On the Inability of Markov Models to Capture Criticality in Human Mobility

We examine the non-Markovian nature of human mobility by exposing the inability of Markov models to capture criticality in human mobility. In particular, the assumed Markovian nature of mobility was used to establish a theoretical upper bound on the predictability of human mobility (expressed as a minimum error probability limit), based on temporally correlated entropy. Since its inception, this bound has been widely used and empirically validated using Markov chains. We show that recurrent-neural architectures can achieve significantly higher predictability, surpassing this widely used upper bound. In order to explain this anomaly, we shed light on several underlying assumptions in previous research works that has resulted in this bias. By evaluating the mobility predictability on real-world datasets, we show that human mobility exhibits scale-invariant long-range correlations, bearing similarity to a power-law decay. This is in contrast to the initial assumption that human mobility follows an exponential decay. This assumption of exponential decay coupled with Lempel-Ziv compression in computing Fano's inequality has led to an inaccurate estimation of the predictability upper bound. We show that this approach inflates the entropy, consequently lowering the upper bound on human mobility predictability. We finally highlight that this approach tends to overlook long-range correlations in human mobility. This explains why recurrent-neural architectures that are designed to handle long-range structural correlations surpass the previously computed upper bound on mobility predictability

Donor Lymphocyte Infusion for Relapsed Hematological Malignancies after Allogeneic Hematopoietic Cell Transplantation: Prognostic Relevance of the Initial CD3(+) T Cell Dose.

AbstractThe impact of donor lymphocyte infusion (DLI) initial cell dose on its outcome is known in patients with chronic myeloid leukemia but limited in patients with other hematological malignancies. In this retrospective study, we evaluated the effect of initial DLI CD3+ cell dose on graft-versus-host disease (GVHD) and overall survival after DLI given for relapse of any hematological malignancies after allogeneic hematopoietic cell transplantation (HCT) with high- or reduced-intensity conditioning. The cohort included 225 patients. Initial DLI CD3+ cell dose per kilogram of recipient body weight was ≤1 × 107 (n = 84; group A), >1.0 to <10 × 107 (n = 58; group B), and ≥10 × 107 (n = 66; group C). The initial cell dose was unknown for the remaining 17 patients. Cumulative incidence rates of GVHD at 12 months after DLI were 21%, 45%, and 55% for groups A, B, and C, respectively. Multivariate analysis showed that initial DLI CD3+ cell ≥10 × 107 dose per kilogram is associated with an increased risk of GVHD after DLI (P = .03). Moreover, an initial DLI CD3+ cell dose of 10 × 107 or higher did not decrease the risk of relapse and did not improve overall survival. Thus, these results support the use of less than 10 × 107 CD3+ cell per kilogram as the initial cell dose of DLI for treatment of persistent or recurrent hematological malignancy after HCT

Fludarabine/2 Gy TBI is Superior to 2 Gy TBI as Conditioning for HLA-Matched Related HCT: A Phase III Randomized Trial.

AbstractThe risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m2 fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P < .0001) and 84 (68% versus 92%; P < .0001), as was NK cell chimerism on day 28 (75% versus 96%; P = .0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high-level donor engraftment early after transplantation

Model Convolution: A Computational Approach to Digital Image Interpretation

Digital fluorescence microscopy is commonly used to track individual proteins and their dynamics in living cells. However, extracting molecule-specific information from fluorescence images is often limited by the noise and blur intrinsic to the cell and the imaging system. Here we discuss a method called “model-convolution,” which uses experimentally measured noise and blur to simulate the process of imaging fluorescent proteins whose spatial distribution cannot be resolved. We then compare model-convolution to the more standard approach of experimental deconvolution. In some circumstances, standard experimental deconvolution approaches fail to yield the correct underlying fluorophore distribution. In these situations, model-convolution removes the uncertainty associated with deconvolution and therefore allows direct statistical comparison of experimental and theoretical data. Thus, if there are structural constraints on molecular organization, the model-convolution method better utilizes information gathered via fluorescence microscopy, and naturally integrates experiment and theory

Plant Trait Diversity Buffers Variability in Denitrification Potential over Changes in Season and Soil Conditions

BACKGROUND: Denitrification is an important ecosystem service that removes nitrogen (N) from N-polluted watersheds, buffering soil, stream, and river water quality from excess N by returning N to the atmosphere before it reaches lakes or oceans and leads to eutrophication. The denitrification enzyme activity (DEA) assay is widely used for measuring denitrification potential. Because DEA is a function of enzyme levels in soils, most ecologists studying denitrification have assumed that DEA is less sensitive to ambient levels of nitrate (NO(3)(-)) and soil carbon and thus, less variable over time than field measurements. In addition, plant diversity has been shown to have strong effects on microbial communities and belowground processes and could potentially alter the functional capacity of denitrifiers. Here, we examined three questions: (1) Does DEA vary through the growing season? (2) If so, can we predict DEA variability with environmental variables? (3) Does plant functional diversity affect DEA variability? METHODOLOGY/PRINCIPAL FINDINGS: The study site is a restored wetland in North Carolina, US with native wetland herbs planted in monocultures or mixes of four or eight species. We found that denitrification potentials for soils collected in July 2006 were significantly greater than for soils collected in May and late August 2006 (p<0.0001). Similarly, microbial biomass standardized DEA rates were significantly greater in July than May and August (p<0.0001). Of the soil variables measured--soil moisture, organic matter, total inorganic nitrogen, and microbial biomass--none consistently explained the pattern observed in DEA through time. There was no significant relationship between DEA and plant species richness or functional diversity. However, the seasonal variance in microbial biomass standardized DEA rates was significantly inversely related to plant species functional diversity (p<0.01). CONCLUSIONS/SIGNIFICANCE: These findings suggest that higher plant functional diversity may support a more constant level of DEA through time, buffering the ecosystem from changes in season and soil conditions

Triptans attenuate capsaicin-induced CREB phosphorylation within the trigeminal nucleus caudalis: a mechanism to prevent central sensitization?

