Miracle-dz/UniFAR-FTUs huggingface dataset:
Research Article: Selectivity‐determining Residues in Plk1

Polo‐like kinase 1 is an important regulator of cell cycle progression whose over‐expression is often associated with oncogenesis. Polo‐like kinase 1 hence represents an attractive target for cancer intervention. BI 2536 (Boehringer Ingelheim, Ingelheim, Germany), a Polo‐like kinase 1 inhibitor currently in clinical trials, exhibits nanomolar potency against Polo‐like kinase isoforms and high selectivity against other kinases. We have previously published the crystal structures of the Polo‐like kinase 1 domain in complex with AMPPNP and an Aurora A inhibitor. In this work, we present the co‐crystal structure of Polo‐like kinase 1 with BI 2536. The structure, in combination with selectivity data for BI 2536 and related compounds, illustrates important features for potency and selectivity. In particular, we show that the methoxy group of BI 2536 is an important specificity determinant against non‐Polo‐like kinases by taking advantage of a small pocket generated by Leu 132 in the hinge region of Polo‐like kinase 1. The work presented here provides a framework for structure‐based drug design of Polo‐like kinase 1‐specific inhibitors.
Gymnastics

Abstract The purpose of the study was to quantify the muscle torques required in the performance of an optimised Yurchenko layout vault based on a five‐segment rigid link model and using input data from an elite female gymnast. At impact, the wrist torque trajectory indicated an extension‐flexion action while the shoulder was characterised by extension. The approximate 100 Nm (wrist flexor) and 125 Nm (shoulder extensor) respective peak torque magnitudes indicated that the impact action is not passive in nature. The contribution of joint torques to the adjoining segments was apportioned to the relative components namely; centripetal, gravity and net joint torque components. Despite the presence of both large wrist and shoulder joint torques, the net turning effect on the upper limb and hand segments about their centre of mass (CM) was small. The principal role of the upper limb joint torques was therefore to effect the appropriate joint motions and to support the weight of the gymnast. The performance of the optimum vault was primarily the result of the interplay between the centripetal and the net joint torque components at the wrist, hip and shoulder joints. This has implications to the performer in that successful execution of the vault is principally concerned with the ability to create a high angular momentum for horse impact and to then apply an appropriate level of joint torques that will make optimal use of the initial kinetic condition.
KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

A key initial event in hair follicle morphogenesis is the localised thickening of the skin epithelium to form a placode, partitioning future hair follicle epithelium from interfollicular epidermis. Although many developmental signalling pathways are implicated in follicle morphogenesis, the role of epidermal growth factor (EGF) and keratinocyte growth factor (KGF, also known as FGF7) receptors are not defined. EGF receptor (EGFR) ligands have previously been shown to inhibit developing hair follicles; however, the underlying mechanisms have not been characterised. Here we show that receptors for EGF and KGF undergo marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persist throughout hair follicle initiation. Using embryonic skin organ culture, we show that when skin from the sites of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time- and dose-dependent manner. We then used downstream molecular markers and microarray profiling to provide evidence that, in response to KGF and EGF signalling, epidermal differentiation is promoted at the expense of hair follicle fate. We propose that hair follicle initiation in placodes requires downregulation of the two pathways in question, both of which are crucial for the ongoing development of the interfollicular epidermis. We have also uncovered a previously unrecognised role for KGF signalling in the formation of hair follicles in the mouse.
Catalytic Mechanism of a Novel Glycoside Hydrolase Family 16 “Elongating” β-Transglycosylase*

