Structure, Stresses and Local Dynamics in Glasses

The interrelations between short range structural and elastic aspects in glasses and glass forming liquids pose important and yet unresolved questions. In this paper these relations are analyzed for mono-atomic glasses and stressed liquids with a short range repulsive-attractive pair potentials. Strong variations of the local pressure are found even in a zero temperature glass, whereas the largest values of pressure are the same in both glasses and liquids. The coordination number z(J) and the effective first peak radius depend on the local pressures J's. A linear relation was found between components of site stress tensor and the local elastic constants. A linear relation was also found between the trace of the squares of the local frequencies and the local pressures. Those relations hold for glasses at zero temperature and for liquids. We explain this by a relation between the structure and the potential terms. A structural similarity between liquids and solids is manifested by similar dependencies of the coordination number on the pressures.Comment: 7 pages, 11 figure

Force distributions near the jamming and glass transitions

We calculate the distribution of interparticle normal forces $P(F)$ near the glass and jamming transitions in model supercooled liquids and foams, respectively. $P(F)$ develops a peak that appears near the glass or jamming transitions, whose height increases with decreasing temperature, decreasing shear stress and increasing packing density. A similar shape of $P(F)$ was observed in experiments on static granular packings. We propose that the appearance of this peak signals the development of a yield stress. The sensitivity of the peak to temperature, shear stress and density lends credence to the recently proposed generalized jamming phase diagram.Comment: 4 pages, 3 postscript figures;Version 3 replaces figure 1 and removes figure 2 from version 1. Significant rewording of version 1 to emphasize the formation of peak in P(F) when these systems jam along five different routes of the recently proposed jamming phase diagram. Version 2 displayed the incorrect abstrac

Inelastic light, neutron, and X-ray scatterings related to the heterogeneous elasticity of glasses

The effects of plasticization of poly(methyl methacrylate) glass on the boson peaks observed by Raman and neutron scattering are compared. In plasticized glass the cohesion heterogeneities are responsible for the neutron boson peak and partially for the Raman one, which is enhanced by the composition heterogeneities. Because the composition heterogeneities have a size similar to that of the cohesion ones and form quasiperiodic clusters, as observed by small angle X-ray scattering, it is inferred that the cohesion heterogeneities in a normal glass form nearly periodic arrangements too. Such structure at the nanometric scale explains the linear dispersion of the vibrational frequency versus the transfer momentum observed by inelastic X-ray scattering.Comment: 9 pages, 2 figures, to be published in J. Non-Cryst. Solids (Proceedings of the 4th IDMRCS

Voronoi-Delaunay analysis of normal modes in a simple model glass

We combine a conventional harmonic analysis of vibrations in a one-atomic model glass of soft spheres with a Voronoi-Delaunay geometrical analysis of the structure. ``Structure potentials'' (tetragonality, sphericity or perfectness) are introduced to describe the shape of the local atomic configurations (Delaunay simplices) as function of the atomic coordinates. Apart from the highest and lowest frequencies the amplitude weighted ``structure potential'' varies only little with frequency. The movement of atoms in soft modes causes transitions between different ``perfect'' realizations of local structure. As for the potential energy a dynamic matrix can be defined for the ``structure potential''. Its expectation value with respect to the vibrational modes increases nearly linearly with frequency and shows a clear indication of the boson peak. The structure eigenvectors of this dynamical matrix are strongly correlated to the vibrational ones. Four subgroups of modes can be distinguished

РИСК РАННЕЙ ДИСФУНКЦИИ ТРАНСПЛАНТАТА ПЕЧЕНИ АССОЦИИРОВАН С ГЕНОТИПОМ ГЕНА TLR-4 В ПОСЛЕДОВАТЕЛЬНОСТИ RS913930 И РЕАЛИЗУЕТСЯ ЧЕРЕЗ АКТИВАЦИЮ ЯДЕРНОГО БЕЛКА HMGB1, КЛЕТОК КУПФЕРА И IL-23

Aim. To evaluate the associations of genotypes of clinically relevant nucleotides rs11536865, rs913930 and rs5030717 of the TLR-4 gene with the risk of development and severity of early allograft dysfunction after liver transplantation. Materials and methods. A case-control study enrolling 71 patients was organized. Inclusion criteria: DBD liver transplantation. Exclusion criteria: living related liver transplantation, reduced graft transplantation, recipient’s age fewer than 18. Results. Within rs5030717 there were identifi ed three genotypes: AA (81.6%) and two genotypes with the minor G-allele: AG (12.6%) and GG (5.6%). Within rs913930 there identi- fi ed three genotypes: TT (59.1%) and two genotypes with the minor C-allele: C/T (29.5%) and CC (11.2%). The rs11536865 studying revealed no polymorphism (GG genotype). The early allograft liver dysfunction (EAD) developed in 19.7% of patients, the severe EAD in 11.2% of patients, septic complications in 14%, acute cellular rejection in 23.9% of cases. The C/T genotype of the TLR-4 gene in the SNP rs913930 sequence was closely associated with the EAD development (OR 4.8 to 1; p = 0.047; 95% CI 1–23.4). Рatients with the donor’s liver C/T genotype had a reliably higher proportion (%) of the HMGB1 positive hepatocytes in the donor’s bioptate, 21 (17–29%) vs the СС+TT genotypes, 16 (10–19%) (Mann–Whitney test, p = 0.01). The CD68 expression in the liver bioptate at the donor’s stage was reliably higher in the carriers of heterozygotes in the SNP rs913930 (C/T genotype) and in the SNP rs5030717 (AG genotype), (Mann–Whitney test, p = 0.03). Signifi cant positive correlation between the CD68 expression in the donor’s liver bioptates and the IL-23 level in the hepatic vein has been determined in an hour after the portal reperfusion (ρ = 0.62; p = 0.04) as well as between the HMGB1 expression in the donor’s liver bioptates and the АSТ level in 24 hours after the reperfusion (r = 0.4; p = 0.02). The HMGB1 staining in the donor’s liver bioptates was higher in the EAD patients, 21 (20; 29) cells/mm2 in comparison with the patients without EAD, 16 (12; 18) (Mann–Whitney test, p = 0.0036). Conclusion. The early allograft liver dysfunction is associated with the genetic predisposition caused by the TLR-4 gene polymorphism and is implemented via the HMGB1, Kupffer cells and IL-23 activation. Цель исследования. Оценить ассоциации генотипов клинически значимых последовательностей нуклеотидов rs11536865, rs913930 и rs5030717 гена TLR-4 с риском возникновения и выраженностью ранней дисфункции трансплантатов печени. Материалы и методы. Для достижения поставленной цели было организованно исследование «случай–контроль», включавшее 71 пациента. Критерии включения: трансплантация печени от умершего донора. Критерии исключения: трансплантация от родственного донора, редуцированный графт, возраст реципиента менее 18 лет. Результаты. В пределах rs5030717 были выявлены три генотипа: AA (81,6%) и два генотипа с минорной аллелью G – AG (12,6%) и GG (5,6%). В пределах rs913930 были выявлены 3 генотипа: TT (59,1%) и два генотипа с минорной аллелью С – TC (29,5%), CC (11,2%). Изучение rs11536865 не выявило полиморфизма (генотип – GG). Ранняя дисфункция трансплантата печени развилась у 19,7% пациентов, тяжелая ранняя дисфункция трансплантата – 11,2%, септические осложнения – 14%, острое клеточное отторжение – 23,9%. Генотип C/T гена TLR-4 в последовательности SNP rs913930 имеет сильную связь с развитием ранней дисфункции трансплантата (Отношение шансов 4,8:1; p = 0,047; 95% ДИ 1–23,4). Пациенты с генотипом донорской печени С/T имели достоверно большую пропорцию HMGB1 (%) положительных гепатоцитов в донорском биоптате, 21 (17–29)%, по сравнению с генотипами СС+TT, 16 (10–19)% (Mann–Whitney p = 0,01). Экспрессии CD68 в биоптате печени на этапе донорского забора достоверно выше у носителей гетерозигот по SNP rs913930 (генотип C/T) и SNP rs5030717 (генотип AG), (Mann–Whitney test, p = 0,03). Получена достоверная корреляция между экспрессией CD68 в биоптатах печени доноров и уровнем IL-23 в печеночных венах трансплантата через 1 час после реперфузии (ρ = 0,62; p = 0,04) и между экспрессией HMGB1 в биоптатах печени доноров и уровнем АСТ через 24 часа после реперфузии (r = 0,4; p = 0,02). Экспрессия HMGB1 в биоптатах печени доноров была больше у пациентов с РДТ, 21 (20; 29) кл/мм2 , по сравнению с пациента- ми без РДТ 16 (12; 18) (Mann–Whitney test, p = 0,0036). Заключение. Ранняя дисфункция трансплантата имеет генетические предпосылки, обусловленные полиморфизмом гена TLR-4 и реализующиеся через активацию HMGB1, клеток Купфера и IL-23.

Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.Comment: in press at HFSP Journal, vol 3 16 text pages, 1 table, 4 figures, plus Supplementary Material include

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm&lt; 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Connecting Peptide Physicochemical and Antimicrobial Properties by a Rational Prediction Model

The increasing rate in antibiotic-resistant bacterial strains has become an imperative health issue. Thus, pharmaceutical industries have focussed their efforts to find new potent, non-toxic compounds to treat bacterial infections. Antimicrobial peptides (AMPs) are promising candidates in the fight against antibiotic-resistant pathogens due to their low toxicity, broad range of activity and unspecific mechanism of action. In this context, bioinformatics' strategies can inspire the design of new peptide leads with enhanced activity. Here, we describe an artificial neural network approach, based on the AMP's physicochemical characteristics, that is able not only to identify active peptides but also to assess its antimicrobial potency. The physicochemical properties considered are directly derived from the peptide sequence and comprise a complete set of parameters that accurately describe AMPs. Most interesting, the results obtained dovetail with a model for the AMP's mechanism of action that takes into account new concepts such as peptide aggregation. Moreover, this classification system displays high accuracy and is well correlated with the experimentally reported data. All together, these results suggest that the physicochemical properties of AMPs determine its action. In addition, we conclude that sequence derived parameters are enough to characterize antimicrobial peptides