bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Bark Application With Beauveria bassiana and Permethrin Insecticide on the Walnut Twig Beetle (Coleoptera: Curculionidae) in Black Walnut Bolts
Authors: Mayfield Albert E , Juzwik Jennifer , Scholer Jamison , Vandenberg John D , Taylor Adam
Published: May 2019

Formulations of entomopathogenic (insect-killing) fungi represent alternatives to synthetic insecticides in the management of forest and shade tree insects. We evaluated bark spray applications of the entomopathogen Beauveria bassiana (Balsamo) Vuillemin (Hypocreales: Cordycipitaceae) strain GHA (BotaniGardES), permethrin insecticide (Astro), and water (control) on colonization of black walnut (Juglans nigra L.) (Fagales: Juglandaceae) bolts by the walnut twig beetle (Pityophthorus juglandis Blackman) (Coleoptera: Curculionidae), vector of the fungus that causes thousand cankers disease. Treated bolts were baited with a P. juglandis aggregation pheromone lure and deployed in infested walnut trees. Bark application of permethrin prevented P. juglandis colonization of the phloem. Although treatment of bolts with the B. bassiana suspension did not reduce P. juglandis colonization or short-term emergence relative to the control treatment, it increased the B. bassiana infection rate from 25 to 62% of emerged adults. Results suggest that commercial applications of B. bassiana strain GHA may help augment natural levels of infection by this entomopathogen in the eastern United States, and support continued exploration of entomopathogens for biological control of the walnut twig beetle.
Immunotherapy for Colorectal Cancer: A Review of Current and Novel Therapeutic Approaches
Authors: Franke Aaron J , Skelton William Paul , Starr Jason S , Parekh Hiral , Lee James J , Overman Michael J , Allegra Carmen , George Thomas J
Published: May 2019

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%–5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today’s clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.
Combined Effects of Hemlock Woolly Adelgid (Adelges tsugae) Infestation and Treatment with Imidacloprid on Eastern Hemlock (Tsuga canadensis) Leaf Radiometry
Authors: Garris Heath W , Settle Thomas H , Crossman Jonathan E , Grider Stephen J , Michaels Shawnté L
Published: May 2019

The neonicotinoid systemic insecticide imidacloprid has proven to be an effective treatment for the prevention and control of hemlock woolly adelgid (Adelges tsugae Annand) in southeastern populations of eastern hemlock (Tsuga canadensis L.). Recent studies have demonstrated that imidacloprid and A. tsugae both stimulate salicylic acid-dependent physiological responses in plant tissues responsible for plant defenses against pathogens, timing of developmental outcomes including flowering and leaf senescence, and resilience to abiotic stressors. We evaluated the interacting effects of A. tsugae presence/absence and treatment with imidacloprid on leaf optical properties indicative of photosynthetic potential, photosynthetic efficiency, and tissue senescence. Our results indicated that A. tsugae changes lower canopy leaf optical properties indicative of reduced photosynthetic potential/efficiency and accelerated senescence in mature leaves. Imidacloprid was associated with declines in photosynthetic potential and showed a largely similar, though less pronounced, effect on leaf spectral properties to that of A. tsugae.
Computing three-point correlation function randoms counts without the randoms catalogue
Authors: Pearson David W , Samushia Lado
Published: May 2019

As we move towards future galaxy surveys, the three-point statistics will be increasingly leveraged to enhance the constraining power of the data on cosmological parameters. An essential part of the three-point function estimation is performing triplet counts of synthetic data points in random catalogues. Since triplet counting algorithms scale at best as $\mathcal {O}(N^2\log N)$ with the number of particles and the random catalogues are typically at least 50 times denser than the data; this tends to be by far the most time-consuming part of the measurements. Here, we present a simple method of computing the necessary triplet counts involving uniform random distributions through simple one-dimensional integrals. The method speeds up the computation of the three-point function by orders of magnitude, eliminating the need for random catalogues, with the simultaneous pair and triplet counting of the data points alone being sufficient.
ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma
Authors: Tsvankin Vadim , Hashizume Rintaro , Katagi Hiroaki , Herndon James E , Lascola Christopher , Venkatraman Talaignair N , Picard Daniel , Burrus Brainard , Becher Oren J , Thompson Eric M
Published: May 2019

BACKGROUND

An impermeable blood–brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG).

OBJECTIVE

To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG.

METHODS

The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed.

RESULTS

Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305).

