Bernal and the structure of water

Bernal recognised early on the importance of water in biological systems and processes, and hence the need to understand the structure of the liquid if he was to understand its biological functionality. Although the structure of crystalline ice had been solved only a few years earlier, and little was understood about the structures of liquids in general, in 1933 he published what is still regarded as a seminal paper which treated not only the structure of liquid water itself, but also addressed an impressively wide range of problems of ice and ionic solutions. Imaginatively exploiting ideas that were developing at the time, he proposed a model for water that reproduced the main features of its x-ray diffraction pattern. Despite the success of this model, however, he subsequently found it unsatisfactory – ''a delusive approach, postulating a greater degree of order in the liquid than actually exists there''. Building on the very successful ''random packing'' model of simple liquids that he developed in the 1950s and 60s, he was ultimately led to a ''random network'' model that was consistent with the known properties of the individual water molecules, and that again could reproduce a range of experimental data – but this time without the model being too ordered. Todays state of the art experiments essentially verify the underlying validity of his ideal model. And even his 1933 model of the water molecule itself is mimicked in some of the more successful molecular models used in todays computer simulations of aqueous systems

Snapshots

Musing over half a century of interactions with Alan Mackay, a rich array of images of past occasions emerges, personal as well as professional. Some are serious, some playful and some approaching the bizarre. Leafing through a few of these snapshots, I attempt to illustrate some of those aspects of Alan that have demonstrated to me not just his broad radical intellectual imagination, but also his generosity and humanity

Structure of a new dense amorphous ice

The detailed structure of a new dense amorphous ice, VHDA, is determined by isotope substitution neutron diffraction. Its structure is characterized by a doubled occupancy of the stabilizing interstitial location that was found in high density amorphous ice, HDA. As would be expected for a thermally activated unlocking of the stabilizing "interstitial," the transition from VHDA to LDA (low-density amorphous ice) is very sharp. Although its higher density makes VHDA a better candidate than HDA for a physical manifestation of the second putative liquid phase of water, as for the HDA case, the VHDA to LDA transition also appears to be kinetically controlled

Bernal's road to random packing and the structure of liquids

Until the 1960s, liquids were generally regarded as either dense gases or disordered solids, and theoretical attempts at understanding their structures and properties were largely based on those concepts. Bernal, himself a crystallographer, was unhappy with either approach, preferring to regard simple liquids as ‘homogeneous, coherent and essentially irregular assemblages of molecules containing no crystalline regions’. He set about realizing this conceptual model through a detailed examination of the structures and properties of random packings of spheres. In order to test the relevance of the model to real liquids, ways had to be found to realize and characterize random packings. This was at a time when computing was slow and in its infancy, so he and his collaborators set about building models in the laboratory, and examining aspects of their structures in order to characterize them in ways which would enable comparison with the properties of real liquids. Some of the imaginative – often time consuming and frustrating – routes followed are described, as well the comparisons made with the properties of simple liquids. With the increase of the power of computers in the 1960s, computational approaches became increasingly exploited in random packing studies. This enabled the use of packing concepts, and the tools developed to characterize them, in understanding systems as diverse as metallic glasses, crystal–liquid interfaces, protein structures, enzyme–substrate interactions and the distribution of galaxies, as well as their exploitation in, for example, oil extraction, understanding chromatographic separation columns, and packed beds in industrial processes

Detailed crystallographic analysis of the ice V to ice XIII hydrogen-ordering phase transition

Ice V is a structurally highly complex material with 28 water molecules in its monoclinic unit cell. It is classified as a hydrogen-disordered phase of ice. Yet, some of its hydrogen-bonded water molecules display significant orientational order. Upon cooling pure ice V, additional orientational ordering cannot be achieved on the experimental time scale. Doping with hydrochloric acid has been shown to be most effective in enabling the phase transition of ice V to its hydrogen-ordered counterpart ice XIII. Here, we present a detailed crystallographic study of this phase transition investigating the effects of hydrochloric and hydrofluoric acid as well as lithium and potassium hydroxide doping. The magnitudes of the stepwise changes in the lattice constants during the phase transition are found to be more sensitive indicators for the extent of hydrogen order in ice XIII than the appearance of new Bragg peaks. Hydrofluoric acid and lithium hydroxide doping enable similar ordering processes as hydrochloric acid but with slower kinetics. The various possible space groups and ordered configurations of ice XIII are examined systematically, and the previously determined P21/a structure is confirmed. Interestingly, the partial hydrogen order already present in ice V is found to perpetuate into ice XIII, and these ordering processes are found to be independent of pressure. Overall, the hydrogen ordering goes along with a small increase in volume, which appears to be the origin of the slower hydrogen-ordering kinetics under pressure. Heating pressure-quenched samples at ambient pressure revealed low-temperature "transient ordering" features in both diffraction and calorimetry