The c-AMP-responsive element binding protein (CREB) and its phosphorylated product (P-CREB) are nuclear proteins expressed after stimulation of pain-producing areas of the spinal cord. There is evidence indicating that central sensitization within dorsal horn neurons is dependent on P-CREB transcriptional regulation. The objectives of the study were to investigate the expression of P-CREB in cells in rat trigeminal nucleus caudalis after noxious stimulation and to determine whether pre-treatment with specific anti-migraine agents modulate this expression. CREB and P-CREB labelling was investigated within the trigeminal caudalis by immunohistochemistry after capsaicin stimulation. Subsequently, the effect of i.v. pre-treatment with either sumatriptan (n = 5), or naratriptan (n = 7) on P-CREB expression was studied. Five animals pre-treated with i.v. normal saline were served as controls. CREB and P-CREB labelling was robust in all animal groups within Sp5C. Both naratriptan and sumatriptan decreased P-CREB expression (p = 0.0003 and 0.0013) within the Sp5C. Triptans attenuate activation of CREB within the central parts of the trigeminal system, thereby leading to potential inhibition of central sensitization. P-CREB may serve as a new marker for post-synaptic neuronal activation within Sp5C in animal models relevant to migraine

Anaerobic Energy Expenditure and Mechanical Efficiency during Exhaustive Leg Press Exercise

Information about anaerobic energy production and mechanical efficiency that occurs over time during short-lasting maximal exercise is scarce and controversial. Bilateral leg press is an interesting muscle contraction model to estimate anaerobic energy production and mechanical efficiency during maximal exercise because it largely differs from the models used until now. This study examined the changes in muscle metabolite concentration and power output production during the first and the second half of a set of 10 repetitions to failure (10RM) of bilateral leg press exercise. On two separate days, muscle biopsies were obtained from vastus lateralis prior and immediately after a set of 5 or a set of 10 repetitions. During the second set of 5 repetitions, mean power production decreased by 19% and the average ATP utilisation accounted for by phosphagen decreased from 54% to 19%, whereas ATP utilisation from anaerobic glycolysis increased from 46 to 81%. Changes in contraction time and power output were correlated to the changes in muscle Phosphocreatine (PCr; r = −0.76; P<0.01) and lactate (r = −0.91; P<0.01), respectively, and were accompanied by parallel decreases (P<0.01-0.05) in muscle energy charge (0.6%), muscle ATP/ADP (8%) and ATP/AMP (19%) ratios, as well as by increases in ADP content (7%). The estimated average rate of ATP utilisation from anaerobic sources during the final 5 repetitions fell to 83% whereas total anaerobic ATP production increased by 9% due to a 30% longer average duration of exercise (18.4±4.0 vs 14.2±2.1 s). These data indicate that during a set of 10RM of bilateral leg press exercise there is a decrease in power output which is associated with a decrease in the contribution of PCr and/or an increase in muscle lactate. The higher energy cost per repetition during the second 5 repetitions is suggestive of decreased mechanical efficiency

Factors that influence children's gambling attitudes and consumption intentions: Lessons for gambling harm prevention research, policies and advocacy strategies

Background: Harmful gambling is a public health issue that affects not only adults but also children. With the development of a range of new gambling products, and the marketing for these products, children are potentially exposed to gambling more than ever before. While there have been many calls to develop strategies which protect children from harmful gambling products, very little is known about the factors that may influence children's attitudes towards these products. This study aimed to explore children's gambling attitudes and consumption intentions and the range of consumer socialisation factors that may influence these attitudes and behaviours. Methods: Children aged 8 to 16 years old (n = 48) were interviewed in Melbourne, Australia. A semi-structured interview format included activities with children and open-ended questions. We explored children's perceptions of the popularity of different gambling products, their current engagement with gambling, and their future gambling consumption intentions. We used thematic analysis to explore children's narratives with a focus on the range of socialising factors that may shape children's gambling attitudes and perceptions. Results: Three key themes emerged from the data. First, children's perceptions of the popularity of different products were shaped by what they had seen or heard about these products, whether through family activities, the media (and in particular marketing) of gambling products, and/or the alignment of gambling products with sport. Second, children's gambling behaviours were influenced by family members and culturally valued events. Third, many children indicated consumption intentions towards sports betting. This was due to four key factors: (1) the alignment of gambling with culturally valued activities; (2) their perceived knowledge about sport; (3) the marketing and advertising of gambling products (and in particular sports betting); and (4) the influence of friends and family. Conclusions: This study indicates that there is a range of socialisation factors, particularly family and the media (predominantly via marketing), which may be positively shaping children's gambling attitudes, behaviours and consumption intentions. There is a need for governments to develop effective policies and regulations to reduce children's exposure to gambling products and ensure they are protected from the harms associated with gambling. © 2017 The Author(s)

Dihydrotestosterone Ameliorates Degeneration in Muscle, Axons and Motoneurons and Improves Motor Function in Amyotrophic Lateral Sclerosis Model Mice

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon