bluuebunny/crossref_metadata_2025 huggingface dataset:
Scale-free resilience of real traffic jams
Authors: Zhang Limiao , Zeng Guanwen , Li Daqing , Huang Hai-Jun , Stanley H. Eugene , Havlin Shlomo
Published: April 2019

Significance

Traffic congestion has become the most stubborn disease for the health of a city. Like the self-healing ability of a biological unit from diseases, transportation can also recover spontaneously from various disturbances. To describe this recovery, we define the resilience metric as the spatiotemporal congestion cluster, which can be used for other network systems. Based on large-scale GPS datasets, we reveal that the recovery behavior of transportation from congestion is governed by three scaling laws for all of the congestion scales. These scaling laws are found independent of microscopic details, including fluctuation of traffic demand and corresponding management. Our results of resilience scaling can help to better characterize and improve the adaptation and recovery of city traffic from various perturbations.
Environmental DNA for improved detection and environmental surveillance of schistosomiasis
Authors: Sengupta Mita E. , Hellström Micaela , Kariuki Henry C. , Olsen Annette , Thomsen Philip F. , Mejer Helena , Willerslev Eske , Mwanje Mariam T. , Madsen Henry , Kristensen Thomas K. , Stensgaard Anna-Sofie , Vennervald Birgitte J.
Published: April 2019

Significance

Accurate detection and delineation of schistosomiasis transmission sites will be vital in ongoing efforts to control and ultimately eliminate one of the most neglected tropical parasitic diseases affecting >250 million people worldwide. Conventional methods to detect parasites in the environment are cumbersome and have low sensitivity. We therefore developed an environmental DNA (eDNA)-based method for schistosome detection in aquatic environments. Aquatic eDNA showed higher sensitivity than conventional snail surveys. We conclude that eDNA is a promising noninvasive and sensitive tool for environmental surveillance of schistosomiasis transmission. As the efforts and aims to control the disease are transitioning toward complete transmission interruption, this could be the robust and cost-effective surveillance tool needed in the “endgame” of schistosomiasis.
Evolution of social norms and correlated equilibria
Authors: Morsky Bryce , Akçay Erol
Published: April 2019

Significance

We consider social norms as collections of beliefs or superstitions about events occurring in nature. These events have no inherent meaning, but individuals can choose to believe that they do. Specifically, individuals can interpret events as prescribing behaviors for themselves along with expectations of the behaviors of others. We show how evolutionary competition between such beliefs can give rise to both prescriptive and descriptive self-enforcing norms that can allow populations to coordinate behavior. Our model provides an evolutionary account for how normative meaning emerges in an inherently meaningless world.
Correlated interfacial water transport and proton conductivity in perfluorosulfonic acid membranes
Authors: Ling Xiao , Bonn Mischa , Domke Katrin F. , Parekh Sapun H.
Published: April 2019

Significance

Fuel-cell proton-exchange membranes (PEMs) are central to hydrogen fuel-cell technology. The mechanism and optimization of proton transport in these materials is intimately linked with hydration and water transport. Studies of water transport in PEMs have previously been limited to macroscopic permeability measurements. Our work connects the macroscopic proton transport in PEMs to the molecular water arrangement: Two distinct types of water, differing in their degree of molecular coordination, transit the membrane at very different rates. The more weakly coordinated water species consistently exhibits faster transit across five different PEMs and shows a direct correlation to the proton conductivity, suggesting that designing PEMs to maximize the fraction of undercoordinated water is key for maximizing overall transport.
Shock growth of ice crystal near equilibrium melting pressure under dynamic compression
Authors: Kim Yong-Jae , Lee Yun-Hee , Lee Sooheyong , Nada Hiroki , Lee Geun Woo
Published: April 2019

Significance

Crystal growth and morphological transitions are crucial for fundamental science and wide applications. Nevertheless, their mechanisms under local nonequilibrium growth condition are unclear due to severe interference of thermal and mass transports on the interplay between thermodynamic driving force and interface kinetics. Here, we reveal the origin of the pressure-induced 2D shock growth of ice VI crystal by using dynamic compression, in which a dimensional transition from 3D to 2D is observed. Unlike generally expected, the 2D shock growth occurs from 3D crystal edges rather than from its corners upon fast compression, even near equilibrium growth condition. This is due to similar interface structure to the crystal edge plane facilitating the fast interface kinetics under local nonequilibrium growth.
Testing the role of trait reversal in evolutionary diversification using song loss in wild crickets
Authors: Bailey Nathan W. , Pascoal Sonia , Montealegre-Z Fernando
Published: April 2019

