bluuebunny/crossref_metadata_2025 huggingface dataset:
External Validity in a Stochastic World: Evidence from Low-Income Countries
Authors: Rosenzweig Mark R , Udry Christopher
Published: March 2019

We examine empirically the generalizability of internally valid micro-estimates of causal effects in a fixed population over time when that population is subject to aggregate shocks. Using panel data, we show that the returns to investments in agriculture in India and Ghana, small and medium non-farm enterprises in Sri Lanka, and schooling in Indonesia fluctuate significantly across time periods. We show how the returns to these investments interact with specific, measurable, and economically relevant aggregate shocks, focusing on rainfall and price fluctuations. We also obtain lower-bound estimates of confidence intervals of the returns based on estimates of the parameters of the distributions of rainfall shocks in our two agricultural samples. We find that even these lower-bound confidence intervals are substantially wider than those based solely on sampling error that are commonly provided in studies, most of which are based on single-year samples. We also find that cross-sectional variation in rainfall cannot be confidently used to replicate within-population rainfall variability. Based on our findings, we discuss methods for incorporating information on external shocks into evaluations of the returns to policy.
Integrating Reproductive Health Services Into Opioid Treatment Facilities: A Missed Opportunity to Prevent Opioid-exposed Pregnancies and Improve the Health of Women Who Use Drugs
Authors: Wright Tricia E.
Published: March 2019

Opioid treatment programs (OTPs) are federally mandated to provide certain medical services to patients, and are often the only place where people with substance use disorders (SUD) obtain medical care. Just as medication for addiction treatment (MAT) should be part of comprehensive addiction care, so should reproductive health care be a part of comprehensive medical care. The most significant barrier that must be overcome is that the majority of OTPs believe that it is outside their scope of service to provide reproductive health services. Reproductive health care is basic medical care. It is imperative for the long-term health of women with SUD, their children and the community that they receive this care. OTPs can and should do better for their female clients.
Radiation Treatment for Ewing Sarcoma Family of Tumors in Adult Patients
Authors: Kharod Shivam M. , Spiguel Andre R. , Lagmay Joanne P. , Jones Charles , Morris Christopher G. , Gibbs Charles Parker , Zlotecki Robert A.
Published: March 2019

Purpose/Objectives:

To report prognostic factors and long-term outcomes in adults with Ewing sarcoma treated with definitive radiotherapy.

Materials and Methods:

We reviewed patients 18 years old and above with nonmetastatic Ewing sarcoma treated with radiotherapy +/− chemotherapy or surgery. Outcomes were stratified by age (30 and above vs. younger than 30 y), soft tissue extension, tumor size (≥8.5 vs. <8.5 cm), tumor location, resection (yes vs. no), and treatment era (1970–1992 vs. 1993–2012). Toxicities were scored using the RTOG criteria.

Results:

Fifty-five patients (21 women) were treated with radiotherapy. Average age at diagnosis: 26.7 years (38 patients below 30 vs. 17 patients 30 y and above). A total of 43 had soft tissue extension (78%). Median tumor size: 8.5 cm. Most tumors were in the pelvis (40%), followed by the lower (27%) and upper (24%) extremities. All but 1 patient received chemotherapy; 13 underwent resection. Median dose: 55 Gy. Median follow-up: 3.6 years; 17.5 years for living patients. The 5-year overall (OS) and cause-specific survival (CSS) rates were both 46%. OS and CSS rates were unaffected by age (P=0.97), tumor size (P=0.12), or tumor location (P=0.99). Soft tissue extension portended a significantly poorer prognosis for 5-year OS and CSS: 37% vs. 82% (with and without, respectively; P=0.04). Patients who underwent resection had improved 5-year OS and CSS: 77% vs. 37%, respectively (P=0.01). Patients treated after 1993 had improved 5-year OS: 58% vs. 37% (P=0.0264).

Conclusions:

Adult patients with Ewing sarcoma experience similar treatment outcomes regardless of age at diagnosis. Soft tissue extension represents a poor prognostic factor. Aggressive trimodality therapy achieved the highest OS and CSS.
A Simple and Cost-effective Method for Practicing Microsurgery
Authors: Almarghoub Mohammed A.
Published: March 2019

Practicing microsurgery is usually expensive. This is because living animals, artificial vessels, and synthetic models are not always available. Here, I report a simple and cost-effective method to practice microsurgical techniques by using sterile gloves.
Immediate Soft-Tissue Reconstruction for Chronic Infected Tibia Nonunions Treated with an Ilizarov Frame
Authors: Jubbal Kevin T. , Zavlin Dmitry , Doval Andres F. , Cherney Steven M. , Brinker Mark R. , Dinh Tue A. , Echo Anthony
Published: March 2019

