Non-Markovian effects of conformational fluctuations on the global diffusivity in Langevin equation with fluctuating diffusivity.

Local diffusivity of a protein depends crucially on the conformation, and the conformational fluctuations are often non-Markovian. Here, we investigate the Langevin equation with non-Markovian fluctuating diffusivity, where the fluctuating diffusivity is modeled by a generalized Langevin equation under a double-well potential. We find that non-Markovian fluctuating diffusivity affects the global diffusivity, i.e., the diffusion coefficient obtained by the long-time trajectories when the memory kernel in the generalized Langevin equation is a power-law form. On the other hand, the diffusion coefficient does not change when the memory kernel is exponential. More precisely, the global diffusivity obtained by a trajectory whose length is longer than the longest relaxation time in the memory kernel is not affected by the non-Markovian fluctuating diffusivity. We show that these non-Markovian effects are the consequences of an everlasting effect of the initial condition on the stationary distribution in the generalized Langevin equation under a double-well potential due to long-term memory.

Gas of sub-recoiled laser cooled atoms described by infinite ergodic theory.

The velocity distribution of a classical gas of atoms in thermal equilibrium is the normal Maxwell distribution. It is well known that for sub-recoiled laser cooled atoms, Lévy statistics and deviations from usual ergodic behavior come into play. In a recent letter, we showed how tools from infinite ergodic theory describe the cool gas. Here, using the master equation, we derive the scaling function and the infinite invariant density of a stochastic model for the momentum of laser cooled atoms, recapitulating results obtained by Bertin and Bardou [Am. J. Phys. 76, 630 (2008)] using life-time statistics. We focus on the case where the laser trapping is strong, namely, the rate of escape from the velocity trap is R(v) ∝ |v|α for v → 0 and α > 1. We construct a machinery to investigate time averages of physical observables and their relation to ensemble averages. The time averages are given in terms of functionals of the individual stochastic paths, and here we use a generalization of Lévy walks to investigate the ergodic properties of the system. Exploring the energy of the system, we show that when α = 3, it exhibits a transition between phases where it is either an integrable or a non-integrable observable with respect to the infinite invariant measure. This transition corresponds to very different properties of the mean energy and to a discontinuous behavior of fluctuations. While the integrable phase is described by universal statistics and the Darling-Kac law, the more challenging case is the exploration of statistical properties of non-integrable observables. Since previous experimental work showed that both α = 2 and α = 4 are attainable, we believe that both phases could also be explored experimentally.

Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia.

Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB, SFTPC, ABCA3, CSF2RA, CSF2RB, and GATA2. We identified a heterozygous missense variation in OAS1, encoding 2,'5'-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members. Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother. We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia. PAP in the two simplex individuals resolved after hematopoietic stem cell transplantation, indicating that OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs.

Transitions in the Ergodicity of Subrecoil-Laser-Cooled Gases.

With subrecoil-laser-cooled atoms, one may reach nanokelvin temperatures while the ergodic properties of these systems do not follow usual statistical laws. Instead, due to an ingenious trapping mechanism in momentum space, power-law-distributed sojourn times are found for the cooled particles. Here, we show how this gives rise to a statistical-mechanical framework based on infinite ergodic theory, which replaces ordinary ergodic statistical physics of a thermal gas of atoms. In particular, the energy of the system exhibits a sharp discontinuous transition in its ergodic properties. Physically, this is controlled by the fluorescence rate, but, more profoundly, it is a manifestation of a transition for any observable, from being an integrable to becoming a nonintegrable observable, with respect to the infinite (non-normalized) invariant density.

Universal Relation between Instantaneous Diffusivity and Radius of Gyration of Proteins in Aqueous Solution.

Protein conformational fluctuations are highly complex and exhibit long-term correlations. Here, molecular dynamics simulations of small proteins demonstrate that these conformational fluctuations directly affect the protein's instantaneous diffusivity D_{I}. We find that the radius of gyration R_{g} of the proteins exhibits 1/f fluctuations that are synchronous with the fluctuations of D_{I}. Our analysis demonstrates the validity of the local Stokes-Einstein-type relation D_{I}∝1/(R_{g}+R_{0}), where R_{0}∼0.3 nm is assumed to be a hydration layer around the protein. From the analysis of different protein types with both strong and weak conformational fluctuations, the validity of the Stokes-Einstein-type relation appears to be a general property.