The mechanisms underlying rapid macroevolution are controversial. One largely untested hypothesis that could inform this debate is that evolutionary reversals might release variation in vestigial traits, which then facilitates subsequent diversification. We evaluated this idea by testing key predictions about vestigial traits arising from sexual trait reversal in wild field crickets. In HawaiianTeleogryllus oceanicus, the recent genetic loss of sound-producing and -amplifying structures on male wings eliminates their acoustic signals. Silence protects these “flatwing” males from an acoustically orienting parasitoid and appears to have evolved independently more than once. Here, we report that flatwing males show enhanced variation in vestigial resonator morphology under varied genetic backgrounds. Using laser Doppler vibrometry, we found that these vestigial sound-producing wing features resonate at highly variable acoustic frequencies well outside the normal range for this species. These results satisfy two important criteria for a mechanism driving rapid evolutionary diversification: Sexual signal loss was accompanied by a release of vestigial morphological variants, and these could facilitate the rapid evolution of novel signal values. Widespread secondary trait losses have been inferred from fossil and phylogenetic evidence across numerous taxa, and our results suggest that such reversals could play a role in shaping historical patterns of diversification.
Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma
Authors: Xu Jie , Chen Li-Juan , Yang Shuang-Shuang , Sun Yan , Wu Wen , Liu Yuan-Fang , Xu Ji , Zhuang Yan , Zhang Wu , Weng Xiang-Qin , Wu Jing , Wang Yan , Wang Jin , Yan Hua , Xu Wen-Bin , Jiang Hua , Du Juan , Ding Xiao-Yi , Li Biao , Li Jun-Min , Fu Wei-Jun , Zhu Jiang , Zhu Li , Chen Zhu , Fan Xiao-Hu (Frank) , Hou Jian , Li Jian-Yong , Mi Jian-Qing , Chen Sai-Juan
Published: April 2019

Significance

Multiple myeloma (MM) is one of the most common hematological malignancies. Developing an effective treatment strategy for refractory/relapsed (R/R) MM represents a major challenge. In this trial, 17 R/R MM patients, who had previously experienced multiple lines of treatments, received a chimeric antigen receptor modified T (CAR T) cell preparation targeting two epitopes of BCMA, and a remarkable overall response of 88.2% was achieved. This work confirms the feasibility and importance of CAR T cell therapy in the treatment of patients with R/R MM. Meanwhile, the adverse events encountered in this study are analyzed, providing a reference for other studies. We also suggest that CAR T treatment can eventually be combined with other effective therapeutics to treat newly diagnosed MM for achieving a better result in future trials.
Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals
Authors: Hu Yuzheng , Salmeron Betty Jo , Krasnova Irina N. , Gu Hong , Lu Hanbing , Bonci Antonello , Cadet Jean L. , Stein Elliot A. , Yang Yihong
Published: April 2019

Significance

Addiction is characterized by compulsive drug use despite negative consequences. In a rat model of methamphetamine self-administration, we found that compulsive-like drug taking was correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal “go” circuit and a decreased prelimbic cortex-ventrolateral striatal “stop” circuit only in an addictive-like subgroup resistant to foot shock punishment paired with drug taking. In nonaddictive-like rats, the go-stop balance, which was similarly changed after repeated self-administration without punishment, normalized toward baseline levels after punishment. These results indicate that restoring the go-stop physiological balance, perhaps with noninvasive brain stimulation, may provide a promising avenue for addiction treatment when coupled with neuroimaging to assess clinical responses to determine the adequacy of a course of treatment.
Unified energetics analysis unravels SpCas9 cleavage activity for optimal gRNA design
Authors: Zhang Dong , Hurst Travis , Duan Dongsheng , Chen Shi-Jie
Published: April 2019

While CRISPR/Cas9 is a powerful tool in genome engineering, the on-target activity and off-target effects of the system widely vary because of the differences in guide RNA (gRNA) sequences and genomic environments. Traditional approaches rely on separate models and parameters to treat on- and off-target cleavage activities. Here, we demonstrate that a free-energy scheme dominates the Cas9 editing efficacy and delineate a method that simultaneously considers on-target activities and off-target effects. While data-driven machine-learning approaches learn rules to model particular datasets, they may not be as transferrable to new systems or capable of producing new mechanistic insights as principled physical approaches. By integrating the energetics of R-loop formation under Cas9 binding, the effect of the protospacer adjacent motif sequence, and the folding stability of the whole single guide RNA, we devised a unified, physical model that can apply to any cleavage-activity dataset. This unified framework improves predictions for both on-target activities and off-target efficiencies of spCas9 and may be readily transferred to other systems with different guide RNAs or Cas9 ortholog proteins.
Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1
Authors: Lee JuYeon , Bai Yugang , Chembazhi Ullas V. , Peng Shaohong , Yum Kevin , Luu Long M. , Hagler Lauren D. , Serrano Julio F. , Chan H. Y. Edwin , Kalsotra Auinash , Zimmerman Steven C.
Published: April 2019

Significance

Multivalent ligands have tremendous potential as therapeutic agents; however, their efficacy is limited by delivery issues, poor cell permeability, and toxicity. We report here a strategy wherein multivalent ligands are designed to be intrinsically cell-penetrating, allowing them to target the expanded trinucleotide repeat sequences of DNA and RNA that cause myotonic dystrophy type 1 (DM1). The multivalent ligand studied shows cell permeability and low toxicity both in cells and in mice. Importantly, the ligand reduced or eliminated DM1 defects in DM1 cells and in vivo, validating the multivalent strategy. The approach should be broadly applicable to other repeat expansion diseases and to any multivalent oligomeric therapeutic agent whose activity can accommodate structural elements that mimic cell-penetrating peptides.
DNA threads released by activated CD4
+
T lymphocytes provide autocrine costimulation
Authors: Costanza Massimo , Poliani Pietro L. , Portararo Paola , Cappetti Barbara , Musio Silvia , Pagani Francesca , Steinman Lawrence , Colombo Mario P. , Pedotti Rosetta , Sangaletti Sabina
Published: April 2019