There are multiple options available for the management of large tibial defects. The Ilizarov frame is one of the most widely used techniques due to the physiological bone growth and the symmetrical distribution of axial forces permitting adequate bone distribution. However, disadvantages still remain including obtaining additional soft-tissue access for defect coverage. We present our experience with soft-tissue reconstruction for chronic infected tibial nonunions using free tissue transfers simultaneously with Ilizarov device placement. A retrospective review was performed from 2014 to 2016 of patients presenting with a chronically infected tibia nonunion and treated by our senior orthopedic and plastic surgeons. Demographic data, comorbidities, intraoperative details and postoperative outcomes were collected. A total of 6 patients were identified with a mean age of 46.2 ± 11.6 years. Complete flap survival and resolved active infection were achieved in 5 of our patients, 4 demonstrated body union on imaging, and all of them reached complete ambulance. Flap revisions with allografting for partial flap loss were performed in 1 patient. Preoperative planning is critical for immediate lower extremity reconstruction in the setting of an Ilizarov frame. From our institutional experience, free tissue transfer can safely be placed after frame placement.
The place of ART in Africa
Authors: Serour Gamal I. , Serour Ahmed G. , El Faysal Yehia , Islam Youmna
Published: March 2019

Since the birth of Louis Brown on July 25th, 1978 through in vetro fertilization, assisted reproductive technology (ART) now is widely used for the treatment of both male and female infertility. Today globally almost 2 million ART cycles are performed every year. Although Africa constitutes 16% of the world population, yet its share of ART is much less than its fair share of 320,000 cycles per year. There are several barriers to the wide application of ART in Africa. These include epidemiological, geographic, financial, and socio-cultured barriers in addition to the health education barrier, restrictive health policy barrier and health systems barrier. In Africa there is an increasing demand for ART. Africa, like many parts in the world, is witnessing a changing life style which affects fertility. In Africa infertility is a medico-socio cultural problem with sex-based sufferings. Furthermore there is a higher prevalence of STIs and postpartum and postabortion infections which contributes to both male and female infertility. This coupled with the fact that treatment of infertility is a human right issue which should not be discriminated on economic, geographic, or racial basis, necessitates finding ways to overcome such disparity in the provision of ART for infertile patients in Africa. The paper discusses the various possible ways to improve availability and access to ART in Africa. The infertile couples in Africa should not suffer the health, psychological, and societal burden of infertility simply because others in the African continent reproduce too many. The 2030 SDGs agenda has envisaged a better future. One where we collectively tear down the barriers and correct disparities, focusing first on those left further behind.
Dose Reconstruction Using Electron Paramagnetic Resonance Dosimetry on Tooth Enamel From Wild Boar Living in the Fukushima Exclusion Zone
Authors: Harshman Amber , Johnson Thomas
Published: March 2019

The goal of the study was to establish characteristics of Japanese wild boar tooth enamel in the dose region of 0.25–2.0 Gy and to reconstruct external absorbed doses to wild boar native to the Fukushima exclusion zone using electron paramagnetic resonance dosimetry. The significance of Japanese wild boar in their ecosystem and their position within the trophic hierarchy make the wild boar a species of particular importance and therefore, the focus of this study. Dose response linearity and variability of enamel originating from various wild boar were investigated. Radiation dose response of Japanese wild boar tooth enamel in the range of 0.25–2.0 Gy was found to be linear, and the average variation in dose response between teeth originating from the same boar specimen was nearly 30%. No statistically significant difference in dose response was found based on sex of the boar or in permanent molar teeth of boar of differing ages. Electron paramagnetic resonance absorbed doses to boar tooth enamel were successfully reconstructed using the calibration curve method and converted into estimates of absorbed dose to soft tissue with large associated confidence intervals. The critical level dose value for the calibration curve was 1.0 Gy and the detection limit dose was 1.8 Gy, suggesting that this method would be more beneficial for boar with lifetime absorbed doses greater than 1.0 Gy. The method of reconstructing external absorbed doses using electron paramagnetic resonance dosimetry with tooth enamel from Japanese wild boar as dosimeters has proven to be a viable method which can be used to reconstruct absorbed doses to wildlife in accident-stricken areas in the absence of alternative dosimetry.
Development of the Environmental Radiation Survey Program and Its Application to In Situ Gamma-Ray Spectrometry
Authors: Ji Young-Yong , Jang Mee , Lee Wanno
Published: March 2019

An environmental radiation survey using a gamma-ray spectrometer is used to rapidly detect radioactive contamination over a wide area of ground that was released from nuclear events. For the successful application of a gamma-ray spectrometer to the calculation of the radioactivity concentration in the ground and the dose rate at 1 m above the ground, it is necessary to build a calibration procedure to obtain the counting efficiency at the in situ measurement, which means in situ calibration factor to report the calculation results from the measured net count rate according to the diverse detection geometries. This study is focused on the development of a program to calculate the in situ calibration factor and report the survey results in the environmental radiation surveys using three kinds of gamma-ray spectrometers, which have been widely used in the field of in situ measurements: a coaxial HPGe detector, cylindrical NaI(Tl), and rectangular NaI(Tl). The program is based on the results of diverse theoretical calculations of the unscattered photon fluence at the detector height, detector responses of three detectors, and their angular corrections. The developed program was successfully applied to the estimation of the radioactivity concentration of nuclides in the ground and the dose rate at 1 m height above the ground induced from them.
Intercomparison of Commercially Available Active Radon Measurement Devices in a Discovered Radon Chamber
Authors: Carmona Marco A. , Kearfott Kimberlee J.
Published: March 2019