Carbohydrates are complex macromolecules in biological metabolism. Enzymatic synthesis of carbohydrates is recognized as a powerful tool to overcome the problems associated with large scale synthesis of carbohydrates. Novel enzymes with significant transglycosylation ability are still in great demand in glycobiology studies. Here we report a novel glycoside hydrolase family 16 “elongating” β-transglycosylase from Paecilomyces thermophila (PtBgt16A), which efficiently catalyzes the synthesis of higher polymeric oligosaccharides using β-1,3/1,4-oligosaccharides as donor/acceptor substrates. Further structural information reveals that PtBgt16A has a binding pocket around the −1 subsite. The catalytic mechanism of PtBgt16A is partly similar to an exo-glycoside hydrolase, which cleaves the substrate from the non-reducing end one by one. However, PtBgt16A releases the reducing end product and uses the remainder glucosyl as a transglycosylation donor. This catalytic mechanism has similarity with the catalytic mode of amylosucrase, which catalyzes the transglycosylation products gradually extend by one glucose unit. PtBgt16A thus has the potential to be a tool enzyme for the enzymatic synthesis of new β-oligosaccharides and glycoconjugates.
Distributed asymptotic consensus control of linearly parameterized multiagent systems with unknown control gain

A class of linearly parameterized multiagent systems with unknown parameters and unknown control gain are investigated in this paper. An adaptive algorithm is implemented for such multiagent systems to obtain consensus. In most previous cases, consensus approaches usually induce uniformly ultimately bounded consensus error because of the uncertainties existing in the system dynamics. By contrast, this paper introduces a novel robust consensus algorithm which can ensure that the consensus error converges to zero asymptotically. More specifically, an adaptive controller will be designed for on-line unknown parameter identification, and a robust continuous term will be applied to ease the effects of the external disturbances. Besides, the control signal is insured continuously to neglect actuator bandwidth requirement and avoid the caused chattering phenomenon. Noting that, for multiagent systems studied in this paper, each agent only needs to exchange information with its neighbor agents, i.e., the proposed consensus algorithm is distributed. The theoretical verification of asymptotic consensus result is given through Lyapunov synthesis and several simulation tests on a linearly parameterized multiagent system are conducted to demonstrate the performance of the algorithm.
Amplatzer vascular plug as an embolic agent in different vascular pathologies: A pictorial essay

Abstract The Amplatzer Vascular Plug (AVP) is a cylindrical plug made of self-expanding nitinol wire mesh with precise delivery control, which can be used for a variety of vascular pathologies. An AVP is an ideal vascular occlusion device particularly in high-flow vessels, where there is high risk of migration and systemic embolization with traditional occlusion devices. We performed 28 embolizations using the AVP from 2009 to 2014 and achieved complete occlusion without complications.
Inclusive Education:the Way of the Future

"Inclusive Education:the Way of the Future" will be the theme at the 48th International Conference on Education,organized by UNESCO's International Bureau of Education(IBE) in November in Geneva.Inclusive education is a process of answering the diversified requirements of all learners and responding to them by increasing participation in learning,culture and communication,and decreasing the internal and external rejection in educational system.As one of the largest developing countries,China should still take pushing forward inclusive education as a basic task and promote the development of inclusive education in the world.
DESCRIBING POPULATION HEALTH IN SIX DOMAINS: COMPARABLE RESULTS FROM 66 HOUSEHOLD SURVEYS

One of the World Health Organization's longest standing mandates is the collection and routine reporting of information on population health. In addition to estimates of mortality and disease, assessment of health status from population based surveys contribute to estimates of population health. The first section of the paper briefly introduces the conceptual and operational basis to measure health, where health is measured through six domains (affect, cognition, pain, mobility, self-care and usual activities). The second section briefly notes that the main objective of this paper is to report on the average levels of health by age and sex groups for each domain of health across 66 population based surveys. The third section of this paper describes how we have applied the hierarchical ordered probit (HOPIT) model using vignettes to calibrate responses across survey populations, to self-reported levels of health on six domains. The data comes from the WHO Health Survey Study 2000-2001, from 66 population based surveys in 57 countries, representative of individuals 18 years and older. The fourth section provides results on comparable levels of health for each domain across populations, by age groups and sex. In order to further facilitate comparisons across countries, age-standardized aggregated results across all age groups, by sex, are also presented and compared to external data, such as GDP per capita (PPP) and life expectancy. The fifth section discusses the information content of the surveys, the added-value of the multi-dimensional approach and the comparability of responses across countries. The final section recommends additional analyses to be conducted. Comments on this discussion paper are most welcome and should be forwarded to: Dr. Ritu Sadana Evidence and Information for Policy World Health Organization Avenue Appia 20 CH-1211 Geneva 27 Switzerland Email: sadanar@who.int
Regional Pancreatic Concentration and In-vitro Secretion of Canine Pancreatic Polypeptide, Insulin, and Glucagon

