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Funding: This work was partially supported by the UK Engineering and Physical Sciences Research Council under grant number EP/N007565/1 (Science of Sensor Systems Software). In this paper we examine the structure of random networks that have undergone bond percolation an arbitrary, but finite, number of times. We define two types of sequential branching processes: a competitive branching process - in which each iteration performs bond percolation on the residual graph (RG) resulting from previous generations; and, collaborative branching process - where percolation is performed on the giant connected component (GCC) instead. We investigate the behaviour of these models, including the expected size of the GCC for a given generation, the critical percolation probability and other topological properties of the resulting graph structures using the analytically exact method of generating functions. We explore this model for Erds-Renyi and scale free random graphs. This model can be interpreted as a seasonal n-strain model of disease spreading. Publisher PDF

Funding: This work was supported through a studentship from BBSRC in the EastBio doctoral training programme for E. S.-P. Is-PETase has become an enzyme of significant interest due to its ability to catalyse the degradation of polyethylene terephthalate (PET) at mesophilic temperatures. We performed hybrid quantum mechanics and molecular mechanics (QM/MM) at the DSD-PBEP86-D3/ma-def2-TZVP/CHARMM27//rev-PBE-D3/dev2-SVP/CHARMM level to calculate the energy profile for the degradation of a suitable PET model by this enzyme. Very low overall barriers are computed for serine protease-type hydrolysis steps (as low as 34.1 kJ mol-1). Spontaneous deprotonation of the final product, terephthalic acid, with a high computed driving force indicates that product release could be rate limiting. Publisher PDF

D.S.P. and D.J.F. thank the EPSRC for funding via Prosperity Partnership EP/S035990/1. D.S.P. and D.J.F. thank the ARCHIE-WeSt High-Performance Computing Centre (www.archie-west.ac.uk) for computational resources. The UCL authors thank Prof. Keith Refson for guidance with the phonon calculations, which used the ARCHER U.K. National Supercomputing Service (http://www.archer.ac.uk) as part of the U.K. HEC Materials Chemistry Consortium, which is funded by the EPSRC (EP/L000202, EP/R029431). R.G. was funded by MagnaPharm, a project funded by the European Union’s Horizon 2020 Research and Innovation programme under grant agreement number 736899. We demonstrate that physics-based calculations of intrinsic aqueous solubility can rival cheminformatics-based machine learning predictions. A proof-of-concept was developed for a physics-based approach via a sublimation thermodynamic cycle, building upon previous work that relied upon several thermodynamic approximations, notably the 2RT approximation, and limited conformational sampling. Here, we apply improvements to our sublimation free-energy model with the use of crystal phonon mode calculations to capture the contributions of the vibrational modes of the crystal. Including these improvements with lattice energies computed using the model-potential-based Ψmol method leads to accurate estimates of sublimation free energy. Combining these with hydration free energies obtained from either molecular dynamics free-energy perturbation simulations or density functional theory calculations, solubilities comparable to both experiment and informatics predictions are obtained. The application to coronene, succinic acid, and the pharmaceutical desloratadine shows how the methods must be adapted for the adoption of different conformations in different phases. The approach has the flexibility to extend to applications that cannot be covered by informatics methods. Publisher PDF

This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) (Grant BB/M010996/1) via EASTBIO Doctoral Training Partnership studentships to B.J.R. and G.F., and by the Engineering and Physical Sciences Research Council (EPSRC) [grant number EP/L016419/1] via a CRITICAT Centre for Doctoral Training studentship to T.F.G.M. ATP phosphoribosyltransferase (ATPPRT) catalyzes the first step of histidine biosynthesis in bacteria, namely, the condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate N1-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate. Catalytic (HisGS) and regulatory (HisZ) subunits assemble in a hetero-octamer where HisZ activates HisGS and mediates allosteric inhibition by histidine. In Acinetobacter baumannnii, HisGS is necessary for the bacterium to persist in the lung during pneumonia. Inhibition of ATPPRT is thus a promising strategy for specific antibiotic development. Here, A. baumannii ATPPRT is shown to follow a rapid equilibrium random kinetic mechanism, unlike any other ATPPRT. Histidine noncompetitively inhibits ATPPRT. Binding kinetics indicates histidine binds to free ATPPRT and to ATPPRT:PRPP and ATPPRT:ATP binary complexes with similar affinity following a two-step binding mechanism, but with distinct kinetic partition of the initial enzyme:inhibitor complex. The dipeptide histidine-proline inhibits ATPPRT competitively and likely uncompetitively, respectively, against PRPP and ATP. Rapid kinetics analysis shows His-Pro binds to the ATPPRT:ATP complex via a two-step binding mechanism. A related HisZ that shares 43% sequence identity with A. baumannii HisZ is a tight-binding allosteric inhibitor of A. baumannii HisGS. These findings lay the foundation for inhibitor design against A. baumannii ATPPRT. Postprint

The authors would like to thank the School of Computer Science, the School of Chemistry, and the School of Biology of the University of St Andrews for funding this work. We present exact solutions for the size of the giant connected component of complex networks composed of cliques following bond percolation. We use our theoretical result to find the location of the percolation threshold of the model, providing analytical solutions where possible. We expect the results derived here to be useful to a wide variety of applications including graph theory, epidemiology, percolation, and lattice gas models, as well as fragmentation theory. We also examine the Erdős-Gallai theorem as a necessary condition on the graphicality of configuration model networks comprising clique subgraphs. Publisher PDF

Networks provide a mathematically rich framework to represent social contacts sufficient for the transmission of disease. Social networks are often highly clustered and fail to be locally tree-like. In this paper, we study the effects of clustering on the spread of sequential strains of a pathogen using the generating function formulation under a complete cross-immunity coupling, deriving conditions for the threshold of coexistence of the second strain. We show that clustering reduces the coexistence threshold of the second strain and its outbreak size in Poisson networks, whilst exhibiting the opposite effects on uniform-degree models. We conclude that clustering within a population must increase the ability of the second wave of an epidemic to spread over a network. We apply our model to the study of multilayer clustered networks and observe the fracturing of the residual graph at two distinct transmissibilities., 9 pages, 5 figures

Background:Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation.Results:Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity, searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile.Conclusion:In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.

In this paper we introduce a novel description of the equilibrium state of a bond percolation process on random graphs using the exact method of generating functions. This allows us to find the expected size of the giant connected component (GCC) of two sequential bond percolation processes in which the bond occupancy probability of the second process is modulated (increased or decreased) by a node being inside or outside of the GCC created by the first process. In the context of epidemic spreading this amounts to both a antagonistic partial immunity or a synergistic partial coinfection interaction between the two sequential diseases. We examine configuration model networks with tunable clustering. We find that the emergent evolutionary behaviour of the second strain is highly dependent on the details of the coupling between the strains. Contact clustering generally reduces the outbreak size of the second strain relative to unclustered topologies; however, positive assortativity induced by clustered contacts inverts this conclusion for highly transmissible disease dynamics., 10 pages, 5 figures

Funding: This work was partially supported by the UK Engineering and Physical Sciences Research Council under grant number EP/N007565/1 (Science of Sensor Systems Software). Correlations among the degrees of nodes in random graphs often occur when clustering is present. In this paper we define a joint-degree correlation function for nodes in the giant component of clustered configuration model networks which are comprised of higher-order subgraphs. We use this model to investigate, in detail, the organisation among nearest-neighbour subgraphs for random graphs as a function of subgraph topology as well as clustering. We find an expression for the average joint degree of a neighbour in the giant component at the critical point for these networks. Finally, we introduce a novel edge-disjoint clique decomposition algorithm and investigate the correlations between the subgraphs of empirical networks. Postprint

Percolation theory can be used to describe the structural properties of complex networks using the generating function formulation. This mapping assumes that the network is locally tree-like and does not contain short-range loops between neighbours. In this paper we use the generating function formulation to examine clustered networks that contain simple cycles and cliques of any order. We use the natural generalisation to the Molloy-Reed criterion for these networks to describe their critical properties and derive an analytical description of the size of the giant component, providing solutions for Poisson and power-law networks. We find that networks comprising larger simple cycles behave increasingly more tree-like. Conversley, clustering comprised of larger cliques increasingly deviate from the tree-like solution, although the behaviour is strongly dependent on the degree-assortativity., 11 pages, 6 figures

The structure of many real networks is not locally tree-like and hence, network analysis fails to characterise their bond percolation properties. In a recent paper [P. Mann, V. A. Smith, J. B. O. Mitchell, and S. Dobson, Percolation in random graphs with higher-order clustering, arXiv e-prints, p. arXiv:2006.06744, June 2020.], we developed analytical solutions to the percolation properties of random networks with homogeneous clustering (clusters whose nodes are degree-equivalent). In this paper, we extend this model to investigate networks that contain clusters whose nodes are not degree-equivalent, including multilayer networks. Through numerical examples we show how this method can be used to investigate the properties of random complex networks with arbitrary clustering, extending the applicability of the configuration model and generating function formulation., Comment: 11 pages, 10 figures

Introduction Increasingly, health care is delivered through a patient-centered model, and patients engage in shared decision-making with their medical providers. As a result, medical educators are placing more emphasis on patient-centered communication skills. However, few published curricula currently offer a comprehensive discussion of skills for providing patient-centered education (PCE), a key component of shared decision-making. We developed an interactive, two-session workshop aiming to improve students’ abilities to provide PCE. Methods Our workshop included didactic instruction, group discussion, and interactive simulations. The workshop was delivered to 50 clinical clerkship medical students. The first session concentrated on educating patients about their diagnoses, while the second session focused on providing patients with information about medications and other treatments. We used detailed and realistic role-play exercises as a core tool for student practice and demonstration of confidence. To evaluate the workshop, we used pre- and postsurveys. Results The sessions were well received by students, who strongly agreed both before and after the workshop that PCE was an important skill. Students also strongly agreed that the role-play exercises were an effective tool for learning PCE. They demonstrated significant improvements in their confidence to name important elements of PCE and to deliver PCE in the future. Discussion This workshop fills a curricular gap in offering a comprehensive and interactive curriculum for improving students’ abilities to provide critical PCE. The format and content should be easily adaptable to various disciplines, learners, and teaching modalities.

We describe three machine learning models submitted to the 2019 Solubility Challenge. All are founded on tree-like classifiers, with one model being based on Random Forest and another on the related Extra Trees algorithm. The third model is a consensus predictor combining the former two with a Bagging classifier. We call this consensus classifier Vox Machinarum, and here discuss how it benefits from the Wisdom of Crowds. On the first 2019 Solubility Challenge test set of 100 low-variance intrinsic aqueous solubilities, Extra Trees is our best classifier. One the other, a high-variance set of 32 molecules, we find that Vox Machinarum and Random Forest both perform a little better than Extra Trees, and almost equally to one another. We also compare the gold standard solubilities from the 2019 Solubility Challenge with a set of literature-based solubilities for most of the same compounds.

Coinfection is the process by which a host that is infected with a pathogen becomes infected by a second pathogen at a later point in time. An immunosuppressant host response to a primary disease can facilitate spreading of a subsequent emergent pathogen among the population. Social contact patterns within the substrate populace can be modelled using complex networks and it has been shown that contact patterns vastly influence the emergent disease dynamics. In this paper, we consider the effect of contact clustering on the coinfection dynamics of two pathogens spreading over a network. We use the generating function formulation to describe the expected outbreak sizes of each pathogen and numerically study the threshold criteria that permit the coexistence of each strain among the network. We find that the effects of clustering on the levels of coinfection are governed by the details of the contact topology., Comment: 9 page, 5 figures

The third flight of the High-Resolution Coronal Imager (Hi-C 2.1) occurred on May 29, 2018, the Sounding Rocket was launched from White Sands Missile Range in New Mexico. The instrument has been modified from its original configuration (Hi-C 1) to observe the solar corona in a passband that peaks near 172 Angstrom and uses a new, custom-built low-noise camera. The instrument targeted Active Region 12712, and captured 78 images at a cadence of 4.4 sec (18:56:22 - 19:01:57 UT; 5 min and 35 sec observing time). The image spatial resolution varies due to quasi-periodic motion blur from the rocket; sharp images contain resolved features of at least 0.47 arcsec. There are coordinated observations from multiple ground- and space-based telescopes providing an unprecedented opportunity to observe the mass and energy coupling between the chromosphere and the corona. Details of the instrument and the data set are presented in this paper., Comment: 26 pages, 15 figures, submitted to Solar Physics

Hydrilla, Hydrilla verticillata (L.f.) Royle (Hydrocharitaceae), is an invasive aquatic macrophyte found in fresh water. The introduction of hydrilla by the aquarium plant trade has led to its invasion throughout much of the southern US and its current listing as a federal noxious weed. Hydrilla employs many pathways of reproduction and once established can rapidly fill the water column, impeding recreation and negatively affecting the environment. Waterways infested with hydrilla typically experience matting of vegetation at the surface that results in less light penetration, and changes in dissolved oxygen levels, which disturb native species richness and diversity. Efforts to minimize hydrilla populations include using biological control agents such as the hydrilla tip mining midge, Cricotopus lebetis Sublette (Diptera: Chironomidae). The larvae of C. lebetis feed on the apical meristem of hydrilla tips, disabling further vertical growth and forcing growth into a branched horizontal direction. Currently, a colony of C. lebetis is being mass-reared to augment midge populations throughout hydrilla-infested waters. In order to maintain colony viability for effective releases, midge eggs must be collected and placed on hydrilla before larvae exhaust endogenous nutrient reserves. To understand the effects of larval starvation on survival and subsequent development to adult eclosion, neonates at 0, 1, 2, and 3 d post-hatch were studied with and without access to food. Midge survival and adult eclosion decreased significantly after continued starvation post-hatch. Larvae starved for 2 d post-hatch did not eclose. Highest survival to adult eclosion occurred when midge larvae were placed on hydrilla as soon as they hatched (48 h post-oviposition). This study highlights fundamental information necessary for efficient midge rearing for effective biological control of hydrilla.

Coventry Cathedral was completed in the early 1960s and has some prestressed concrete elements to resist lateral thrust from the roof. Other prestressed structures of a similar age have had corrosion problems and this has drawn attention to the fact that there is little publicly available information about the structural system at Coventry. This paper addresses that issue and is in three sections. The first summarises the four different prestressing systems in the Cathedral and estimates the amount of prestress and its purpose in each location. By placing the information in the public domain it will be useful for both historians of church architecture and engineers in future generations who may have to work on the building. Although there is no evidence of corrosion in the building at the moment, it is impossible to inspect the existing tendons, so the second section considers what might happen to the structure if corrosion of the tendons were to occur. It is concluded that very little warning of failure would be given, which would be especially important for the tendons over the baptistry window and those in the nave ties. The final section considers what could be monitored to give as much warning as possible about future problems. The effects of loss of an individual tendon, which would not by itself be sufficient to cause failure of the structure, would cause only very small strains that would be difficult to distinguish from the background strains caused by temperature change. Many of the principles discussed in the second and third sections would be applicable to many other prestressed concrete structures.

The authors thank the University of St Andrews, EPSRC (grant EP/L505079/1). The abundance of crystal structures of solvated organic molecules reflects the common role of solvent in the crystallisation process. An understanding of solvation is therefore important for crystal engineering, with solvent choice often affecting polymorphism as well as influencing the crystal structure. Of particular importance is the role of water, and a number of approaches have previously been considered in the analysis of large datasets of organic hydrates. In this work we attempt to develop a method suitable for application to organic hydrate crystal structures, in order to better understand the distribution of water molecules in such systems. We present a model aimed at combining the distribution functions of multiple atom pairs from a number of crystal structures. From this, we can comment qualitatively on the average distribution of water in organic hydrates. Postprint

This study quantifies the relationship between Tanzanian and external maize markets while also accounting for domestic influences. It concludes that external influences on domestic prices originate from regional, rather than global, markets. It also shows that, compared to external factors, domestic factors exert a greater influence on Tanzanian maize markets. Further, the mechanisms through which trade policies influence maize markets involve interactions with both external market shocks and domestic weather shocks. Overall, it provides evidence that the intermittent imposition of export bans in Tanzania has had adverse impacts on its maize markets, and consequently, on the development of its agrarian economy.

The unprecedented impact of COVID-19 has raised concern for the potential of increased suicides due to a convergence of suicide risk factors. We obtained suicide mortality data to assess completed suicides during the period of strict stay-at-home quarantine measures in Connecticut and compared this data with previous years. While the total age-adjusted suicide mortality rate decreased by 13% during the lockdown period compared with the 5-year average, a significantly higher proportion of suicide decedents were from racial minority groups. This finding may provide early evidence of a disproportionate impact from the social and economic challenges of COVID-19 on minority populations.

JMcD and JBOM would like to thank SULSA for funding. DSP thanks the University of Strathclyde for support through its Strategic Appointment and Investment Scheme. We compare a range of computational methods for the prediction of sublimation thermodynamics (enthalpy, entropy and free energy of sublimation). These include a model from theoretical chemistry that utilizes crystal lattice energy minimization (with the DMACRYS program) and QSPR models generated by both machine learning (Random Forest and Support Vector Machines) and regression (Partial Least Squares) methods. Using these methods we investigate the predictability of the enthalpy, entropy and free energy of sublimation, with consideration of whether such a method may be able to improve solubility prediction schemes. Previous work has suggested that the major source of error in solubility prediction schemes involving a thermodynamic cycle via the solid state is in the modeling of the free energy change away from the solid state. Yet contrary to this conclusion other work has found that the inclusion of terms such as the enthalpy of sublimation in QSPR methods does not improve the predictions of solubility. We suggest the use of theoretical chemistry terms, detailed explicitly in the methods section, as descriptors for the prediction of the enthalpy and free energy of sublimation. A dataset of 158 molecules with experimental sublimation thermodynamics values and some CSD refcodes has been collected from the literature and is provided with their original source references. Postprint

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By measuring the time of flight of scattered X-ray photons, the point of interaction, assuming a single scatter, can be determined, providing 3-D information about an object under inspection. This paper describes experimental ToF Compton scatter measurements conducted at the versatile electron linear accelerator (VELA), a picosecond pulsewidth electron source situated in Daresbury, U.K. The ToF of scattered X-ray photons was measured using a CeBr3 detector, and a full width at half maximum (FWHM) of between 29 and 36 cm was achieved with a 5-cm-thick plastic test object. By implementing a low-energy cutoff, the FWHM was reduced to between 12 and 26 cm. Two test objects placed in series with a 50-cm space between were separable in the data after applying the low energy cutoff.

Impotence, bladder dysfunction, GI symptoms, and orthostatic hypotension can signal autonomic dysfunction. Here's what you'll see and how to respond.

The chalcogen bond, the noncovalent, electrostatic attraction between covalently bonded atoms in group 16 and Lewis bases, is present in protein-ligand interactions based on X-ray structures deposited in the Protein Data Bank (PDB). Discovering protein-ligand chalcogen bonding in the PDB employed a strategy that focused on searching the database for protein complexes of five-membered, heterocyclic ligands containing endocyclic sulfur with endo electron-withdrawing groups (isothiazoles; thiazoles; 1,2,3-, 1,2.4-, 1,2,5-, 1,3,4-thiadiazoles) and thiophenes with exo electron-withdrawing groups, e.g., 2-chloro, 2-bromo, 2-amino, 2-alkylthio. Out of 930 ligands investigated, 33 or 3.5% have protein-ligand S---O interactions of which 31 are chalcogen bonds and two appear to be S---HO hydrogen bonds. The bond angles for some of the chalcogen bonds found in the PDB are less than 90°, and an electrostatic model is proposed to explain this phenomenon.