An unventilated 70 m3 underground space, with 2.1 m high ceilings and an inner set of concrete walls to damp vibrations, was discovered to have relatively stable radon levels of ~1,080 Bq m−3 over a 1-y period. The addition of radium sources was not required to achieve high and somewhat variable radon levels, as these arise naturally in the space. Several active radon monitoring devices designed for homeowners, radon screeners, radon mitigation professionals, and researchers were tested in the space. These devices were variable in both cost and intended user sophistication. Data were collected at specific time intervals that varied for each device. A cellphone was deployed with an available camera application to periodically capture photographs of the displays of devices not enabled for automatic temporal recording. Attempts were made to alter the radon concentration using fans, radium-laden objects, and radon impermeable sheets. Statistical methods were employed to compare the device's performance under the minor radon transients produced by the addition of 226Ra sources during the test period. The evaluation of the overall accuracy, noise, and response to transients revealed highly affordable devices that may be useful for future research applications. While unsuitable for precise calibrations at stable radon levels, the space was determined to be adequate as a radon chamber for general research purposes.
Small Benign Storiform Fibrous Tumor (Fibrous Histiocytoma) of the Conjunctival Substantia Propria in a Child: Review and Clarification of Biologic Behavior
Authors: Tieger Marisa G. , Jakobiec Frederick A. , Ma Lina , Wolkow Natalie
Published: March 2019

Purpose:

A case of a small benign storiform fibrous tumor of the conjunctival substantia propria is described to clarify the category of fibrous histiocytoma. In addition, a comparison of the various spindle cell tumors of the conjunctival substantia propria is explored.

Methods:

The patient underwent a complete tumor excision, and the specimen was analyzed by histopathologic and immunohistochemical investigations.

Results:

A cellular mass, composed solely of spindle cells in a storiform pattern without a component of histiocytic cells, was found beneath an undisturbed nonkeratinizing squamous epithelium and was separated from the epithelium by a grenz zone of uninvolved collagen. The lesion was sharply demarcated but not encapsulated. The Masson trichrome stain revealed scant deposition of intercellular collagen. The reticulin stain displayed numerous and delicate wiry fibers between the tumor cells and encircling capillaries. The Alcian blue stain demonstrated faint positivity in the interstitium. Immunohistochemistry revealed positivity for vimentin, factor XIIIa, smooth muscle actin, CD10, and CD45. Negative stains were obtained for CD34, CD56, S100, desmin, and Ki67.

Conclusions:

The broad term of fibrous histiocytoma should be reserved for deep fibroblastic spindle cell tumors (e.g., those of the orbit) that display an aggressive behavior. More benign superficial spindle cell tumors of the dermis are now preferentially characterized as dermatofibromas. It is suggested that equally benign epibulbar tumors should no longer be designated as fibrous histiocytomas but rather as benign storiform fibrous tumors. Tumors completely composed of polygonal histiocytoid (epithelioid) cells that are CD34+ should be excluded from the benign storiform fibrous tumor category. Positive smooth muscle actin and factor XIIIa staining in conjunction with negative staining for CD34 and desmin in the current spindled tumor cells are findings consistent with those of cutaneous dermatofibromas. Both the epibulbar and dermal spindle cell lesions have displayed an indolent and nonaggressive behavior. Microscopically they contain a high proportion of dendrocytic stellate cells that are either factor XIIIa+ or XIIIa−. Given the anatomic differences between the dermis and conjunctiva, the term dermatofibroma is inappropriate for the current tumor; instead the term benign storiform fibrous tumor has been proposed for superficial tumors of the conjunctiva.
Clinical and Personality Characteristics of Problem and Pathological Gamblers With and Without Symptoms of Adult ADHD
Authors: Cairncross Molly , Milosevic Aleks , Struble Cara A. , Ellis Jennifer D. , Ledgerwood David M.
Published: March 2019

The study examined the differential clinical and personality characteristics of problem and pathological gamblers (PPGs) with and without clinically significant symptoms of adult attention deficit hyperactive disorder (ADHD). Adults (N = 150, n = 75 women) with PPG were assessed by the SCID-IV, Conners' Adult ADHD Rating Scales, Multidimensional Personality Questionnaire, Gambling Motivation Questionnaire, and the Barratt Impulsiveness Scale. PPGs who reported symptoms of ADHD were more likely to be male, endorse psychiatric comorbidities (i.e., alcohol dependence, anxiety disorders, and antisocial personality disorder), report maladaptive personality traits (i.e., higher negative emotionality and lower positive emotionality), as well as higher impulsivity (attention impulsiveness, motor impulsiveness, and nonplanning impulsiveness). PPGs with symptoms of ADHD reported gambling for social, coping, and enhancement reasons. A multivariate binary logistic regression revealed that sex, higher scores on social reasons for gambling, and lack of premeditation were associated with an increased likelihood of reporting ADHD symptoms. The findings demonstrate important differences of PPGs with symptoms of ADHD and provide information for treatment consideration.
Validity of the Early Activity Scale for Endurance and the 6-Minute Walk Test for Children With Cerebral Palsy
Authors: Fiss Alyssa LaForme , Jeffries Lynn , Yocum Allison , Westcott McCoy Sarah
Published: March 2019

Purpose:

This study aimed to describe Early Activity Scale for Endurance (EASE) scores and 6-minute walk test (6MWT) distances of children with cerebral palsy (CP) by functional ability level, sex, and age and to examine the convergent validity of the 2 tests.