The regional concentrations and in-vitro secretions of canine pancreatic polypeptide (cPP), insulin, and glucagon were studied. CPP is found predominantly in the uncinate process of the dog pancreas, whereas insulin and, more markedly, glucagon predominate in the body and taO of the pancreas. In-vitro secretion studies of pancreatic pieces indicate that dibutyryl cyclic AMP (dcAMP) alone can stimulate cPP release whereas glucose and arginine alone have no effect. Arginine, but not glucose, potentiates this stknulant effect of dcAMP. These studies suggest that the cAMP generating system may play a role in regulation of cPP secretion.
Biodistribution and Efficacy of Human Adipose-Derived Mesenchymal Stem Cells Following Intranodal Administration in Experimental Colitis

Mesenchymal stem cells (MSCs) have a large potential in cell therapy for treatment of inflammatory and autoimmune diseases, thanks to their immunomodulatory properties. The encouraging results in animal models have initiated the translation of MSC therapy to clinical trials. In cell therapy protocols with MSCs, administered intravenously, several studies have shown that a small proportion of infused MSCs can traffic to the draining lymph nodes (LNs). This is accompanied with an increase of different types of regulatory immune cells in the LNs, suggesting the importance of migration of MSCs to the LNs in order to contribute to immunomodulatory response. Intranodal (IN), also referred as intralymphatic, injection of cells, like dendritic cells, is being proposed in the clinic for the treatment of cancer and allergy, showing that this route of administration is clinically safe and efficient. In this study, we investigated, for the first time, the biodistribution and the efficacy of Luciferase+ adipose-derived MSCs (Luci-eASCs), infused through the inguinal LNs (iLNs), in normal mice and in inflamed mice with colitis. Most of the Luci-eASCs remain in the iLNs and in the adipose tissue surrounding the inguinal LNs. A small proportion of Luci-eASCs can migrate to other locations within the lymphatic system and to other tissues and organs, having a preferential migration toward the intestine in colitic mice. Our results show that the infused Luci-eASCs protected 58% of the mice against induced colitis. Importantly, a correlation between the response to eASC treatment and a higher accumulation of eASCs in popliteal, parathymic, parathyroid, and mesenteric LNs were found. Altogether, these results suggest that IN administration of eASCs is feasible and may represent an effective strategy for cell therapy protocols with human adipose-derived MSCs in the clinic for the treatment of immune-mediated disorders.
Polyhedral 3D structure of human plasma very low density lipoproteins by individual particle cryo-electron tomography1[S]

Human VLDLs assembled in the liver and secreted into the circulation supply energy to peripheral tissues. VLDL lipolysis yields atherogenic LDLs and VLDL remnants that strongly correlate with CVD. Although the composition of VLDL particles has been well-characterized, their 3D structure is elusive because of their variations in size, heterogeneity in composition, structural flexibility, and mobility in solution. Here, we employed cryo-electron microscopy and individual-particle electron tomography to study the 3D structure of individual VLDL particles (without averaging) at both below and above their lipid phase transition temperatures. The 3D reconstructions of VLDL and VLDL bound to antibodies revealed an unexpected polyhedral shape, in contrast to the generally accepted model of a spherical emulsion-like particle. The smaller curvature of surface lipids compared with HDL may also reduce surface hydrophobicity, resulting in lower binding affinity to the hydrophobic distal end of the N-terminal β-barrel domain of cholesteryl ester transfer protein (CETP) compared with HDL. The directional binding of CETP to HDL and VLDL may explain the function of CETP in transferring TGs and cholesteryl esters between these particles. This first visualization of the 3D structure of VLDL could improve our understanding of the role of VLDL in atherogenesis.
European Academy of Allergy and Clinical Immunology task force report on ‘dose–response relationship in allergen‐specific immunotherapy’

To cite this article: Calderón MA, Larenas D, Kleine‐Tebbe J, Jacobsen L, Passalacqua G, Eng PA, Varga EM, Valovirta E, Moreno C, Malling HJ, Alvarez‐Cuesta E, Durham S, Demoly P. European Academy of Allergy and Clinical Immunology task force report on ‘dose–response relationship in allergen‐specific immunotherapy’. Allergy 2011; 66: 1345–1359.
Melanocortin 1 receptor and risk of cutaneous melanoma: A meta‐analysis and estimates of population burden

Polymorphisms in the melanocortin 1 receptor (MC1R) gene have been associated with increased risks of melanoma, but different approaches to study design, analysis, and reporting have hindered comparisons of findings. We aimed to harmonize the published data by conducting a systematic review and meta‐analysis of MC1R variants and thereby estimate relative risks and population attributable fractions (PAFs). We identified 20 analytic studies reporting on 25 populations, which presented quantitative data on melanoma risks associated with any of nine MC1R variants. We separately pooled estimates of risk per person and risk per chromosome using a random effects model. Red hair color (RHC) variants had the highest risk of melanoma [summary odds ratios (OR) 2.44, 95% confidence interval (CI) 1.72–3.45, PAF 16.8% CI 0.119–0.202], but non‐RHC variants were also associated with increased risk (summary OR 1.29, 95% CI 1.10–1.51, PAF 7.4% CI 0.030–0.112). The summary risk of melanoma associated with individual variants ranged from OR 2.40 for R142H to 1.18 for V60L, although significant heterogeneity was evident for most variants. PAFs ranged from 0.55% for I155T to 6.28% for R151C. Our findings suggest the nine most common MC1R variants make a sizeable contribution to the burden of melanoma. Melanoma research would be greatly assisted by standardized classifications for MC1R variants and consistent reporting conventions. More compatible and comparable research would allow for more powerful data that could be clinically applied to predict melanoma risk.
Surface Pressure Poisson Equation Formulation of the Primitive Equations: Numerical Schemes

Numerical methods for the primitive equations (PEs) of oceanic flow are presented in this paper. First, a two-dimensional Poisson equation with a suitable boundary condition is derived to solve the surface pressure. Consequently, we derive a new formulation of the PEs in which the surface pressure Poisson equation replaces the nonlocal incompressibility constraint, which is known to be inconvenient to implement. Based on this new formulation, backward Euler and Crank--Nicolson schemes are presented. The marker and cell scheme, which gives values of physical variables on staggered mesh grid points, are chosen as spatial discretization. The convergence analysis of the fully discretized scheme is established in detail. The accuracy check for the scheme is also shown.
The Handbook For Student Leadership Development

Thank you very much for reading the handbook for student leadership development. Maybe you have knowledge that, people have search hundreds times for their chosen novels like this the handbook for student leadership development, but end up in infectious downloads. Rather than reading a good book with a cup of coffee in the afternoon, instead they are facing with some malicious bugs inside their desktop computer.
Phylogenetics and population genetics of Plotosus canius (Siluriformes: Plotosidae) from Malaysian coastal waters

Plotosus canius (Hamilton, 1822) is a significant marine species in Malaysia from nutritional and commercial perspectives. Despite numerous fundamental research on biological characteristics of P. canius, there are various concerns on the level of population differentiation, genomic structure, and the level of genetic variability among their populations due to deficiency of genetic-based studies. Deficiency on basic contexts such as stock identification, phylogenetic relationship and population genetic structure would negatively impact their sustainable conservation. Hence, this study was conducted to characterize the genetic structure of P. canius for the first time through the application of mitochondrial Cytochrome Oxidase I (COI) gene, cross amplification of Tandanus tandanus microsatellites, and a total of 117 collected specimens across five selected populations of Malaysia. The experimental results of the mitochondrial analysis revealed that the haplotype diversity and nucleotide diversity varied from 0.395–0.771 and 0.033–0.65 respectively. Moreover, the statistical analysis of microsatellites addressed a considerable heterozygote insufficiency in all populations, with average observed heterozygosity (Ho) value of 0.2168, which was lower than the standard heterozygosity in marine populations (Ho = 0.79). This alongside the high Fis values estimation, high pairwise differentiation among populations and low within population variations are supposed to be associated with small sample size, and inbreeding system. Besides, the significant finding of this study was the sharing of common haplotype KR086940, which reflects a historical genetic connectivity between Peninsular Malaysia and Borneo populations due to the geological history of Southeast Asia during Pleistocene era. Demographic analyses showed that all populations were in an equilibrium state with no significant evidence of population expansion. To put it briefly, the current study has managed to provide an initial genomic database toward understanding of the genetic characterization, phylogenetic, molecular diversification and population structure in P. canius, and should be necessary highlighted for appropriate management and conservation of species. Further studies must be carried out involving more geographical and sampling sites, larger population size per site, and utilization of species specific microsatellites loci.
Associations between aerobic and muscular fitness and cardiovascular disease risk: the northern Ireland young hearts study.

BACKGROUND It is not clear what the relative contribution is of specific components of physical fitness (aerobic and muscular) to cardiovascular disease (CVD) risk. We investigated associations between aerobic fitness (endurance) and muscular fitness (power) and CVD risk factors. METHODS Data were obtained from the Young Hearts project, a representative sample of 12- and 15-year-old boys and girls from Northern Ireland (N = 2016). Aerobic fitness was determined by the 20-m shuttle run test, muscular fitness by the Sargent jump test. CVD risk factors included sum of skinfolds, systolic and diastolic blood pressure, serum total cholesterol (TC), HDL cholesterol, and TC:HDL ratio. Several linear regression analyses were conducted for 4 age and gender groups separately, with the risk factor as the outcome variable. RESULTS Significant associations between aerobic fitness and a healthy CVD risk profile were found. These observed relationships were independent of power, whereas the (few) relationships between muscular fitness and the risk factors were partly explained by endurance. CONCLUSIONS Tailored, preventive strategies during adolescence, incorporating endurance rather than power sports, could be encouraged to help prevent CVD. This is important because existing studies propose that healthiness during adulthood is founded on healthiness in adolescence.
Artesunate versus Chloroquine Infection–Treatment–Vaccination Defines Stage-Specific Immune Responses Associated with Prolonged Sterile Protection against Both Pre-erythrocytic and Erythrocytic Plasmodium yoelii Infection

Sterile protection against malaria infection can be achieved through vaccination of mice and humans with whole Plasmodium spp. parasites. One such method, known as infection–treatment–vaccination (ITV), involves immunization with wild type sporozoites (spz) under drug coverage. In this work, we used the different effects of antimalarial drugs chloroquine (CQ) and artesunate (AS) on blood stage (BS) parasites to dissect the stage-specific immune responses in mice immunized with Plasmodium yoelii spz under either drug, as well as their ability to protect mice against challenge with spz or infected RBCs (iRBCs). Whereas CQ-ITV induced sterile protection against challenge with both spz and iRBCs, AS-ITV only induced sterile protection against spz challenge. Importantly, AS-ITV delayed the onset of BS infection, indicating that both regimens induced cross-stage immunity. Moreover, both CQ- and AS-ITV induced CD8+ T cells in the liver that eliminated malaria-infected hepatocytes in vitro, as well as Abs that recognized pre-erythrocytic parasites. Sera from both groups of mice inhibited spz invasion of hepatocytes in vitro, but only CQ-ITV induced high levels of anti-BS Abs. Finally, passive transfer of sera from CQ-ITV–treated mice delayed the onset of erythrocytic infection in the majority of mice challenged with P. yoelii iRBCs. Besides constituting the first characterization, to our knowledge, of AS-ITV as a vaccination strategy, our data show that ITV strategies that lead to subtle differences in the persistence of parasites in the blood enable the characterization of the resulting immune responses, which will contribute to future research in vaccine design and malaria interventions.