Significance

A growing body of literature has shown that, aside from carrying genetic information, both nuclear and mitochondrial DNA can be released by innate immune cells and promote inflammatory responses. Here we show that when CD4
+
T lymphocytes, key orchestrators of adaptive immunity, are activated, they form a complex extracellular architecture composed of oxidized threads of DNA that provide autocrine costimulatory signals to T cells. We named these DNA extrusions “T helper-released extracellular DNA” (THREDs). We suggest that inhibiting this inflammatory process might represent a new therapeutic modality for CD4
+
T cell-mediated autoimmune disorders, such as experimental autoimmune encephalomyelitis, the varied forms of which provide animal models for multiple sclerosis and neuromyelitis optica.
Bootstrapping variables in algebraic circuits
Authors: Agrawal Manindra , Ghosh Sumanta , Saxena Nitin
Published: April 2019

Significance

Zero testing [or polynomial identity testing (PIT)] for circuits is a computational algebra problem with numerous practical applications and a beautiful theory (e.g., primality testing and graph matching are solved using PIT). It strongly relates to showing that there are explicit/natural polynomials that require exponentially large circuits. The latter is also called the algebraic version of the P≠NP question (or VP≠?VNP) and lies in the intersection of mathematics and computing. This work provides a plausible route to it if we can design a polynomial-time computable, but small enough, hitting set for trivariate depth-4 circuits [merelyΣΠΣ∧(3)].
Machine learning-assisted directed protein evolution with combinatorial libraries
Authors: Wu Zachary , Kan S. B. Jennifer , Lewis Russell D. , Wittmann Bruce J. , Arnold Frances H.
Published: April 2019

To reduce experimental effort associated with directed protein evolution and to explore the sequence space encoded by mutating multiple positions simultaneously, we incorporate machine learning into the directed evolution workflow. Combinatorial sequence space can be quite expensive to sample experimentally, but machine-learning models trained on tested variants provide a fast method for testing sequence space computationally. We validated this approach on a large published empirical fitness landscape for human GB1 binding protein, demonstrating that machine learning-guided directed evolution finds variants with higher fitness than those found by other directed evolution approaches. We then provide an example application in evolving an enzyme to produce each of the two possible product enantiomers (i.e., stereodivergence) of a new-to-nature carbene Si–H insertion reaction. The approach predicted libraries enriched in functional enzymes and fixed seven mutations in two rounds of evolution to identify variants for selective catalysis with 93% and 79%
ee
(enantiomeric excess). By greatly increasing throughput with in silico modeling, machine learning enhances the quality and diversity of sequence solutions for a protein engineering problem.
Select sequencing of clonally expanded CD8+T cells reveals limits to clonal expansion
Authors: Huang Huang , Sikora Michael J. , Islam Saiful , Chowdhury Roshni Roy , Chien Yueh-hsiu , Scriba Thomas J. , Davis Mark M. , Steinmetz Lars M.
Published: April 2019

To permit the recognition of antigens, T cells generate a vast diversity of T cell receptor (TCR) sequences. Upon binding of the TCR to an antigen–MHC complex, T cells clonally expand to establish an immune response. To study antigen-specific T cell clonality, we have developed a method that allows selection of rare cells, based on RNA expression, before in-depth scRNA-seq (named SELECT-seq). We applied SELECT-seq to collect both TCR sequences and then transcriptomes from single cells of peripheral blood lymphocytes activated by aMycobacterium tuberculosis(Mtb) lysate. TCR sequence analysis allowed us to preferentially select expanded conventional CD8+T cells as well as invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. The iNKT and MAIT cells have a highly similar transcriptional pattern, indicating that they carry out similar immunological functions and differ considerably from conventional CD8+T cells. While there is no relationship between expression profiles and clonal expansion in iNKT or MAIT cells, highly expanded conventional CD8+T cells down-regulate the interleukin 2 (IL-2) receptor alpha (IL2RA, or CD25) protein and show signs of senescence. This suggests inherent limits to clonal expansion that act to diversify the T cell response repertoire.
Interaction between p53 N terminus and core domain regulates specific and nonspecific DNA binding
Authors: He Fan , Borcherds Wade , Song Tanjing , Wei Xi , Das Mousumi , Chen Lihong , Daughdrill Gary W. , Chen Jiandong
Published: April 2019

Significance

The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription to regulate cell survival and proliferation. This report investigates the role of the p53 N-terminal transactivation domain in regulating DNA binding affinity and specificity. The results suggest the N-terminal acidic transactivation region of p53 dynamically interacts with the DNA binding domain near residues that contact DNA, thus inhibiting DNA binding and increasing sequence specificity by nucleic acid mimicry or electrostatic shielding. Furthermore, p53 N-terminal–interacting proteins and posttranslational modifications may regulate DNA binding affinity and specificity partly by modulating the N terminus–DNA binding domain interaction.
Effects of Pilates on fall risk factors in community‐dwelling elderly women: A randomized, controlled trial.
Authors: Aibar‐Almazán Agustín , Martínez‐Amat Antonio , Cruz‐Díaz David , De la Torre‐Cruz Manuel J. , Jiménez‐García José D. , Zagalaz‐Anula Noelia , Pérez‐Herrezuelo Isabel , Hita‐Contreras Fidel
Published: April 2019

