bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the physical processes associated with junction fires at laboratory and field scales
Authors: Raposo J. R. , Viegas D. X. , Xie X. , Almeida M. , Figueiredo A. R. , Porto L. , Sharples J.
Published: January 2018

Junction fires, which involve the merging of two linear fire fronts intersecting at a small angle, are associated with very intense fire behaviour. The dynamic displacement of the intersection point of the two lines and the flow along the symmetry plane of the fire are analysed for symmetric boundary conditions. It is observed that the velocity of displacement of this point increases very rapidly owing to strong convective effects created by the fire that are similar to those of an eruptive fire. The change of fire geometry and of its associated flow gradually blocks the rate of spread increase and creates a strong deceleration of the fire, which ends up behaving like a linear fire front. Results from laboratory and field-scale experiments, using various fuel beds and slope angles and from a large-scale fire show that the processes are similar at a wide range of scales with little dependence on the initial boundary conditions. Numerical simulation of the heat flux from two flame surfaces to an element of the fuel bed show that radiation can be considered as the main mechanism of fire spread only during the deceleration phase of the fire.
Basal forebrain contributes to default mode network regulation
Authors: Nair Jayakrishnan , Klaassen Arndt-Lukas , Arato Jozsef , Vyssotski Alexei L. , Harvey Michael , Rainer Gregor
Published: January 2018

The default mode network (DMN) is a collection of cortical brain regions that is active during states of rest or quiet wakefulness in humans and other mammalian species. A pertinent characteristic of the DMN is a suppression of local field potential gamma activity during cognitive task performance as well as during engagement with external sensory stimuli. Conversely, gamma activity is elevated in the DMN during rest. Here, we document that the rat basal forebrain (BF) exhibits the same pattern of responses, namely pronounced gamma oscillations during quiet wakefulness in the home cage and suppression of this activity during active exploration of an unfamiliar environment. We show that gamma oscillations are localized to the BF and that gamma-band activity in the BF has a directional influence on a hub of the rat DMN, the anterior cingulate cortex, during DMN-dominated brain states. The BF is well known as an ascending, activating, neuromodulatory system involved in wake–sleep regulation, memory formation, and regulation of sensory information processing. Our findings suggest a hitherto undocumented role of the BF as a subcortical node of the DMN, which we speculate may be important for switching between internally and externally directed brain states. We discuss potential BF projection circuits that could underlie its role in DMN regulation and highlight that certain BF nuclei may provide potential target regions for up- or down-regulation of DMN activity that might prove useful for treatment of DMN dysfunction in conditions such as epilepsy or major depressive disorder.
The eardrums move when the eyes move: A multisensory effect on the mechanics of hearing
Authors: Gruters Kurtis G. , Murphy David L. K. , Jenson Cole D. , Smith David W. , Shera Christopher A. , Groh Jennifer M.
Published: January 2018

Interactions between sensory pathways such as the visual and auditory systems are known to occur in the brain, but where they first occur is uncertain. Here, we show a multimodal interaction evident at the eardrum. Ear canal microphone measurements in humans (
n
= 19 ears in 16 subjects) and monkeys (
n
= 5 ears in three subjects) performing a saccadic eye movement task to visual targets indicated that the eardrum moves in conjunction with the eye movement. The eardrum motion was oscillatory and began as early as 10 ms before saccade onset in humans or with saccade onset in monkeys. These eardrum movements, which we dub eye movement-related eardrum oscillations (EMREOs), occurred in the absence of a sound stimulus. The amplitude and phase of the EMREOs depended on the direction and horizontal amplitude of the saccade. They lasted throughout the saccade and well into subsequent periods of steady fixation. We discuss the possibility that the mechanisms underlying EMREOs create eye movement-related binaural cues that may aid the brain in evaluating the relationship between visual and auditory stimulus locations as the eyes move.
Tantalum coating prepared by APCVD and in-vivo biological evaluation
Authors: Li Ying , Han Jianmin , Tan Chengwen , Guo Chuanbin , Yue Junyi , Wang Fuchi , Zhao Mingyu , Mei Xifan , Dai Chunmei
Published: January 2018

Tantalum coating for bio-medical applications is prepared by atmospheric pressure chemical vapour deposition in a TaF5–H2 system on the inner wall of a stainless steel tube. The concentration of hydrogen fluoride (HF) has a significant effect on the morphology and crystallographic orientation of the tantalum coating. As the HF concentration increases, the tantalum coating gradually becomes smooth from roughness. The rougher part and the smoother part of tantalum coating reveal (200) and (110) preferred orientation, respectively. Simultaneously, the kinetic equation containing HF concentration has been developed. The calculated results from the equation show a good correspondence with the experimental results. The performance of tantalum coating with distinct morphologies on the effect of osseointegration was studied by implanting samples in vivo. The coating with a rougher surface was more osteoattractive than the one with a smoother surface.
Modeling Dynamic Food Choice Processes to Understand Dietary Intervention Effects
Authors: Marcum Christopher Steven , Goldring Megan R , McBride Colleen M , Persky Susan
Published: January 2018

Background

Meal construction is largely governed by nonconscious and habit-based processes that can be represented as a collection of in dividual, micro-level food choices that eventually give rise to a final plate. Despite this, dietary behavior intervention research rarely captures these micro-level food choice processes, instead measuring outcomes at aggregated levels. This is due in part to a dearth of analytic techniques to model these dynamic time-series events.

Purpose

The current article addresses this limitation by applying a generalization of the relational event framework to model micro-level food choice behavior following an educational intervention.

Method

Relational event modeling was used to model the food choices that 221 mothers made for their child following receipt of an information-based intervention. Participants were randomized to receive either (a) control information; (b) childhood obesity risk information; (c) childhood obesity risk information plus a personalized family history-based risk estimate for their child. Participants then made food choices for their child in a virtual reality-based food buffet simulation.

Results

Micro-level aspects of the built environment, such as the ordering of each food in the buffet, were influential. Other dynamic processes such as choice inertia also influenced food selection. Among participants receiving the strongest intervention condition, choice inertia decreased and the overall rate of food selection increased.

Conclusions

Modeling food selection processes can elucidate the points at which interventions exert their influence. Researchers can leverage these findings to gain insight into nonconscious and uncontrollable aspects of food selection that influence dietary outcomes, which can ultimately improve the design of dietary interventions.
Relationships Between the Axial Derotation of the Lower Instrumented Vertebra and Uninstrumented Lumbar Curve Correction: Radiographic Outcome in Lenke 1 Adolescent Idiopathic Scoliosis With a Minimum 2-Year Follow-up
Authors: Pasha Saba , Cahill Patrick J. , Flynn John M. , Sponseller Paul , Newton Peter O.
Published: January 2018

Background:

Preoperative spinal parameters are used to guide the fusion levels in adolescent idiopathic scoliosis (AIS) spinal surgery. However, the impact of the factors modifiable by the surgeon in varying levels of preoperative patient-specific variables is not fully explored. The goal of this study was to identify the association between axial rotation correction of the lower instrumented vertebra (LIV) and spontaneous correction of the uninstrumented lumbar spine as a function of preoperative 3 dimensional (3D) curve characteristics in Lenke 1 AIS.

Methods:

Twenty-three Lenke1 AIS with a minimum 2-year follow-up were included. All patients had biplanar spinal x-rays and 3D reconstructions at preoperative, first erect, and 2-year follow-up visits. Five patient factors were measured preoperatively: kyphosis and lumbar modifiers, and thoracic to lumbar curve rotation, translation, and frontal deformity angle ratios. One surgical factor, percentage of LIV rotation correction, was determined from the preoperative and first erect 3D models. A factorial design analysis was implemented to determine the impact of surgical and patient factors, both separately and in combination, on 2-year radiographic outcomes of spontaneous correction of the uninstrumented spine.

Results:

Spontaneous lumbar Cobb and lumbar apical rotation correction were predicted significantly by patient and surgical factors, P<0.05. Lumbar modifier, percentage correction of LIV rotation, the interaction between LIV rotation correction and lumbar modifier, and the interaction between LIV rotation correction and thoracic to lumbar apical vertebrae translation ratio correlated significantly to 2-year outcomes of spontaneous lumbar Cobb correction, P<0.05. Lumbar modifier and the interaction between the Cobb ratio and the percentage of the LIV rotation correction correlated significantly to 2-year outcomes of lumbar apical rotation correction, P<0.05.

Conclusion:

The relationship between LIV rotation correction and spontaneous lumbar curve correction after selective thoracic fusion varied based on the patient’s 3D preoperative curve characteristics. Patients with lumbar modifier C and apical vertebrae translation ratios >1.5 showed improved lumbar Cobb correction in 2-years when 50% or more LIV rotation correction was achieved surgically.
Some Considerations for Chelation Treatment and Surgical Excision Following Incorporation of Plutonium in Wounds
Authors: Poudel Deepesh , Bertelli Luiz , Klumpp John A. , Waters Tom L.
Published: January 2018

After a plutonium-contaminated wound, the role of an internal dosimetrist is to inform the patient and the physician of the dosimetric considerations. The doses averted due to medical treatments (excision or chelation) are higher if the treatments are administered early; therefore, the internal dosimetrist needs to rely on limited information on wound counts and process knowledge for advising the physician. Several wound cases in the literature were reviewed to obtain estimates of the efficacies of surgical excision and chelation treatment after plutonium-contaminated wounds. The dose coefficients calculated by coupling the NCRP 156 wound model with the systemic model were used to derive the decision guidelines that may indicate medical treatment based on 1) the concept of saved doses proposed by the NCRP 156 wound model, 2) the limits recommended by the CEC/DOE guidebook, and 3) the Clinical Decision Guidelines proposed in NCRP Report No. 161. These guidelines by themselves, however, are of limited use for several reasons, including 1) large uncertainties associated with wound measurements, 2) exposure to forms of radionuclides that cannot be assigned to a single category in the NCRP 156 framework, 3) inability of the NCRP 156 model to explain some of the wound cases in the literature, 4) neglect of the local doses to the wound site and the pathophysiological response of the tissue, 5) poorly understood relationship between effective doses and risks of late health effects, and 6) disregard of the psychological aspects of radionuclide intake.
THREE-DIMENSIONAL ANALYSIS OF RETINAL MICROANEURYSMS WITH ADAPTIVE OPTICS OPTICAL COHERENCE TOMOGRAPHY
Authors: Karst Sonja G. , Salas Matthias , Hafner Julia , Scholda Christoph , Vogl Wolf-Dieter , Drexler Wolfgang , Pircher Michael , Schmidt-Erfurth Ursula
Published: January 2018

Purpose:

To characterize retinal microaneurysms (MAs) in patients with diabetes using adaptive optics optical coherence tomography (AOOCT) and compare details found in AOOCT with those found in commercially available retinal imaging techniques.

Methods:

Patients with diabetes and MA in the macular area were included in this pilot study. The area of interest, identified in standard fluorescein angiography, was imaged using an AO fundus camera and AOOCT. Microaneurysms were characterized in AOOCT (visibility, reflectivity, feeding/draining vessels, and intraretinal location) and compared with findings in AO fundus camera, OCT angiography, and fluorescein angiography.

Results:

Fifty-three MAs were imaged in 15 eyes of 10 patients. Feeding and/or draining vessels from both capillary plexus could be identified in 34 MAs in AOOCT images. Of 45 MAs imaged with OCT angiography, 18 (40%) were visible in the superior plexus, 12 (27%) in the deep capillary plexus, and 15 MAs (33%) could not be identified at all. Intraluminal hyperreflectivity, commonly seen in AO fundus camera, corresponded only in 8 of 27 cases (30%) to intraluminal densities seen in AOOCT.

Conclusion:

Adaptive optics OCT imaging revealed that MAs located in the inner nuclear layer were connected to the intermediate and/or deep capillary plexus. Intraluminal hyperreflectivity seen on AO fundus camera images originated from a strong reflection from the vessel wall and only in a third of the cases from intraluminal clots. Currently, AOOCT is the most expedient in vivo imaging method to capture morphologic details of retinal microvasculature in 3D and in the context of the surrounding retinal anatomy.
Does Occupation Influence Selection of Contact Lens Material?
Authors: Rajan Rajni , Mahadevan Rajeswari , Bhattacharya Pradipta
Published: January 2018

Objective:

Long-term follow-up of contact lens (CL) wearers leads to better understanding of the factors leading to changes in CL trends. This study is an attempt to ascertain these factors in an emerging market like India. Factors like occupation were analyzed to determine if these contributed to changes in selection of CL materials in this article.

Methods:

Occupations were categorized as per the norms of International Standard Classification of Occupations-2008 (International Labor Organization, United Nations organization).

Results:

A majority of lens wearers were professionals and hydrogel lens materials were the lenses of choice among most of the lens wearers. There was a significant variation in CL material with different occupations (χ2=19.29, P=0.037).

Conclusion:

To conclude, employment and affordability influenced the selection of lens materials.
Survey of Ophthalmologists Regarding Practice Patterns for Dry Eye and Sjogren Syndrome
Authors: Bunya Vatinee Y. , Fernandez Karen B. , Ying Gui-Shuang , Massaro-Giordano Mina , Macchi Ilaria , Sulewski Michael E. , Hammersmith Kristin M. , Nagra Parveen K. , Rapuano Christopher J. , Orlin Stephen E.
Published: January 2018

Objective:

To survey ophthalmologists about current practice patterns regarding the evaluation of dry eye patients and referrals for a Sjogren syndrome (SS) workup.

Methods:

An online survey was sent to ophthalmologists affiliated with the Scheie Eye Institute or Wills Eye Hospital using REDCap in August 2015. Descriptive statistics were used to summarize the data.

Results:

Four hundred seventy-four survey invitations were sent out and 101 (21%) ophthalmologists completed the survey. The common traditional dry eye test performed was corneal fluorescein staining (62%) and the most common newer dry eye test performed was tear osmolarity (18%). Half of respondents (51%) refer fewer than 5% of their dry eye patients for SS workups, with 18% reporting that they never refer any patients. The most common reasons for referrals included positive review of systems (60%), severe dry eye symptoms (51%) or ocular signs (47%), or dry eye that is refractory to treatment (42%). The majority (83%) felt that there is a need for an evidence-based standardized screening tool for dry eye patients to decide who should be referred for evaluation for SS.

Conclusions:

Ophthalmologists continue to prefer the use of traditional dry eye tests in practice, with the most common test being corneal fluorescein staining. There is an underreferral of dry eye patients for SS workups, which is contributing to the continued underdiagnosis of the disease. Most respondents felt that there was a need for an evidence-based standardized screening tool to decide which dry eye patients should be referred for SS evaluations.
Age at disease onset of inflammatory bowel disease is associated with later extraintestinal manifestations and complications
Authors: Herzog Denise , Fournier Nicolas , Buehr Patrick , Rueger Vanessa , Koller Rebekka , Heyland Klaas , Nydegger Andreas , Spalinger Johannes , Schibli Susanne , Petit Laetitia-Marie , Braegger Christian P.
Published: January 2018

Introduction

A small but increasing number of patients with inflammatory bowel disease are diagnosed during childhood or adolescence, and disease distribution and severity at onset vary according to the age at diagnosis. Clinical factors present at the time of diagnosis can be predictive of the disease course.