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Foot pain and foot health in an educated population of adults: results from the Glasgow Caledonian University Alumni Foot Health Survey

Abstract Background Foot pain is common amongst the general population and impacts negatively on physical function and quality of life. Associations between personal health characteristics, lifestyle/behaviour factors and foot pain have been studied; however, the role of wider determinants of health on foot pain have received relatively little attention. Objectives of this study are i) to describe foot pain and foot health characteristics in an educated population of adults; ii) to explore associations between moderate-to-severe foot pain and a variety of factors including gender, age, medical conditions/co-morbidity/multi-morbidity, key indicators of general health, foot pathologies, and social determinants of health; and iii) to evaluate associations between moderate-to-severe foot pain and foot function, foot health and health-related quality-of-life. Methods Between February and March 2018, Glasgow Caledonian University Alumni with a working email address were invited to participate in the cross-sectional electronic survey (anonymously) by email via the Glasgow Caledonian University Alumni Office. The survey was constructed using the REDCap secure web online survey application and sought information on presence/absence of moderate-to-severe foot pain, patient characteristics (age, body mass index, socioeconomic status, occupation class, comorbidities, and foot pathologies). Prevalence data were expressed as absolute frequencies and percentages. Multivariate logistic and linear regressions were undertaken to identify associations 1) between independent variables and moderate-to-severe foot pain, and 2) between moderate-to-severe foot pain and foot function, foot health and health-related quality of life. Results Of 50,228 invitations distributed, there were 7707 unique views and 593 valid completions (median age [inter-quartile range] 42 [31–52], 67.3% female) of the survey (7.7% response rate). The sample was comprised predominantly of white Scottish/British (89.4%) working age adults (95%), the majority of whom were overweight or obese (57.9%), and in either full-time or part-time employment (82.5%) as professionals (72.5%). Over two-thirds (68.5%) of the sample were classified in the highest 6 deciles (most affluent) of social deprivation. Moderate-to-severe foot pain affected 236/593 respondents (39.8%). High body mass index, presence of bunions, back pain, rheumatoid arthritis, hip pain and lower occupation class were included in the final multivariate model and all were significantly and independently associated with moderate-to-severe foot pain (p < 0.05), except for rheumatoid arthritis (p = 0.057). Moderate-to-severe foot pain was significantly and independently associated lower foot function, foot health and health-related quality of life scores following adjustment for age, gender and body mass index (p < 0.05). Conclusions Moderate-to-severe foot pain was highly prevalent in a university-educated population and was independently associated with female gender, high body mass index, bunions, back pain, hip pain and lower occupational class. Presence of moderate-to-severe foot pain was associated with worse scores for foot function, foot health and health-related quality-of-life. Education attainment does not appear to be protective against moderate-to-severe foot pain

Inference of hidden structures in complex physical systems by multi-scale clustering

We survey the application of a relatively new branch of statistical physics--"community detection"-- to data mining. In particular, we focus on the diagnosis of materials and automated image segmentation. Community detection describes the quest of partitioning a complex system involving many elements into optimally decoupled subsets or communities of such elements. We review a multiresolution variant which is used to ascertain structures at different spatial and temporal scales. Significant patterns are obtained by examining the correlations between different independent solvers. Similar to other combinatorial optimization problems in the NP complexity class, community detection exhibits several phases. Typically, illuminating orders are revealed by choosing parameters that lead to extremal information theory correlations.Comment: 25 pages, 16 Figures; a review of earlier work

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application