Phase behaviors of deeply supercooled bilayer water unseen in bulk water.

Akin to bulk water, water confined to an isolated nanoslit can show a wealth of new 2D phases of ice and amorphous ice, as well as unusual phase behavior. Indeed, 2D water phases, such as bilayer hexagonal ice and monolayer square ice, have been detected in the laboratory, confirming earlier computational predictions. Herein, we report theoretical evidence of a hitherto unreported state, namely, bilayer very low density amorphous ice (BL-VLDA), as well as evidence of a strong first-order transition between BL-VLDA and the BL amorphous ice (BL-A), and a weak first-order transition between BL-VLDA and the BL very low density liquid (BL-VLDL) water. The diffusivity of BL-VLDA is typically in the range of 10-9 cm2/s to 10-10 cm2/s. Similar to bulk (3D) water, 2D water can exhibit two forms of liquid in the deeply supercooled state. However, unlike supercooled bulk water, for which the two forms of liquid can coexist and merge into one at a critical point, the 2D BL-VLDL and BL high-density liquid (BL-HDL) phases are separated by the highly stable solid phase of BL-A whose melting line exhibits the isochore end point (IEP) near 220 K in the temperature-pressure diagram. Above the IEP temperature, BL-VLDL and BL-HDL are indistinguishable. At negative pressures, the metastable BL-VLDL exhibits a spatially and temporally heterogeneous structure induced by dynamic changes in the nanodomains, a feature much less pronounced in the BL-HDL.

Unveiling diffusive states from center-of-mass trajectories in glassy dynamics.

We propose a method to detect alternating diffusive states undergoing a free diffusive state and a trapped state described by the Ornstein-Uhlenbeck process. Using a stochastic model with alternating diffusive states, a phenomenological model of glassy dynamics, we show that control parameters in the method may be determined by the mean square displacement and the non-Gaussianity parameter. Our method works when diffusivities for the two states are clearly distinct and all the states last longer than a specified relaxation time. Applying our method to molecular dynamics simulation data of supercooled liquids, we show that trapped states last for a long time and the sojourn-time distribution for trapped states becomes a power-law form as the temperature approaches the glass temperature.

Genetic basis for childhood interstitial lung disease among Japanese infants and children.

BackgroundGenetic variants responsible for childhood interstitial lung disease (chILD) have not been studied extensively in Japanese patients.MethodsThe study population consisted of 62 Japanese chILD patients. Twenty-one and four patients had pulmonary hypertension resistant to treatment (PH) and hypothyroidism, respectively. Analyses of genetic variants were performed in all 62 patients for SFTPC and ABCA3, in all 21 PH patients for FOXF1, and in a limited number of patients for NKX2.1.ResultsCausative genetic variants for chILD were identified in 11 (18%) patients: SFTPC variants in six, NKX2.1 variants in three, and FOXF1 variants in two patients. No patients had ABCA3 variants. All three and two patients with NKX2.1 variants had hypothyroidism and developmental delay, respectively. We found six novel variants in this study.ConclusionMutations in SFTPC, NKX2.1, and FOXF1 were identified among Japanese infants and children with chILD, whereas ABCA3 mutations were rare.

Biased continuous-time random walks for ordinary and equilibrium cases: facilitation of diffusion, ergodicity breaking and ageing.

We examine renewal processes with power-law waiting time distributions (WTDs) and non-zero drift via computing analytically and by computer simulations their ensemble and time averaged spreading characteristics. All possible values of the scaling exponent α are considered for the WTD ψ(t) ∼ 1/t1+α. We treat continuous-time random walks (CTRWs) with 0 < α < 1 for which the mean waiting time diverges, and investigate the behaviour of the process for both ordinary and equilibrium CTRWs for 1 < α < 2 and α > 2. We demonstrate that in the presence of a drift CTRWs with α < 1 are ageing and non-ergodic in the sense of the non-equivalence of their ensemble and time averaged displacement characteristics in the limit of lag times much shorter than the trajectory length. In the sense of the equivalence of ensemble and time averages, CTRW processes with 1 < α < 2 are ergodic for the equilibrium and non-ergodic for the ordinary situation. Lastly, CTRW renewal processes with α > 2-both for the equilibrium and ordinary situation-are always ergodic. For the situations 1 < α < 2 and α > 2 the variance of the diffusion process, however, depends on the initial ensemble. For biased CTRWs with α > 1 we also investigate the behaviour of the ergodicity breaking parameter. In addition, we demonstrate that for biased CTRWs the Einstein relation is valid on the level of the ensemble and time averaged displacements, in the entire range of the WTD exponent α.