Objective: the main objective was to analyze the effects that an exercise programme based on the Pilates method would have on balance confidence, fear of falling, and postural control among women ≥60 years old. Methods: a total of 110 women (69.15 ± 8.94 years) participated in this randomized, controlled trial that took place in Jaén (Spain). The participants were randomly assigned to either a control group (n = 55), which received no intervention, or to a Pilates group (n = 55), which carried out an exercise programme based on the Pilates method in 60‐minute sessions for 12 weeks. The Falls Efficacy Scale‐International and the activity‐specific balance confidence scale were respectively used to assess fear of falling and balance confidence in performing activities of daily living. Postural control was evaluated using a stabilometric platform. Results: Regarding balance confidence, the Pilates group showed higher values compared to the control group (77.52 ± 18.27 vs 72.35 ± 16.39, Cohen's d = 0.030). Women in the Pilates group showed lower fear of falling, compared to those of the control group (22.07 ± 5.73 vs 27.9 ± 6.95, Cohen's d = 0.041). Finally, concerning static balance, participants of the Pilates group experienced statistically significant improvements on the velocity and anteroposterior movements of the centre of pressure with eyes open and closed respectively (Cohen's d = 0.44 and 0.35 respectively). Conclusion: A 12‐week Pilates training programme has beneficial effects on balance confidence, fear of falling and postural stability, in elderly women.
Robustness of ballistic transport in antidot superlattices
Authors: Datseris George , Geisel Theo , Fleischmann Ragnar
Published: April 2019

The magneto-resistance of antidot lattices shows pronounced peaks, which became a hallmark of ballistic electron transport. While most studies agree that they reflect the interplay of regular and chaotic motion in the quasi-classical dynamics, the exact mechanism has been surprisingly controversial. Inspired by recent experiments on graphene antidot lattices showing that the effect survives strong impurity scattering, we give a new explanation of the peaks linked to a fundamental relation between collision times and accessible phase space volumes, accounting for their robustness. Due to the fundamental nature of the mechanism described it will be relevant in many mesoscopic transport phenomena.
Determination of CaOH and CaOCH3 vibrational branching ratios for direct laser cooling and trapping
Authors: Kozyryev Ivan , Steimle Timothy C , Yu Phelan , Nguyen Duc-Trung , Doyle John M
Published: April 2019

Alkaline earth monoalkoxide free radicals (MORs) have molecular properties conducive to direct laser cooling to sub-millikelvin temperatures. Using dispersed laser induced fluorescence measurements from a pulsed supersonic molecular beam source we determine vibrational branching ratios and Franck–Condon factors for the MORs CaOH and CaOCH3. With narrow linewidth continuous-wave dye laser excitation, we precisely measure fluorescence branching for both

X

˜

–

A

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and

X

˜

–

B

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electronic systems in each molecule. Weak symmetry-forbidden decays to excited bending states with non-zero vibrational angular momentum are observed. Normal mode theoretical analysis combined with ab initio structural calculations are performed and compared to experimental results. Our measurements and analysis pave the way for direct laser cooling of these (and other) complex nonlinear polyatomic molecules. We also describe a possible approach to laser cooling and trapping of molecules with fewer symmetries like chiral species.
Structure, thermal and electrical properties of PVDF-HFP/LiBOB solid polymer electrolyte
Authors: Lestariningsih T , Sabrina Q , Ratri C R , Nuroniah I
Published: April 2019

Solid polymer electrolyte (SPE), which is composed of poly (vinylidenefluroride-co-hexafluoropropylene) (PVDF-HFP), lithium bis(oxalate) borate (LiBOB) salt and various concentrations of TiO2 as filler, has been prepared by solution casting technique. Structure, thermal and electrical properties of the SPE were examined using XRD and SEM, TG/DSC, and impedance spectroscopy, respectively. XRD analysis reveals amorphous nature of PVDF-HFP / LiBOB and TiO2 composite matrix. SEM photographs of polymer electrolyte membrane indicate good compatibility between polymer, salt, and other contents as well as amorphous phase formation in the fabricate of SPE. We obtained that (SPE) with composition of 70 wt% polymer, 28 wt% LiBOB and 2 wt% TiO2 has highest conductivity. XRD and DSC analysis indicate that the conductivity increases due to high amount of amorphous nature content. We suggest that the amorphous nature content may enhance segmental flexibility of polymeric chains and disordered structure of the electrolyte.
International comparison of health care carbon footprints
Authors: Pichler Peter-Paul , Jaccard Ingram S , Weisz Ulli , Weisz Helga
Published: April 2019

Climate change confronts the health care sector with a dual challenge. Accumulating climate impacts are putting an increased burden on the service provision of already stressed health care systems in many regions of the world. At the same time, the Paris agreement requires rapid emission reductions in all sectors of the global economy to stay well below the 2 °C target. This study shows that in OECD countries, China, and India, health care on average accounts for 5% of the national CO2 footprint making the sector comparable in importance to the food sector. Some countries have seen reduced CO2 emissions related to health care despite growing expenditures since 2000, mirroring their economy wide emission trends. The average per capita health carbon footprint across the country sample in 2014 was 0.6 tCO2, varying between 1.51 tCO2/cap in the US and 0.06 tCO2/cap in India. A statistical analysis shows that the carbon intensity of the domestic energy system, the energy intensity of the domestic economy, and health care expenditure together explain half of the variance in per capita health carbon footprints. Our results indicate that important leverage points exist inside and outside the health sector. We discuss our findings in the context of the existing literature on the potentials and challenges of reducing GHG emissions in the health and energy sector.
Greater Adherence to Life’s Simple 7 Is Associated With Less Arterial Stiffness: the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Oyenuga Abayomi O , Folsom Aaron R , Cheng Susan , Tanaka Hirofumi , Meyer Michelle L
Published: April 2019

Background

Greater arterial stiffness is associated independently with increased cardiovascular disease risk. The American Heart Association (AHA) has recommended following “Life’s Simple 7 (LS7)” to optimize cardiovascular health; we tested whether better LS7 in middle age is associated with less arterial stiffness in later life.

