Polymorph Selection Research Articles

Entire crystallization process of Lennard-Jones liquids: A large-scale molecular dynamics study.

By using a graphics processing unit-accelerated parallel algorithm on a compute unified device architecture platform, we perform large-scale molecular dynamics simulations in a Lennard-Jones system to observe the entire crystallization process, including metastable stage, critical nuclei formation, and the stage of crystal growth. Although the intermediated precursors that play a role in determining the polymorphs are predominantly bcc ordered, the polymorph selection is rather different at different stages. The precursors that have a relatively high orientational order will be on average in a denser region than uniform liquids, but microscopically the crystal nucleation happens without a density change. The average density of nuclei first increases significantly, and then almost keeps independent on the crystallite size after the growing post-critical nucleus becomes large enough. With such a large enough system, the crystal growth rate is able to be calculated directly by doing a linear fit to the temporal evolution of growing crystallite size. The obtained value of the growth rate indicates that the actual crystal growth in the Lennard-Jones system where the crystal-liquid interface has several kinds of structures is possibly driven by both collision-controlled and diffusion-controlled mechanisms.

Antifouling mechanism of the additive-free β-PVDF membrane in water purification process: Relating the surface electron donor monopolarity to membrane-foulant interactions

Although the antifouling modification of polyvinylidene fluoride (PVDF) membrane has attracted much attentions recently, the underlying fouling/antifouling mechanism of the PVDF membranes having different polymorphs have rarely been mentioned. In this study, two PVDF membranes with similar pore structure but distinct polymorphs were prepared, and their antifouling performance was systematically investigated by using synthetic solutions containing complex foulants relevant to surface water sources (e.g., humic acid, bovine serum albumin and dextran). A remarkable correlation between PVDF polymorph, membrane surface chemistry and fouling resistance was observed, demonstrating the exceptional ability of β-PVDF phase (i.e., β-PVDF membrane) in fouling mitigations when compared to α-PVDF phase (i.e., α-PVDF membrane). In order to unravel the fouling mechanism of PVDF membrane having different polymorphs, interaction forces between foulant-coated particle probes, simulating foulant molecules, and each membrane surface were measured by AFM and theoretical calculated depended on surface energy components. It is clearly shown that the enhanced fouling resistance of β-PVDF membrane was mainly driven by the reduced adhesion tendency of foulants, which could further attribute to the strong electron donor monopolarity of β-PVDF phase (γAB− = 25.3 mJ/m2) compared to α-PVDF phase (γAB− = 3.3 mJ/m2). Moreover, for each SSW-fouled membrane, depth profiling of the external fouling layer and composition of the extracted internal foulants were carefully investigated by variable angle FTIR and UV–vis spectrometer, respectively, suggesting the strong relationship between membrane fouling behavior and membrane-foulant and foulant-foulant interactions. This work emphasized the selection of proper polymorph of PVDF membrane should be valued so as to mitigate membrane fouling, and we anticipate the advantage of β-PVDF phase in membrane fouling control can boost the development of additive-free and sustainable antifouling strategy in future.

Crystallisation of iPB-1 based on preserved helix conformation

The intriguing problem during polymer crystallisation is to understand the crystal formation and transition, in particular the initiation in a liquid melt close to solid crystals and one solid crystal close to another. Polymorphic isotactic polybutene-1 (iPB-1) usually crystallises into kinetically favoured metastable form II from melt and then spontaneously transits to thermodynamically stable form I. Keeping in mind that polymer crystallisation is controlled by temperature-dependent prior chain conformation formation, we first successfully conserved form-I-favoured 3/1 helix conformation at low temperatures and determined its decomposition temperature as Td,3/1 = 132 °C. The detailed temperature-dependent helix conformation evolution of iPB-1 during the cooling/heating processes was outlined and the subsequent easy direct form I crystallisation via necessary diffusion and alignment of the preserved 3/1 helix conformation was deduced. The results would be helpful to understand the helix conformation roles in polymer crystallisation, polymorph selection and crystal transition.

Manufacture and characterization of two distinct quasi-polymorphs of empagliflozin

Abstract We investigated the polymorphic behaviors of empagliflozin (EMP), an SGLT2 inhibitor focusing on the preparation and characterization of its two distinct quasi-polymorphs combined with in-line monitoring of crystallization processes. EMP has only been reported as a single polymorph without pseudo-polymorphs so far. In this study, two differentiable crystal forms, the needle-shaped ‘Form I’ and platy-shaped ‘Form P’, were reproducibly created using an anti-solvent approach. Although the two forms of EMP yielded the same results in many of these analyses, they could be differentiated by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and microscopy. Based on a detailed analysis of DSC thermograms, a small but obvious transition was detected during the melting of crystalline EMP at 152–157 °C. This transition, which occurred at a low activation energy, was identified as a polymorphic transformation from Form P to Form I. The anti-solvent crystallization process was monitored by in-line NIR absorbance measurements and interpreted using principal component analysis (PCA). The crystal form was dependent on the crystallization solvent. Two different solvent/anti-solvent pairs (ethanol-water and ethanol-hexane) yielded substantially different PCA results, indicating distinct pathways to the creation of each crystal form. Rapid nucleation and high crystal growth rate was achieved by crystallization under Scheme P, which also exhibited fluctuation in its PC score plot. This was associated with reversible polymorphic selection between the two crystal forms during the crystallization of EMP.

Genome-wide studies of primary open-angle glaucoma

The article reviews literature on developmental stages of genome-wide association studies (GWAS) of primary open-angle glaucoma (POAG). This problem is currently developing and one of the most complex in ophthalmology. The article considers main GWAS of POAG and established GWAS-significant polymorphisms associated with the disease. The topic of genome-wide studies of primary open-angle glaucoma will be of certain interest to ophthalmologists, materials on GWAS-significant loci can be used both in the selection of polymorphisms in replicative studies of POAG in various populations of Russia, and to expand ideas about the molecular genetic mechanisms of the development of the disease.

Polymorph selection during melt crystallization of the isotactic polybutene-1 homopolymer depending on the melt state and crystallization pressure.

This work investigated the crystalline forms obtained from melt crystallization in the isotactic polybutene-1 (iPB-1) homopolymer via manipulation of the temperature at which samples were melted (Tmelt) and crystallization pressure (Pcry). Unlike the results under atmospheric conditions where the molten sample crystallized into the pure form II and the crystallization temperature and kinetics were affected obviously by Tmelt, the melted sample crystallized into forms II or I' under high pressure, depending on Tmelt and Pcry. The content of form I' decreases with increasing Tmelt or decreasing Pcry. Meanwhile, the critical pressure for the formation of pure form I' increases with increasing Tmelt. The formation of form I' is attributed to the memory effect of the melt which preserved some ordered sequence of crystal and the high pressure (Pcry) which suppressed the nucleation and growth of the kinetically favored form II, which results in the formation of form I'. In addition, the melt crystallized form II transforms to form I under high pressure conditions; thus forms I, I' and II are observed. The relative contents of the three crystalline forms on samples for different Tmelt and Pcry are obtained in this work. The result shows that the crystalline forms in melt crystallization of iPB-1 can be customized by regulating the melt state and crystallization conditions.

JUSTIFICATION OF CANDIDATE POLYMORPHISMS USAGE IN MARKER-ASSISTED SELECTION OF UKRAINIAN MEATY PIG BREED

Effective selection in pig breeding is not possible without involvement of new approaches which involve the assessment animal genotypes at the DNA level. The development of methods for determining the polymorphisms in candidate genes that are responsible for the manifestation of economic traits is the basis of modern marker selection technology (MAS). Currently, a number of DNA markers have been developed for use in the breeding of farm animals. In this case, the most informative were single nucleotide polymorphisms (SNPs) of genes. However, despite the significant amount of scientific research, the problem of development and implementation of DNA markers for breeds of Ukrainian selection remains relevant. The results of SNPs study of RYR1, CTSF and CTSD genes by PCR-RFLP method are presented. The initial stage for implementing marker selection for single nucleotide polymorphisms is conducting genetic-population analysis in the studied population of Ukrainian Meaty pig breed. It was found that SNP RYR1 g. 1843 C>T was characterized by low polymorphism, the minor allele g. 1843 T met with a frequency of q = 0.05. SNP CTSD g. 70 G>A had a low level of representativeness, allele g. 70 A prevailed at a frequency of q = 0.92. It was found that SNP CTSF g. 22 G>C was characterized by a sufficient level of representativeness, both alleles were detected with a predominance of the allele frequency g. 22 G (q=0.80). In the population of Ukrainian Meaty pig breed, there was a statistically confirmed deviation of genotype frequencies from SNP-balanced CTSF g. 22 G> C (χ2 = 28.125) and CTSD g. 70 G> A (χ2 = 26,518). In the future, SNPs of CTSF, CTSD genes can be used for associative studies to find a link between markers and signs of pig productivity and the introduction of marker-associated selection in the UM pig breed.

Coral acid rich protein selects vaterite polymorph in vitro

Corals and other biomineralizing organisms use proteins and other molecules to form different crystalline polymorphs and biomineral structures. In corals, it’s been suggested that proteins such as Coral Acid Rich Proteins (CARPs) play a major role in the polymorph selection of their calcium carbonate (CaCO3) aragonite exoskeleton. To date, four CARPs (1–4) have been characterized: each with a different amino acid composition and different temporal and spatial expression patterns during coral developmental stages. Interestingly, CARP3 is able to alter crystallization pathways in vitro, yet its function in this process remains enigmatic. To better understand the CARP3 function, we performed two independent in vitro CaCO3 polymorph selection experiments using purified recombinant CARP3 at different concentrations and at low or zero Mg2+ concentration. Our results show that, in the absence of Mg2+, CARP3 selects for the vaterite polymorph and inhibits calcite. However, in the presence of a low concentration of Mg2+ and CARP3 both Mg-calcite and vaterite are formed, with the relative amount of Mg-calcite increasing with CARP3 concentration. In all conditions, CARP3 did not select for the aragonite polymorph, which is the polymorph associated to CARP3 in vivo, even in the presence of Mg2+ (Mg:Ca molar ratio equal to 1). These results further emphasize the importance of Mg:Ca molar ratios similar to that in seawater (Mg:Ca equal to 5) and the activity of the biological system in a aragonite polymorph selection in coral skeleton formation.

Polymers and Solvent-Induced Polymorphic Selection and Preferential Orientation of Pyrazinamide Crystal

Induced crystallization plays an important role in polymorphism control of active pharmaceutical ingredients. Crystallization processes of pyrazinamide on templates of glass, nylon-66 (PA66), polyt...

Crystallization of Sulfathiazole in Gel: Polymorph Selectivity and Cross-Nucleation

Form II, Form III, and Form IV of sulfathiazole (STZ) crystallized simultaneously from water by a cooling crystallization method. Thus, how to obtain the pure form of STZ represents a major challenge during the sulfathiazole crystallization process. Here we report that the pure Form III or Form IV of STZ can be selectively grown in agarose matrix by only adjusting the concentration of agarose. Interestingly, at a specific concentration range of agarose, the cross-nucleation of Form III on Form IV was observed. Furthermore, the mechanisms of agarose that affect the process of cooling crystallization of STZ were investigated, which indicated that the crystalline outcomes correlate strongly with the state of agarose gel that existed in solution. The highly reproducible and controllable results will help to broaden the application of gel in controlling crystallization of polymorph in the pharmaceutical industry. It also can be used as a guide for polymorphic screening of STZ from cooling crystallization.

HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint.