Frequency of malformed infants in a tertiary center in Hokkaido, Japan over a period of 10 years.

AIM: This retrospective study was performed to determine the frequency of malformed infants born at a tertiary center in Hokkaido, Japan. The accuracy of prenatal diagnosis rates was also investigated. METHODS: An observational study was performed using data of 1509 and 1743 newborn infants at a single center during two study periods, 2005-2009 (first) and 2010-2014 (second), respectively. Cases including minor anomalies (accessory auricle, nevus and fistula auris congenita) were not included. RESULTS: In total, 274 and 569 malformations were identified in 191 and 337 newborn infants in the first and second study periods, respectively. The number of malformed infants increased significantly over time (13% [191/1509] vs 19% [337/1743], respectively; P < 0.001), mainly as a result of an increase in cases of congenital heart disease (CHD), from 59 to 141 (31% [59/191] vs 42% [141/337] of all malformed infants in the first and second periods, respectively). The overall accurate prenatal diagnosis rate improved over time from 47% (128/274) to 58% (329/569) because of significant improvements in accurate prenatal diagnosis of CHD subtypes (23% [16/70] vs 65% [151/232] in the first and second periods, respectively, P < 0.0001). CONCLUSIONS: The frequency of malformed newborns was higher in the tertiary center than in the general population. The increased number of cases with prenatal suspicion and diagnosis of CHD contributed to the increased frequency of malformed infants during the study period.

Universal Fluctuations of Single-Particle Diffusivity in a Quenched Environment.

Local diffusion coefficients in disordered materials such as living cells are highly heterogeneous. We consider finite systems with quenched disorder in order to investigate the effects of sample disorder fluctuations and confinement on single-particle diffusivity. While the system is ergodic in a single disorder realization, the time-averaged mean square displacement depends crucially on the disorder; i.e., the system is ergodic but non-self-averaging. Moreover, we show that the disorder average of the time-averaged mean square displacement decreases with the system size. We find a universal distribution for diffusivity in the sense that the shape of the distribution does not depend on the dimension. Quantifying the degree of the non-self-averaging effect, we show that fluctuations of single-particle diffusivity far exceed the corresponding annealed theory and also find confinement effects. The relevance for experimental situations is also discussed.

Dexmedetomidine (12.5 µg/mL) improves tissue distribution, anesthetic action, and hemodynamic effects of lidocaine after palatal infiltration in rats.

Dexmedetomidine hydrochloride (DEX) is a α2-adrenergic receptor agonist that causes vasoconstriction by acting on α2B-adrenergic receptors in peripheral blood vessels. The authors aimed to determine the influence of DEX on tissue distribution, anesthetic action, and hemodynamic effects of lidocaine in rats. The investigators injected indigo carmine-containing (14)C-labeled lidocaine hydrochloride (2 %) without and with 3.1, 12.5, or 50 µg/mL DEX or 10 µg/mL epinephrine into the right palatal mucosa mesial to the maxillary first molar of specific pathogen-free male Wistar rats. Autoradiography and liquid scintillation counting were performed to evaluate (14)C-labeled lidocaine concentrations in the palatal mucosa, maxillary bone, maxillary nerve, and peripheral blood. Somatosensory-evoked potentials were measured to analyze anesthetic action, and blood pressure and pulse rate were measured to compare hemodynamic effects. DEX extended the tissue distribution of lidocaine in a concentration-dependent manner. Lidocaine with 12.5 µg/mL DEX had similar blood peak arrival time and peak-to-peak amplitude as lidocaine with 10 µg/mL epinephrine, but it reduced pulse rate. The results of this study suggest that 12.5 µg/mL DEX improves tissue distribution, anesthetic action, and hemodynamic effects of lidocaine in rats. Therefore, 12.5 µg/mL DEX may be a suitable alternative to epinephrine in lidocaine formulations, especially for patients with ischemic heart disease and hypertension.

