Improved identifiability of myocardial material parameters by an energy-based cost function

Myocardial stiffness is a valuable clinical biomarker for the monitoring and stratification of heart failure (HF). Cardiac finite element models provide a biomechanical framework for the assessment of stiffness through the determination of the myocardial constitutive model parameters. The reported parameter intercorrelations in popular constitutive relations, however, obstruct the unique estimation of material parameters and limit the reliable translation of this stiffness metric to clinical practice. Focusing on the role of the cost function (CF) in parameter identifiability, we investigate the performance of a set of geometric indices (based on displacements, strains, cavity volume, wall thickness and apicobasal dimension of the ventricle) and a novel CF derived from energy conservation. Our results, with a commonly used transversely isotropic material model (proposed by Guccione et al.), demonstrate that a single geometry-based CF is unable to uniquely constrain the parameter space. The energy-based CF, conversely, isolates one of the parameters and in conjunction with one of the geometric metrics provides a unique estimation of the parameter set. This gives rise to a new methodology for estimating myocardial material parameters based on the combination of deformation and energetics analysis. The accuracy of the pipeline is demonstrated in silico, and its robustness in vivo, in a total of 8 clinical data sets (7 HF and one control). The mean identified parameters of the Guccione material law were \(C_1=3000\pm 1700\,\hbox {Pa}\) and \(\alpha =45\pm 25\) (\(b_f=25\pm 14\), \(b_{ft}=11\pm 6\), \(b_{t}=9\pm 5\)) for the HF cases and \(C_1=1700\,\hbox {Pa}\) and \(\alpha =15\) (\(b_f=8\), \(b_{ft}=4\), \(b_{t}=3\)) for the healthy case.     

Oestrogen regulates the expression of cathepsin E-A-like gene through ER$$\upbeta $$ in liver of chicken ( Gallus gallus)

The cathepsin E-A-like, also known as ‘similar to nothepsin’, is a new member of the aspartic protease family, which may take part in processing of egg yolk macromolecules, due to it was identified in the chicken egg-yolk. Previously, studies have suggested that the expression of cathepsin E-A-like increased gradually during sexual maturation of pullets, but the exact regulation mechanism is poorly understood. In this study, to gain insight into the function and regulation mechanism of the gene in egg-laying hen, we cloned the cathepsin E-A-like gene and evaluated its evolutionary origin by using both phylogenetic and syntenic methods. The mode of the gene expression regulation was analysed through stimulating juvenile hens with \(17\upbeta \)-estradiol and chicken embryo hepatocytes with \(17\upbeta \)-estradiol combined with oestrogen receptor antagonists including MPP, ICI 182,780 and tamoxifen. Our results showed that cathepsin E-A-like was an orthologoues gene with nothepsin, which is present in birds but not in mammals. The expression of cathepsin E-A-like significantly increased in a dose-dependent manner after the juvenile hens were treated with \(17\upbeta \)-estradiol (\(P~<~0.05\)). Compared with the \(17\upbeta \)-estradiol treatment group, the expression of cathepsin E-A-like was not significantly changed when the hepatocytes were treated with \(17\upbeta \)-estradiol combined with MPP (\(P~<~0.05\)). In contrast, compared with the \(17\upbeta \)-estradiol combined with MPP treatment group, the expression of cathepsin E-A-like was significantly downregulated when the hepatocytes were treated with \(17\upbeta \)-estradiol combined with tamoxifen or ICI 182,780 (\(P~<~0.05\)). These results demonstrated that cathepsin E-A-like shared the same evolutionary origin with nothepsin. The expression of cathepsin E-A-like was regulated by oestrogen, and the regulative effect was predominantly mediated through ER-\(\upbeta \) in liver of chicken.     

