimal scales for observing habitat dynamics. A time series of three spatial maps of benthic habitats on a Caribbean coral reef was constructed from aerial photographs, Compact Airborne Spectrographic Imager (CASI) images, and IKONOS satellite images, providing the short time sequence required for this technique. We estimated the CLS based on the dynamics of three distinct habitat types: dense stands of seagrass, sparse stands of seagrass, and Montastrea patch reefs. Despite notable differences in the areal extent of and relative change in these habitats over the 21-year observation period, analyses based on each habitat type indicated a similar CLS of similar to 300 m. We interpret the consistency of CLSs among habitats to indicate that the dynamics of the three habitat types are linked. The results are encouraging, and they indicate that CLS techniques can be used to identify the appropriate scale at which to monitor ecosystem trends on the basis of the dynamics of only one of a disparate suite of habitat types

An octameric PqiC toroid stabilises the outer-membrane interaction of the PqiABC transport system

The E. coli Paraquat Inducible (Pqi) Pathway is a putative Gram-negative phospholipid transport system. The pathway comprises three components: an integral inner membrane protein (PqiA), a periplasmic spanning MCE family protein (PqiB) and an outer membrane lipoprotein (PqiC). Interactions between all complex components, including stoichiometry, remain uncharacterised; nevertheless, once assembled into their quaternary complex, the trio of Pqi proteins are anticipated to provide a continuous channel between the inner and outer membranes of diderms. Here, we present X-ray structures of both the native and a truncated, soluble construct of the PqiC lipoprotein, providing insight into its biological assembly, and utilise neutron reflectometry to characterise the nature of the PqiB-PqiC-membrane interaction. Finally, we employ phenotypic complementation assays to probe specific PqiC residues, which imply the interaction between PqiB and PqiC is less intimate than previously anticipated.</p

Structure of the MlaC-MlaD complex reveals molecular basis of periplasmic phospholipid transport

The Maintenance of Lipid Asymmetry (Mla) pathway is a multicomponent system found in all gram-negative bacteria that contributes to virulence, vesicle blebbing and preservation of the outer membrane barrier function. It acts by removing ectopic lipids from the outer leaflet of the outer membrane and returning them to the inner membrane through three proteinaceous assemblies: the MlaA-OmpC complex, situated within the outer membrane; the periplasmic phospholipid shuttle protein, MlaC; and the inner membrane ABC transporter complex, MlaFEDB, proposed to be the founding member of a structurally distinct ABC superfamily. While the function of each component is well established, how phospholipids are exchanged between components remains unknown. This stands as a major roadblock in our understanding of the function of the pathway, and in particular, the role of ATPase activity of MlaFEDB is not clear. Here, we report the structure of E. coli MlaC in complex with the MlaD hexamer in two distinct stoichiometries. Utilising in vivo complementation assays, an in vitro fluorescence-based transport assay, and molecular dynamics simulations, we confirm key residues, identifying the MlaD β6-β7 loop as essential for MlaCD function. We also provide evidence that phospholipids pass between the C-terminal helices of the MlaD hexamer to reach the central pore, providing insight into the trajectory of GPL transfer between MlaC and MlaD

Inherent limits of light-level geolocation may lead to over-interpretation

In their 2015 Current Biology paper, Streby et al. [1] reported that Golden-winged Warblers (Vermivora chrysoptera), which had just migrated to their breeding location in eastern Tennessee, performed a facultative and up to “>1,500 km roundtrip” to the Gulf of Mexico to avoid a severe tornadic storm. From light-level geolocator data, wherein geographical locations are estimated via the timing of sunrise and sunset, Streby et al. [1] concluded that the warblers had evacuated their breeding area approximately 24 hours before the storm and returned about five days later. The authors presented this finding as evidence that migratory birds avoid severe storms by temporarily moving long-distances. However, the tracking method employed by Streby et al. [1] is prone to considerable error and uncertainty. Here, we argue that this interpretation of the data oversteps the limits of the used tracking technique. By calculating the expected geographical error range for the tracked birds, we demonstrate that the hypothesized movements fell well within the geolocators’ inherent error range for this species and that such deviations in latitude occur frequently even if individuals remain stationary

An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8 Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrated transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P<0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL. These observations provide valuable guidance for further characterisation of 7q deletion

The retrospective analysis of Antarctic tracking data project

The Retrospective Analysis of Antarctic Tracking Data (RAATD) is a Scientific Committee for Antarctic Research project led jointly by the Expert Groups on Birds and Marine Mammals and Antarctic Biodiversity Informatics, and endorsed by the Commission for the Conservation of Antarctic Marine Living Resources. RAATD consolidated tracking data for multiple species of Antarctic meso- and top-predators to identify Areas of Ecological Significance. These datasets and accompanying syntheses provide a greater understanding of fundamental ecosystem processes in the Southern Ocean, support modelling of predator distributions under future climate scenarios and create inputs that can be incorporated into decision making processes by management authorities. In this data paper, we present the compiled tracking data from research groups that have worked in the Antarctic since the 1990s. The data are publicly available through biodiversity.aq and the Ocean Biogeographic Information System. The archive includes tracking data from over 70 contributors across 12 national Antarctic programs, and includes data from 17 predator species, 4060 individual animals, and over 2.9 million observed locations

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin’s Lymphoma in Children

BACKGROUND: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.)

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches