A Novel Paradigm Between Leukocytosis, G-CSF Secretion, Neutrophil-to-Lymphocyte Ratio, Myeloid-Derived Suppressor Cells, and Prognosis in Non-small Cell Lung Cancer

Leukocytosis is a common feature of malignancies. While controversial, there appears to be an association between the degree of tumor-related leukocytosis and prognosis. In this paper, we provide evidence supporting an untapped clinical paradigm linking G-CSF secretion to the induction of leukocytosis and expansion of myeloid-derived suppressor cells, providing an explanation for the association between leukocytosis, elevated neutrophil-to-lymphocyte ratios and prognosis in non-small cell lung cancer. Clinically validating this mechanism may identify MDSCs and G-CSF as dynamic markers of early disease progression and therapeutic response, and shed light onto novel therapeutic avenues for the treatment of patients with non-small cell lung cancer

Comparing the hierarchy of keywords in on-line news portals

The tagging of on-line content with informative keywords is a widespread phenomenon from scientific article repositories through blogs to on-line news portals. In most of the cases, the tags on a given item are free words chosen by the authors independently. Therefore, relations among keywords in a collection of news items is unknown. However, in most cases the topics and concepts described by these keywords are forming a latent hierarchy, with the more general topics and categories at the top, and more specialised ones at the bottom. Here we apply a recent, cooccurrence-based tag hierarchy extraction method to sets of keywords obtained from four different on-line news portals. The resulting hierarchies show substantial differences not just in the topics rendered as important (being at the top of the hierarchy) or of less interest (categorised low in the hierarchy), but also in the underlying network structure. This reveals discrepancies between the plausible keyword association frameworks in the studied news portals

Hierarchy measure for complex networks

Nature, technology and society are full of complexity arising from the intricate web of the interactions among the units of the related systems (e.g., proteins, computers, people). Consequently, one of the most successful recent approaches to capturing the fundamental features of the structure and dynamics of complex systems has been the investigation of the networks associated with the above units (nodes) together with their relations (edges). Most complex systems have an inherently hierarchical organization and, correspondingly, the networks behind them also exhibit hierarchical features. Indeed, several papers have been devoted to describing this essential aspect of networks, however, without resulting in a widely accepted, converging concept concerning the quantitative characterization of the level of their hierarchy. Here we develop an approach and propose a quantity (measure) which is simple enough to be widely applicable, reveals a number of universal features of the organization of real-world networks and, as we demonstrate, is capable of capturing the essential features of the structure and the degree of hierarchy in a complex network. The measure we introduce is based on a generalization of the m-reach centrality, which we first extend to directed/partially directed graphs. Then, we define the global reaching centrality (GRC), which is the difference between the maximum and the average value of the generalized reach centralities over the network. We investigate the behavior of the GRC considering both a synthetic model with an adjustable level of hierarchy and real networks. Results for real networks show that our hierarchy measure is related to the controllability of the given system. We also propose a visualization procedure for large complex networks that can be used to obtain an overall qualitative picture about the nature of their hierarchical structure.Comment: 29 pages, 9 figures, 4 table

AMPK Modulation Ameliorates Dominant Disease Phenotypes of CTRP5 Variant in Retinal Degeneration

Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder caused by a missense substitution in CTRP5. Distinctive clinical features include sub-retinal pigment epithelium (RPE) deposits, choroidal neovascularization, and RPE atrophy. In induced pluripotent stem cells-derived RPE from L-ORD patients (L-ORD-iRPE), we show that the dominant pathogenic CTRP5 variant leads to reduced CTRP5 secretion. In silico modeling suggests lower binding of mutant CTRP5 to adiponectin receptor 1 (ADIPOR1). Downstream of ADIPOR1 sustained activation of AMPK renders it insensitive to changes in AMP/ATP ratio resulting in defective lipid metabolism, reduced Neuroprotectin D1(NPD1) secretion, lower mitochondrial respiration, and reduced ATP production. These metabolic defects result in accumulation of sub-RPE deposits and leave L-ORD-iRPE susceptible to dedifferentiation. Gene augmentation of L-ORD-iRPE with WT CTRP5 or modulation of AMPK, by metformin, re-sensitize L-ORD-iRPE to changes in cellular energy status alleviating the disease cellular phenotypes. Our data suggests a mechanism for the dominant behavior of CTRP5 mutation and provides potential treatment strategies for L-ORD patients. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply

Using metadynamics to explore complex free-energy landscapes

Metadynamics is an atomistic simulation technique that allows, within the same framework, acceleration of rare events and estimation of the free energy of complex molecular systems. It is based on iteratively \u2018filling\u2019 the potential energy of the system by a sum of Gaussians centred along the trajectory followed by a suitably chosen set of collective variables (CVs), thereby forcing the system to migrate from one minimum to the next. The power of metadynamics is demonstrated by the large number of extensions and variants that have been developed. The first scope of this Technical Review is to present a critical comparison of these variants, discussing their advantages and disadvantages. The effectiveness of metadynamics, and that of the numerous alternative methods, is strongly influenced by the choice of the CVs. If an important variable is neglected, the resulting estimate of the free energy is unreliable, and predicted transition mechanisms may be qualitatively wrong. The second scope of this Technical Review is to discuss how the CVs should be selected, how to verify whether the chosen CVs are sufficient or redundant, and how to iteratively improve the CVs using machine learning approaches

Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease:A randomized controlled trial

Objective: The aim of the study is to determine the effect of lutein combined with vitamin and mineral supplementation on contrast sensitivity in people with age-related macular disease (ARMD). Design: A prospective, 9-month, double-masked randomized controlled trial. Setting: Aston University, Birmingham, UK and a UK optometric clinical practice. Subjects: Age-related maculopathy (ARM) and atrophic age-related macular degeneration (AMD) participants were randomized (using a random number generator) to either placebo (n = 10) or active (n=15) groups. Three of the placebo group and two of the active group dropped out. Interventions: The active group supplemented daily with 6 mg lutein combined with vitamins and minerals. The outcome measure was contrast sensitivity (CS) measured using the Pelli-Robson chart, for which the study had 80% power at the 5% significance level to detect a change of 0.3log units. Results: The CS score increased by 0.07 ± 0.07 and decreased by 0.02 ± 0.18 log units for the placebo and active groups, respectively. The difference between these values is not statistically significant (z = 0.903, P = 0.376). Conclusion: The results suggest that 6 mg of lutein supplementation in combination with other antioxidants is not beneficial for this group. Further work is required to establish optimum dosage levels

Phylogenetic placement of Adalatherium hui (Mammalia, Gondwanatheria) from the Late Cretaceous of Madagascar : implications for allotherian relationships

The phylogenetic position of Gondwanatheria within Mammaliaformes has historically been controversial. The well-preserved skeleton of Adalatherium hui from the Late Cretaceous of Madagascar offers a unique opportunity to address this issue, based on morphological data from the whole skeleton. Gondwanatheria were, until recently, known only from fragmentary dental and mandibular material, as well as a single cranium. The holotype of A. hui provides the first postcranial skeleton for gondwanatherians and substantially increases the amount of character data available to score. We sampled 530 characters and 84 cynodonts (including 34 taxa historically affiliated with Allotheria) to test the phylogenetic relationships of Gondwanatheria and Allotheria using parsimony, undated Bayesian, and tip-dated Bayesian methods. We tested three lower dental formulae for Adalatherium, because its postcanines are distinctly different from those of other mammaliaforms and cannot readily be homologized with any known dental pattern. In all analyses, Adalatherium is recovered within Gondwanatheria, most frequently outside of Sudamericidae or Ferugliotheriidae, which is congruent with establishment of the family Adalatheriidae. The different dental coding schemes do not greatly impact the position of Adalatherium, although there are differences in character optimization. In all analyses, Gondwanatheria are placed within Allotheria, either as sister to Multituberculata, nested within Multituberculata, or as sister to Cifelliodon (and Euharamiyida), or in a polytomy with other allotherians. The composition of Allotheria varies in our analyses. The haramiyidans Haramiyavia and Thomasia are placed outside of Allotheria in the parsimony and tip-dated Bayesian analyses, but in a polytomy with other allotherians in the undated Bayesian analyses

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Paleobiology of titanosaurs: reproduction, development, histology, pneumaticity, locomotion and neuroanatomy from the South American fossil record

Fil: García, Rodolfo A.. Instituto de Investigación en Paleobiología y Geología. Museo Provincial Carlos Ameghino. Cipolletti; ArgentinaFil: Salgado, Leonardo. Instituto de Investigación en Paleobiología y Geología. General Roca. Río Negro; ArgentinaFil: Fernández, Mariela. Inibioma-Centro Regional Universitario Bariloche. Bariloche. Río Negro; ArgentinaFil: Cerda, Ignacio A.. Instituto de Investigación en Paleobiología y Geología. Museo Provincial Carlos Ameghino. Cipolletti; ArgentinaFil: Carabajal, Ariana Paulina. Museo Carmen Funes. Plaza Huincul. Neuquén; ArgentinaFil: Otero, Alejandro. Museo de La Plata. Universidad Nacional de La Plata; ArgentinaFil: Coria, Rodolfo A.. Instituto de Paleobiología y Geología. Universidad Nacional de Río Negro. Neuquén; ArgentinaFil: Fiorelli, Lucas E.. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica. Anillaco. La Rioja; Argentin