Plausibility and parameter sensitivity of micro-finite element-based joint load prediction at the proximal femur

A micro-finite element-based method to estimate the bone loading history based on bone architecture was recently presented in the literature. However, a thorough investigation of the parameter sensitivity and plausibility of this method to predict joint loads is still missing. The goals of this study were (1) to analyse the parameter sensitivity of the joint load predictions at one proximal femur and (2) to assess the plausibility of the results by comparing load predictions of ten proximal femora to in vivo hip joint forces measured with instrumented prostheses (available from www.orthoload.com). Joint loads were predicted by optimally scaling the magnitude of four unit loads (inclined \(-20^{\circ }\) to \(100^{\circ }\) with respect to the vertical axis) applied to micro-finite element models created from high-resolution computed tomography scans (\(30.3~\upmu \)m voxel size). Parameter sensitivity analysis was performed by varying a total of nine parameters and showed that predictions of the peak load directions (range 10\(^{\circ }\)–\(30^{\circ }\)) are more robust than the predicted peak load magnitudes (range 2344.8–4689.5 N). Comparing the results of all ten femora with the in vivo loading data of ten subjects showed that peak loads are plausible both in terms of the load direction (in vivo: \(18.2\pm 2.0^{\circ }\), predicted: \(20.0^{\circ }\)) and magnitude (in vivo: \(2707.6\pm 443.3~\hbox {N}\), predicted: \(3372.2\pm 597.9~\hbox {N}\)). Overall, this study suggests that micro-finite element-based joint load predictions are both plausible and robust in terms of the predicted peak load direction, but predicted load magnitudes should be interpreted with caution.     

Backbone resonance assignments for the SET domain of the human methyltransferase NSD2

Aberrant NSD2 methyltransferase activity is implicated as the oncogenic driver in multiple myeloma, suggesting opportunities for novel therapeutic intervention. The methyltransferase activity of NSD2 resides in its catalytic SET domain, which is conserved among most lysine methyltransferases. Here we report the backbone \(\hbox {H}^{\mathrm{N}}\), N, C\(^{\prime }\), \(\hbox {C}^\alpha\) and side-chain \(\hbox {C}^\beta\) assignments of a 25 kDa NSD2 SET domain construct, spanning residues 991–1203. A chemical shift analysis of C\(^{\prime }\), \(\hbox {C}^\alpha\) and \(\hbox {C}^\beta\) resonances predicts a secondary structural pattern that is in agreement with homology models.     

Towards the prediction of flow-induced shear stress distributions experienced by breast cancer cells in the lymphatics

Tumour metastasis in the lymphatics is a crucial step in the progression of breast cancer. The dynamics by which breast cancer cells (BCCs) travel in the lymphatics remains poorly understood. The goal of this work is to develop a model capable of predicting the shear stresses metastasising BCCs experience using numerical and experimental techniques. This paper models the fluidic transport of large particles (\(\eta =d_{\mathrm{p}}/W=0.1-0.4\) where \(d_{\mathrm{p}}\) is the particle diameter and W is the channel width) subjected to lymphatic flow conditions (\({ Re}=0.04\)), in a \(100\times 100\,\upmu \hbox {m}\) microchannel. The feasibility of using the dynamic fluid body interaction (DFBI) method to predict particle motion was assessed, and particle tracking experiments were performed. The experiments found that particle translational velocity decreased from the undisturbed fluid velocity with increasing particle size (5–14% velocity lag for \(\eta =0.1-0.3\)). DFBI simulations were found to better predict particle behaviour than theoretical predictions; however, mesh restrictions in the near-wall region (\(0.2\,\mathrm{W}>y>0.8\,\mathrm{W}\)) result in computationally expensive models. The simulations were in good agreement with the experiments (\(<12\%\) difference) across the channel (\(0.2\,\mathrm{W}\le y\le 0.8\,\mathrm{W}\)), with differences up to 25% in the near-wall region. Particles experience a range of shear stresses (0.002–0.12 Pa) and spatial shear gradients (\(0.004-0.137\,\hbox {Pa}/\upmu \hbox {m}\)) depending on their size and radial position. The predicted shear gradients are far in excess of values associated with BCC apoptosis (\(0.004-0.023\,\hbox {Pa}/\upmu \hbox {m}\)). Increasing our understanding of the shear stress magnitudes and gradients experienced by BCCs could be leveraged to elucidate whether a particular BCC size or location exists that encourages metastasis within the lymphatics.     