Aim

The aim of this study was to characterize disease behavior and the cumulative complications and extraintestinal manifestations 10 years after the diagnosis and to assess their association with age at diagnosis.

Patients and methods

Data of patients participating with the Swiss IBD cohort study registry, a disease duration of 10 years and a complete data set were analyzed. The outcome was defined as the cumulative change of disease behavior, the occurrence of extra-intestinal manifestations or complications, and the necessity for medical or surgical interventions.

Results

A total of 481 patients with Crohn’s disease (CD) and 386 patients with ulcerative colitis (UC), grouped according to disease onset before 10, 17, 40, or after 40 years of age, were analyzed. Despite differences in sex, initial disease location, and smoking habits, at 10 years after the diagnosis, no difference was found regarding disease behavior in CD or regarding progression of disease extension in UC. Similarly, no age-of-onset-dependent cumulative need for medical or surgical therapies was found. However, higher rates of anemia and lower rates of arthralgia and osteopenia were found in both pediatric-onset CD and UC, and a tendency toward higher rates of stomatitis in pediatric-onset CD, and of primary sclerosing cholangitis and ankylosing spondylitis in pediatric-onset UC.

Conclusion

After 10 years of disease evolution, age at disease onset is not anymore associated with disease behavior but only with a small difference in the occurrence of specific extraintestinal manifestations and complications.
Advocating to Protect Our Nurses
Authors: Shaffer Franklin , Bakhshi Mukul , Jacobs Arielle
Published: January 2018

Advocacy in the nursing sector is often about advocating for patients. However, nurses have begun to put more effort into protecting their rights as workers. Advocacy on behalf of foreign-educated nurses has been a critical component of this advocacy. While foreign-educated nurses can make our nursing workforce stronger, this can only happen if they are well-treated and well-trained. Organizations across diverse missions and perspectives have come together to promote fair treatment of foreign-educated nurses, which ultimately ensures that all nurses are working as effectively as possible and that patients receive proper care. The Alliance for Ethical International Recruitment Practices' Health Care Code for Ethical Recruitment and Employment Practices represents a bottom-up agreement on which market practices constitute ethical recruitment. From a top-down level, the World Health Organization's Code of Global Practice establishes obligations and reporting requirements for member states that commit to ensuring ethical recruitment. This combination of efforts, bolstered by strong advocacy, is gaining traction as nursing migration grows at the global level. The collaboration across diverse stakeholder groups and the combination of legal, voluntary, and global efforts to promote the rights of foreign-educated nurses provides a model to apply for advocacy in different areas.
Toxicities Associated With PD-1/PD-L1 Blockade
Authors: Wang Daniel Y. , Johnson Douglas B. , Davis Elizabeth J.
Published: January 2018

Immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, produce durable responses in a subset of patients across cancer types. Although often well tolerated, these agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Treatment of these toxicities primarily consists of immune suppression with corticosteroids and other agents. This review briefly discusses the mechanisms of immune-related adverse events, overviews the clinical and pathologic features of major toxicities caused by PD-1/PD-L1 blockade, and reviews their management.
Clinical Development of PD-1 Blockade in Hematologic Malignancies
Authors: Pianko Matthew J. , Goldberg Aaron D. , Lesokhin Alexander M.
Published: January 2018

Clinical development of immune checkpoint inhibitors targeting the PD-1 pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinations in phase 2 studies in multiple myeloma, safety concerns in patients treated with the combination of immunomodulatory drugs and checkpoint inhibitors in myeloma have stalled drug development in this space. Novel combination approaches exploring PD-1 inhibitors with epigenetic modifiers in leukemia are underway.
Mechanisms of Resistance to PD-1 and PD-L1 Blockade
Authors: Nowicki Theodore S. , Hu-Lieskovan Siwen , Ribas Antoni
Published: January 2018

Cancer immunotherapy utilizing blockade of the PD-1/PD-L1 checkpoint has revolutionized the treatment of a wide variety of malignancies, leading to durable therapeutic responses not typically seen with traditional cytotoxic anticancer agents. However, these therapies are ineffective in a significant percentage of patients, and some initial responders eventually develop resistance to these therapies with relapsed disease. The mechanisms leading to both primary and acquired resistance to PD-1/PD-L1 inhibition are varied and can be both multifactorial and overlapping in an individual patient. As the mechanisms of resistance to PD-1/PD-L1 blockade continue to be further characterized, new strategies are being developed to prevent or reverse resistance to therapy, leading to improved patient outcomes.
Plasmodium parasites of birds have the most AT-rich genes of eukaryotes
Authors: Videvall Elin
Published: January 2018

The genomic architecture of organisms, including nucleotide composition, can be highly variable, even among closely-related species. To better understand the causes leading to structural variation in genomes, information on distinct and diverse genomic features is needed. Malaria parasites are known for encompassing a wide range of genomic GC-content and it has long been thought that Plasmodium falciparum, the virulent malaria parasite of humans, has the most AT-biased eukaryotic genome. Here, I perform comparative genomic analyses of the most AT-rich eukaryotes sequenced to date, and show that the avian malaria parasites Plasmodium gallinaceum, P. ashfordi, and P. relictum have the most extreme coding sequences in terms of AT-bias. Their mean GC-content is 21.21, 21.22 and 21.60 %, respectively, which is considerably lower than the transcriptome of P. falciparum (23.79 %) and other eukaryotes. This information enables a better understanding of genome evolution and raises the question of how certain organisms are able to prosper despite severe compositional constraints.
First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy
Authors: Frasch Martin G. , Herry Christophe L. , Niu Youguo , Giussani Dino A.
Published: January 2018

Fetal heart rate variability (FHRV) emerges from influences of the autonomic nervous system, fetal body and breathing movements, and from baroreflex and circadian processes. We tested whether intrinsic HRV exists in the fetal period and whether it is affected by chronic fetal hypoxia. Chronically catheterized ewes carrying male singleton fetuses were exposed to normoxia (n=6) or hypoxia (10% inspired O2, n=9) for the last third of gestation (105-138 dG; term~145 dG) in isobaric chambers. At 138dG, isolated hearts were studied using a Langendorff preparation. We calculated basal iFHRV matrix indices across five signal-analytical domains from the systolic peaks within 15 min segments in each heart. Significance was assumed at p<0.05. Maternal hypoxia yielded chronic fetal PaO2 values of 11.5±0.6 (mean+SEM) relative to controls of 20.9±0.5 mmHg. Hearts of fetuses isolated from hypoxic pregnancy showed approximately 4-fold increases in the Grid transformation as well as the AND similarity index (sgridAND, informational domain) and a 4-fold reduction in the Scale dependent Lyapunov exponent slope (invariant domain). We also detected a 2-fold reduction in the Recurrence quantification analysis, percentage of laminarity and recurrences and maximum diagonal line (dlmax, geometric domain) and in the Multiscale time irreversibility asymmetry index (energetic domain). dlmax and sgridAND correlated with left ventricular end-diastolic pressure across both groups (R2=0.32 and R2=0.63, respectively). This is the first evidence that iHRV originates in fetal life and that chronic fetal hypoxia significantly alters it. Isolated fetal hearts from hypoxic pregnancy exhibit a lower complexity in iFHRV.

Key points summary

We introduce a technique to test whether intrinsic fetal heart rate variability (iFHRV) exists and we show the utility of the technique by testing the hypothesis that iFHRV is affected by chronic fetal hypoxia, one of the most common adverse outcomes of human pregnancy complicated by fetal growth restriction.

Using an established late gestation ovine model of fetal development under chronic hypoxic conditions, we identify iFHRV in isolated fetal hearts and show that it is markedly affected by hypoxic pregnancy.

Therefore, the isolated fetal heart carries a memory of adverse intrauterine conditions experienced during the last third of pregnancy.

Indices of iFHRV may improve fetal health surveillance by helping to diagnose prediction of fetal hypoxia and acidaemia during antenatal or intra-partum fetal compromise.
Open access policies of leading medical journals: a cross-sectional study
Authors: Ellison Tim S , Koder Tim , Schmidt Laura , Williams Amy , Winchester Christopher
Published: January 2018

Objectives: Academic and not-for-profit research funders are increasingly requiring that the research they fund must be published open access, with some insisting on publishing with a Creative Commons Attribution (CC BY) licence to allow the broadest possible use. We set out to clarify the open access variants provided by leading medical journals for research in general and industry-funded research in particular, and record the availability of the CC BY licence for commercially funded research.
Methods: We identified medical journals with a 2015 impact factor of at least 15.0 on 24 May 2017, then excluded from the analysis journals that only publish review articles. Between 29 June 2017 and 26 July 2017, we collected information about each journal's open access policies from their websites and/or by email contact. We contacted the journals by email again between 6 December 2017 and 2 January 2018 to confirm our findings.
Results: Thirty-five medical journals publishing original research from 13 publishers were included in the analysis. All 35 journals offered some form of open access with varying embargo periods of up to 12 months. Of these journals, 21 (60%) provided immediate open access with a CC BY licence under certain circumstances (e.g. to specific research funders). Of these 21, 20 only offered a CC BY licence to authors funded by non-commercial organizations and one offered this option to funders who required it.
Conclusions: Most leading medical journals do not offer to authors reporting commercially funded research an open access licence that allows unrestricted sharing and adaptation of the published material. The journals' policies are therefore not aligned with open access declarations and guidelines. Commercial research funders lag behind academic funders in the development of mandatory open access policies, and it is time for them to work with publishers to advance the dissemination of the research they fund.
A framework for large-scale dynamic metabolome drug profiling in mammalian cells: a case study analysis of the anti-cancer drug dichloroacetate
Authors: Dubuis Sébastien , Ortmayr Karin , Zampieri Mattia
Published: January 2018

Metabolic profiling of cell line collections have become an invaluable tool to study disease etiology, drug modes of action and personalized medicine. However, large-scalein vitrodynamic metabolic profiling is limited by time-consuming sampling and complex measurement procedures. By adapting an MS-based metabolomics workflow for high-throughput profiling of diverse adherent mammalian cells, we establish a technique for the rapid measurement and analysis of drug-induced dynamic changes in intracellular metabolites. This methodology is scalable to large compound libraries and is here applied to study the mechanism underlying the toxic effect of dichloroacetate in ovarian cancer cell lines. System-level analysis of the metabolic responses revealed a key and unexpected role of CoA imbalance in dichloroacetate toxicity. The herein proposed strategy for large-scale drug metabolic profiling is complementary to other molecular profiling techniques, opening new scientific and drug-discovery opportunities.
Comparative analysis of molecular signatures suggests the use of gabapentin for the management of endometriosis-associated pain
Authors: Bellessort Brice , Bachelot Anne , Grouthier Virginie , Lombares Camille de , Narboux-Neme Nicolas , Garagnani Paolo , Pirazzini Chiara , Astigiano Simonetta , Mastracci Luca , Fontaine Anastasia , Alfama Gladys , Duvernois-Berthet Evelyne , Levi Giovanni
Published: January 2018

Capsule

Comparative analysis of gene expression signatures from endometriosis and mouse models shows that CACNAα2δs calcium-channel components involved in nociception are targets for the treatment of endometriosis-associated pain.

Context

Differential gene expression analyses comparing endometriotic lesions to eutopic endometrium have shown that the transcription factors DLX5 and DLX6 are drastically down-regulated in the ectopic implants. These finding suggests that regulatory cascades involving DLX5/6 might be involved in the origin of endometriosis symptoms such as chronic pelvic pain. We have shown that mice in which Dlx5 and Dlx6 are selectively inactivated in the uterus present an endometrial phenotype reminiscent of endometriosis implants.

Objective

Identify new targets for the treatment of endometriosis.

Design

To better focus the search for endometriosis targets we have compared the profile of genes deregulated in normal and ectopic women endometrium to those deregulated in the uterus of normal and Dlx5/Dlx6-null mice.

Settings

Academic research unit and University Hospital research laboratory

Animals

Mice carrying a uterus-specific deletion of Dlx5/Dlx6.

Interventions

Analysis of archive sections from normal endometrium and endometriosis implants.

Main Outcome

A novel endometriosis signature suggests that α2δs subunits of voltage-gated calcium channel are targets for the management of endometriosis-associated pain.

Results

We identify a signature of 30 genes similarly deregulated in human endometriosis implants and in Dlx5/6-null mouse uteri reinforcing the notion that the down-regulation of Dlx5/6 is an early event in the progress of endometriosis. CACNA2D3, a component of the voltage-dependent calcium channel complex is strongly overexpressed both in endometriosis implants and in mutant mouse uteri; other members of the alfa2delta family, CACNA2D1 and CACNA2D2, are also overexpressed in endometriosis.

Conclusion

CACNA2D1, CACNA2D2 and CACNA2D3 are directly involved in pain perception. In particular, CACNA2D3 has been associated to pain sensitization and heat nociception in animal models while, in patients, variants of this gene are associated to reduced sensitivity to acute noxious stimuli. As CACNA2Ds are targets of gabapentinoids analgesics, our results suggest to consider the use of these drugs for the treatment of endometriosis-associated pain. Indeed, recent small-scale clinical studies have shown that gabapentin can be effective in the treatment of women chronic pelvic pain. Our findings reinforce the need for a large definitive trial.
The Neural Architecture of Executive Functions Is Established by Middle Childhood
Authors: Engelhardt Laura E. , Harden K. Paige , Tucker-Drob Elliot M. , Church Jessica A.
Published: January 2018

Executive functions (EFs) are regulatory cognitive processes that support goal-directed thoughts and behaviors and that involve two primary networks of functional brain activity in adulthood. The current study assessed whether the same networks identified in adulthood underlie child EFs. Using task-based fMRI data from a diverse sample of N = 117 children and early adolescents (M age = 10.17 years), we assessed the extent to which neural activity was shared across three EF domains and whether these patterns reflected quantitative or qualitative differences relative to previously reported adult findings. Brain regions that were consistently engaged across switching, updating, and inhibition tasks closely corresponded to the cingulo-opercular and fronto-parietal networks identified in studies of adults. Isolating brain activity during more demanding task periods highlighted contributions of the dACC and anterior insular regions of the cingulo-opercular network. Results were independent of age and time-on-task effects. These results indicate that the two core brain networks that support EFs are in place by middle childhood. Improvement in EFs from middle childhood to adulthood, therefore, are likely due to quantitative changes in activity within these networks, rather than qualitative changes in the organization of the networks themselves. Improved knowledge of how the brain’s functional organization supports EF in childhood has critical implications for understanding the maturation of cognitive abilities.
The soft explosive model of placental mammal evolution
Authors: Phillips Matthew J , Fruciano Carmelo
Published: January 2018

Recent molecular dating estimates for placental mammals echo fossil inferences for an explosive interordinal diversification, but typically place this event some 10-20 million years earlier than the Paleocene fossils, among apparently more “primitive” mammal faunas. However, current models of molecular evolution do not adequately account for parallel rate changes, and result in dramatic divergence underestimates for large, long-lived mammals such as whales and hominids. Calibrating among these taxa shifts the rate model errors deeper in the tree, inflating interordinal divergence estimates. We employ simulations based on empirical rate variation, which show that this “error-shift inflation” can explain previous molecular dating overestimates relative to fossil inferences. Molecular dating accuracy is substantially improved in the simulations by focusing on calibrations for taxa that retain plesiomorphic life-history characteristics. Applying this strategy to the empirical data favours the soft explosive model of placental evolution, in line with traditional palaeontological interpretations – a few Cretaceous placental lineages give rise to a rapid interordinal diversification following the 66 Ma Cretaceous-Paleogene boundary mass extinction. Our soft explosive model for the diversification of placental mammals brings into agreement previously incongruous molecular, fossil, and ancestral life history estimates, and closely aligns with a growing consensus for a similar model for bird evolution. We show that recent criticism of the soft explosive model relies on ignoring both experimental controls and statistical confidence, as well as misrepresentation, and inconsistent interpretations of morphological phylogeny. More generally, we suggest that the evolutionary properties of adaptive radiations may leave current molecular dating methods susceptible to overestimating the timing of major diversification events.
New mining concessions will severely decrease biodiversity and ecosystem services in Ecuador
Authors: Roy Bitty , Zorrilla Martin , Endara Lorena , Thomas Dan , Vandegrift Roo , Rubenstein Jesse M. , Policha Tobias , Rios-Touma Blanca
Published: January 2018

Ecuador has the world’s highest biodiversity, despite being a tiny fraction of the world’s land area. The threat of extinction for much of this biodiversity has dramatically increased since April 2016, during which time the Ecuadorian government has opened approximately 2.9 million hectares of land for mining exploration, with many of the concessions in previously protected forests. Herein, we describe the system of protected lands in Ecuador, their mining laws, and outline the scale of threat by comparing the mammals, amphibians, reptiles, birds, and orchids from several now threatened protected areas, classed as “Bosques Protectores” (BPs), in the NW montane cloud forests. We examine two large (>5,000 ha) BPs, Los Cedros and El Chontal, and two medium BPs, Mashpi (1,178 ha) and Maquipucuna (2,474 ha). Since BP El Chontal is so poorly explored, we used several other small reserves (<500 hectares) in the Intag Valley to gain an idea of its biodiversity. Together, these BPs and reserves form a buffer and a southern corridor for the still-protected Cotacachi-Cayapas Ecological Reserve, which is otherwise now surrounded by mining concessions. We gathered published literature, “gray literature”, information from reserve records and websites, and our previously unpublished observations to make comparative species tables for each reserve. Our results from these still incompletely known reserves reveal the astonishing losses that mining will incur: eight critically endangered species, including two primates (brown-headed spider monkey and white-fronted capuchin), 37 endangered species, 149 vulnerable and 85 near threatened and a large number of less threatened species Our data show that each of the reserves protects a unique subset of taxa in this land of highly localized endemics. Each of the reserves also generates sustainable income for the local people. The short-term national profits from mining will not compensate for the permanent biodiversity losses, and the long-term ecosystem service and economic losses at the local and regional level.
A label-free approach to detect ligand binding to cell surface proteins in real time
Authors: Burtscher Verena , Hotka Matej , Li Yang , Freissmuth Michael , Sandtner Walter
Published: January 2018

Electrophysiological recordings allow for monitoring the operation of proteins with high temporal resolution down to the single molecule level. This technique has been exploited to track either ion flow arising from channel opening or the synchronized movement of charged residues and/or ions within the membrane electric field. Here, we describe a novel type of current by using the serotonin transporter (SERT) as a model. We examined transient currents elicited on rapid application of specific SERT inhibitors. Our analysis shows that these currents originate from ligand binding and not from a conformational change. The Gouy-Chapman model predicts that a ligand-induced elimination/neutralization of surface charge must produce a displacement current and related apparent changes in membrane capacitance. Here we verified these predictions with SERT. Our observations demonstrate that ligand binding to a protein can be monitored in real time and in a label-free manner by recording the membrane capacitance.
Bovine mammary gland development: new insights into the epithelial hierarchy
Authors: Finot Laurence , Chanat Eric , Dessauge Frederic
Published: January 2018

Milk production is highly dependent on the extensive development of the mammary epithelium, which occurs during puberty. It is therefore essential to distinguish the epithelial cells committed to development during this key stage from the related epithelial hierarchy. Using cell phenotyping and sorting, we highlighted three sub-populations that we assume to be progenitors. The CD49fhighCD24negcells expressingKRT14,vimentinandPROCRcorresponded to basal progenitors whereas the CD49flowCD24negcells expressing luminal KRT, progesterone and prolactin receptors, were of luminal lineage. The CD49flowCD24poscells had features of a dual lineage, with luminal and basal characteristics (CD10, ALDH1 andKRT7expression) and were considered to be early common (bipotent) progenitors. The mammary stem cell (MaSC) fraction was recovered in a fourth sub-population of CD49fhighCD24poscells that expressed CD10/KRT14andKRT7. The differential ALDH1 activities observed within the MaSC fraction allowed to discriminate between two states: quiescent MaSCs and lineage-restricted “activated” MaSCs. The in-depth characterization of these epithelial sub-populations provides new insights into the epithelial cell hierarchy in the bovine mammary gland and suggests a common developmental hierarchy in mammals.
Severely impaired bone material quality in Chihuahua zebrafish resembles classical dominant human osteogenesis imperfecta
Authors: Fiedler Imke A.K. , Schmidt Felix N. , Plumeyer Christine , Milovanovic Petar , Gioia Roberta , Tonelli Francesca , Forlino Antonella , Busse Björn
Published: January 2018