Methods:

A total of 708 participants with CP, Gross Motor Function Classification System (GMFCS) levels I to V, completed the EASE, and 376 of the study participants (3-12years), GMFCS levels I to III, completed the 6MWT.

Results:

Children with CP vary in EASE scores and 6MWT distances based on GMFCS level and, to a lesser extent, age. The EASE and the 6MWT demonstrate a statistically significant but low, positive correlation.

Conclusions:

Understanding the relationship between these outcomes and GMFCS levels and age assists clinicians in establishing plans of care targeted at improving endurance for activity and functional walking capacity for children with CP.
An Exploration of Parental Satisfaction With an Advanced Practice Physical Therapy Clinic in Pediatric Orthopedics
Authors: O Mir Marie , O' Sullivan Cliona , Blake Catherine , Lennon Olive
Published: March 2019

Purpose:

To evaluate parent satisfaction of patients attending a novel advanced practice physical therapy clinic in pediatric orthopedics.

Methods:

A cross-sectional survey collected data using 2 approaches: a modified version of the VSQ-9 and open-ended responses. The component structure of the Visit Specific Satisfaction Questionnaire (VSQ) was explored and the Cronbach alpha assessed internal consistency. Responses were summarized as mean (95% CI). An inductive content analysis was performed for open-ended responses.

Results:

Satisfaction ratings were excellent. A 2-component structure for the VSQ was confirmed. The Cronbach alpha coefficient was 0.85, indicating high internal consistency. Emergent themes were mostly positive in relation to Time, Communication, Professionalism, and Service Delivery, with Physical Resources receiving negative comments.

Conclusions:

This study evaluated parent satisfaction with a novel advanced practice in pediatric orthopedics, demonstrating high levels of satisfaction and identifying positive and negative themes that impact parent perceptions of quality of care.
Critical Care Beds With Continuous Lateral Rotation Therapy to Prevent Ventilator-Associated Pneumonia and Hospital-Acquired Pressure Injury: A Cost-effectiveness Analysis
Authors: Kang So-Yeon , DiStefano Michael J. , Yehia Farah , Koszalka Maria V. , Padula William V.
Published: March 2019

Objectives

Mechanical ventilation increases the risk of hospital-acquired conditions (HACs) such as ventilator-associated pneumonia (VAP) and pressure injury (PrI). Beds with continuous lateral rotation therapy (CLRT) are shown to reduce HAC incidence, but the value of switching to CLRT beds is presently unknown. We compared the cost-effectiveness of CLRT beds with standard care in intensive care units.

Methods

A cost-effectiveness analysis from the healthcare sector and societal perspectives was conducted. A Markov model was constructed to predict health state transitions from time of ventilation through 28 days for the healthcare sector perspective and 1 year for the U.S. societal perspective. Value of information was calculated to determine whether parameter uncertainty warranted further research.

Results

Our analysis suggested that CLRT beds dominate standard care from both perspectives. From the healthcare sector perspective, expected cost for CLRT was U.S. $47,165/patient compared with a higher cost of U.S. $49,258/patient for standard care. The expected effectiveness of CLRT is 0.0418 quality-adjusted life years/patient compared with 0.0416 quality-adjusted life years/patient for standard care. Continuous lateral rotation therapy dominated standard care in approximately 93% of Monte Carlo simulations from both perspectives. Value of information analysis suggests that additional research is potentially cost-effective.

Conclusions

Continuous lateral rotation therapy is highly cost-effective compared with standard care by preventing HACs that seriously harm patients in the intensive care unit.
Personal information about danger trumps social information from avian alarm calls
Authors: McLachlan Jessica R. , Ratnayake Chaminda P. , Magrath Robert D.
Published: March 2019

Information about predators can mean the difference between life and death, but prey face the challenge of integrating personal information about predators with social information from the alarm calls of others. This challenge might even affect the structure of interspecific information networks: species vary in response to alarm calls, potentially because different foraging ecologies constrain the acquisition of personal information. However, the hypothesis that constrained personal information explains a greater response to alarm calls has not been experimentally tested. We used a within-species test to compare the antipredator responses of New Holland honeyeaters,
Phylidonyris novaehollandiae
, during contrasting foraging behaviour. Compared with perched birds, which hawk for insects and have a broad view, those foraging on flowers were slower to spot gliding model predators, showing that foraging behaviour can affect predator detection. Furthermore, nectar-foraging birds were more likely to flee to alarm call playbacks. Birds also assessed social information relevance: more distant calls, and those from another species, prompted fewer flights and slower reaction times. Overall, birds made flexible decisions about danger by integrating personal and social information, while weighing information relevance. These findings support the idea that a strategic balance of personal and social information could affect community function.
RACK1 on and off the ribosome
Authors: Johnson Alex G. , Lapointe Christopher P. , Wang Jinfan , Corsepius Nicholas C. , Choi Junhong , Fuchs Gabriele , Puglisi Joseph D.
Published: March 2019

