Plasma CXCL10 correlates with HAND in HIV-infected women.

HIV-associated neurocognitive disorder (HAND) is characterized by chronic immune activation. We aimed to identify biomarkers associated with HAND and to investigate their association with cognitive function and sex, in a homogenous cohort of HIV-infected (HIV+) young adults, parenterally infected during early childhood. One hundred forty-four HIV+ Romanian participants (51% women) without major confounders underwent standardized neurocognitive and medical evaluation in a cross-sectional study. IFN-γ, IL-1ß, IL-6, CCL2, CXCL8, CXCL10, and TNF-α were measured in plasma in all participants and in cerebrospinal fluid (CSF) in a subgroup of 56 study participants. Biomarkers were compared with neurocognitive outcomes, and the influence of sex and HIV disease biomarkers was assessed. In this cohort of young adults (median age of 24 years), the rate of neurocognitive impairment (NCI) was 36.1%. Median current CD4+ count was 479 cells/mm3 and 36.8% had detectable plasma viral load. Women had better HIV-associated overall status. In plasma, controlling for sex, higher levels of IL-6 and TNF-α were associated with NCI (p < 0.05). Plasma CXCL10 showed a significant interaction with sex (p = 0.02); higher values were associated with NCI in women only (p = 0.02). Individuals with undetectable viral load had significantly lower plasma CXCL10 (p < 0.001) and CCL2 (p = 0.02) levels, and CSF CXCL10 (p = 0.01), IL-6 (p = 0.04), and TNF-α (p = 0.04) levels. NCI in young men and women living with HIV was associated with higher IL-6 and TNF-α in plasma, but not in the CSF. CXCL10 was identified as a biomarker of NCI specifically in women with chronic HIV infection.

Histological predictors of renal outcome in lupus nephritis: the importance of tubulointerstitial lesions and scoring of glomerular lesions.

Introduction Lupus nephritis (LN) affects nearly 60% of patients with systemic lupus erythematosus and up to 30% of them will progress to end-stage renal disease (ESRD), despite receiving aggressive immunosuppressive therapy. The prognostic value of ISN/RPS classification is controversial. Therefore, we aimed to identify clinical and pathological predictors of outcome in LN patients independent of this classification. Material and methods Thirty-seven patients with LN who underwent percutaneous kidney biopsy between 1997 and 2016 were included in this study. Twenty clinical and twenty histological variables were tested for their association with a composite end-point of doubling of serum creatinine, ESRD and death. Univariate and multivariate Cox proportional hazard regression analysis were performed to identify independent predictors of outcome. Results During a median follow-up period of 48 months (IQR: 17.5-120 months), 21.6% of patients reached the composite end-point. The overall survival rate of our cohort was 89% at one year, 86% at five years, 74% at 10 years and 64% at 20 years. Patients with Class IV LN showed the worst prognosis with 44% survival at 10 years, while those who additionally showed crescents and global sclerosis on kidney biopsy had an even lower survival of 21% and 0% at 10 years, respectively. After multivariate adjustment, we identified estimated glomerular filtration rate at baseline (HR, 0.91 per ml/min /1.73 m2; 95% CI, 0.84 to 0.99), 24-hour proteinuria at baseline (HR, 2.04 per g/d; 95% CI, 1.19 to 3.5), crescents (HR, 1.068 per %; 95% CI, 1.003 to 1.091), global sclerosis (HR, 1.036 per %; 95% CI, 0.984 to 1.091), presence of adhesions (HR, 9.2; 95% CI, 1.38 to 61.2) and tubulitis (HR, 13.1; 95% CI; 1.3 to 131) as independent predictors of outcome in our cohort of LN. Conclusions Our study identified glomerular (crescents, global sclerosis, adhesions) and tubulointerstitial (tubulitis) lesions, in addition to clinical variables (renal function, 24-hour proteinuria), as important predictors of renal outcome, independent of the ISN/RPS classification. We suggest that the ISN/RPS classification could be improved by a quantitative assessment of glomeruli with active and chronic lesions and by a greater emphasis given to tubulointerstitial lesions.

Dislocation-free growth of quasicrystals from two seeds due to additional phasonic degrees of freedom.