Methods

We studied 4,232 black and white participants aged 45–64 years at the baseline (1987–89) visit of the Atherosclerosis Risk in Communities Study cohort who also had arterial stiffness measured in 2011–13 (mean ± SD interval: 23.6 ± 1.0 years). We calculated a 14-point summary score for baseline LS7 and classified participants as having “poor” (0–4), “average” (5–9), or “ideal” (10–14) cardiovascular health. We used logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CI) for arterial stiffening: a high carotid-femoral pulse wave velocity (cfPWV, ≥13.23 m/s) or a high central pulse pressure (central PP, ≥ 82.35 mm Hg).

Results

The age, race, sex, and heart rate-adjusted ORs (95% CI) for high cfPWV in the “ideal,” “average,” and “poor” LS7 summary categories were 1 (Reference), 1.30 (1.11, 1.53), and 1.68 (1.10,2.56), respectively (P-trend = 0.0003). Similarly, the adjusted ORs (95% CI) for high central PP across LS7 summary categories were 1 (Reference), 1.48 (1.27, 1.74), and 1.63 (1.04, 2.56), respectively (P-trend <0.0001).

Conclusion

Greater LS7 score in middle age is associated with less arterial stiffness 2–3 decades later. These findings further support the AHA recommendation to follow LS7 for cardiovascular disease prevention.
Relationships Between Calcium Channel Blockers and Vascular Function Tests
Authors: Maruhashi Tatsuya , Kajikawa Masato , Kishimoto Shinji , Matsui Shogo , Hashimoto Haruki , Takaeko Yuji , Aibara Yoshiki , Yusoff Farina M , Hidaka Takayuki , Chayama Kazuaki , Noma Kensuke , Nakashima Ayumu , Goto Chikara , Kihara Yasuki , Higashi Yukihito
Published: April 2019

BACKGROUND

Differences between the effects of calcium channel blockers (CCBs) and other antihypertensive drugs on vascular function have not been fully investigated. The purpose of this study was to determine the confounding effect of CCBs on vascular function tests.

METHODS

We measured flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), and brachial–ankle pulse wave velocity (baPWV) in 1,134 subjects who underwent health-screening examinations or who visited the outpatient clinic at Hiroshima University Hospital.

RESULTS

FMD and NID were significantly lower (4.3 ± 3.2% vs. 2.3 ± 2.4% and 14.1 ± 5.8% vs. 10.6 ± 5.3%, P < 0.001, respectively) and baPWV was significantly higher (1,604 ± 412 cm/s vs. 1,715 ± 343 cm/s, P < 0.001) in subjects receiving CCB treatment than in subjects without CCB treatment. Multivariate analyses revealed that CCB treatment was significantly associated with lower FMD (β = –0.151, P < 0.001) and lower NID (β = –0.120, P < 0.001) but not with baPWV (β = 0.017, P = 0.42). Propensity score matching analyses revealed that FMD and NID were significantly lower and baseline brachial artery diameter was significantly larger in subjects receiving CCB monotherapy than in subjects without antihypertensive medication or subjects receiving non-CCB antihypertensive monotherapy.

CONCLUSIONS

CCB treatment was significantly associated with lower FMD and lower NID, which might be, at least in part, due to larger baseline brachia artery diameter, whereas there was no significant association between CCB treatment and baPWV. FMD and NID may be of no use as prognostic markers of cardiovascular events in individuals who have been receiving CCB treatment.

PUBLIC TRIALS REGISTRY NUMBER

Trial Number UMIN000003409
Transcriptional variation in malaria parasites: why and how
Authors: Llorà-Batlle Oriol , Tintó-Font Elisabet , Cortés Alfred
Published: April 2019

Transcriptional differences enable the generation of alternative phenotypes from the same genome. In malaria parasites, transcriptional plasticity plays a major role in the process of adaptation to fluctuations in the environment. Multiple studies with culture-adapted parasites and field isolates are starting to unravel the different transcriptional alternatives available to Plasmodium falciparum and the underlying molecular mechanisms. Here we discuss how epigenetic variation, directed transcriptional responses and also genetic changes that affect transcript levels can all contribute to transcriptional variation and, ultimately, parasite survival. Some transcriptional changes are driven by stochastic events. These changes can occur spontaneously, resulting in heterogeneity within parasite populations that provides the grounds for adaptation by dynamic natural selection. However, transcriptional changes can also occur in response to external cues. A better understanding of the mechanisms that the parasite has evolved to alter its transcriptome may ultimately contribute to the design of strategies to combat malaria to which the parasite cannot adapt.
Multi-SNP mediation intersection-union test
Authors: Zhong Wujuan , Spracklen Cassandra N , Mohlke Karen L , Zheng Xiaojing , Fine Jason , Li Yun
Published: April 2019