A late presenter and long-term survivor of alveolar capillary dysplasia with misalignment of the pulmonary veins.

UNLABELLED: This report demonstrates a late presenter and long-term survivor (38 months old) of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) and with a heterozygous frameshift mutation in FOXF1. The mild phenotype may be due to his residual normal lung tissue as demonstrated in the chest computed tomography (CT) and histopathological findings. CONCLUSION: We report the longest survivor of ACD/MPV. The mild phenotype is most likely due to the patient's residual normal lung tissue.

Exchange transfusion in patients with Down syndrome and severe transient leukemia.

BACKGROUND: Among neonates with Down syndrome (DS) and transient leukemia (TL), hyperleukocytosis (white blood cell [WBC] count >100 × 10(9) /L) is associated with increased blood viscosity, respiratory failure due to pulmonary hypertension, multiorgan failure, and increased risk of early death. There have been no previous studies focusing on the effects of exchange transfusion (ExT) on WBC count, respiratory status, and other parameters in TL patients with hyperleukocytosis. METHODS: An observational retrospective study was carried out at a single center of all five DS neonates with TL, GATA1 mutations, and hyperleukocytosis, born at a median gestational age of 34 weeks (range, 30-38 weeks) with birthweight 2556 g (range, 1756-3268 g) during a 24 month study period between September 2011 and August 2013. All five neonates underwent ExT at a median age of 2 days (range, 0-5 days) before initiation of other cytoreductive therapy with cytarabine, which was carried out in two patients. RESULTS: All patients required respiratory support before ExT. After ExT, respiration status improved in all five patients: WBC count (mean) decreased by 85% from 143 × 10(9) /L to 21 × 10(9) /L. None developed tumor lysis syndrome. Three survived and two died: one hydrops fetalis neonate born at gestational week 30 died at age 5 days, and another died eventually from acute gastroenteritis 40 days after leaving hospital at the age of 155 days with complete remission. Two of the three surviving neonates developed acute megakaryocytic leukemia at age 90 days and 222 days. CONCLUSION: ExT was very effective in improving hyperleukocytosis and may have had favorable effects on respiration.

Hereditary interstitial lung diseases manifesting in early childhood in Japan.

BACKGROUND: Genetic variations associated with interstitial lung diseases (ILD) have not been extensively studied in Japanese infants. METHODS: Forty-three infants with unexplained lung dysfunction were studied. All 43, 22, and 17 infants underwent analyses of surfactant protein (SP)-C gene (SFTPC) and ATP-binding cassette A3 gene (ABCA3), SP-B gene (SFTPB), and SP-B western blotting, respectively. Two and four underwent assessment of granulocyte macrophage colony-stimulating factor-stimulating phosphorylation of signal transducer and activator of transcription-5 (pSTAT-5) and analyses of FOXF1 gene (FOXF1), respectively. RESULTS: ILD were diagnosed clinically in nine infants: four, three, and two had interstitial pneumonitis, hereditary pulmonary alveolar proteinosis (hPAP), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), respectively. Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). None showed SFTPB mutations or defects in pSTAT-5. The 17 bronchoalveolar lavage or tracheal aspirates contained enough SP-B protein. CONCLUSION: The SP-C abnormality was most prevalent, and SP-B deficiency was rare in Japanese infants with hereditary ILD.

Poisson property of the occurrence of flip-flops in a model membrane.

How do lipid molecules in membranes perform a flip-flop? The flip-flops of lipid molecules play a crucial role in the formation and flexibility of membranes. However, little has been determined about the behavior of flip-flops, either experimentally, or in molecular dynamics simulations. Here, we provide numerical results of the flip-flops of model lipid molecules in a model membrane and investigate the statistical properties, using millisecond-order coarse-grained molecular simulations (dissipative particle dynamics). We find that there are three different ways of flip-flops, which can be clearly characterized by their paths on the free energy surface. Furthermore, we found that the probability of the number of the flip-flops is well fitted by the Poisson distribution, and the probability density function for the inter-occurrence times of flip-flops coincides with that of the forward recurrence times. These results indicate that the occurrence of flip-flops is a Poisson process, which will play an important role in the flexibilities of membranes.