We explore the growth of two-dimensional quasicrystals, i.e., aperiodic structures that possess long-range order, from two seeds at various distances and with different orientations by using dynamical phase-field crystal calculations. We compare the results to the growth of periodic crystals from two seeds. There, a domain border consisting of dislocations is observed in case of large distances between the seed and large angles between their orientation. Furthermore, a domain border is found if the seeds are placed at a distance that does not fit to the periodic lattice. In the case of the growth of quasicrystals, we only observe domain borders for large distances and different orientations. Note that all distances do inherently not match to a perfect domain wall-free quasicrystalline structure. Nevertheless, we find dislocation-free growth for all seeds at a small enough distance and for all seeds that approximately have the same orientation. In periodic structures, the stress that occurs due to incommensurate distances between the seeds results in phononic strain fields or, in the case of too large stresses, in dislocations. In contrast, in quasicrystals an additional phasonic strain field can occur and suppress dislocations. Phasons are additional degrees of freedom that are unique to quasicrystals. As a consequence, the additional phasonic strain field helps to distribute the stress and facilitates the growth of dislocation-free quasicrystals from multiple seeds. In contrast, in the periodic case the growth from multiple seeds most likely leads to a structure with multiple domains. Our work lays the theoretical foundations for growing perfect quasicrystals from different seeds and is therefore relevant for many applications.

Latent toxoplasmosis is associated with neurocognitive impairment in young adults with and without chronic HIV infection.

We evaluated the impact of latent toxoplasmosis (LT) on neurocognitive (NC) and neurobehavioural functioning in young adults with and without chronic HIV infection, using a standardised NC test battery, self-reported Beck Depression Inventory, Frontal System Behavior Scale, MINI-International Neuropsychiatric Interview and risk-assessment battery. 194 young adults (median age 24years, 48.2% males) with chronic HIV infection (HIV+) since childhood and 51 HIV seronegative (HIV-) participants were included. HIV+ individuals had good current immunological status (median CD4: 479 cells/µl) despite a low CD4 nadir (median: 93 cells/µl). LT (positive anti-Toxoplasma IgG antibodies) was present in one third of participants. The impairment rates in the HIV- with and without Toxo were not significantly different (p=0.17). However, we observed an increasing trend (p<0.001) in impairment rates with HIV and LT status: HIV-/LT- (6.1%); HIV-/LT+ (22%), HIV+/LT- (31%), HIV+/LT+ (49%). In a multivariable analysis using the entire study group there were main effects on cognition for HIV and also for LT. Within the HIV+ group LT was associated with worse performance globally (p=0.006), in memory (p=0.009), speed of information processing (p=0.01), verbal (p=0.02) and learning (p=0.02) domains. LT was not associated with depressive symptoms, frontal systems dysfunction or risk behaviors in any of the groups. HIV participants with lower Toxoplasma antibody concentration had worse NC performance, with higher GDS values (p=0.03) and worse learning (p=0.002), memory (p=0.006), speed of information processing (p=0.01) T scores. Latent Toxoplasmosis may contribute to NC impairment in young adults, including those with and without chronic HIV infection.

Long-wavelength properties of phase-field-crystal models with second-order dynamics.

The phase-field-crystal (PFC) approach extends the notion of phase-field models by describing the topology of the microscopic structure of a crystalline material. One of the consequences is that local variation of the interatomic distance creates an elastic excitation. The dynamics of these excitations poses a challenge: pure diffusive dynamics cannot describe relaxation of elastic stresses that happen through phonon emission. To this end, several different models with fast dynamics have been proposed. In this article we use the amplitude expansion of the PFC model to compare the recently proposed hydrodynamic PFC amplitude model with two simpler models with fast dynamics. We compare these different models analytically and numerically. The results suggest that in order to have proper relaxation of elastic excitations, the full hydrodynamical description of the PFC amplitudes is required.

Consistent Hydrodynamics for Phase Field Crystals.

We use the amplitude expansion in the phase field crystal framework to formulate an approach where the fields describing the microscopic structure of the material are coupled to a hydrodynamic velocity field. The model is shown to reduce to the well-known macroscopic theories in appropriate limits, including compressible Navier-Stokes and wave equations. Moreover, we show that the dynamics proposed allows for long wavelength phonon modes and demonstrate the theory numerically showing that the elastic excitations in the system are relaxed through phonon emission.

Hepatitis B virus compartmentalization in the cerebrospinal fluid of HIV-infected patients.

We detected hepatitis B virus (HBV) DNA in the cerebrospinal fluid (CSF) of 26 adolescents co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) with neurological disease and studied compartmentalization of HBV in the CSF. More than half of the subjects with positive HBV DNA plasma also had CSF positive for HBV. CSF HBV DNA was found in subjects with preserved blood-brain barrier integrity. In a subgroup of these subjects, compartmentalized evolution of HBV was demonstrated by distinct profiles of resistance mutations. Future studies are warranted to determine the clinical significance of HBV presence in the CSF and its contribution to HIV-associated neurological disease.