Structural alteration of the endothelial glycocalyx: contribution of the actin cytoskeleton

The endothelial glycocalyx is a carbohydrate–protein layer that lines the luminal surface of the endothelium. It anchors to the cell membrane via its core proteins that share extended link to the actin cytoskeleton. It is widely accepted that those protein domains and the attached carbohydrates are susceptible to pathological changes. It is unclear, however, to what extent the actin cytoskeleton contributes to the glycocalyx stability. In this study, we investigate the role of the actin cytoskeleton in the maintenance of the glycocalyx under static and laminar flow conditions in vitro. Our results show that in the static culture medium neither rapid actin depolymerisation nor prolonged actin disturbance leads to glycocalyx disruption from the apical surface of human umbilical vein endothelial cells. However, when endothelial cells are exposed to laminar flow for 24 h, the glycocalyx is seen to shift to the downstream peripheral region of the cell surface. The mean fluorescence intensity decreases to \(91.9 \pm 2.5\%\) of the control. When actin depolymerisation is introduced, the intensity decreases significantly to \(54.7 \pm 1.3\%\), indicating a severe disruption of the glycocalyx. Similar changes are observed in human aortic endothelial cells, where the intensity of the glycocalyx is reduced to \(72.8 \pm 1.6\%\) of the control. Collectively, we demonstrate that the actin cytoskeleton contributes to structural stability of the glycocalyx under shear stress. Our results can be used to develop new strategies to prevent shedding of the glycocalyx in cardiovascular diseases.     

Ultrasound palpation for fast in-situ quantification of articular cartilage stiffness,thickness and relaxation capacity

Most current cartilage testing devices require the preparation of excised samples and therefore do not allow intra-operative application for diagnostic purposes. The gold standard during open or arthroscopic surgery is still the subjective perception of manual palpation. This work presents a new diagnostic method of ultrasound palpation (USP) to acquire applied stress and strain data during manual palpation of articular cartilage. With the proposed method, we obtain cartilage thickness and stiffness. Moreover, repeated palpations allow the quantification of relaxation effects. USP measurements on elastomer phantoms demonstrated very good repeatability for both, stage-guided (97.2%) and handheld (96.0%) applications. The USP measurements were compared with conventional indentation experiments and revealed very good agreement on elastomer phantoms (\(r = 0.98\)) and good agreement on porcine cartilage samples (\(r = 0.76\)). Artificially degenerated cartilage samples showed reduced stiffness, weak capacity to relax after palpation and an increase of stiffness of approximately 50% with each single palpation. Intact cartilage was measured by USP directly at the patella (in situ) and after excision and removal of the subchondral bone (ex situ), leading to stiffness values of \(12.1\pm 5.5\) and \(8.5\pm 5.9\,\hbox {MPa}\) (\(p<0.05\)), respectively. The results demonstrate the potential of the USP system for cartilage testing, its sensitivity to degenerative changes and as a method for quantifying relaxation processes by means of repeated palpations. Furthermore, the differences in the results of in-situ and ex-situ measurements are of general interest, since such comparison has not been reported previously. We point out the limited comparability of ex-situ cartilage with its in-situ biomechanical behavior.     

Glutathione <Emphasis Type="BoldItalic">S</Emphasis>-transferase P1 gene polymorphisms and susceptibility to coronary artery disease in a subgroup of north Indian population

The present study aimed to investigate the association of \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) and \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) polymorphisms of GSTP1 with coronary artery disease (CAD) in a subgroup of north Indian population. In the present case–control study, CAD patients (\(n = 200\)) and age-matched, sex-matched and ethnicity-matched healthy controls (\(n = 200\)) were genotyped for polymorphisms in GSTP1 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotype distribution of \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) and \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) polymorphisms of GSTP1 gene was significantly different between cases and controls (\(P = 0.005\) and 0.024, respectively). Binary logistic regression analysis showed significant association of A/G (odds ratio (OR): 1.6, 95% CI: 1.08–2.49, \(P = 0.020\)) and G/G (OR: 3.1, 95% CI: 1.41–6.71, P \(=\) 0.005) genotypes of GSTP1 \(\hbox {g}.313\hbox {A}{\!>\!}\hbox {G}\), and C/T (OR: 5.8, 95% CI: 1.26–26.34, \(P = 0.024\)) genotype of GSTP1 \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) with CAD. The A/G and G/G genotypes of \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) and C/T genotype of \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) conferred 6.5-fold increased risk for CAD (OR: 6.5, 95% CI: 1.37–31.27, \(P = 0.018\)). Moreover, the recessive model of GSTP1 \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) is the best fit inheritance model to predict the susceptible gene effect (OR: 2.3, 95% CI: 1.11–4.92, \(P = 0.020\)). In conclusion, statistically significant associations of GSTP1 \(\hbox {g}.313\hbox {A}{>}\hbox {G}\) (A/G, G/G) and \(\hbox {g}.341\hbox {C}{>}\hbox {T}\) (C/T) genotypes with CAD were observed.     