Receptor for activated C kinase 1 (RACK1) is a eukaryote-specific ribosomal protein implicated in diverse biological functions. To engineer ribosomes for specific fluorescent labeling, we selected RACK1 as an target given its location on the small ribosomal subunit and other properties. However, prior results suggested that RACK1 has roles both on and off the ribosome, and such an exchange might be related to its various cellular functions and hinder our ability to use RACK1 as a stable fluorescent tag for the ribosome. In addition, the kinetics of spontaneous exchange of RACK1 or any ribosomal protein from a mature ribosomein vitroremain unclear. To address these issues, we engineered fluorescently-labeled human ribosomes via RACK1, and applied bulk and single-molecule biochemical analyses to track RACK1 on and off the human ribosome. Our results demonstrate that, despite its cellular non-essentiality from yeast to humans, RACK1 readily re-associates with the ribosome, displays limited conformational dynamics, and remains stably bound to the ribosome for hoursin vitro. This work sheds insight onto the biochemical basis of ribosomal protein exchange on and off a mature ribosome and provides tools for single-molecule analysis of human translation.
Smoking, asthma and airway microbial disruption
Authors: Turek Elena M. , Cox Michael J. , Hunter Michael , Hui Jennie , James Phillip , Willis-Owen Saffron A.G. , Cuthbertson Leah , James Alan , Musk A. William , Moffatt Miriam F. , Cookson William O.C.M.
Published: March 2019

Background

Normal airway microbial communities play a central role in respiratory health but are poorly characterized. Cigarette smoking is the dominant global environmental influence on lung function, and asthma has become the most prevalent chronic respiratory disease worldwide. Both conditions have major microbial components that are also poorly defined.

Methods

We investigated airway bacterial communities in a general population sample of 529 Australian adults. Posterior oropharyngeal swabs were analysed by sequencing of the 16S rRNA and methionine aminopeptidase genes. The microbiota were characterised according to their prevalence, abundance, and network memberships.

Findings

Microbial communities were similar across the population and were strongly organized into co-abundance networks. Smoking associated with diversity loss, negative effects on abundant taxa, profound alterations to network structure and expansion ofStreptococcusspp. By contrast, the asthmatic microbiota were selectively affected by an increase inNeisseriaspp. and by reduced numbers of low abundance but prevalent organisms.

Interpretation

Our study shows healthy airway microbiota are contained within a highly structured ecosystem, indicating balanced relationships between the microbiome and human host factors. The marked abnormalities in smokers may be pathogenic for chronic obstructive pulmonary disease (COPD) and lung cancer. The narrow spectrum of abnormalities in asthmatics encourages investigation of damaging and protective effects of specific bacteria.

Funding

The study was funded by the Asmarley Trust and a Wellcome Senior Investigator Award to WOCC and MFM (P46009). The Busselton Healthy Ageing Study is supported by the Government of Western Australia (Office of Science, Department of Health) the City of Busselton, and private donations.
Novel cholinesterase paralogs ofSchistosoma mansonihave perceived roles in cholinergic signaling, glucose scavenging and drug detoxification and are essential for parasite survival
Authors: Tedla Bemnet , Sotillo Javier , Pickering Darren , Eichenberger Ramon M. , Becker Luke , Loukas Alex , Pearson Mark S.
Published: March 2019

Cholinesterase (ChE) function in schistosomes is essential for orchestration of parasite neurotransmission but has been poorly defined with respect to the molecules responsible. Interrogation of theS. mansonigenome has revealed the presence of three ChE domain-containing genes (Smche)s, which we have shown to encode two functional acetylcholinesterases (AChE)s (Smache1– smp_154600 andSmache3– smp_136690) and a butyrylcholinesterase (BChE) (Smbche1– smp_125350). Antibodies to recombinant forms of eachSmChE localized the proteins to the tegument and neuromusculature of adults and schistosomula and developmental expression profiling differed among the three molecules, suggestive of functions extending beyond traditional cholinergic signaling. For the first time in schistosomes, we identified ChE enzymatic activity in fluke excretory/secretory (ES) products and, using proteomic approaches, attributed this activity to the presence ofSmAChE1 andSmBChE1. To address the hypothesis that tegumental AChE mediates exogenous glucose scavenging by the parasite, we show that RNAi-mediated knockdown ofsmache1andsmache3, but notsmbche1, significantly reduces glucose uptake by schistosomes. Parasite survivalin vitroandin vivowas significantly impaired by silencing of eachsmche, either individually or in combination, attesting to the essential roles of these molecules. Lastly, in the first characterization study of a BChE from helminths, evidence is provided thatSmBChE1 may act as a bio-scavenger of AChE inhibitors as the addition of recombinantSmBChE1 to parasite cultures mitigated the effect of the anti-schistosome AChE inhibitor DDVP (DDVP), whereassmbche1-silenced parasites displayed increased sensitivity to DDVP.