Growth modes of quasicrystals.

The growth of quasicrystals, i.e., aperiodic structures with long-range order, seeded from the melt is investigated using a dynamical phase field crystal model. Depending on the thermodynamic conditions, two different growth modes are detected, namely defect-free growth of the stable quasicrystal and a mode dominated by phasonic flips which are incorporated as local defects into the grown structure such that random tilinglike ordering emerges. The latter growth mode is unique to quasicrystals and can be verified in experiments on one-component mesoscopic systems.

Intracellular mannose binding lectin mediates subcellular trafficking of HIV-1 gp120 in neurons.

Human immunodeficiency virus-1 (HIV-1) enters the brain early during infection and leads to severe neuronal damage and central nervous system impairment. HIV-1 envelope glycoprotein 120 (gp120), a neurotoxin, undergoes intracellular trafficking and transport across neurons; however mechanisms of gp120 trafficking in neurons are unclear. Our results show that mannose binding lectin (MBL) that binds to the N-linked mannose residues on gp120, participates in intravesicular packaging of gp120 in neuronal subcellular organelles and also in subcellular trafficking of these vesicles in neuronal cells. Perinuclear MBL:gp120 vesicular complexes were observed and MBL facilitated the subcellular trafficking of gp120 via the endoplasmic reticulum (ER) and Golgi vesicles. The functional carbohydrate recognition domain of MBL was required for perinuclear organization, distribution and subcellular trafficking of MBL:gp120 vesicular complexes. Nocodazole, an agent that depolymerizes the microtubule network, abolished the trafficking of MBL:gp120 vesicles, suggesting that these vesicular complexes were transported along the microtubule network. Live cell imaging confirmed the association of the MBL:gp120 complexes with dynamic subcellular vesicles that underwent trafficking in neuronal soma and along the neurites. Thus, our findings suggest that intracellular MBL mediates subcellular trafficking and transport of viral glycoproteins in a microtubule-dependent mechanism in the neurons.

Trypanosomal TAC40 constitutes a novel subclass of mitochondrial ß-barrel proteins specialized in mitochondrial genome inheritance.

Mitochondria cannot form de novo but require mechanisms allowing their inheritance to daughter cells. In contrast to most other eukaryotes Trypanosoma brucei has a single mitochondrion whose single-unit genome is physically connected to the flagellum. Here we identify a ß-barrel mitochondrial outer membrane protein, termed tripartite attachment complex 40 (TAC40), that localizes to this connection. TAC40 is essential for mitochondrial DNA inheritance and belongs to the mitochondrial porin protein family. However, it is not specifically related to any of the three subclasses of mitochondrial porins represented by the metabolite transporter voltage-dependent anion channel (VDAC), the protein translocator of the outer membrane 40 (TOM40), or the fungi-specific MDM10, a component of the endoplasmic reticulum-mitochondria encounter structure (ERMES). MDM10 and TAC40 mediate cellular architecture and participate in transmembrane complexes that are essential for mitochondrial DNA inheritance. In yeast MDM10, in the context of the ERMES, is postulated to connect the mitochondrial genomes to actin filaments, whereas in trypanosomes TAC40 mediates the linkage of the mitochondrial DNA to the basal body of the flagellum. However, TAC40 does not colocalize with trypanosomal orthologs of ERMES components and, unlike MDM10, it regulates neither mitochondrial morphology nor the assembly of the protein translocase. TAC40 therefore defines a novel subclass of mitochondrial porins that is distinct from VDAC, TOM40, and MDM10. However, whereas the architecture of the TAC40-containing complex in trypanosomes and the MDM10-containing ERMES in yeast is very different, both are organized around a ß-barrel protein of the mitochondrial porin family that mediates a DNA-cytoskeleton linkage that is essential for mitochondrial DNA inheritance.

Phase-field-crystal models and mechanical equilibrium.

Phase-field-crystal (PFC) models constitute a field theoretical approach to solidification, melting, and related phenomena at atomic length and diffusive time scales. One of the advantages of these models is that they naturally contain elastic excitations associated with strain in crystalline bodies. However, instabilities that are diffusively driven towards equilibrium are often orders of magnitude slower than the dynamics of the elastic excitations, and are thus not included in the standard PFC model dynamics. We derive a method to isolate the time evolution of the elastic excitations from the diffusive dynamics in the PFC approach and set up a two-stage process, in which elastic excitations are equilibrated separately. This ensures mechanical equilibrium at all times. We show concrete examples demonstrating the necessity of the separation of the elastic and diffusive time scales. In the small-deformation limit this approach is shown to agree with the theory of linear elasticity.

Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes.

Viability of the tsetse fly-transmitted African trypanosome Trypanosoma brucei depends on maintenance and expression of its kinetoplast (kDNA), the mitochondrial genome of this parasite and a putative target for veterinary and human antitrypanosomatid drugs. However, the closely related animal pathogens T. evansi and T. equiperdum are transmitted independently of tsetse flies and survive without a functional kinetoplast for reasons that have remained unclear. Here, we provide definitive evidence that single amino acid changes in the nuclearly encoded F1FO-ATPase subunit γ can compensate for complete physical loss of kDNA in these parasites. Our results provide insight into the molecular mechanism of compensation for kDNA loss by showing FO-independent generation of the mitochondrial membrane potential with increased dependence on the ADP/ATP carrier. Our findings also suggest that, in the pathogenic bloodstream stage of T. brucei, the huge and energetically demanding apparatus required for kDNA maintenance and expression serves the production of a single F1FO-ATPase subunit. These results have important implications for drug discovery and our understanding of the evolution of these parasites.

Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNA interference library screening for resistance to the phosphodiesterase inhibitor CpdA.

One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development.

Bcc crystal-fluid interfacial free energy in Yukawa systems.

We determine the orientation-resolved interfacial free energy between a body-centered-cubic (bcc) crystal and the coexisting fluid for a many-particle system interacting via a Yukawa pair potential. For two different screening strengths, we compare results from molecular dynamics computer simulations, density functional theory, and a phase-field-crystal approach. Simulations predict an almost orientationally isotropic interfacial free energy of 0.12k(B)T/a(2) (with k(B)T denoting the thermal energy and a the mean interparticle spacing), which is independent of the screening strength. This value is in reasonable agreement with our Ramakrishnan-Yussouff density functional calculations, while a high-order fitted phase-field-crystal approach gives about 2-3 times higher interfacial free energies for the Yukawa system. Both field theory approaches also give a considerable anisotropy of the interfacial free energy. Our result implies that, in the Yukawa system, bcc crystal-fluid free energies are a factor of about 3 smaller than face-centered-cubic crystal-fluid free energies.

Patterning of heteroepitaxial overlayers from nano to micron scales.

Thin heteroepitaxial overlayers have been proposed as templates to generate stable, self-organized nanostructures at large length scales, with a variety of important technological applications. However, modeling strain-driven self-organization is a formidable challenge due to different length scales involved. In this Letter, we present a method for predicting the patterning of ultrathin films on micron length scales with atomic resolution. We make quantitative predictions for the type of superstructures (stripes, honeycomb, triangular) and length scale of pattern formation of two metal-metal systems, Cu on Ru(0001) and Cu on Pd(111). Our findings are in excellent agreement with previous experiments and call for future experimental investigations of such systems.

Electrostatic correlations in inhomogeneous charged fluids beyond loop expansion.

Electrostatic correlation effects in inhomogeneous symmetric electrolytes are investigated within a previously developed electrostatic self-consistent theory [R. R. Netz and H. Orland, Eur. Phys. J. E 11, 301 (2003)]. To this aim, we introduce two computational approaches that allow to solve the self-consistent equations beyond the loop expansion. The first method is based on a perturbative Green's function technique, and the second one is an extension of a previously introduced semiclassical approximation for single dielectric interfaces to the case of slit nanopores. Both approaches can handle the case of dielectrically discontinuous boundaries where the one-loop theory is known to fail. By comparing the theoretical results obtained from these schemes with the results of the Monte Carlo simulations that we ran for ions at neutral single dielectric interfaces, we first show that the weak coupling Debye-Huckel theory remains quantitatively accurate up to the bulk ion density ρ(b) ≃ 0.01 M, whereas the self-consistent theory exhibits a good quantitative accuracy up to ρ(b) ≃ 0.2 M, thus improving the accuracy of the Debye-Huckel theory by one order of magnitude in ionic strength. Furthermore, we compare the predictions of the self-consistent theory with previous Monte Carlo simulation data for charged dielectric interfaces and show that the proposed approaches can also accurately handle the correlation effects induced by the surface charge in a parameter regime where the mean-field result significantly deviates from the Monte Carlo data. Then, we derive from the perturbative self-consistent scheme the one-loop theory of asymmetrically partitioned salt systems around a dielectrically homogeneous charged surface. It is shown that correlation effects originate in these systems from a competition between the salt screening loss at the interface driving the ions to the bulk region, and the interfacial counterion screening excess attracting them towards the surface. This competition can be quantified in terms of the characteristic surface charge σ(s)*=√(2ρ(b)/(πl(B)), where l(B) = 7 Å is the Bjerrum length. In the case of weak surface charges σ(s)≪σ(s)* where counterions form a diffuse layer, the interfacial salt screening loss is the dominant effect. As a result, correlation effects decrease the mean-field density of both coions and counterions. With an increase of the surface charge towards σ(s)*, the surface-attractive counterion screening excess starts to dominate, and correlation effects amplify in this regime the mean-field density of both type of ions. However, in the regime σ(s)>σ(s)*, the same counterion screening excess also results in a significant decrease of the electrostatic mean-field potential. This reduces in turn the mean-field counterion density far from the charged surface. We also show that for σ(s)≫σ(s)*, electrostatic correlations result in a charge inversion effect. However, the electrostatic coupling regime where this phenomenon takes place should be verified with Monte Carlo simulations since this parameter regime is located beyond the validity range of the one-loop theory.