CONCLUSION

ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.
Observation of acoustic spin
Authors: Shi Chengzhi , Zhao Rongkuo , Long Yang , Yang Sui , Wang Yuan , Chen Hong , Ren Jie , Zhang Xiang
Published: May 2019

Unlike optical waves, acoustic waves in fluids are described by scalar pressure fields, and therefore are considered spinless. Here, we demonstrate experimentally the existence of spin in acoustics. In the interference of two acoustic waves propagating perpendicularly to each other, we observed the spin angular momentum in free space as a result of the rotation of local particle velocity. We successfully measured the acoustic spin, and spin-induced torque acting on a designed lossy acoustic probe that results from absorption of the spin angular momentum. The acoustic spin is also observed in the evanescent field of a guided mode traveling along a metamaterial waveguide. We found spin–momentum locking in acoustic waves whose propagation direction is determined by the sign of spin. The observed acoustic spin could open a new door in acoustics and its applications for the control of wave propagation and particle rotation.
Impact of Availability of Telehealth Programs on Documented HIV Viral Suppression: A Cluster-Randomized Program Evaluation in the Veterans Health Administration
Authors: Ohl Michael E , Richardson Kelly , Rodriguez-Barradas Maria C , Bedimo Roger , Marconi Vincent , Morano Jamie P , Jones Michael P , Vaughan-Sarrazin Mary
Published: May 2019

Background

Telehealth may improve care for people with HIV who live far from HIV specialty clinics. We conducted a cluster-randomized evaluation to determine the impact of availability of HIV telehealth programs on documented viral suppression in Veterans Administration clinics.

Methods

In 2015–2016, people who previously traveled to HIV specialty clinics were offered telehealth visits in nearby primary care clinics. Patients were cluster-randomized to immediate telehealth availability (n = 925 patients in service areas of 13 primary care clinics offering telehealth) or availability 1 year later (n = 745 patients in 12 clinics). Measures during the evaluation year included telehealth use among patients in areas where telehealth was available and documented HIV viral suppression (viral load performed and <200 copies/mL). Impact of telehealth availability was determined using intention-to-treat (ITT) analyses that compared outcomes for patients in areas where telehealth was available with outcomes for patients where telehealth was not available, regardless of telehealth use. Complier average causal effects (CACEs) compared outcomes for telehealth users with outcomes for control patients with equal propensity to use telehealth, when available.

Results

Overall, 120 (13.0%) patients utilized telehealth when it was available. Availability of telehealth programs led to small improvements in viral suppression in ITT analyses (78.3% vs 74.1%; relative risk [RR], 1.06; 95% confidence interval [CI], 1.01 to 1.11) and large improvements among telehealth users in CACE analyses (91.5% vs 80.0%; RR, 1.14; 95% CI, 1.01 to 1.30).

Conclusions

Availability of telehealth programs improved documented viral suppression. HIV clinics should offer telehealth visits for patients facing travel burdens.
Assessing Endogenous Pain Inhibition: Test–Retest Reliability of Exercise-Induced Hypoalgesia in Local and Remote Body Parts After Aerobic Cycling
Authors: Gomolka Stefan , Vaegter Henrik Bjarke , Nijs Jo , Meeus Mira , Gajsar Hannah , Hasenbring Monika I , Titze Christina
Published: May 2019

Objective

Acute exercise can trigger a hypoalgesic response (exercise-induced hypoalgesia [EIH]) in healthy subjects. Despite promising application possibilities of EIH in the clinical context, its reliability has not been sufficiently examined. This study therefore investigated the between-session and within-subject test–retest reliability of EIH at local and remote body parts after aerobic cycling at a heart rate–controlled intensity.

Methods

Thirty healthy adults (15 women) performed 15 minutes of aerobic cycling in two sessions. Pressure pain thresholds (PPTs) were assessed at the leg (local), the back (semilocal), and the hand (remote) before, immediately after, and 15 minutes after exercise. Intraclass correlation coefficients (ICCs) were calculated for absolute and percent changes in PPT from baseline to immediately postexercise, and between-session agreement of EIH responders was examined.

Results

PPTs significantly increased at the leg during both sessions (all P < 0.001) and at the back during session 2 (P < 0.001), indicating EIH. Fair between-session reliability was shown for absolute changes at the leg (ICC = 0.54) and the back (ICC = 0.40), whereas the reliability of percent changes was poor (ICC < 0.33). Reliability at the hand was poor for both absolute and percent changes (ICC < 0.33). Agreement in EIH responders was not significant for EIH at the leg or the back (all P > 0.05).