Peptide-dependent engagement between human leucocyte antigens class I (HLA-I) molecules and their cognate receptors has been extensively analyzed. HLA-F belongs to the non-classical HLA-Ib molecules with marginal polymorphic nature and tissue restricted distribution. The three common allelic variants HLA-F*01:01/01:03/01:04 are distinguished by polymorphism outside the peptide binding pockets (residue 50, α1 or residue 251, α3) and are therefore not considered relevant for attention. However, peptide selection and presentation undergoes a most elaborated extraction from the whole available proteome. It is known that HLA-F confers a beneficial effect on disease outcome during HIV-1 infections. The interaction with the NK cell receptor initiates an antiviral downstream immune response and lead to delayed disease progression. During the time of HIV infection, HLA-F expression is upregulated, while its interaction with KIR3DS1 is diminished. The non-polymorphic nature of HLA-F facilitates the conclusion that understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response. Utilizing soluble HLA technology we recovered stable pHLA-F*01:01, 01:03 and 01:04 complexes from K562 cells and analyzed the peptides presented. Utilizing a sophisticated LC-MS-method, we analyzed the complete K562 proteome and matched the peptides presented by the respective HLA-F subtypes with detected proteins. All peptides featured a length of 8 to 24 amino acids and are not N-terminally anchored; the C-terminus is preferably anchored by Lys. To comprehend the alteration of the pHLA-F surface we structurally compared HLA-F variants bound to selected peptides. The peptides were selected from the same cellular content; however, no overlap between the proteomic source of F*01:01, 01:03 or 01:04 selected peptides could be observed. Recognizing the balance between HLA-F expression, HLA-F polymorphism and peptide selection will support to understand the role of HLA-F in viral pathogenesis.

Polymorphism and natural selection in the merozoite surface protein 3F2 (PVX_97710) locus of Plasmodium vivax among field isolates

Plasmodium vivax, the chronic relapsing human malaria parasite with the most widespread distribution, possesses proteins associated with the merozoite surface that could be targets for host immune responses and potential vaccine candidates. Of these, the merozoite surface protein 3 of P. vivax (PvMSP3) is an attractive vaccine target as well as a genetic marker for epidemiological surveillance. PvMSP3 comprises a group of protein members encoded by a multigene family. Although some protein members, i.e. PvMSP3α and PvMSP3β, have been targets for molecular and immunological investigations, the most abundantly expressed protein member during late asexual erythrocytic stages, PvMSP3F2 (PVX_97710), remains unexplored.To address domain organization and evolution of this locus, the complete coding sequences of 31 P. vivax isolates from diverse malaria endemic areas of Thailand were analyzed and compared with 10 previously reported sequences. Results revealed that all PvMSP3F2 sequences differed but could be divided into 5 repeat-containing domains flanked by 6 non-repeat domains. Repeat domains II and IV at the 5′ portion and domain X at the 3′ portion exhibited extensive sequence and length variation whereas repeat domains VI and VIII located at the central region were relatively conserved. Despite a repertoire of PvMSP3F2 variants, predicted coiled-coil tertiary structure and predicted B-cell epitopes seem to be maintained. Evidence of intragenic recombination has been detected among field isolates in Thailand that could enhance sequence diversity at this locus. Non-repeat domains I and IX located at the 5′ end and at the 3′ portion, respectively, seem to have evolved under purifying selection. Evidence of positive selection was found in non-repeat domains III, V and VII where a number of predicted HLA class I epitopes were identified. Amino acid substitutions in these predicted epitopes could alter predicted peptide binding affinity or abolish peptide epitope property, suggesting that polymorphism in these epitopes conferred host immune evasion. Further studies on PvMSP3F2 are warranted, particularly on interaction with host immune system and the potential role of this PvMSP3 protein member as a vaccine target.

Molecular Dynamics Simulations of Crystal Nucleation from Solution at Constant Chemical Potential.

A widespread method of crystal preparation is to precipitate it from a supersaturated solution. In such a process, control of solution concentration is of paramount importance. The nucleation process, polymorph selection, and crystal habits depend crucially on this thermodynamic parameter. When performing molecular dynamics simulations with a fixed number of molecules in the canonical ensemble, crystal growth is accompanied by a decrease in the solution concentration. This modification of the thermodynamic condition leads to significant artifacts. Inspired by the recent development of the constant chemical potential molecular dynamics simulation method by Perego et al. [ J. Chem. Phys. 2015 , 142 , 144113 ] , we develop a spherical variant of it to study nucleation from solution. Our method allows determining the crystal nucleus size and nucleation rates at constant supersaturation. As an example, we study the homogeneous nucleation of sodium chloride from its supersaturated aqueous solution.