Tens of thousands of reproducibly identified GWAS (Genome-Wide Association Studies) variants, with the vast majority falling in non-coding regions resulting in no eventual protein products, call urgently for mechanistic interpretations. Although numerous methods exist, there are few, if any methods, for simultaneously testing the mediation effects of multiple correlated SNPs via some mediator (e.g. the expression of a gene in the neighborhood) on phenotypic outcome. We propose multi-SNP mediation intersection-union test (SMUT) to fill in this methodological gap. Our extensive simulations demonstrate the validity of SMUT as well as substantial, up to 92%, power gains over alternative methods. In addition, SMUT confirmed known mediators in a real dataset of Finns for plasma adiponectin level, which were missed by many alternative methods. We believe SMUT will become a useful tool to generate mechanistic hypotheses underlying GWAS variants, facilitating functional follow-up.

Availability and implementation

The R package SMUT is publicly available from CRAN at https://CRAN.R-project.org/package=SMUT.

Supplementary information

Supplementary data are available at Bioinformatics online.
BDNF Controls Bidirectional Endocannabinoid Plasticity at Corticostriatal Synapses
Authors: Gangarossa Giuseppe , Perez Sylvie , Dembitskaya Yulia , Prokin Ilya , Berry Hugues , Venance Laurent
Published: April 2019

The dorsal striatum exhibits bidirectional corticostriatal synaptic plasticity, NMDAR and endocannabinoids (eCB) mediated, necessary for the encoding of procedural learning. Therefore, characterizing factors controlling corticostriatal plasticity is of crucial importance. Brain-derived neurotrophic factor (BDNF) and its receptor, the tropomyosine receptor kinase-B (TrkB), shape striatal functions, and their dysfunction deeply affects basal ganglia. BDNF/TrkB signaling controls NMDAR plasticity in various brain structures including the striatum. However, despite cross-talk between BDNF and eCBs, the role of BDNF in eCB plasticity remains unknown. Here, we show that BDNF/TrkB signaling promotes eCB-plasticity (LTD and LTP) induced by rate-based (low-frequency stimulation) or spike-timing–based (spike-timing–dependent plasticity, STDP) paradigm in striatum. We show that TrkB activation is required for the expression and the scaling of both eCB-LTD and eCB-LTP. Using 2-photon imaging of dendritic spines combined with patch-clamp recordings, we show that TrkB activation prolongs intracellular calcium transients, thus increasing eCB synthesis and release. We provide a mathematical model for the dynamics of the signaling pathways involved in corticostriatal plasticity. Finally, we show that TrkB activation enlarges the domain of expression of eCB-STDP. Our results reveal a novel role for BDNF/TrkB signaling in governing eCB-plasticity expression in striatum and thus the engram of procedural learning.
Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome
Authors: Tarui Tomo , Im Kiho , Madan Neel , Madankumar Rajeevi , Skotko Brian G , Schwartz Allie , Sharr Christianne , Ralston Steven J , Kitano Rie , Akiyama Shizuko , Yun Hyuk Jin , Grant Ellen , Bianchi Diana W
Published: April 2019

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P < 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.
Implementation of Syringe Services Programs to Prevent Rapid Human Immunodeficiency Virus Transmission in Rural Counties in the United States: A Modeling Study
Authors: Goedel William C , King Maximilian R F , Lurie Mark N , Galea Sandro , Townsend Jeffrey P , Galvani Alison P , Friedman Samuel R , Marshall Brandon D L
Published: April 2019

Background

Syringe services programs (SSPs) are effective venues for delivering harm-reduction services to people who inject drugs (PWID). However, SSPs often face significant barriers to implementation, particularly in the absence of known human immunodeficiency virus (HIV) outbreaks.

Methods

Using an agent-based model, we simulated HIV transmission in Scott County, Indiana, a rural county with a 1.7% prevalence of injection drug use. We compared outcomes arising in the absence of an SSP, in the presence of a pre-existing SSP, and with implementation of an SSP after the detection of an HIV outbreak among PWID over 5 years following the introduction of a single infection into the network.

Results

In the absence of an SSP, the model predicted an average of 176 infections among PWID over 5 years or an incidence rate of 12.1/100 person-years. Proactive implementation averted 154 infections and decreased incidence by 90.3%. With reactive implementation beginning operations 10 months after the first infection, an SSP would prevent 107 infections and decrease incidence by 60.8%. Reductions in incidence were also observed among people who did not inject drugs.

Conclusions

Based on model predictions, proactive implementation of an SSP in Scott County had the potential to avert more HIV infections than reactive implementation after the detection of an outbreak. The predicted impact of reactive SSP implementation was highly dependent on timely implementation after detecting the earliest infections. Consequently, there is a need for expanded proactive SSP implementation in the context of enhanced monitoring of outbreak vulnerability in Scott County and similar rural contexts.
Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany
Authors: Keller Karsten , Hobohm Lukas , Ebner Matthias , Kresoja Karl-Patrik , Münzel Thomas , Konstantinides Stavros V , Lankeit Mareike
Published: April 2019

Aims

Pulmonary embolism (PE) is the third most common cardiovascular cause of death; systemic thrombolysis is potentially lifesaving treatment in patients presenting with haemodynamic instability. We investigated trends in the use of systemic thrombolysis and the outcome of patients with acute PE.