Conclusions

Our results suggest fair test–retest reliability of EIH after aerobic cycling for local and semilocal body parts, but only in men, demonstrating the need for more standardized methodological approaches to improve EIH as a clinical parameter.
Disease activity and patient reported outcome measures in Sjögren’s – what are the best tools to evaluate?
Authors: Seror Raphaèle , Rauz Saaeha , Gosset Marjolaine , Bowman Simon J
Published: May 2019

In primary SS (pSS), clinical features in SS can be divided into two facets: the patient perceived manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, with efforts made by an international collaboration, consensual clinical indexes were developed for assessing both facets: one patient reported outcome, the EULAR SS Patients Reported Index (ESSPRI), and one activity index for systemic manifestations, the EULAR SS Disease Activity Index (ESSDAI). In addition, objective measures were developed to quantify the importance and consequence of ocular and oral dryness, few being specific of pSS. Work is ongoing to develop indexes combining all these approaches. Recent changes in the assessment of pSS patients, and the emergence of new targeted therapies, have put a greater emphasis on the design of clinical trials in pSS, and led for the first time to a positive randomized clinical trial.
Drug retention of biological DMARD in rheumatoid arthritis patients: the role of baseline characteristics and disease evolution
Authors: Lauper Kim , Mongin Denis , Alpizar-Rodriguez Deshire , Codreanu Catalin , Iannone Florenzo , Kristianslund Eirik K , Kvien Tore K , Pavelka Karel , Pombo-Suarez Manuel , Santos Maria J , Gabay Cem , Finckh Axel , Courvoisier Delphine S
Published: May 2019

Objective

To examine the association of the evolution in physician-reported and patient-reported outcomes with decision to stop biological DMARDs (bDMARDs) in RA. The contribution of baseline characteristics is well established, but little is known about how the disease evolution influences the decision to discontinue therapy.

Methods

RA patients who initiated a bDMARD treatment from 2009 and with information on date of visit were pooled from seven European RA registers. Each outcome was divided into baseline assessments (capturing the inter-individual differences at drug initiation) and changes from baseline at subsequent visits (capturing the individual evolution). Cox regression models were used to examine their association with drug discontinuation, adjusting for baseline patient and co-therapy characteristics and stratifying by register and calendar year of drug initiation.

Results

A total of 25 077 patients initiated a bDMARDs (18 507 a TNF-inhibitor, 3863 tocilizumab and 2707 abatacept) contributing an amount of 46 456.8 patient-years. Overall, drug discontinuation was most strongly associated with a poor evolution of the DAS28, with a hazard ratio of 1.34 (95% CI 1.29, 1.40), followed by its baseline value. A change of Physician Global Assessment was the next strongest predictor of discontinuation, then the Patient Global Assessment.

Conclusions

The decision to discontinue treatments appears to be mostly influenced by DAS28 and particularly its evolution over time, followed by Physician Global Assessment evolution, suggesting that the decision to stop bDMARDs relies more on the physician’s than on the patient’s global assessment.
Bridging evolutionary game theory and metabolic models for predicting microbial metabolic interactions
Authors: Cai Jingyi , Tan Tianwei , Joshua Chan Siu Hung
Published: May 2019

Microbial metabolic interactions impact ecosystems, human health and biotechnological processes profoundly. However, their determination remains elusive, invoking an urgent need for predictive models that seamlessly integrate metabolic details with ecological and evolutionary principles which shape the interactions within microbial communities. Inspired by the evolutionary game theory, we formulated a bi-level optimization framework termed NECom for the prediction of Nash equilibria of microbial community metabolic models with significantly enhanced accuracy. NECom is free of a long hidden ‘forced altruism’ setup in previous static algorithm while allowing for ‘sensing and responding’ between microbial members that is missing in dynamic methods. We successfully predicted several classical games in the context of metabolic interactions that were falsely or incompletely predicted by existing methods, including prisoner’s dilemma, snowdrift game and mutualism. The results provided insights into why mutualism is favorable despite seemingly costly cross-feeding metabolites, and demonstrated the potential to predict heterogeneous phenotypes among the same species. NECom was then applied to a reported algae-yeast co-culture system that shares typical cross-feeding features of lichen, a model system of mutualism. More than 1200 growth conditions were simulated, of which 488 conditions correspond to 3221 experimental data points. Without fitting any ad-hoc parameters, an overall 63.5% and 81.7% reduction in root-mean-square error in predicted growth rates for the two species respectively was achieved when compared with the standard flux balance analysis. The simulation results further show that growth-limiting crossfeeding metabolites can be pinpointed by shadow price analysis to explain the predicted frequency-dependent growth pattern, offering insights into how stabilizing microbial interactions control microbial populations.
Tracking progress towards malaria elimination in China: estimates of reproduction numbers and their spatiotemporal variation
Authors: Routledge Isobel , Lai Shengjie , Battle Katherine E , Ghani Azra C , Gomez-Rodriguez Manuel , Gustafson Kyle B , Mishra Swapnil , Proctor Joshua L , Tatem Andrew J , Li Zhongjie , Bhatt Samir
Published: May 2019

China reported zero locally-acquired malaria cases in 2017 and 2018. Understanding the spatio-temporal pattern underlying this decline, especially the relationship between locally-acquired and imported cases, can inform efforts to maintain elimination and prevent re-emergence. This is particularly pertinent in Yunnan province, where the potential for local transmission is highest. Using a geo-located individual-level dataset of cases recorded in Yunnan province between 2011 and 2016, we jointly estimate the case reproduction number, Rc, and the number of unobserved sources of infection. We use these estimates within spatio-temporal geostatistical models to map how transmission varied over time and space, estimate the timeline to elimination and the risk of resurgence. Our estimates suggest that, maintaining current intervention efforts, Yunnan is unlikely to experience sustained local transmission up to 2020. However, even with a mean Rc of 0.005 projected for the year 2019, locally-acquired cases are possible due to high levels of importation.
Informed and uninformed empirical therapy policies
Authors: Houy Nicolas , Flaig Julien
Published: May 2019

We argue that a proper distinction must be made between informed and uninformed decision making when setting empirical therapy policies, as this allows to estimate the value of gathering more information and to set research priorities. We rely on the stochastic version of a compartmental model to describe the spread of an infecting organism in a health care facility, and the emergence and spread of resistance to two drugs. We focus on information and uncertainty regarding the parameters of this model. We consider a family of adaptive policies. In the uninformed setting, the best adaptive policy allows to reduce the average cumulative infected patient-days over two years by 39.3% (95% CI: 30.3% – 48.1%) compared to the combination therapy. Choosing empirical therapy policies while knowing the exact parameter values allows to further decrease the cumulative infected patient-days on average by 3.9% (95% CI: 2.1% – 5.8%). In our setting, the benefit of perfect information might be offset by increased drug consumption.
Revealing architectural order with quantitative label-free imaging and deep learning
Authors: Guo Syuan-Ming , Yeh Li-Hao , Folkesson Jenny , Ivanov Ivan , Krishnan Anitha Priya , Keefe Matthew G. , Shin David , Chhun Bryant , Cho Nathan , Leonetti Manuel , Nowakowski Tomasz J. , Mehta Shalin B.
Published: May 2019

Quantitative imaging of biological architecture with fluorescent labels is not as scalable as genomic or proteomic measurements. Here, we combine quantitative label-free imaging and deep neural networks for scalable analysis of complex structures. We reconstruct quantitative three-dimensional density, anisotropy, and orientation in live cells and tissue slices from polarization- and depth-resolved images. We report a computationally efficient variant of U-Net architecture that predicts a 3D fluorescent structure from its morphology and physical properties. We evaluate the performance of our models by predicting F-actin and nuclei in mouse kidney tissue. Further, we report label-free imaging of axon tracts and predict level of myelination in human brain tissue sections. We demonstrate the model's ability to rescue inconsistent labeling. We anticipate that the proposed approach will enable quantitative analysis of architectural order across scales of organelles to tissues.
A toolbox of nanobodies developed and validated for diverse neuroscience research applications
Authors: Dong Jie-Xian , Lee Yongam , Kirmiz Michael , Palacio Stephanie , Dumitras Camelia , Moreno Claudia M. , Sando Richard , Santana L. Fernando , Südhof Thomas C. , Gong Belvin , Murray Karl D. , Trimmer James S.
Published: May 2019

Nanobodies (nAbs) are small, minimal antibodies that have distinct attributes that make them uniquely suited for certain biomedical research, diagnostic and therapeutic applications. Prominent uses include as intracellular antibodies or intrabodies to bind and deliver cargo to specific proteins and/or subcellular sites within cells, and as nanoscale immunolabels for enhanced tissue penetration and improved spatial imaging resolution. Here, we report the generation and validation of nAbs against a set of proteins prominently expressed at specific subcellular sites in brain neurons. We describe a novel hierarchical validation pipeline to systematically evaluate nAbs isolated by phage display for effective and specific use as intrabodies and immunolabels in mammalian cells including brain neurons. These nAbs form part of a robust toolbox for targeting proteins with distinct and highly spatially-restricted subcellular localization in mammalian brain neurons, allowing for visualization and/or modulation of structure and function at those sites.
Patch Testing in Lao medical students
Authors: Wootton Catriona I. , Soukavong Mick , Kidoikhammouan Sonexai , Samountry Bounthome , English John S.C. , Mayfong Mayxay
Published: May 2019

Background

Dermatological services in Laos, South East Asia are limited to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this population.

Objectives

The aim of this study was to document common allergens in medical students in Laos. Patients/Materials/Methods

One hundred and fifty medical students were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4.

Results

Thirty-eight students (25.3%) had a positive reaction to at least one allergen, accounting for 52 reactions in total. The proportion of the students with positive patch test reading was significantly higher in the female [33/96 (34%)] than in the male [5/54 (9%)], p<0.001. The most common allergens were: nickel (10%), gold (6.6%), thiomersal (6.6%), cobalt dichloride (2%) and p-tert-Butylphenol formaldehyde resin (2%). Balsam of Peru (0.66%), black rubber mix (0.66%), Cl+Me-Isothiazolinone (0.66%), fragrance mix 1 (0.66%), quinolone mix (0.66%), methyldibromo glutaronitrile (0.66%), mercapto mix (0.66%), epoxy resin (0.66%), paraben mix (0.66%), thiuram (0.66%) and wool alcohols (0.66%) accounted for all of the other positive reactions.

Conclusion

This study represents the first documented patch test results in Lao medical students and in the adult Lao population. The results of this study will inform any future research into contact allergy in Laos and give an insight into the background level of contact sensitivity in this population.
TractoFlow: A robust, efficient and reproducible diffusion MRI pipeline leveraging Nextflow & Singularity
Authors: Theaud Guillaume , Houde Jean-Christophe , Boré Arnaud , Rheault François , Morency Felix , Descoteaux Maxime
Published: May 2019

A diffusion MRI (dMRI) tractography processing pipeline should be: i) reproducible in immediate test-test, ii) reproducible in time, iii) efficient and iv) easy to use. Two runs of the same processing pipeline with the same input data should give the same output today, tomorrow and in 2 years. However, processing dMRI data requires a large number of steps (20+ steps) that, at this time, may not be reproducible between runs or over time. If parameters such as the number of threads or the random number generator are not carefully set in the brain extraction, registration and fiber tracking steps, the end tractography results obtained can be far from reproducible and limit brain connectivity studies. Moreover, processing can take several hours to days of computation for a large database, even more so if the steps are running sequentially.

To handle these issues, we presentTractoFlow, a fully automated pipeline that processes datasets from the raw diffusion weighted images (DWI) to tractography. It also outputs classical diffusion tensor imaging measures (fractional anisotropy (FA) and diffu-sivities) and several HARDI measures (Number of Fiber Orientation (NuFO), Apparent Fiber Density (AFD)). The pipeline requires a DWI and T1-weighted image as NIfTI files and b-values/b-vectors in FSL format. An optional reversed phase encoded b=0 image can also be used. This pipeline is based on two technologies:NextflowandSingularity, as well as recommended pre-processing and processing steps from the dMRI community. In this work, the TractoFlow pipeline is evaluated on three databases and shown to be efficient and reproducible from 98% to 100% depending on parameter choices. For example, 105 subjects from the Human Connectome Project (HCP) were fully ran in twenty-five (25) hours to produce, for each subject, a whole-brain tractogram with 4 million streamlines. The contribution of this paper is to introduce the importance of a robust pipeline in terms of runtime and reproducibility over time. In the era of open data and open science, efficiency and reproducibility is critical in neuroimaging projects. Our TractoFlow pipeline is publicly available for academic research and is an important step forward for better structural brain connectivity mapping.
Inferring the ecological drivers of arboviral outbreaks
Authors: Tennant Warren , McKinley Trevelyan , Recker Mario
Published: May 2019

The emergence and wide-spread circulation of mosquito-transmitted viral diseases, such as dengue, Zika and Chikungunya, is a global public health concern. In the absence of effective vaccines, current control measures are mostly targeted against the mosquito vector and have so far only shown limited success. The reliance on mosquitoes for transmission also imposes strong ecological constraints that can introduce significant spatial and temporal variations in disease incidence. However, the way that epidemiological and ecological factors interact and determine population-level disease dynamics is only partially understood. Here we fit a spatially-explicit individual based model defined within a Bayesian framework to Zika incidence data from Feira de Santana, allowing us to more precisely quantify the relationships between socio-ecological factors and arboviral outbreaks. Our results further demonstrated that the virus was likely introduced into multiple spatially segregated locations at the start of the outbreak, highlighting the benefits that spatio-temporal incidence data would bring in making modelling approaches more realistic for public health planning.
Systematic comparative analysis of single cell RNA-sequencing methods
Authors: Ding Jiarui , Adiconis Xian , Simmons Sean K. , Kowalczyk Monika S. , Hession Cynthia C. , Marjanovic Nemanja D. , Hughes Travis K. , Wadsworth Marc H. , Burks Tyler , Nguyen Lan T. , Kwon John Y. H. , Barak Boaz , Ge William , Kedaigle Amanda J. , Carroll Shaina , Li Shuqiang , Hacohen Nir , Rozenblatt-Rosen Orit , Shalek Alex K. , Villani Alexandra-Chloé , Regev Aviv , Levin Joshua Z.
Published: May 2019

A multitude of single-cell RNA sequencing methods have been developed in recent years, with dramatic advances in scale and power, and enabling major discoveries and large scale cell mapping efforts. However, these methods have not been systematically and comprehensively benchmarked. Here, we directly compare seven methods for single cell and/or single nucleus profiling from three types of samples – cell lines, peripheral blood mononuclear cells and brain tissue – generating 36 libraries in six separate experiments in a single center. To analyze these datasets, we developed and applied scumi, a flexible computational pipeline that can be used for any scRNA-seq method. We evaluated the methods for both basic performance and for their ability to recover known biological information in the samples. Our study will help guide experiments with the methods in this study as well as serve as a benchmark for future studies and for computational algorithm development.
Mutational mimics of allosteric effectors: a genome editing design to validate allosteric drug targets
Authors: Tang Qingling , Villar Maria T. , Artigues Antonio , Thyfault John P. , Apte Udayan , Zhu Hao , Peterson Kenneth R. , Fenton Aron W.
Published: May 2019

Development of drugs that allosterically regulate enzyme functions to treat disease is a costly venture. Screening mutations that mimic allosteric effectorsin vitrowill identify therapeutic regulatory targets enhancing the likelihood of developing a disease treatment at a reasonable cost. We demonstrate the potential of this approach utilizing human liver pyruvate kinase (hLPYK) as a model. Inhibition of hLPYK was the first desired outcome of our screen. We identified individual point mutations that: 1) mimicked allosteric inhibition by alanine, 2) mimicked inhibition by protein phosphorylation, and 3) prevented binding of fructose-1,6-bisphosphate (Fru-1,6-BP). Our second desired screening outcome was activation of hLPYK. We identified individual point mutations that: 1) prevented hLPYK from binding alanine, the allosteric inhibitor, 2) prevented inhibitory protein phosphorylation, or 3) mimicked allosteric activation by Fru-1,6-BP. Combining the three activating point mutations produced a constitutively activated enzyme that was unresponsive to regulators. Expression of a mutant hLPYK transgene containing these three mutations in a mouse model was not lethal. Thus, mutational mimics of allosteric effectors will be useful to confirm whether allosteric activation of hLPYK will control glycolytic flux in the diabetic liver to reduce hepatic glucose production and, in turn, reduce or prevent hyperglycemia.
Predicting neurodevelopmental outcomes in children with perinatal HIV using a novel machine learning algorithm
Authors: Paul Robert , Cho Kyu , Mellins Claude , Malee Kathleen , Robbins Reuben , Kerr Stephen , Sophonphan Jiratchaya , Jahanshad Neda , Aurpibul Linda , Thongpibul Kulvadee , Kosalaraksa Pope , Kanjanavanit Suparat , Ngampiyaskul Chaiwat , Luesomboon Wicharn , Wongsawat Jurai , Vonthanak Saphonn , Chettra Kea , Suwanlerk Tulathip , Valcour Victor , Balla Lila , Garcia-Egan Paola M. , Preston Rebecca , Ananworanich Jintanat , Puthanakit Thanyawee ,   on behalf of the PREDICT Study Group
Published: May 2019

Background

A subset of children with perinatal HIV (pHIV) experience long-term neurocognitive symptoms despite treatment with antiretroviral therapy. However, predictors of neurocognitive outcomes remain elusive, particularly for children with pHIV residing in low-to-middle income countries. The present study utilized a novel data analytic approach to identify clinically-relevant predictors of neurocognitive development in children with pHIV.

Methods

Analyses were conducted on a large repository of longitudinal data from 285 children with pHIV in Thailand (n=170) and Cambodia (n=115). Participants were designated as neurocognitively resilient (i.e., positive slope; n=143) or at risk (i.e., negative slope; n=142) according to annual performances on the Beery-Buktenica Developmental Test of Visual-Motor Integration over an average of 5.4 years. Gradient-boosted multivariate regression (GBM) with 5-fold cross validation was utilized to identify the optimal combination of demographic, HIV disease, blood markers, and emotional health indices that predicted classification into the two neurocognitive subgroups. Model performance was assessed using Receiver Operator Curves and sensitivity/specificity.

Results

The analytic approach distinguished neurocognitive subgroups with high accuracy (93%; sensitivity and specificity each > 90%). Dynamic change indices and interactions between mental health and biological indices emerged as key predictors.

Conclusion

Machine learning-based regression defined a unique explanatory model of neurocognitive outcomes among children with pHIV. The predictive algorithm included a combination of HIV, physical health, and mental health indices extracted from readily available clinical measures. Studies are needed to explore the clinical relevance of the data-driven explanatory model, including potential to inform targeted interventions aimed at modifiable risk factors.
Cell cycle regulators control mesoderm specification in human pluripotent stem cells
Authors: Yiangou Loukia , Grandy Rodrigo A. , Sinha Sanjay , Vallier Ludovic
Published: May 2019

Mesoderm is one of the three germ layers produced during gastrulation from which muscle, bones, kidneys and the cardiovascular system originate. Understanding the mechanisms controlling mesoderm specification could be essential for a diversity of applications, including the development of regenerative medicine therapies against diseases affecting these tissues. Here, we use human pluripotent stem cells (hPSCs) to investigate the role of cell cycle in mesoderm formation. For that, proteins controlling G1 and G2/M cell cycle phases were inhibited during differentiation of hPSCs into lateral plate, cardiac and presomitic mesoderm using small molecules or by conditional knock down. These loss of function experiments revealed that CDKs and pRb phosphorylation are necessary for efficient mesoderm formation in a context-dependent manner. Further investigations showed that inhibition of the G2/M regulator CDK1 decreases BMP signaling activity specifically during lateral plate mesoderm formation while reducing FGF/ERK1/2 activity in all mesoderm subtypes. Taken together, our findings reveal that cell cycle regulators direct mesoderm formation by controlling the activity of key developmental pathways.
DEAD-box protein family member DDX28 is a negative regulator of HIF-2α and eIF4E2-directed hypoxic translation
Authors: Evagelou Sonia L. , Bebenek Olivia , Specker Erin J. , Uniacke James
Published: May 2019

Hypoxia occurs when there is a deficiency in oxygen delivery to tissues and is connected to physiological and pathophysiological processes such as embryonic development, wound healing, heart disease and cancer. The master regulators of oxygen homeostasis in mammalian cells are the heterodimeric hypoxia-inducible transcription factors HIF-1 and HIF-2. The oxygen-labile HIF-2α subunit has not only been implicated in transcription, but also as a regulator of eIF4E2-directed hypoxic translation. Here, we have identified the DEAD-box protein family member DDX28 as a novel interactor and negative regulator of HIF-2α that suppresses its ability to activate eIF4E2-directed translation. We demonstrate that stable silencing of DDX28 via shRNA in hypoxic human U87MG glioblastoma cells caused an increase, relative to control, to: HIF-2α protein levels, the ability of eIF4E2 to bind the m7GTP cap structure, and the translation of select eIF4E2 target mRNAs. DDX28 depletion elevated both nuclear and cytoplasmic HIF-2α, but HIF-2α transcriptional activity did not increase possibly due to its already high nuclear abundance in hypoxic control cells. Depletion of DDX28 conferred a proliferative advantage to hypoxic, but not normoxic cells, which is likely a consequence of the translational upregulation of a subset of hypoxia-response mRNAs. DDX28 protein levels are reduced in several cancers, including glioma, relative to normal tissue. Therefore, we uncover a regulatory mechanism for this potential tumor suppressor in the repression of HIF-2α- and eIF4E2-mediated translation activation of oncogenic mRNAs.
The role of tectonics and hydrothermalism in early human evolution at Olduvai Gorge
Authors: Sistiaga Ainara , Husain Fatima , Uribelarrea David , Martín-Perea David , Domínguez-Rodrigo Manuel , Ferland Troy , Freeman Katherine H. , Diez-Martín Fernando , Baquedano Enrique , Mabulla Audax , Summons Roger E.
Published: May 2019