Invasions Slow Down or Collapse in the Presence of Reactive Boundaries

Motivated by the propagation of thin bacterial films around planar obstacles, this paper considers the dynamics of travelling wave solutions to the Fisher–KPP equation \(u_t = u(1-u) + u_{xx} + u_{yy}\) in a planar strip \(-\infty< x < \infty \), \(0 \le y \le L\). We examine the propagation of fronts in the presence of a mixed boundary condition (also referred to as a ‘partially absorbing’ or ‘reactive’ boundary) \(u_y = \alpha u\), with \(\alpha >0\), at \(y=0\). The presence of boundary conditions of this kind leads to the development of front solutions that propagate in x but contain transverse structure in y. Motivated by the observation that the speed of propagation in the Fisher–KPP equation is determined (for exponentially decaying initial conditions) by the behaviour at the leading edge, we analyse the linearised Fisher–KPP equation in order to estimate the speed of the stable travelling front, a function of the width L and the imposed boundary conditions. For wide strips the speed estimate based on the linearised equation agrees well with the results of numerical simulations. For narrow channels numerical simulations indicate that the stable front propagates more slowly, and for sufficiently small L or sufficiently large \(\alpha \) the front speed falls to zero and the front collapses. The reason for the collapse is the non-existence, far behind the front, of a stable positive equilibrium solution u(x, y). While existence of these equilibrium states can be demonstrated via phase plane arguments, the investigation of stability is similar to calculations of critical patch sizes carried out in similar ecological models.     

Contribution of left ventricular residual stress by myocytes and collagen: existence of inter-constituent mechanical interaction

We quantify the contribution of myocytes, collagen fibers and their interactions to the residual stress field found in the left ventricle (LV) using both experimental and theoretical methods. Ring tissue samples extracted from normal rat, male and female, LV were treated with collagenase and decellularization to isolate myocytes and collagen fibers, respectively. Opening angle tests were then performed on these samples as well as intact tissue samples containing both constituents that served as control. Our results show that the collagen fibers are the main contributor to the residual stress fields found in the LV. Specifically, opening angle measured in collagen-only samples (106.45\(^\circ \) ± 23.02\(^\circ \)) and myocytes-only samples (21.00\(^\circ \) ± 4.37\(^\circ \)) was significantly higher and lower than that of the control (57.88\(^\circ \) ± 12.29\(^\circ \)), respectively. A constrained mixture (CM) modeling framework was then used to infer these experimental results. We show that the framework cannot reproduce the opening angle found in the intact tissue with measurements made on the collagen-only and myocytes-only samples. Given that the CM framework assumes that each constituent contributes to the overall mechanics simply by their mere presence, this result suggests the existence of some myocyte–collagen mechanical interaction that cannot be ignored in the LV. We then propose an extended CM formulation that takes into account of the inter-constituent mechanical interaction in which constituents are deformed additionally when they are physically combined into a mixture. We show that the intact tissue opening angle can be recovered in this framework.     

Cell Volume Regulation in the Proximal Tubule of Rat Kidney

We developed a dynamic model of a rat proximal convoluted tubule cell in order to investigate cell volume regulation mechanisms in this nephron segment. We examined whether regulatory volume decrease (RVD), which follows exposure to a hyposmotic peritubular solution, can be achieved solely via stimulation of basolateral K\(^+\) and \(\hbox {Cl}^-\) channels and \(\hbox {Na}^+\)–\(\hbox {HCO}_3^-\) cotransporters. We also determined whether regulatory volume increase (RVI), which follows exposure to a hyperosmotic peritubular solution under certain conditions, may be accomplished by activating basolateral \(\hbox {Na}^+\)/H\(^+\) exchangers. Model predictions were in good agreement with experimental observations in mouse proximal tubule cells assuming that a 10% increase in cell volume induces a fourfold increase in the expression of basolateral K\(^+\) and \(\hbox {Cl}^-\) channels and \(\hbox {Na}^+\)–\(\hbox {HCO}_3^-\) cotransporters. Our results also suggest that in response to a hyposmotic challenge and subsequent cell swelling, \(\hbox {Na}^+\)–\(\hbox {HCO}^-_3\) cotransporters are more efficient than basolateral K\(^+\) and \(\hbox {Cl}^-\) channels at lowering intracellular osmolality and reducing cell volume. Moreover, both RVD and RVI are predicted to stabilize net transcellular \(\hbox {Na}^+\) reabsorption, that is, to limit the net \(\hbox {Na}^+\) flux decrease during a hyposmotic challenge or the net \(\hbox {Na}^+\) flux increase during a hyperosmotic challenge.     