Homogeneous connectivity of potential energy network in a solidlike state of water cluster.

A novel route to the exponential trapping-time distribution within a solidlike state in water clusters is described. We propose a simple homogeneous network (SHN) model to investigate dynamics on the potential energy networks of water clusters. In this model, it is shown that the trapping-time distribution in a solidlike state follows the exponential distribution, whereas the trapping-time distribution in local potential minima within the solidlike state is not exponential. To confirm the exponential trapping-time distribution in a solidlike state, we investigate water clusters, (H2O)6 and (H2O)12, by molecular dynamics simulations. These clusters change dynamically from solidlike to liquidlike state and vice versa. We find that the probability density functions of trapping times in a solidlike state are described by the exponential distribution whereas those of interevent times of large fluctuations in potential energy within the solidlike state follow the Weibull distributions. The results provide a clear evidence that transition dynamics between solidlike and liquidlike states in water clusters are well described by the SHN model, suggesting that the exponential trapping-time distribution within a solidlike state originates from the homogeneous connectivity in the potential energy network.

Statistics of the number of renewals, occupation times, and correlation in ordinary, equilibrium, and aging alternating renewal processes.

The renewal process is a point process where an interevent time between successive renewals is an independent and identically distributed random variable. Alternating renewal process is a dichotomous process and a slight generalization of the renewal process, where the interevent time distribution alternates between two distributions. We investigate statistical properties of the number of renewals and occupation times for one of the two states in alternating renewal processes. When both means of the interevent times are finite, the alternating renewal process can reach an equilibrium. On the other hand, an alternating renewal process shows aging when one of the means diverges. We provide analytical calculations for the moments of the number of renewals, occupation time statistics, and the correlation function for several case studies in the interevent-time distributions. We show anomalous fluctuations for the number of renewals and occupation times when the second moment of interevent time diverges. When the mean interevent time diverges, distributional limit theorems for the number of events and occupation times are shown analytically. These are known as the Mittag-Leffler distribution and the generalized arcsine law in probability theory.

Sample-to-sample fluctuations of transport coefficients in the totally asymmetric simple exclusion process with quenched disorder.

We consider the totally asymmetric simple exclusion processes on quenched random energy landscapes. We show that the current and the diffusion coefficient differ from those for homogeneous environments. Using the mean-field approximation, we analytically obtain the site density when the particle density is low or high. As a result, the current and the diffusion coefficient are described by the dilute limit of particles or holes, respectively. However, in the intermediate regime, due to the many-body effect, the current and the diffusion coefficient differ from those for single-particle dynamics. The current is almost constant and becomes the maximal value in the intermediate regime. Moreover, the diffusion coefficient decreases with the particle density in the intermediate regime. We obtain analytical expressions for the maximal current and the diffusion coefficient based on the renewal theory. The deepest energy depth plays a central role in determining the maximal current and the diffusion coefficient. As a result, the maximal current and the diffusion coefficient depend crucially on the disorder, i.e., non-self-averaging. Based on the extreme value theory, we find that sample-to-sample fluctuations of the maximal current and diffusion coefficient are characterized by the Weibull distribution. We show that the disorder averages of the maximal current and the diffusion coefficient converge to zero as the system size is increased and quantify the degree of the non-self-averaging effect for the maximal current and the diffusion coefficient.

Non-self-averaging of current in a totally asymmetric simple exclusion process with quenched disorder.

We investigate the current properties in the totally asymmetric simple exclusion process (TASEP) on a quenched random energy landscape. In low- and high-density regimes, the properties are characterized by single-particle dynamics. In the intermediate one, the current becomes constant and is maximized. Based on the renewal theory, we derive accurate results for the maximum current. The maximum current significantly depends on a disorder realization, i.e., non-self-averaging (SA). We demonstrate that the disorder average of the maximum current decreases with the system size, and the sample-to-sample fluctuations of the maximum current exceed those of current in the low- and high-density regimes. We find a significant difference between single-particle dynamics and the TASEP. In particular, the non-SA behavior of the maximum current is always observed, whereas the transition from non-SA to SA for current in single-particle dynamics exists.