Methods and results

We analysed data on the characteristics, comorbidities, treatment, and in-hospital outcome of 885 806 PE patients in Germany between 2005 and 2015. Incidence of acute PE was 99/100 000 population/year and increased from 85/100 000 in 2005 to 109/100 000 in 2015 [β 0.32 (0.26–0.38), P < 0.001]. During the same period, in-hospital case fatality rates decreased from 20.4% to 13.9% [β −0.51 (−0.52 to −0.49), P < 0.001]. The overall proportion of patients treated with systemic thrombolysis increased from 3.1% in 2005 to 4.4% in 2015 [β 0.28 (0.25–0.31), P < 0.001]. Thrombolysis was associated with lower in-hospital mortality rates in patients with haemodynamic instability, both in those with shock not necessitating cardiopulmonary resuscitation (CPR) or mechanical ventilation [odds ratio (OR) 0.42 (0.37–0.48), P < 0.001], and in those who underwent CPR [OR 0.92 (0.87–0.97), P = 0.002]. This association was independent from age, sex, and comorbidities. However, systemic thrombolysis was administered to only 23.1% of haemodynamically unstable patients.

Conclusion

Although the proportion of PE patients treated with systemic thrombolysis increased slightly in Germany between 2005 and 2015, only the minority of haemodynamically unstable patients currently receive this treatment. In the nationwide inpatient cohort, thrombolytic therapy was associated with reduced in-hospital mortality rates in PE patients with shock, and also in those who underwent CPR.
Stereotactic radiosurgery for ablation of ventricular tachycardia
Authors: Neuwirth Radek , Cvek Jakub , Knybel Lukas , Jiravsky Otakar , Molenda Lukas , Kodaj Michal , Fiala Martin , Peichl Petr , Feltl David , Januška Jaroslav , Hecko Jan , Kautzner Josef
Published: April 2019

Aims

Stereotactic body radiotherapy (SBRT) for ventricular tachycardias (VTs) could be an option after failed catheter ablation. In this study, we analysed the long-term efficacy and toxicity of SBRT applied as a bail-out procedure.

Methods and results

Patients with structural heart disease and unsuccessful catheter ablations for VTs underwent SBRT. The planning target volume (PTV) was accurately delineated using exported 3D electroanatomical maps with the delineated critical part of re-entry circuits. This was defined by detailed electroanatomic mapping and by pacing manoeuvres during the procedure. Using the implantable cardioverter-defibrillator lead as a surrogate contrast marker for respiratory movement compensation, 25 Gy was delivered to the PTV using CyberKnife. We evaluated occurrences of sustained VT, electrical storm, antitachycardia pacing, and shock; time to death; and radiation-induced events. From 2014 until March 2017, 10 patients underwent radiosurgical ablation (mean PTV, 22.15 mL; treatment duration, 68 min). After radiosurgery, four patients experienced nausea and one patient presented gradual progression of mitral regurgitation. During the follow-up (median 28 months), VT burden was reduced by 87.5% compared with baseline (P = 0.012) and three patients suffered non-arrhythmic deaths. After the blanking period, VT recurred in eight of 10 patients. The mean time to first antitachycardia pacing and shock were 6.5 and 21 months, respectively.

Conclusion

Stereotactic body radiotherapy appears to show long-term safety and effectiveness for VT ablation in structural heart disease inaccessible to catheter ablation. We report one possible radiation-related toxicity and promising overall survival, warranting evaluation in a prospective multicentre clinical trial.
Predicted highly derived class 1 CRISPR-Cas system in Haloarchaea containing diverged Cas5 and Cas7 homologs but no CRISPR array
Authors: Makarova Kira S , Karamycheva Svetlana , Shah Shiraz A , Vestergaard Gisle , Garrett Roger A , Koonin Eugene V
Published: April 2019

Screening of genomic and metagenomic databases for new variants of CRISPR-Cas systems increasingly results in the discovery of derived variants that do not seem to possess the interference capacity and are implicated in functions distinct from adaptive immunity. We describe an extremely derived putative class 1 CRISPR-Cas system that is present in many Halobacteria and consists of distant homologs of the Cas5 and Cas7 protein along with an uncharacterized conserved protein and various nucleases. We hypothesize that, although this system lacks typical CRISPR effectors or a CRISPR array, it functions as a RNA-dependent defense mechanism that, unlike other derived CRISPR-Cas, utilizes alternative nucleases to cleave invader genomes.
The Impact of Retirement on Cardiovascular Disease and Its Risk Factors: A Systematic Review of Longitudinal Studies
Authors: Xue Baowen , Head Jenny , McMunn Anne
Published: April 2019

Background and Objectives

People are now spending longer in retirement than ever before and retirement has been found to influence health. This study systematically reviewed the impact of retirement on cardiovascular disease (CVD) and its risk factors (metabolic risk factors, blood biomarkers, physical activity, smoking, drinking, and diet).

Research Design and Methods

Longitudinal studies published in Medline, Embase, Social Science Citation Index, PsycINFO, and Social Policy and Practice were searched. No language restrictions were applied if there was an English abstract. Eighty-two longitudinal studies were included after critical appraisals.