Optimal Therapy Scheduling Based on a Pair of Collaterally Sensitive Drugs

Despite major strides in the treatment of cancer, the development of drug resistance remains a major hurdle. One strategy which has been proposed to address this is the sequential application of drug therapies where resistance to one drug induces sensitivity to another drug, a concept called collateral sensitivity. The optimal timing of drug switching in these situations, however, remains unknown. To study this, we developed a dynamical model of sequential therapy on heterogeneous tumors comprised of resistant and sensitive cells. A pair of drugs (DrugA, DrugB) are utilized and are periodically switched during therapy. Assuming resistant cells to one drug are collaterally sensitive to the opposing drug, we classified cancer cells into two groups, \(A_\mathrm{R}\) and \(B_\mathrm{R}\), each of which is a subpopulation of cells resistant to the indicated drug and concurrently sensitive to the other, and we subsequently explored the resulting population dynamics. Specifically, based on a system of ordinary differential equations for \(A_\mathrm{R}\) and \(B_\mathrm{R}\), we determined that the optimal treatment strategy consists of two stages: an initial stage in which a chosen effective drug is utilized until a specific time point, T, and a second stage in which drugs are switched repeatedly, during which each drug is used for a relative duration (i.e., \(f \Delta t\)-long for DrugA and \((1-f) \Delta t\)-long for DrugB with \(0 \le f \le 1\) and \(\Delta t \ge 0\)). We prove that the optimal duration of the initial stage, in which the first drug is administered, T, is shorter than the period in which it remains effective in decreasing the total population, contrary to current clinical intuition. We further analyzed the relationship between population makeup, \(\mathcal {A/B} = A_\mathrm{R}/B_\mathrm{R}\), and the effect of each drug. We determine a critical ratio, which we term \(\mathcal {(A/B)}^{*}\), at which the two drugs are equally effective. As the first stage of the optimal strategy is applied, \(\mathcal {A/B}\) changes monotonically to \(\mathcal {(A/B)}^{*}\) and then, during the second stage, remains at \(\mathcal {(A/B)}^{*}\) thereafter. Beyond our analytic results, we explored an individual-based stochastic model and presented the distribution of extinction times for the classes of solutions found. Taken together, our results suggest opportunities to improve therapy scheduling in clinical oncology.     

Simulation of extracellular matrix remodeling by fibroblast cells in soft three-dimensional bioresorbable scaffolds

To culture functional soft tissues and organs in three-dimensional scaffolds, it is essential to elucidate the optimal scaffold mechanical properties. However, mechanoregulated soft tissue remodeling is not well understood. In this study, we hypothesized that individual cells are capable of remodeling extracellular matrix within a short proximity of themselves in order to match the stiffness of the broader surrounding matrix. This theory was implemented in a three-dimensional finite element model to simulate soft tissue remodeling of human fibroblast cells in two collagen–chitosan scaffolds with different mechanical properties. Simulation results closely matched with previously reported experimental data, showing that soft tissue growth in compliant (Scaf-A, 4.30 kPa) and stiff (Scaf-B, 17.03 kPa) scaffolds led to an almost eightfold difference in the resulting stiffnesses after 10 days (8.40 kPa for Scaf-A, 59.25 kPa for Scaf-B). Furthermore, varying the simulated rate for tissue remodeling by \(\pm \)50 % caused unequal changes in the resulting stiffness (+3.6 and \(-\)23 % for Scaf-A, +5 and \(-\)17 % for Scaf-B), and \(\pm \)50 % changes in the assumed upper limit on tissue stiffness only had larger effects on the stiff scaffold (+42 and \(-\)44 % for Scaf-B). These results reinforce the notion that soft tissue remodeling is governed by the stiffness of the surrounding matrix, until meeting an upper limit on tissue stiffness.     

Physical parameter estimation from porcine ex vivo vocal fold dynamics in an inverse problem framework

This study presents a framework for a direct comparison of experimental vocal fold dynamics data to a numerical two-mass-model (2MM) by solving the corresponding inverse problem of which parameters lead to similar model behavior. The introduced 2MM features improvements such as a variable stiffness and a modified collision force. A set of physiologically sensible degrees of freedom is presented, and three optimization algorithms are compared on synthetic vocal fold trajectories. Finally, a total of 288 high-speed video recordings of six excised porcine larynges were optimized to validate the proposed framework. Particular focus lay on the subglottal pressure, as the experimental subglottal pressure is directly comparable to the model subglottal pressure. Fundamental frequency, amplitude and objective function values were also investigated. The employed 2MM is able to replicate the behavior of the porcine vocal folds very well. The model trajectories’ fundamental frequency matches the one of the experimental trajectories in \(98.6\%\) of the recordings. The relative error of the model trajectory amplitudes is on average \(9.5\%\). The experiments feature a mean subglottal pressure of 10.16 (SD \(= 2.31\)) \({\text {cmH}}_2{\text {O}}\); in the model, it was on average 7.61 (SD \(= 2.40\)) \({\text {cmH}}_2{\text {O}}\). A tendency of the model to underestimate the subglottal pressure is found, but the model is capable of inferring trends in the subglottal pressure. The average absolute error between the subglottal pressure in the model and the experiment is 2.90 (SD \(= 1.80\)) \({\text {cmH}}_2{\text {O}}\) or \(27.5\%\). A detailed analysis of the factors affecting the accuracy in matching the subglottal pressure is presented.     

Morphology and the gradient of a symmetric potential predict gait transitions of dogs

Gaits and gait transitions play a central role in the movement of animals. Symmetry is thought to govern the structure of the nervous system, and constrain the limb motions of quadrupeds. We quantify the symmetry of dog gaits with respect to combinations of bilateral, fore–aft, and spatio-temporal symmetry groups. We tested the ability of symmetries to model motion capture data of dogs walking, trotting and transitioning between those gaits. Fully symmetric models performed comparably to asymmetric with only a \(22\%\) increase in the residual sum of squares and only one-quarter of the parameters. This required adding a spatio-temporal shift representing a lag between fore and hind limbs. Without this shift, the symmetric model residual sum of squares was \(1700\%\) larger. This shift is related to (linear regression, \(n=5\), \(p=0.0328\)) dog morphology. That this symmetry is respected throughout the gaits and transitions indicates that it generalizes outside a single gait. We propose that relative phasing of limb motions can be described by an interaction potential with a symmetric structure. This approach can be extended to the study of interaction of neurodynamic and kinematic variables, providing a system-level model that couples neuronal central pattern generator networks and mechanical models.     

Analysis of two susceptibility SNPs in HLA region and evidence of interaction between rs6457617 in <Emphasis Type="BoldItalic">HLA-DQB1</Emphasis> and <Emphasis Type="BoldItalic">HLA-DRB1</Emphasis>*04 locus on Tunisian rheumatoid arthritis