Glassy phases and driven response of the phase-field-crystal model with random pinning.

We study the structural correlations and the nonlinear response to a driving force of a two-dimensional phase-field-crystal model with random pinning. The model provides an effective continuous description of lattice systems in the presence of disordered external pinning centers, allowing for both elastic and plastic deformations. We find that the phase-field crystal with disorder assumes an amorphous glassy ground state, with only short-ranged positional and orientational correlations, even in the limit of weak disorder. Under increasing driving force, the pinned amorphous-glass phase evolves into a moving plastic-flow phase and then, finally, a moving smectic phase. The transverse response of the moving smectic phase shows a vanishing transverse critical force for increasing system sizes.

Dynamical transitions and sliding friction of the phase-field-crystal model with pinning.

We study the nonlinear driven response and sliding friction behavior of the phase-field-crystal (PFC) model with pinning including both thermal fluctuations and inertial effects. The model provides a continuous description of adsorbed layers on a substrate under the action of an external driving force at finite temperatures, allowing for both elastic and plastic deformations. We derive general stochastic dynamical equations for the particle and momentum densities including both thermal fluctuations and inertial effects. The resulting coupled equations for the PFC model are studied numerically. At sufficiently low temperatures, we find that the velocity response of an initially pinned commensurate layer shows hysteresis with dynamical melting and freezing transitions for increasing and decreasing applied forces at different critical values. The main features of the nonlinear response in the PFC model are similar to the results obtained previously with molecular dynamics simulations of particle models for adsorbed layers.

Thermodynamics of bcc metals in phase-field-crystal models.

We examine the influence of different forms of the free-energy functionals used in the phase-field-crystal (PFC) model, and compare them with the second-order density-functional theory (DFT) of freezing, by using bcc iron as an example case. We show that there are large differences between the PFC and the DFT and it is difficult to obtain reasonable parameters for existing PFC models directly from the DFT. Therefore, we propose a way of expanding the correlation function in terms of gradients that allows us to incorporate the bulk modulus of the liquid as an additional parameter in the theory. We show that this functional reproduces reasonable values for both bulk and surface properties of bcc iron, and therefore it should be useful in modeling bcc materials. As a further demonstration, we also calculate the grain boundary energy as a function of misorientation for a symmetric tilt boundary close to the melting transition.

Nonlinear driven response of a phase-field crystal in a periodic pinning potential.

We study numerically the phase diagram and the response under a driving force of the phase field crystal model for pinned lattice systems introduced recently for both one- and two-dimensional systems. The model describes the lattice system as a continuous density field in the presence of a periodic pinning potential, allowing for both elastic and plastic deformations of the lattice. We first present results for phase diagrams of the model in the absence of a driving force. The nonlinear response to a driving force on an initially pinned commensurate phase is then studied via overdamped dynamic equations of motion for different values of mismatch and pinning strengths. For large pinning strength the driven depinning transitions are continuous, and the sliding velocity varies with the force from the threshold with power-law exponents in agreement with analytical predictions. Transverse depinning transitions in the moving state are also found in two dimensions. Surprisingly, for sufficiently weak pinning potential we find a discontinuous depinning transition with hysteresis even in one dimension under overdamped dynamics. We also characterize structural changes of the system in some detail close to the depinning transition.