bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploratory Ingestions of Novel Anticoagulants and Antiplatelets
Authors: Levine Michael , Pizon Anthony , Beuhler Michael , Cantrell F. Lee , LoVecchio Frank , Spyres Meghan , Skolnik Aaron B. , Brooks Daniel E.
Published: November 2018

Background

Historically, anticoagulants and antiplatelet agents included warfarin and aspirin, respectively. In recent years, numerous novel anticoagulants (eg, direct thrombin inhibitors and factor Xa inhibitors) as well as the adenosine diphosphate receptor antagonists have increased significantly. Little information on the bleeding risk after exploratory ingestion of these agents is available. The primary purpose of this study is to evaluate the bleeding risk of these agents after an exploratory ingestion in children 6 years or younger.

Methods

This retrospective multicenter poison control center study was conducted on calls between 2005 and 2014. The following agents were included: apixaban, clopidogrel, dabigatran, edoxaban, prasugrel, rivaroxaban, or ticagrelor. Bleeding characteristics and treatment rendered were recorded.

Results

A total of 638 cases were identified. Most cases involved antiplatelet agents. No patient developed any bleeding complication. The administration of charcoal was independent of the amount of drug ingested.

Conclusion

Accidental, exploratory ingestions of these agents seem well tolerated, with no patient developing bleeding complications.
Pediatric Transport Triage
Authors: Steffen Katherine M. , Noje Corina , Costabile Philomena M. , Henderson Eric , Hunt Elizabeth A. , Klein Bruce L. , McMillan Kristen Nelson
Published: November 2018

Objectives

We developed a Pediatric Transport Triage Tool (PT3) to objectively guide selection of team composition and transport mode, thereby standardizing transport planning. Previously, modified Pediatric Early Warning Score for transport has been used to assess illness severity but not to guide transport decision making.

Methods

The PT3 was created for pediatric transport by combining objective evaluations of neurologic, cardiovascular, and respiratory systems with a systems-based medical condition list to identify diagnoses requiring expedited transport and/or advanced team composition not captured by neurologic, cardiovascular, and respiratory systems alone. A scoring algorithm was developed to guide transport planning. Transport data (mode, team composition, time to dispatch, patient disposition, and complications) were collected before and after PT3 implementation at a single tertiary care center over an 18-month period.

Results

We reviewed 2237 inbound pediatric transports. Transport mode, patient disposition, and dispatch time were unchanged over the study period. Fewer calls using a transport nurse were noted after PT3 implementation (33.9% vs 30%, P = 0.05), with a trend toward fewer rotor-wing transports and transports requiring physicians. The majority of users, regardless of experience level, reported improved transport standardization with the tool. Need to upgrade team composition or mode during transport was not different during the study period. No adverse patient safety events occurred with PT3 use.

Conclusions

The PT3 represents an objective triage tool to reduce variability in transport planning. The PT3 decreased resource utilization and was not associated with adverse outcomes. Teams with dynamic staffing models, various experience levels, and multiple transport modes may benefit from this standardized assessment tool.
Uncommon Presentation of Childhood Leukemia in Emergency Department
Authors: Boccuzzi Elena , Ferro Valentina A. , Cinicola Bianca , Schingo Paolo M. , Strocchio Luisa , Raucci Umberto
Published: November 2018

Leukemia is the most common childhood malignancy, and it is often characterized by pallor, fatigue, cytopenia, and organomegaly; sometimes musculoskeletal symptoms, mainly characterized by diffuse bone pain in the lower extremities, are the onset clinical characteristics of the disease. In these cases, the disease may initially be misdiagnosed as reactive arthritis, osteomyelitis, or juvenile idiopathic arthritis delaying appropriate diagnosis and management. Even if leukopenia, thrombocytopenia, and a history of nighttime pain are reported to be the most important predictive factors for a pediatric leukemia, blood examinations can sometimes be subtle or within normal limits, and this represents a further diagnostic difficulty. Radiological findings of leukemic bone involvement are described in patients with musculoskeletal symptoms of acute lymphoblastic leukemia and often appear before hematologic anomalies, but they are not specific for the disease. However, they could be helpful to get the right diagnosis if integrated with other features; thus, it is important knowing them, and it is mandatory for the multidisciplinary comparison to talk about dubious cases even in an emergency setting. We describe 4 patients visited in the emergency department for musculoskeletal complaints and having radiological lesions and a final diagnosis of acute lymphoblastic leukemia, in whom the onset of the manifestations could mimic orthopedic/rheumatologic diseases.
Scaling up pre-exposure prophylaxis in sub-Saharan Africa
Authors: Ahmed Nadia , Pike Carey , Bekker Linda-Gail
Published: November 2018

Purpose of review

Pre-exposure prophylaxis (PrEP) is highly efficacious for preventing HIV. Demonstrations worldwide show growing acceptability with nonoral formulations in the pipeline. Despite these successes, oral PrEP scale-up in sub-Saharan Africa (SSA), the region hardest hit by HIV, remains sub-optimal. This review details emerging practises and addresses challenges in PrEP scale-up and delivery within SSA.

Recent findings

PrEP scale-up varies across SSA. Some countries face implementation challenges, whereas most have not applied for or received regulatory approval. As governments balance treatment and prevention costs, PrEP advocacy is growing. Demand has been slow, because of low-risk perception, HIV treatment conflation or poor information. Challenges in SSA are markedly different than elsewhere, as delivery is targeted to generalized heterosexuals, rather than only key populations. SSA requires public sector engagement and innovative delivery platforms.

PrEP scale-up in SSA is sub-optimal, hindered by regulatory processes, implementation challenges, poor community engagement and inadequate funding. Approaches that acknowledge overburdened, under-resourced health sectors, and seek opportunities to integrate, task-shift, decentralize and even de-medicalize, with a tailored approach, while campaigning to educate and stimulate demand are most likely to work. Solutions to oral PrEP scale-up will apply to other formulations, opening new avenues for ARV (microbicides and injectables) and non-ARV-based (future vaccine) biomedical prevention provision.
Madelung Disease
Authors: Wan Shao-Chen , Huang Man-Hsu , Perng Cherng-Kang , Liao Wen-Chieh
Published: November 2018

Background

The main feature of Madelung disease (MD), a rare condition, is the growth of adipose tissue without a capsule. Usually, this disease is known for its prominent features with fat deposition around the neck, shoulder, back, or chest wall. Clinically, the patient is likely to exhibit alcohol, neuropathy, and metabolic disorders; however, no clear cause has been confirmed.

Aims

The aim of this study was to analyze the morphological, pathophysiological, and various treatment methods of MD. We have presented and discussed 16 cases of treatment of this disease at our hospital and reviewed the literature on this subject.

Methods

We carried out a retrospective chart review of 16 consecutive patients with MD treated from 1989 through 2017. Patient demographic data, tumor size and location, and follow-up data were evaluated. Patients usually seek treatment because of the disfigured appearance, restricted range of the motion of the head and neck, inconvenience in daily activity such as eating or speaking, and worry about the mass effect. All patients underwent surgical resection and/or combined liposuction.

Results

Among the patients, 14 were men, aged 38 to 80 years, with a history of disease ranging from 6 months to 7 years. The mean duration from symptoms to diagnosis of MD was 4.4 years. The mean duration of follow-up was 82.8 months (range, 5–192 months). Three patients died of coronary artery disease at follow-up of 27, 78, and 141 months. The functional results were satisfactory in all patients. Severe complications were not observed.

Conclusions

According to our experience, surgical resection is the main method of improving the appearance, ensuring eradication of the tumor, and reducing the possibility of recurrence. In addition, we have a case in which atypical changes were confirmed by histological examination in fractional surgery. A long follow-up period is recommended considering the high propensity and mean time to recurrence. Although malignant transformation of MD is rare occurrence, it occurred in 1 of the 16 patients.
Endovenous Photocoagulation Using a Diode Laser for Complicated Varicose Veins Related to Stasis Ulcers
Authors: Lee Jing-Syuan , Hsiao Yen-Chang , Chang Cheng-Jen
Published: November 2018

Background

The objective of this study was to assess the efficacy and safety of endovenous laser photocoagulation (EVLP) at a wavelength of 810 nm for treating complicated venous insufficiency associated with venous ulcers.

Materials and Methods

A retrospective review of 110 patients with 180 legs having chronic venous insufficiencies associated with varicose veins treated over an 8-year period was conducted. Patients ranged from 16 to 80 years of age and included 85 women and 25 men. Of the 110 patients, 32 (29.10%) patients with 40 legs having varicose veins were defined as having complicated varicose veins associated with venous ulcers. All 32 patients received EVLP treatment using a diode laser. Complications were evaluated at 3 weeks (early), 6 weeks (late), and 6 months (final) after EVLP treatment. The primary efficacy and final outcome measurement were determined through quantitative assessment using Hach's and clinical, etiological, anatomical, and pathophysiological classification. Safety was evaluated for each treatment group by monitoring adverse effects.

Results

Early complications were swelling, local paresthesia, pigmentation, minor superficial thermal injury, superficial phlebitis, and localized hematomas. All complications and ulcerations resolved completely within 2 weeks. No recurrence occurred after the study's 6-month follow-up period. Based on paired t test analysis, clinically significant differences in severity scores were discovered, which were based on Hach's classification before and after EVLP treatment at a wavelength of 810 nm. All patients achieved improvement from clinical, etiological, anatomical, and pathophysiological class C6 to C5. Permanent adverse effects were not observed.

Conclusions

Endovenous laser photocoagulation at the wavelength of 810 nm permitted the use of appropriate light doses for treating complicated varicose veins associated with venous ulcers and resulted in significant improvement in lesions.
Foreign-Body Reaction to Bioabsorbable Plate and Screw in Craniofacial Surgery
Authors: Kamata Masafumi , Sakamoto Yoshiaki , Kishi Kazuo
Published: November 2018

Hydroxyapatite and poly-l-lactide plates are often used for maxillofacial surgery. These plates take 3 to 4 years to resorb completely, leading to the possibility of a foreign-body reaction. A 20-year-old woman who developed a foreign-body reaction to the plates was reported. Based on review of the relevant literature, foreign-body reactions have often been reported with this plate. Long-term follow-up is warranted to evaluate patients using this plate in maxillofacial surgery.
The Effects of Oxygenation on Ex Vivo Kidneys Undergoing Hypothermic Machine Perfusion
Authors: Patel Kamlesh , Smith Thomas B. , Neil Desley A.H. , Thakker Alpesh , Tsuchiya Yugo , Higgs Ellen B. , Hodges Nikolas J. , Ready Andrew R. , Nath Jay , Ludwig Christian
Published: November 2018

Background

Supplemental oxygenation of the standard hypothermic machine perfusion (HMP) circuit has the potential to invoke favorable changes in metabolism, optimizing cadaveric organs before transplantation.

Methods

Eight pairs of porcine kidneys underwent 18 hours of either oxygenated (HMP/O2) or aerated (HMP/Air) HMP in a paired donation after circulatory death model of transplantation. Circulating perfusion fluid was supplemented with the metabolic tracer universally labeled glucose.

Perfusate, end-point renal cortex, and medulla samples underwent metabolomic analysis using 1-dimension and 2-dimension nuclear magnetic resonance experiments in addition to gas chromatography-mass spectrometry. Analysis of 13C-labeled metabolic products was combined with adenosine nucleotide levels and differences in tissue architecture.

Results

Metabolomic analysis revealed significantly higher concentrations of universally labeled lactate in the cortex of HMP/Air versus HMP/O2 kidneys (0.056 mM vs 0.026 mM, P < 0.05). Conversely, newly synthesized [4,5-13C] glutamate concentrations were higher in the cortex of HMP/O2 kidneys inferring relative increases in tricarboxylic acid cycle activity versus HMP/Air kidneys (0.013 mmol/L vs 0.003 mmol/L, P < 0.05). This was associated with greater amounts of adenoside triphosphate in the cortex HMP/O2 versus HMP/Air kidneys (19.8 mmol/mg protein vs 2.8 mmol/mg protein, P < 0.05). Improved flow dynamics and favorable ultrastructural features were also observed in HMP/O2 kidneys. There were no differences in thiobarbituric acid reactive substances and reduced glutathione levels, tissue markers of oxidative stress, between groups.

Conclusions

The supplementation of perfusion fluid with high-concentration oxygen (95%) results in a greater degree of aerobic metabolism versus aeration (21%) in the nonphysiological environment of HMP, with reciprocal changes in adenoside triphosphate levels.
Racial Disparities in the Administration of ECT in Texas, 1998–2013
Authors: Dennis Paul A. , Thomas Shaun N. , Husain Mustafa M. , Dennis Nora M.
Published: November 2018

Objective

Electroconvulsive therapy (ECT) is a treatment of choice for severe depression but has been underutilized among black patients. This study investigates racial disparities in the administration of ECT in the state of Texas between 1998 and 2013 using population data.

Design

Data from the Texas Department of State Health Services were obtained corresponding to the use for all ECT conducted in nonfederal settings during the period from January 2, 1998, to August 30, 2013. The data set comprised quarterly reports generated for each patient, totaling 27,931 patient quarters. Using year-by-year intercensal population estimates for the state of Texas, ECT treatments per capita were compared among black, white, Latina/Latino, and other individuals during this time period.

Results

Significantly more white patients were treated each quarter than minority patients (P < 0.001), with Latina/Latino patients recording fewer treatment quarters than any other racial group (P < 0.005). Large discrepancies in diagnosis by race were observed. Black patients were less likely than white and Latina/Latino patients to be diagnosed with depression and 4 times as likely as white patients to carry a diagnosis of schizophrenia.

Conclusions

Concordant with previous data, large racial disparities in the administration of ECT were found in this Texas data set. Despite the limited nature of this data set, these results suggest that continued investigation is required to determine factors responsible for these disparities.
Transnasal Humidified Rapid-Insufflation Ventilatory Exchange During Electroconvulsive Therapy
Authors: Jonker Yori , Rutten Dennis J. , van Exel Eric R. , Stek Max L. , de Bruin Paul E. , Huitink Johannes M.
Published: November 2018

Background

In electroconvulsive therapy (ECT), a generalized seizure is provoked under general anesthesia. Standard airway management is done by face mask ventilation, but this is difficult during generalized seizure. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is a method to increase apnea tolerance and permit apnea oxygenation. We hypothesize that THRIVE can oxygenate the patient during ECT and that it is comfortable for patients.

Methods

In this single-center feasibility study, 13 patients with a pharmacotherapy-resistant depressive disorder underwent 20 ECT sessions with the use of THRIVE. They received general anesthesia under standard monitoring and transcutaneous carbon dioxide monitoring. Afterward, they completed a survey comparing their prior experience with face mask oxygenation.

Results

There were no desaturations during the procedure, and patient comfort showed no difference in comparison to face mask. Compared with data from earlier ECT with face mask ventilation in the same patient, THRIVE did not seem to shorten seizure duration.

Conclusions

THRIVE is a novel, safe oxygenation method during ECT.
An exceptionally preserved association of complete dinosaur skeletons reveals the oldest long-necked sauropodomorphs
Authors: Müller Rodrigo Temp , Langer Max Cardoso , Dias-da-Silva Sérgio
Published: November 2018

The rise of sauropodomorphs is still poorly understood due to the scarcity of well-preserved fossils in early Norian rocks. Here, we present an association of complete and exceptionally well-preserved dinosaur skeletons that helps fill that gap. They represent a new species, which is recovered as a member of a clade solely composed of Gondwanan Triassic taxa. The new species allows the definition of a set of anatomical changes that shaped sauropodomorph evolution along a period from 233 to 225 Ma, as recorded in the well dated Late Triassic beds of Brazil. In that time span, apart from achieving a more herbivorous diet, sauropodomorph dinosaurs increased their size in a ratio of 230% and their typical long neck was also established, becoming proportionally twice longer than those of basal taxa. Indeed, the new dinosaur is the oldest-known sauropodomorph with such an elongated neck, suggesting that the ability to feed on high vegetation was a key trait achieved along the early Norian. Finally, the clustered preservation mode of the skeletons represents the oldest evidence of gregarious behaviour among sauropodomorphs.
Is biasing offspring sex ratio adaptive? A test of Fisher's principle across multiple generations of a wild mammal in a fluctuating environment
Authors: Wishart Andrea E. , Williams Cory T. , McAdam Andrew G. , Boutin Stan , Dantzer Ben , Humphries Murray M. , Coltman David W. , Lane Jeffrey E.
Published: November 2018

