Hybrid bounds for twisted L-functions

The aim of this paper is to derive bounds on the critical line Rs 1/2 for L- functions attached to twists f circle times chi of a primitive cusp form f of level N and a primitive character modulo q that break convexity simultaneously in the s and q aspects. If f has trivial nebentypus, it is shown that L(f circle times chi, s) << (N vertical bar s vertical bar q)(epsilon) N-4/5(vertical bar s vertical bar q)(1/2-1/40), where the implied constant depends only on epsilon > 0 and the archimedean parameter of f. To this end, two independent methods are employed to show L(f circle times chi, s) << (N vertical bar s vertical bar q)(epsilon) N-1/2 vertical bar S vertical bar(1/2)q(3/8) and L(g,s) << D-2/3 vertical bar S vertical bar(5/12) for any primitive cusp form g of level D and arbitrary nebentypus (not necessarily a twist f circle times chi of level D vertical bar Nq(2))

c-Fms-Mediated Differentiation and Priming of Monocyte Lineage Cells Play a Central Role in Autoimmune Arthritis

Introduction: Tyrosine kinases are key mediators of multiple signaling pathways implicated in rheumatoid arthritis (RA). We previously demonstrated that imatinib mesylate--a Food and Drug Administration (FDA)-approved, antineoplastic drug that potently inhibits the tyrosine kinases Abl, c-Kit, platelet-derived growth factor receptor (PDGFR), and c-Fms--ameliorates murine autoimmune arthritis. However, which of the imatinib-targeted kinases is the principal culprit in disease pathogenesis remains unknown. Here we examine the role of c-Fms in autoimmune arthritis. Methods: We tested the therapeutic efficacy of orally administered imatinib or GW2580, a small molecule that specifically inhibits c-Fms, in three mouse models of RA: collagen-induced arthritis (CIA), anti-collagen antibody-induced arthritis (CAIA), and K/BxN serum transfer-induced arthritis (K/BxN). Efficacy was evaluated by visual scoring of arthritis severity, paw thickness measurements, and histological analysis. We assessed the in vivo effects of imatinib and GW2580 on macrophage infiltration of synovial joints in CIA, and their in vitro effects on macrophage and osteoclast differentiation, and on osteoclast-mediated bone resorption. Further, we determined the effects of imatinib and GW2580 on the ability of macrophage colony-stimulating factor (M-CSF; the ligand for c-Fms) to prime bone marrow-derived macrophages to produce tumor necrosis factor (TNF) upon subsequent Fc receptor ligation. Finally, we measured M-CSF levels in synovial fluid from patients with RA, osteoarthritis (OA), or psoriatic arthritis (PsA), and levels of total and phosphorylated c-Fms in synovial tissue from patients with RA. Results: GW2580 was as efficacious as imatinib in reducing arthritis severity in CIA, CAIA, and K/BxN models of RA. Specific inhibition of c-Fms abrogated (i) infiltration of macrophages into synovial joints of arthritic mice; (ii) differentiation of monocytes into macrophages and osteoclasts; (iii) osteoclast-mediated bone resorption; and (iv) priming of macrophages to produce TNF upon Fc receptor stimulation, an important trigger of synovitis in RA. Expression and activation of c-Fms in RA synovium were high, and levels of M-CSF were higher in RA synovial fluid than in OA or PsA synovial fluid. Conclusions: These results suggest that c-Fms plays a central role in the pathogenesis of RA by mediating the differentiation and priming of monocyte lineage cells. Therapeutic targeting of c-Fms could provide benefit in RA

Efficient snap-through of spherical caps by applying a localized curvature stimulus

In bistable actuators and other engineered devices, a homogeneous stimulus (e.g., mechanical, chemical, thermal, or magnetic) is often applied to an entire shell to initiate a snap-through instability. In this work, we demonstrate that restricting the active area to the shell boundary allows for a large reduction in its size, thereby decreasing the energy input required to actuate the shell. To do so, we combine theory with 1D finite element simulations of spherical caps with a non-homogeneous distribution of stimulus-responsive material. We rely on the effective curvature stimulus, i.e., the natural curvature induced by the non-mechanical stimulus, which ensures that our results are entirely stimulus-agnostic. To validate our numerics and demonstrate this generality, we also perform two sets of experiments, wherein we use residual swelling of bilayer silicone elastomers-a process that mimics differential growth-as well as a magneto-elastomer to induce curvatures that cause snap-through. Our results elucidate the underlying mechanics, offering an intuitive route to optimal design for efficient snap-through.CMMI-1824882 - National Science Foundation; CMMI-1824882 - National Science FoundationAccepted manuscrip

Microwave Spin Control of a Tin-Vacancy Qubit in Diamond

The negatively charged tin-vacancy (SnV-) center in diamond is a promising solid-state qubit for applications in quantum networking due to its high quantum efficiency, strong zero phonon emission, and reduced sensitivity to electrical noise. The SnV- has a large spin-orbit coupling, which allows for long spin lifetimes at elevated temperatures, but unfortunately suppresses the magnetic dipole transitions desired for quantum control. Here, by use of a naturally strained center, we overcome this limitation and achieve high-fidelity microwave spin control. We demonstrate a pi-pulse fidelity of up to 99.51+/0.03%$ and a Hahn-echo coherence time of T2echo = 170.0+/-2.8 microseconds, both the highest yet reported for SnV- platform. This performance comes without compromise to optical stability, and is demonstrated at 1.7 Kelvin where ample cooling power is available to mitigate drive induced heating. These results pave the way for SnV- spins to be used as a building block for future quantum technologies

Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in Zucker fatty rats (Fa/Fa)

Peer reviewedPublisher PD

Comparison of intima-media thickness and ophthalmic artery resistance index for assessing subclinical atherosclerosis in HIV-1-infected patients

<p>Abstract</p> <p>Background</p> <p>Human immunodeficiency virus (HIV) infection and antiretroviral treatment are associated with metabolic and cardiovascular complications that potentially increase the risk of atherosclerosis and cardiovascular disease in this population. Measurement of arterial wall thickness has been used as a surrogate of extent, severity and progression of atherosclerosis. A cross-sectional cohort study was performed to compare the validity of two non-invasive arterial measures: carotid intima-media thickness (IMT), a parameter of atherosclerosis, and ophthalmic artery resistance index (OARI), an index of occlusive carotid artery disease.</p> <p>Methods</p> <p>A total of 95 patients receiving highly active antiretroviral therapy (HAART) for more than 12 months were consecutively enrolled. IMT and OARI were measured by 7.5 MHz linear probe.</p> <p>Results</p> <p>There was a significant linear increase in IMT and OARI values as the grade of cardiovascular risk (0.70 and 0.69 for very low risk, 0.86 and 0.72 for low risk and 0.98 and 0.74 for medium/high risk, p < 0.001). A IMT > 0.83 and an OARI > 0.72 were the most discriminatory values for predicting a cardiovascular risk ≥ 10% (sensibility 89.6% and 75.8%; sensitivity 70.5% and 68.4%; p < 0.001).</p> <p>Conclusions</p> <p>Our data indicate that OARI may have a potential as a new precocious marker of subclinical atherosclerosis in HIV-1-infected patients.</p

Seatbelt use and risk of major injuries sustained by vehicle occupants during motor-vehicle crashes: A systematic review and meta-analysis of cohort studies

BackgroundIn 2004, a World Health Report on road safety called for enforcement of measures such as seatbelt use, effective at minimizing morbidity and mortality caused by road traffic accidents. However, injuries caused by seatbelt use have also been described. Over a decade after publication of the World Health Report on road safety, this study sought to investigate the relationship between seatbelt use and major injuries in belted compared to unbelted passengers.MethodsCohort studies published in English language from 2005 to 2018 were retrieved from seven databases. Critical appraisal of studies was carried out using the Scottish Intercollegiate Guidelines Network (SIGN) checklist. Pooled risk of major injuries was assessed using the random effects meta-analytic model. Heterogeneity was quantified using I-squared and Tau-squared statistics. Funnel plots and Egger's test were used to investigate publication bias. This review is registered in PROSPERO (CRD42015020309).ResultsEleven studies, all carried out in developed countries were included. Overall, the risk of any major injury was significantly lower in belted passengers compared to unbelted passengers (RR 0.47; 95%CI, 0.29 to 0.80; I-2=99.7; P=0.000). When analysed by crash types, belt use significantly reduced the risk of any injury (RR 0.35; 95%CI, 0.24 to 0.52). Seatbelt use reduces the risk of facial injuries (RR=0.56, 95% CI=0.37 to 0.84), abdominal injuries (RR=0.87; 95% CI=0.78 to 0.98) and, spinal injuries (RR=0.56, 95% CI=0.37 to 0.84). However, we found no statistically significant difference in risk of head injuries (RR=0.49; 95% CI=0.22 to 1.08), neck injuries (RR=0.69: 95%CI 0.07 to 6.44), thoracic injuries (RR 0.96, 95%CI, 0.74 to 1.24), upper limb injuries (RR=1.05, 95%CI 0.83 to 1.34) and lower limb injuries (RR=0.77, 95%CI 0.58 to 1.04) between belted and non-belted passengers.ConclusionIn sum, the risk of most major road traffic injuries is lower in seatbelt users. Findings were inconclusive regarding seatbelt use and susceptibility to thoracic, head and neck injuries during road traffic accidents. Awareness should be raised about the dangers of inadequate seatbelt use. Future research should aim to assess the effects of seatbelt use on major injuries by crash type

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Severe consequences of habitat fragmentation on genetic diversity of an endangered Australian freshwater fish: A call for assisted gene flow

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Genetic diversity underpins the ability of populations to persist and adapt to environmental changes. Substantial empirical data show that genetic diversity rapidly deteriorates in small and isolated populations due to genetic drift, leading to reduction in adaptive potential and fitness and increase in inbreeding. Assisted gene flow (e.g. via translocations) can reverse these trends, but lack of data on fitness loss and fear of impairing population “uniqueness” often prevents managers from acting. Here, we use population genetic and riverscape genetic analyses and simulations to explore the consequences of extensive habitat loss and fragmentation on population genetic diversity and future population trajectories of an endangered Australian freshwater fish, Macquarie perch Macquaria australasica. Using guidelines to assess the risk of outbreeding depression under admixture, we develop recommendations for population management, identify populations requiring genetic rescue and/or genetic restoration and potential donor sources. We found that most remaining populations of Macquarie perch have low genetic diversity, and effective population sizes below the threshold required to retain adaptive potential. Our simulations showed that under management inaction, smaller populations of Macquarie perch will face inbreeding depression within a few decades, but regular small-scale translocations will rapidly rescue populations from inbreeding depression and increase adaptive potential through genetic restoration. Despite the lack of data on fitness loss, based on our genetic data for Macquarie perch populations, simulations and empirical results from other systems, we recommend regular and frequent translocations among remnant populations within catchments. These translocations will emulate the effect of historical gene flow and improve population persistence through decrease in demographic and genetic stochasticity. Increasing population genetic connectivity within each catchment will help to maintain large effective population sizes and maximize species adaptive potential. The approach proposed here could be readily applicable to genetic management of other threatened species to improve their adaptive potential