Author summary

Cholinesterases - aceytlcholinesterases (AChE)s and butyrylcholinesterases (BChE)s - are multi-functional enzymes that play a pivotal role in the nervous system of parasites by regulating neurotransmission through acetylcholine hydrolysis. Herein, we provide a detailed characterization of schistosome cholinesterases using molecular, enzymatic and gene-silencing approaches and show evidence for these molecules having roles in glucose scavenging and drug detoxification, in addition to their neuronal function. Further, we demonstrate the importance of these proteins to parasite development and survival through gene knockdown experiments in laboratory animals, providing evidence for the use of these proteins in the development of novel intervention strategies against schistosomiasis.
Learning hierarchical sequence representations across human cortex and hippocampus
Authors: Henin Simon , Turk-Browne Nicholas B. , Friedman Daniel , Liu Anli , Dugan Patricia , Flinker Adeen , Doyle Werner , Devinsky Orrin , Melloni Lucia
Published: March 2019

Sensory input arrives in continuous sequences that humans experience as units, e.g., words and events. The brain’s ability to discover extrinsic regularities is called statistical learning. Structure can be represented at multiple levels, including transitional probabilities, ordinal position, and identity of units. To investigate sequence encoding in cortex and hippocampus, we recorded from intracranial electrodes in human subjects as they were exposed to auditory and visual sequences containing temporal regularities. We find neural tracking of regularities within minutes, with characteristic profiles across brain areas. Early processing tracked lower-level features (e.g., syllables) and learned units (e.g., words); while later processing tracked only learned units. Learning rapidly shaped neural representations, with a gradient of complexity from early brain areas encoding transitional probability, to associative regions and hippocampus encoding ordinal position and identity of units. These findings indicate the existence of multiple, parallel computational systems for sequence learning across hierarchically organized cortico-hippocampal circuits.
Untapped viral diversity in global soil metagenomes
Authors: Graham Emily B. , Paez-Espino David , Brislawn Colin , Hofmockel Kirsten S. , Wu Ruonan , Kyrpides Nikos C. , Jansson Janet K. , McDermott Jason E.
Published: March 2019

Viruses outnumber every other biological entity on Earth, and soil viruses are particularly diverse compared to other habitats. However, we have limited understanding of soil viruses because of the tremendous variation in soil ecosystems and because of the lack of appropriate screening tools. Here, we determined the global distribution of more than 24,000 soil viral sequences and their potential hosts, including >1,600 sequences associated with giant viruses. The viral sequences, derived from 668 terrestrial metagenomes, greatly extend existing knowledge of soil viral diversity and viral biogeographical distribution. We screened these sequences to identify a suite of cosmopolitan auxiliary metabolic genes (AMGs) encoding enzymes involved in soil organic carbon decomposition across soil biomes. Additionally, we provide evidence for viral facilitation of multi-domain linkages in soils by locating a fungal chitosanase in bacteriophages, generating a new paradigm of how viruses can serve as exchange vectors of carbon metabolism across domains of life.
Topological analysis reveals state transitions in human gut and marine bacterial communities
Authors: Chang William K. , VanInsberghe Dave , Kelly Libusha
Published: March 2019

Microbiome dynamics influence the health and functioning of human physiology and the environment and are driven in part by interactions between large numbers of microbial taxa, making large-scale prediction and modeling a challenge. Here, using topological data analysis, we identify states and dynamical features relevant to macroscopic processes.We show that gut disease processes and marine geochemical events are associated with transitions between community states, defined as topological features of the data density. We find a reproducible two-state succession during recovery from cholera in the gut microbiomes of multiple patients, evidence of dynamic stability in the gut microbiome of a healthy human after experiencing diarrhea during travel, and periodic state transitions in a marine Prochlorococcus community driven by water column cycling. Our approach bridges small-scale fluctuations in microbiome composition and large-scale changes in phenotype without details of underlying mechanisms, and provides a novel assessment of microbiome stability and its relation to human and environmental health.
Evaluating the Role of Fish as Surrogates for Amphibians in Pesticide Ecological Risk Assessment
Authors: Glaberman Scott , Kiwiet Jean , Aubee Catherine
Published: March 2019

Ecological risk of chemicals to aquatic-phase amphibians has historically been evaluated by comparing estimated environmental concentrations in surface water to surrogate toxicity data from standard fish species. Despite their obvious similarities, there are biological disparities among fish and amphibians that could affect their exposure and response to chemicals. Given the alarming decline in amphibians in which anthropogenic pollutants play at least some role, evaluating the potential risk of chemicals to amphibians is becoming increasingly important. Here, we evaluate relative sensitivity of fish and larval aquatic-phase amphibians to 45 different pesticides using existing data for three standardized toxicity tests: (1) amphibian metamorphosis assay (AMA) with the African clawed frog (Xenopus laevis); (2) fish short-term reproductive assay (FSTRA) with freshwater fathead minnow (Pimephales promelas); (3) fish early life stage test withP. promelasor rainbow trout (Oncorhynchus mykiss). The advantage of this dataset over previous work is that these studies show high consistency in exposure method and exposure concentration validation, study duration, test species, endpoints measured, and number of concentrations tested. We found very strong positive relationships between fish and tadpole lowest adverse effect concentrations (LOAEC) for survival (r2=0.85, slope=0.97), body weight (r2=0.77, slope=0.98), and length (r2=0.77, slope=0.92) with only one out of 45 chemicals exhibiting 100-folder greater sensitivity in frogs relative to fish. While these results suggest comparable toxicity for pesticides between these two groups of vertebrates, testing with a greater diversity of amphibians will help determine the generalizability of these results across all amphibians.