Olfactory neuroblastoma (ONB) is a rare malignant neoplasm of the sinonasal tract that arises from olfactory epithelium. There have been reports, mainly in tumors treated with chemoradiation or with distant metastases, describing focal histologic changes of divergent cell populations within archetypal ONB. Only three cases have been reported of ONB coexisting with non-neuroendocrine tumors. We describe our experience with a 35-year-old male with a nasal cavity mass extending into the anterior cranial fossa. Pathology revealed this to be a high grade malignant neoplasm with features of olfactory neuroblastoma and a significant divergent population of pancytokeratin and epithelial membrane antigen-reactive cells. The patient underwent combined endoscopic and open craniofacial resection followed by adjuvant chemoradiation. We describe the clinical presentation, treatment, and outcome followed by a review of the literature. Surgical pathology clearly demonstrated two cell populations evenly distributed and displaying classic histologic and immunohistochemical markers of ONB, as well as poorly differentiated cells with an epithelial immunophenotype. The patient is now 16 months status post completion of treatment with no evidence of recurrence. Our patient's presentation is unique and unusual in that the tumor demonstrated a high grade olfactory neuroblastoma and a divergent, epithelial-marker reactive cell population in the same tumor. This combined appearance is unusual and may represent an "olfactory carcinoma". Only one previous case has reported carcinomatous involvement of an ONB. There is insufficient information in the literature to draw conclusions on the impact these divergent cell populations have on prognosis or treatment.

D.S.P. is grateful for funding from the European Commission through a Marie Curie Intra-European Fellowship within the seventh European Community Framework Programme (FP7-PEOPLE-2010-IEF). D.S.P. thanks the University of Strathclyde for support through its Strategic Appointment and Investment Scheme. Computations were performed at the EPSRC funded ARCHIE-WeSt High Performance Computer (www.archie-west.ac.uk, EPSRC grant no. EP K0005861). J.B.O.M. thanks the Scottish Universities Life Sciences Alliance (SULSA) for financial support and EaStCHEM for access to the EaStCHEM Research Computing Facility. We report the results of testing quantitative structure-property relationships (QSPR) that were trained upon the same druglike molecules but two different sets of solubility data: (i) data extracted from several different sources from the published literature, for which the experimental uncertainty is estimated to be 0.6-0.7 log S units (referred to mol/L); (ii) data measured by a single accurate experimental method (CheqSol), for which experimental uncertainty is typically

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial resistance and vessel remodeling. Patients living with human immunodeficiency virus-1 (HIV-1) have an increased susceptibility to develop severe pulmonary hypertension (PH) irrespective of their CD4+ lymphocyte counts. While the underlying cause of HIV-PAH remains unknown, the interaction of HIV-1 proteins with the vascular endothelium may play a critical role in HIV-PAH development. Hypoxia promotes PH in experimental models and in humans, but the impact of HIV-1 proteins on hypoxia-induced pulmonary vascular dysfunction and PAH has not been examined. Therefore, we hypothesize that the presence of HIV-1 proteins and hypoxia synergistically augment the development of pulmonary vascular dysfunction and PH. We examined the effect of HIV-1 proteins on pulmonary vascular resistance by measuring pressure-volume relationships in isolated lungs from wild-type (WT) and HIV-1 Transgenic (Tg) rats. WT and HIV-1 Tg rats were exposed to 10% O2 for four weeks to induce experimental pulmonary hypertension to assess whether HIV-1 protein expression would impact the development of hypoxia-induced PH. Our results demonstrate that HIV-1 protein expression significantly increased pulmonary vascular resistance (PVR). HIV-1 Tg mice demonstrated exaggerated pulmonary vascular responses to hypoxia as evidenced by greater increases in right ventricular systolic pressures, right ventricular hypertrophy and vessel muscularization when compared to wild-type controls. This enhanced PH was associated with enhanced expression of HIF-1α and PCNA. In addition, in vitro studies reveal that medium from HIV-infected monocyte derived macrophages (MDM) potentiates hypoxia-induced pulmonary artery endothelial proliferation. These results indicate that the presence of HIV-1 proteins likely impact pulmonary vascular resistance and exacerbate hypoxia-induced PH.