Previous genomewide association studies (GWAS) and meta-analyses have enumerated several genes/loci in major histocompatibility complex region, which are consistently associated with rheumatoid arthritis (RA) in different ethnic populations. Given the genetic heterogeneity of the disease, it is necessary to replicate these susceptibility loci in other populations. In this case, we investigate the analysis of two SNPs, rs13192471 and rs6457617, from the human leukocyte antigen (HLA) region with the risk of RA in Tunisian population. These SNPs were previously identified to have a strong RA association signal in several GWAS studies. A case–control sample composed of 142 RA patients and 123 healthy controls was analysed. Genotyping of rs13192471 and rs6457617 was carried out using real-time PCR methods by TaqMan allelic discrimination assay. A trend of significant association was found in rs6457617 TT genotype with susceptibility to RA (\(P = 0.04\), \(p_{c} = 0.08\), \(\hbox {OR} = 1.73\)). Moreover, using multivariable analysis, the combination of rs6457617*TT–HLA-DRB1*\(04^{+}\) increased risk of RA (\(\hbox {OR} = 2.38\)), which suggest a gene–gene interaction event between rs6457617 located within the HLA-DQB1 and HLA-DRB1. Additionally, haplotypic analysis highlighted a significant association of rs6457617*T–HLA-DRB1*\(04^{+}\) haplotype with susceptibility to RA (\(P = 0.018\), \(p_{c} = 0.036\), \(\hbox {OR} = 1.72\)). An evidence of association was shown subsequently in \(\hbox {antiCCP}^{+}\) subgroup with rs6457617 both in T allele and TT genotype (\(P = 0.01\), \(p_{c} = 0.03\), \(\hbox {OR} = 1.66\) and \(P = 0.008\), \(p_{c} = 0.024\), \(\hbox {OR} = 1.28\), respectively). However, no association was shown for rs13192471 polymorphism with susceptibility and severity to RA. This study suggests the involvement of rs6457617 locus as risk variant for susceptibility/severity to RA in Tunisian population. Secondly, it highlights the gene–gene interaction between HLA-DQB1 and HLA-DRB1.     

Trend analysis of variations in carbon stock using stock big data

Changes in land use affect the terrestrial carbon stock through changes in the land cover. Research on land use and analysis of variations in carbon stock have practical applications in the optimization of land use and the mitigation of climate change effects. This study was conducted in Baixiang and Julu counties in the Taihang Piedmont by employing the trend analysis method to characterize the variation in county land use and carbon stock. The findings show that in both counties, agricultural and unused land areas decreased while built-up land area increased, and the reduction in cropland was the main reason behind the agricultural land reduction. An inflection point appeared on the cropland curves of Julu, because the cropland area decreased by 1576.97 hm\(^{2}\) from 2004 to 2006. Cropland area in Baixiang decreased from 1996 to 1998 by a total of 129.89 hm\(^{2}\) and then remained relatively stable after 1998. The total carbon storage and variation in land use in the two counties displayed similar trends. Total carbon reserves in Julu increased by 2.76 \(\times \) 10\(^{4}\) tC (carbon equivalent), while those in Baixiang decreased by 0.63 \(\times \) 10\(^{4}\) tC. Carbon stock of built-up land in Julu and Baixiang increased by 2.44 \(\times \) 10\(^{4}\) and 1.22 \(\times \) 10\(^{4}\) tC, respectively.     

Understanding the effects of isolation on seed and pollen flow,spatial genetic structure and effective population size of the dioecious tropical tree species <Emphasis Type="Italic">Myracrodruon urundeuva</Emphasis>

This study examines the levels of gene flow, the distance and the patterns of pollen and seed dispersal, the intra-population spatial genetic structure (SGS) and the effective population size of a spatially isolated Myracrodruon urundeuva population using five microsatellite loci. The study was carried out in the Paulo de Faria Ecological Station, São Paulo State, Brazil and included the sampling and mapping of 467 adult-trees and 149 juveniles. Open-pollinated seeds (514) from 29 seed-trees were also sampled and genotyped. Significant SGS was detected in both adult (S _p  = 0.0269) and juveniles trees (S _p  = 0.0246), indicating short-distance seed dispersal. Using maternity analysis, all juveniles had the mother-tree assigned within the stand. A father-tree within the stand was also assigned for 97.3% of the juveniles and 98.4% of offspring. The average pollen dispersal distance measured in juveniles \( \left( {\hat{\delta } = 1 3 8\pm 1 6 9 {\text{ m}},{\text{ mean}} \pm {\text{SD}}} \right) \) and offspring \( \left( {\hat{\delta } = 2 5 2\pm 20 4 {\text{ m}}} \right) \) were higher than the average seed dispersal distance measured in juveniles \( \left( {\hat{\delta } = 1 2 4\pm 1 50{\text{ m}}} \right) \). About 70% of the pollen from juveniles and 51% from offspring traveled less than 200 m and, 72% of the seeds traveled less than 50 m. The effective population size of the studied sample indicates that the 467 adult-trees and 145 juveniles correspond respectively to 335 and 63 individuals that are neither inbred nor relatives. The results are discussed in relation to their impact on seed collection practices and genetic conservation.