DISCLAIMER

The views expressed in this manuscript are solely those of the authors and do not represent the policies of the U.S. Environmental Protection Agency. Mention of trade names of commercial products should not be interpreted as an endorsement by the U.S. Environmental Protection Agency.
Pathogen Evolution when Transmission and Virulence are Stochastic
Authors: Aavani Pooya , Rice Sean H.
Published: March 2019

Evolutionary processes are inherently stochastic, since we can never know with certainty exactly how many descendants an individual will leave, or what the phenotypes of those descendants will be. Despite this, models of pathogen evolution have nearly all been deterministic, treating values such as transmission and virulence as parameters that can be known ahead of time. We present a broadly applicable analytic approach for modeling pathogen evolution in which vital parameters such as transmission and virulence are treated as random variables, rather than as fixed values. Starting from a general stochastic model of evolution, we derive specific equations for the evolution of transmission and virulence, and then apply these to a particular special case; the SIR model of pathogen dynamics. We show that adding stochasticity introduces new directional components to pathogen evolution. In particular, two kinds of covariation between traits emerge as important: covariance across the population (what is usually measured), and covariance between random variables within an individual. We show that these different kinds of trait covariation can be of opposite sign and contribute to evolution in very different ways. In particular, probability covariation between random variables within an individual is sometimes a better way to capture evolutionarily important tradeoffs than is covariation across a population. We further show that stochasticity can influence pathogen evolution through directional stochastic effects, which results from the inevitable covariance between individual fitness and mean population fitness.
Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity
Authors: Itabangi Herbert , Sephton-Clark Poppy C. S. , Zhou Xin , Starling Georgina P. , Mahamoud Zamzam , Insua Ignacio , Probert Mark , Correia Joao , Moynihan Patrick J. , Gebremariam Teklegiorgis , Gu Yiyou , Ibrahim Ashraf S. , Brown Gordon D. , King Jason S. , Ballou Elizabeth R. , Voelz Kerstin
Published: March 2019

Opportunistic infections by environmental fungi are a growing clinical problem, driven by an increasing population of people with immunocompromising conditions. Spores of the Mucorales order are ubiquitious in the environment but can also cause acute invasive infections in humans through germination and evasion of the mammalian host immune system. How they achieve this, and the evolutionary drivers underlying the acquisition of virulence mechanisms, are poorly understood. Here we show that a clinical isolate ofRhizopus microsporuscontains aRalstonia pickettiibacterial endosymbiont required for virulence in both zebrafish and mice, and that this endosymbiosis enables secretion of factors that potently suppress growth of the soil amoebaDictyostelium discoideum, as well as their ability to engulf and kill other microbes. As amoebae are natural environmental predators of both bacteria and fungi, we propose this tri-kingdom interaction contributes to establishing the endosymbiosis, and acquisition of anti-phagocyte activity. Importantly, we show this activity also protects fungal spores from phagocytosis and clearance by human macrophages, and endosymbiont removal renders the fungal spores avirulentin vivo. Together, these findings describe a novel role for a bacterial endosymbiont inRhizopus microsporuspathogenesis in animals, and suggest a mechanism of virulence acquisition through environmental interactions with amoebae.

In brief

How environmental fungi evolved the mechanisms that enable them to cause opportunistic infections in humans is unclear. Here, we identify a novel tri-kingdom interaction, whereby a bacterial endosymbiont, living within a clinical isolate of the ubiquitous environmental fungusRhizopus microsporus, causes the generation of a secreted activity that blocks the growth and predatory activity of amoebae. We suggest this provides a new evolutionary driver for the establishment of bacterial/fungal endosymbiosis and demonstrate this is critical for fungal pathogenicityin vivo.
Effects of healthy ageing on activation pattern within the brain during movement and motor imagery: an fMRI study
Authors: Budhdeo Sanjay , Baron Jean-Claude , Sharma Nikhil
Published: March 2019

Introduction

Motor imagery (MI) has potential as an intervention to improve performance in neurological disease affecting the motor system and to modulate brain computer interfaces (BCI). We hypothesized that the shared networks of MI and executed movement (EM) would be affected by age. Understanding these changes is important in application of MI in neurological disorders.

Methods

Using tensor-independent component analysis (TICA), we mapped the neural networks involved during MI and EM in 31 healthy volunteers (ages 20-72), who were recruited and screened for their ability to perform imagery. We used an fMRI block-design with MI & rest and EM & rest.

Results

TICA defined 37 independent components (ICs). Eight remained after excluding ICs representing artifacts. These ICs accounted for 35% of variance. While all ICs had greater activation in EM than MI. Two ICs increased with greater age for EM only. These ICs contained a bilateral network of brain areas, including primary motor cortex and cerebellum.