Understanding Polymorph Selection of Sulfamerazine in Solution

Polymorphism can have a significant impact on important physical and chemical properties of pharmaceutical products. Empirical screening of polymorphs by using different solvent systems is often la...

2D Monte Carlo Simulation of Patchy Particles Association and Protein Crystal Polymorph Selection

Typically, protein crystals inherit the polymorphic form selected by nuclei arising in the solution. However, a transition of a polymorphic form may also occur at a later crystal growth stage. Unfortunately, due to the molecular-scale processes involved, the earliest stages of protein crystal nucleation and polymorph selection remain poorly understood. This paper attempts to elucidate the polymorph selection and crystal growth process in proteins (and colloidal crystals) using 2D Monte Carlo simulations and a computational model with short-range attraction for ‘protein-like’ patchy particles (PPs) of a specific patch geometry, bond width and strength. A relatively narrow temperature range is established whereby parts of the PPs monomers arrange initially in a rapidly growing unstable rhombohedral lattice (Rh). Stable trimers form simultaneously from the monomers remaining in the solution and monomers released from the Rh lattice. These trimers serve as building blocks of a more stable Kagome trihexagonal lattice (TriHex), which appears after a prolonged simulation time. The step-by-step scenario of this polymorphic transition and the specific role of PPs’ geometric and interaction anisotropies are discussed in detail.

Validity of polygenic risk scores: are we measuring what we think we are?

Polygenic risk scores (PRSs) have become the standard for quantifying genetic liability in the prediction of disease risks. PRSs are generally constructed as weighted sum scores of risk alleles using effect sizes from genome-wide association studies as their weights. The construction of PRSs is being improved with more appropriate selection of independent single-nucleotide polymorphisms (SNPs) and optimized estimation of their weights but is rarely reflected upon from a theoretical perspective, focusing on the validity of the risk score. Borrowing from psychometrics, this paper discusses the validity of PRSs and introduces the three main types of validity that are considered in the evaluation of tests and measurements: construct, content, and criterion validity. This introduction is followed by a discussion of three topics that challenge the validity of PRS, namely, their claimed independence of clinical risk factors, the consequences of relaxing SNP inclusion thresholds and the selection of SNP weights. This discussion of the validity of PRS reminds us that we need to keep questioning if weighted sums of risk alleles are measuring what we think they are in the various scenarios in which PRSs are used and that we need to keep exploring alternative modeling strategies that might better reflect the underlying biological pathways.

A restrictive polymorphic ant colony algorithm for the optimal band selection of hyperspectral remote sensing images

ABSTRACTWith hundreds of spectral bands, the rise of the issue of dimensionality in the classification of hyperspectral images is usually inevitable. In this paper, a restrictive polymorphic ant colony algorithm (RPACA) based band selection algorithm (RPACA-BS) was proposed to reduce the dimensionality of hyperspectral images. In the proposed algorithm, both local and global searches were conducted considering band similarity. Moreover, the problem of falling into local optima, due to the selection of similar band subsets although travelling different paths, was solved by varying the pheromone matrix between ants moving in opposite directions. The performance of the proposed RPACA-BS algorithm was evaluated using three public datasets (the Indian Pines, Pavia University and Botswana datasets) based on average overall classification accuracy (OA) and CPU processing time. The experimental results showed that average OA of RPACA-BS was up to 89.80%, 94.96% and 92.17% for the Indian Pines, Pavia University and Botswana dataset, respectively, which was higher than that of the benchmarks, including the ant colony algorithm-based band selection algorithm (ACA-BS), polymorphic ant colony algorithm-based band selection algorithm (PACA-BS) and other band selection methods (e.g. the ant lion optimizer-based band selection algorithm). Meanwhile, the time consumed by RPACA-BS and PACA-BS were slightly lower than that of ACA-BS but obviously lower than that of other benchmarks. The proposed RPACA-BS method is thus able to effectively enhance the search abilities and efficiencies of the ACA-BS and PACA-BS algorithms to handle the complex band selection issue for hyperspectral remotely sensed images.

Three-dimensional architecture and surface functionality of coccolith base plates

Coccolithophores are marine phytoplankton that are among the most prolific calcifiers widespread in Earth’s oceans, playing a crucial role in the carbon cycle and in the transport of organic matter to the deep sea. These organisms produce highly complex mineralized scales that are composed of hierarchical assemblies of nano-crystals of calcium carbonate in the form of calcite. Coccolith formation in vivo occurs within compartmentalized mineralisation vesicles derived from the Golgi body, which contain coccolith-associated polysaccharides (‘CAPs’) providing polymorph selection and mediating crystal growth kinetics, and oval organic mineralisation templates, also known as base plates, which promote heterogenous nucleation and further mechanical interlocking of calcite single crystals. Although the function of coccolith base plates in controlling crystal nucleation have been widely studied, their 3D spatial organization and the chemical functional groups present on the crystal nucleation sites, which are two crucial features impacting biomineralization, remain unsolved. Utilising cryo-electron tomography we show that base plates derived from an exemplary coccolithophore Pleurochrysis carterae (Pcar) in their native hydrated state have a complex 3-layered structure. We further demonstrate, for the first time, the edge and rim of the base plate – where the crystals nucleate – are rich in primary amine functionalities that provide binding targets for negatively charged complexes composed of synthetic macromolecules and Ca2+ ions. Our results indicate that electrostatic interactions between the negatively charged biogenic CAPs and the positively charged rim of the base plate are sufficient to mediate the transport of Ca2+ cations to the mineralization sites.

Crystalline clusters in mW water: Stability, growth, and grain boundaries.

With numerical simulations of the mW model of water, we investigate the energetic stability of crystalline clusters both for Ice I (cubic and hexagonal ice) and for the metastable Ice 0 phase as a function of the cluster size. Under a large variety of forming conditions, we find that the most stable cluster changes as a function of size: at small sizes, the Ice 0 phase produces the most stable clusters, while at large sizes, there is a crossover to Ice I clusters. We further investigate the growth of crystalline clusters with the seeding technique and study the growth patterns of different crystalline clusters. While energetically stable at small sizes, the growth of metastable phases (cubic and Ice 0) is hindered by the formation of coherent grain boundaries. A fivefold symmetric twin boundary for cubic ice, and a newly discovered coherent grain boundary in Ice 0, promotes cross nucleation of cubic ice. Our work reveals that different local structures can compete with the stable phase in mW water and that the low energy cost of particular grain boundaries might play an important role in polymorph selection.

1-nm-Wide Hydrated Dipole Arrays Regulate AuNW Assembly on Striped Monolayers in Nonpolar Solvent

Summary We show that striped phases of horizontally oriented phospholipids presenting 1-nm-wide orientable dipole arrays can order and straighten flexible 2-nm-diameter gold nanowires (AuNWs) with lengths (up to 1 μm) that greatly exceed the template pitch (∼7.5 nm). AuNW ordering can extend over areas > 100 μm2. Whereas wires bundle in solution, with contact between ligand shells, wires adsorbing to the template separate to much larger center-to-center distances (e.g., 12–30 nm) near multiples of the template pitch, consistent with repulsive interactions between wires emerging during interactions with dipole arrays in the template. AuNW assembly was carried out in cyclohexane, a nonpolar solvent. Interestingly, we found that wire ordering was contingent on the extent of phospholipid headgroup hydration and the presence of excess oleylamine, which assembled into hemicylindrical micelles around the hydrated headgroups. Together, these components generated a protected polar environment that enabled the phospholipid headgroups to function collectively to regulate AuNW assembly.