Excessive skeletal deformations and brittle fractures in the vast majority of patients suffering from osteogenesis imperfecta (OI) are a result of substantially reduced bone quality. Since the mechanical competence of bone is dependent on the tissue characteristics at small length scales, it is of crucial importance to assess how osteogenesis imperfecta manifests at the micro- and nanoscale of bone. In this context, the Chihuahua (Chi/+) zebrafish, carrying a heterozygous glycine substitution in the α1 chain of collagen type I, has recently been proposed as suitable animal model of dominant OI. Similar to human severe OI type III, Chi/+ show skeletal deformities, altered mineralization patterns and a smaller body size. Using a multimodal approach targeting bone quality parameters, this study aims at quantifying the changes in bone morphology, structure and tissue composition of Chi/+ at multiple length scales. Morphological changes were assessed with high-resolution micro-CT imaging and showed that the vertebrae in Chi/+ had a significantly smaller size, thinner cortical shell and distorted shape. Tissue composition in vertebrae was investigated with quantitative backscattered electron microscopy and Fourier-transform infrared spectroscopy, showing higher mean calcium content, greater matrix porosity, as well as lower mineral crystallinity and collagen maturity in comparison to controls. This study provides comprehensive quantitative data on bone quality indices in Chi/+ and thus further validates this mutant as an important model reflecting osseous characteristics associated with human classical dominant osteogenesis imperfecta, both at the whole bone level and the tissue level.
Timing malaria transmission with mosquito fluctuations
Authors: Pigeault R. , Caudron Q. , Nicot A. , Rivero A. , Gandon S.
Published: January 2018

Temporal variations in the activity of arthropod vectors can dramatically affect the epidemiology and evolution of vector-borne pathogens. Here we explore the “Hawking hypothesis” stating that these pathogens may evolve the ability to time investment in transmission to match the activity of their vectors. First, we use a theoretical model to identify the conditions promoting the evolution of time-varying transmission strategies in pathogens. Second, we experimentally test the “Hawking hypothesis” by monitoring the within-host dynamics of Plasmodium relictum throughout the acute and the chronic phases of the bird infection. To explore the periodicity in the host parasite density, we develop a new methodology to correct for non-stationarities in the host parasitaemia. We detect a periodic increase of parasitaemia and mosquito infection in the late afternoon that coincides with an increase in the biting activity of its natural vector. We also detect a positive effect of mosquito bites on Plasmodium replication in the birds both in the acute and in the chronic phases of the infection. This study highlights that Plasmodium parasites use two different strategies to increase the match between transmission potential and vector availability. We discuss the adaptive nature of these unconditional and plastic transmission strategies with respect to the time-scale and the predictability of the fluctuations in the activity of the vector.

Impact Summary

Seasonal and daily fluctuations in the environment affect the abundance and the activity of vectors and may therefore have profound consequences on the transmission of infectious diseases. Here we show that, in accord with evolutionary theory, malaria parasites have evolved two different and complementary strategies to cope with fluctuations in mosquito availability. First, Plasmodium relictum adopts an unconditional strategy whereby within-host parasitaemia and mosquito infection increases in the afternoon and in the evening, when its vector, the Culex pipiens mosquito, is most active. Second, we find evidence for a plastic strategy allowing the parasitaemia to rapidly increase after exposure to mosquito bites.
The neural representation of missing speech and the influence of prior knowledge on cortical fidelity and latency
Authors: Constantino Francisco Cervantes , Simon Jonathan Z.
Published: January 2018

In naturally noisy listening conditions, for example at a cocktail party, noise disruptions may completely mask significant parts of a sentence, and yet listeners may still perceive the missing speech as being present. Here we demonstrate that dynamic speech-related auditory cortical activity, as measured by magnetoencephalography (MEG), which can ordinarily be used to directly reconstruct to the physical speech stimulus, can also be used to “reconstruct” acoustically missing speech. The extent to which this occurs depends on the extent that listeners are familiar with the missing speech, which is consistent with this neural activity being a dynamic representation of perceived speech even if acoustically absence. Our findings are two-fold: first, we find that when the speech is entirely acoustically absent, the acoustically absent speech can still be reconstructed with performance up to 25% of that of acoustically present speech without noise; and second, that this same expertise facilitates faster processing of natural speech by approximately 5 ms. Both effects disappear when listeners have no or very little prior experience with a given sentence. Our results suggest adaptive mechanisms of consolidation of detailed representations about speech, and the enabling of strong expectations this entails, as identifiable factors assisting automatic speech restoration over ecologically relevant timescales.