Conclusion

This study demonstrates the prominence of shared cerebral networks between MI and EM. There are age-dependent changes to EM activation, while MI activation appeared age independent. This strengthens the rationale for using MI to access the motor networks independent of age.
Accelerated brain ageing and disability in multiple sclerosis
Authors: Cole JH , Raffel J , Friede T , Eshaghi A , Brownlee W , Chard D , De Stefano N , Enzinger C , Pirpamer L , Filippi M , Gasperini C , Rocca MA , Rovira A , Ruggieri S , Sastre-Garriga J , Stromillo ML , Uitdehaag BMJ , Vrenken H , Barkhof F , Nicholas R , Ciccarelli O ,   on behalf of the MAGNIMS study group
Published: March 2019

Background

Brain atrophy occurs in both normal ageing and in multiple sclerosis (MS), but it occurs at a faster rate in MS, where it is the major driver of disability progression. Here, we employed a neuroimaging biomarker of structural brain ageing to explore how MS influences the brain ageing process.

Methods

In a longitudinal, multi-centre sample of 3,565 MRI scans in 1,204 MS/clinically isolated syndrome (CIS) patients and 150 healthy controls (HCs) (mean follow-up time: patients 3⋅41 years, HCs 1⋅97 years) we measured ‘brain-predicted age’ using T1-weighted MRI. Brain-predicted age difference (brain-PAD) was calculated as the difference between the brain-predicted age and chronological age. Positive brain-PAD indicates a brain appears older than its chronological age. We compared brain-PAD between MS/CIS patients and HCs, and between disease subtypes. In patients, the relationship between brain-PAD and Expanded Disability Status Scale (EDSS) at study entry and over time was explored.

Findings

Adjusted for age, sex, intracranial volume, cohort and scanner effects MS/CIS patients had markedly older-appearing brains than HCs (mean brain-PAD 11⋅8 years [95% CI 9⋅1—14⋅5] versus −0⋅01 [−3⋅0—3⋅0], p<0⋅0001). All MS subtypes had greater brain-PAD scores than HCs, with the oldest-appearing brains in secondary-progressive MS (mean brain-PAD 18⋅0 years [15⋅4—20⋅5], p<0⋅05). At baseline, higher brain-PAD was associated with a higher EDSS, longer time since diagnosis and a younger age at diagnosis. Brain-PAD at study entry significantly predicted time-to-EDSS progression (hazard ratio 1⋅02 [1⋅01—1⋅03], p<0⋅0001): for every 5 years of additional brain-PAD, the risk of progression increased by 14⋅2%.

Interpretation

MS increases brain ageing across all MS subtypes. An older-appearing brain at baseline was associated with more rapid disability progression, suggesting ‘brain-age’ could be an individualised prognostic biomarker from a single, cross-sectional assessment.

Funding

UK MS Society; National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Selection on VPS13A linked to long-distance migratory behavior in a songbird
Authors: Toews David P. L. , Taylor Scott A. , Streby Henry M. , Kramer Gunnar R. , Lovette Irby J.
Published: March 2019

Animal migration demands an interconnected suite of physiological, behavioral, and neurological adaptations for individuals to successfully navigate and travel over long distances1–3. This trait complex is especially crucial for small songbirds whose migratory behaviors—like directionality and orientation—are innate4,5, rather than being learned as in many large, longer-lived birds. Identifying causal genes involved in these traits has been a central goal of migration ecology, and this endeavor has been furthered by genome-scale comparisons6. However, even the most successful studies of migration genetics have only achieved low resolution associations, identifying large chromosomal regions, across multiple haplotype blocks, that encompass hundreds of putatively causal genes7,8. Here we leverage the extreme genomic similarity among golden-winged (Vermivora chrysoptera) and blue-winged warblers (Vermivora cyanoptera)9 to identify a single gene—Vacuolar Protein Sorting 13 Homolog A (VPS13A)—that is associated with distinct differences in migration directionality to Central American (CA) versus South American (SA) wintering areas10. Moreover, we find significantly reduced sequence variation in this gene-region for SA wintering birds, and show this is the result of strong natural selection on this gene. In humans, VPS13A codes for chorein, and variants of this gene are associated with the neurodegenerative disorder chorea-acanthocytosis11. This new association provides the strongest gene-level linkage for avian migration directionality, and further interrogation of this gene will allow for a better understanding of its role in neuro-muscular processes across vertebrates.
Evaluation of BMP-mediated patterning in a 3D mathematical model of the zebrafish blastula embryo
Authors: Li Linlin , Wang Xu , Mullins Mary C. , Umulis David M.
Published: March 2019

Bone Morphogenetic Proteins (BMPs) play an important role in dorsal-ventral (DV) patterning of the early zebrafish embryo. BMP signaling is regulated by a network of extracellular and intracellular factors that impact the range and signaling of BMP ligands. Recent advances in understanding the mechanism of pattern formation support a source-sink mechanism, however it is not clear how the source-sink mechanism shapes patterns in 3D, nor how sensitive the pattern is to biophysical rates and boundary conditions along both the anteroposterior (AP) and DV axes of the embryo. We propose a new three-dimensional growing Partial Differential Equation (PDE)-based model to simulate the BMP patterning process during the blastula stage. This model provides a starting point to elucidate how different mechanisms and components work together in 3D to create and maintain the BMP gradient in the embryo. We also show how the 3D model fits the BMP signaling gradient data at multiple time points along both axes. Furthermore, sensitivity analysis of the model suggests that the spatiotemporal patterns of Chordin and BMP ligand gene expression are dominant drivers of shape in 3D and more work is needed to quantify the spatiotemporal profiles of gene and protein expression to further refine the models.