Hominin encephalization has been at the centre of debates concerning human evolution with a consensus on a greater role for improved dietary quality. To sustain the energetic demands of larger brains, cooking was likely essential for increasing the digestibility and energy gain of meat and readily available, yet toxic starches. Here, we present the oldest geochemical evidence for a landscape influenced by tectonic activity and hydrothermal features that potentially shaped early hominin behaviour at Olduvai Gorge. Although use of fire at this time is controversial, hot springs may have provided an alternative way to thermally process dietary resources available in the 1.7 Myo Olduvai wetland. Our data supports the presence of an aquatic-dominated landscape with hydrothermal features that offered hominins new opportunities to hunt and cook readily available tubers and herbivore prey at the emergence of the Acheulean technology. Future studies should further examine whether hydrothermalism similarly influenced other critical aspects of human evolution.
Cholinergic modulation of dentate gyrus processing through dynamic reconfiguration of inhibitory circuits
Authors: Ogando Mora B. , Pedroncini Olivia , Federman Noel , Romano Sebastián A. , Brum Luciano A. , Lanuza Guillermo M. , Refojo Damian , Marin-Burgin Antonia
Published: May 2019

The dentate gyrus (DG) of the hippocampus plays a key role in memory formation and it is known to be modulated by septal projections. By performing electrophysiology and optogenetics we evaluated the role of cholinergic modulation in the processing of afferent inputs in the DG. We showed that mature granule cells (GCs), but not adult-born immature neurons, have increased responses to afferent perforant path stimuli upon cholinergic modulation. This is due to a highly precise reconfiguration of inhibitory circuits, differentially affecting Parvalbumin and Somatostatin interneurons, resulting in a nicotinic-dependent perisomatic disinhibition of GCs. This circuit reorganization provides a mechanism by which mature GCs could escape the strong inhibition they receive, creating a window of opportunity for plasticity. Indeed, coincident activation of perforant path inputs with optogenetic release of acetylcholine produced a long-term potentiated response in GCs, essential for memory formation.
The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions
Authors: Park Calvin , Ponath Gerald , Levine-Ritterman Maya , Bull Edward , Swanson Eric C. , De Jager Philip L. , Segal Benjamin M. , Pitt David
Published: May 2019

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled acute MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In a demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In a post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation.
Identification of biochemically neutral positions in liver pyruvate kinase
Authors: Martin Tyler A. , Wu Tiffany , Tang Qingling , Dougherty Larissa L. , Parente Daniel J. , Swint-Kruse Liskin , Fenton Aron W.
Published: May 2019

Understanding how each residue position contributes to protein function has been a long-standing goal in protein science. Substitution studies have historically focused on conserved protein positions. However, substitutions of nonconserved positions can also modify function. Indeed, we recently identified nonconserved positions that have large substitution effects in human liver pyruvate kinase (hLPYK), including altered allosteric coupling. To facilitate a comparison of which characteristics determine when a nonconserved position does vs. does not contribute to function, the goal of the current work was to identify neutral positions in hLPYK. However, existing hLPYK data showed that three features commonly associated with neutral positions – high sequence entropy, high surface exposure, and alanine scanning – lacked the sensitivity needed to guide experimental studies. We used multiple evolutionary patterns identified in a sequence alignment of the PYK family to identify which positions were least patterned, reasoning that these were most likely to be neutral. Nine positions were tested with a total of 117 amino acid substitutions. Although exploring all potential functions is not feasible for any protein, five parameters associated with substrate/effector affinities and allosteric coupling were measured for hLPYK variants. For each position, the aggregate functional outcomes of all variants were used to quantify a “neutrality” score. Three positions showed perfect neutral scores for all five parameters. Furthermore, the nine positions showed larger neutral scores than 17 positions located near allosteric binding sites. Thus, our strategy successfully enriched the dataset for positions with neutral and modest substitutions.
Simulating bout-and-pause patterns with reinforcement learning
Authors: Yamada Kota , Kanemura Atsunori
Published: May 2019

Animal responses occur according to a specific temporal structure composed of two states, where a bout is followed by a long pause until the next bout. Such about-and-pause pattern has three components: the bout length, the within-bout response rate, and the bout initiation rate. Previous studies have investigated how these three components are affected by experimental manipulations. However, it remains unknown what underlying mechanisms cause bout-and-pause patterns. In this article, we propose two mechanisms and examine computational models developed based on reinforcement learning. The model is characterized by two mechanisms. The first mechanism is choice—an agent makes a choice between operant and other behaviors. The second mechanism is cost—a cost is associated with the changeover of behaviors. These two mechanisms are extracted from past experimental findings. Simulation results suggested that both the choice and cost mechanisms are required to generate bout-and-pause patterns and if either of them is knocked out, the model does not generate bout-and-pause patterns. We further analyzed the proposed model and found that it reproduced the relationships between experimental manipulations and the three components that have been reported by previous studies. In addition, we showed alternative models can generate bout-and-pause patterns as long as they implement the two mechanisms.