Results

Studies in the United States often found no significant effect of retirement on CVD, while studies in European countries, except France, showed a detrimental effect of retirement on CVD. Results from the United States and several European countries consistently show that retirement increase adiposity measures among those retired from physically demanding jobs. For diabetes and hypertension, five out of nine studies suggest no effect of retirement. Retirement has been repeatedly linked to increasing leisure-time physical activity but may reduce work- and transport-related physical activity in turn. Most studies showed that retirement either decreased smoking or had no effect on smoking. The evidence did not show a clear conclusion on drinking. Only a few studies have assessed the impact on diet and blood biomarkers.

Discussion and Implications

Effect of retirement varies according to the health outcomes studied and country of the study population. Policy concerning extending the retirement age needs to focus on ensuring they are suited to the individual.
Making space for Aboriginal and Torres Strait Islander community health workers in health promotion
Authors: Conte Kathleen P , Gwynn Josephine , Turner Nicole , Koller Claudia , Gillham Karen E
Published: April 2019

Despite a clear need, ‘closing the gap’ in health disparities for Aboriginal and Torres Strait Islander communities (hereafter, respectfully referred to as Aboriginal) continues to be challenging for western health care systems. Globally, community health workers (CHWs) have proven effective in empowering communities and improving culturally appropriate health services. The global literature on CHWs reflects a lack of differentiation between the types of roles these workers carry out. This in turn impedes evidence syntheses informing how different roles contribute to improving health outcomes. Indigenous CHW roles in Australia are largely operationalized by Aboriginal Health Workers (AHWs)—a role situated primarily within the clinical health system. In this commentary, we consider whether the focus on creating professional AHW roles, although important, has taken attention away from the benefits of other types of CHW roles particularly in community-based health promotion. We draw on the global literature to illustrate the need for an Aboriginal CHW role in health promotion; one that is distinct from, but complementary to, that of AHWs in clinical settings. We provide examples of barriers encountered in developing such a role based on our experiences of employing Aboriginal health promoters to deliver evidence-based programmes in rural and remote communities. We aim to draw attention to the systemic and institutional barriers that persist in denying innovative employment and engagement opportunities for Aboriginal people in health.
Identifying key elements to inform HIV-testing interventions for primary care in Belgium
Authors: Apers Hanne , Nöstlinger Christiana , Van Beckhoven Dominique , Deblonde Jessika , Apers Ludwig , Verheyen Katleen , Loos Jasna ,   HERMETIC Study Group, Kaupe Ruta , Kïvïte Anda , Lemsalu Liis , Marty Lise , Michels David , Supervie Virginie , Castr Daniela Rojas , Upmace Inga
Published: April 2019

General practitioners (GPs) play a key role in reducing the hidden HIV-epidemic, but many diagnostic opportunities are missed in primary care. This study aimed at informing the development of an HIV-testing intervention for GPs in Flanders (Belgium) using formative research with a participatory approach. Through the active involvement of an advisory board and 16 group discussions with 122 Flemish GPs, GPs’ current HIV-testing practices and perceived practical relevance of 2 distinct HIV-testing strategies (i.e. provider-initiated testing of key populations and indicator condition-based testing) were explored in terms of their relevance and feasibility in routine primary care. Self-reported HIV-testing practices revealed that most tests performed were patient-initiated, pretest counseling was rarely done, and post-test counseling was offered mainly for patients with an HIV-diagnosis. GPs reported multiple barriers to provider-initiated HIV-testing, i.e. personal discomfort, fear of offending their patient, limited knowledge of benefits of early HIV-diagnosis, misconceptions about HIV-risks, lack of guidelines and time. Difficulties to identify patient’s sexual orientation or ethical concerns were mentioned as barriers for target group-based HIV testing. GPs assessed the current list of 64 indicator conditions as too difficult to integrate in routine care, deeming a reduced list of GP-relevant conditions as more feasible. Combined strategies (i.e. target group- and indicator-based testing) supported by official screening recommendations were perceived as successful strategies for provider-initiated HIV-testing in primary care. This formative research delivered qualitative evidence for the development of an HIV-testing intervention for primary care settings.
Quantum Teleportation and Super-Dense Coding in Operator Algebras
Authors: Gao Li , Harris Samuel J , Junge Marius
Published: April 2019

We show for any $d,m\ge 2$ with $(d,m)\neq (2,2)$, the matrix-valued generalization of the (tensor product) quantum correlation set of $d$ inputs and $m$ outputs is not closed. Our argument uses a reformulation of super-dense coding and teleportation in terms of $C^*$-algebra isomorphisms. Namely, we prove that for certain actions of cyclic group ${{\mathbb{Z}}}_d$, $$\begin{equation*}M_d(C^*({{\mathbb{F}}}_{d^2}))\cong{{\mathcal{B}}}_d\rtimes{{\mathbb{Z}}}_d\rtimes{{\mathbb{Z}}}_d , M_d({{\mathcal{B}}}_d)\cong C^*({{\mathbb{F}}}_{d^2})\rtimes{{\mathbb{Z}}}_d\rtimes{{\mathbb{Z}}}_d,\end{equation*}$$where ${{\mathcal{B}}}_d$ is the universal unital $C^*$-algebra generated by the elements $u_{jk}, \, 0 \le i, j \le d-1$, satisfying the relations that $[u_{j,k}]$ is a unitary operator, and $C^*({{\mathbb{F}}}_{d^2})$ is the universal $C^*$-algebra of $d^2$ unitaries. These isomorphisms provide a nice connection between the embezzlement of entanglement and the non-closedness of quantum correlation sets.