Fisher's principle explains that population sex ratio in sexually reproducing organisms is maintained at 1 : 1 owing to negative frequency-dependent selection, such that individuals of the rare sex realize greater reproductive opportunity than individuals of the more common sex until equilibrium is reached. If biasing offspring sex ratio towards the rare sex is adaptive, individuals that do so should have more grandoffspring. In a wild population of North American red squirrels (Tamiasciurus hudsonicus) that experiences fluctuations in resource abundance and population density, we show that overall across 26 years, the secondary sex ratio was 1 : 1; however, stretches of years during which adult sex ratio was biased did not yield offspring sex ratios biased towards the rare sex. Females that had litters biased towards the rare sex did not have more grandoffspring. Critically, the adult sex ratio was not temporally autocorrelated across years, thus the population sex ratio experienced by parents was independent of the population sex ratio experienced by their offspring at their primiparity. Expected fitness benefits of biasing offspring sex ratio may be masked or negated by fluctuating environments across years, which limit the predictive value of the current sex ratio.
Frogs adapt to physiologically costly anthropogenic noise
Authors: Tennessen Jennifer B. , Parks Susan E. , Swierk Lindsey , Reinert Laura K. , Holden Whitney M. , Rollins-Smith Louise A. , Walsh Koranda A. , Langkilde Tracy
Published: November 2018

Human activities impose novel pressures on amphibians, which are experiencing unprecedented global declines, yet population-level responses are poorly understood. A growing body of literature has revealed that noise is an anthropogenic stressor that impacts ecological processes spanning subcellular to ecosystem levels. These consequences can impose novel selective pressures on populations, yet whether populations can adapt to noise is unknown. We tested for adaptation to traffic noise, a widespread sensory ‘pollutant’. We collected eggs of wood frogs (
Rana sylvatica
) from populations from different traffic noise regimes, reared hatchlings under the same conditions, and tested frogs for differences in sublethal fitness-relevant effects of noise. We show that prolonged noise impaired production of antimicrobial peptides associated with defence against disease. Additionally, noise and origin site interacted to impact immune and stress responses. Noise exposure altered leucocyte production and increased baseline levels of the stress-relevant glucocorticoid, corticosterone, in frogs from quiet sites, but noise-legacy populations were unaffected. These results suggest noise-legacy populations have adapted to avoid fitness-relevant physiological costs of traffic noise. These findings advance our understanding of the consequences of novel soundscapes and reveal a pathway by which anthropogenic disturbance can enable adaptation to novel environments.
Sex bias in ability to cope with cancer: Tasmanian devils and facial tumour disease
Authors: Ruiz-Aravena Manuel , Jones Menna E. , Carver Scott , Estay Sergio , Espejo Camila , Storfer Andrew , Hamede Rodrigo K.
Published: November 2018

Knowledge of the ecological dynamics between hosts and pathogens during the initial stages of disease emergence is crucial to understanding the potential for evolution of new interspecific interactions. Tasmanian devil (
Sarcophilus harrisii
) populations have declined precipitously owing to infection by a transmissible cancer (devil facial tumour disease, DFTD) that emerged approximately 20 years ago. Since the emergence of DFTD, and as the disease spreads across Tasmania, the number of devils has dropped up to 90% across 80% of the species's distributional range. As a result, the disease is expected to act as a strong selective force on hosts to develop mechanisms of tolerance and/or resistance to the infection. We assessed the ability of infected devils to cope with infection, which translates into host tolerance to the cancer, by using the reaction norm of the individual body condition by tumour burden. We found that body condition of infected hosts is negatively affected by cancer progression. Males and females presented significant differences in their tolerance levels to infection, with males suffering declines of up to 25% of their body condition, in contrast to less than 5% in females. Sex-related differences in tolerance to cancer progression may select for changes in life-history strategies of the host and could also alter the selective environment for the tumours.
DAZL is a master translational regulator of murine spermatogenesis
Authors: Li Haixin , Liang Zhuqing , Yang Jian , Wang Dan , Wang Hanben , Zhu Mengyi , Geng Baobao , Xu Eugene Yujun
Published: November 2018

Expression ofDAZ-like(DAZL) is a hallmark of vertebrate germ cells and essential for embryonic germ cell development and differentiation, yet gametogenic function ofDAZLhas not been fully characterized with most of its in vivo direct targets unknown. We showed that postnatal stage-specific deletion ofDazlin mouse germ cells did not affect female fertility, but caused complete male sterility with gradual loss of spermatogonial stem cells (SSCs), meiotic arrest and spermatid arrest respectively. Using the genome-wide HITS-CLIP and mass spectrometry approach, we found that DAZL bound to a large number of testicular mRNA transcripts (at least 3008) at 3′ UnTranslated Region (3′ UTR) and interacted with translation proteins including PABP. In the absence of DAZL, polysome-associated target transcripts, but not their total transcripts were significantly decreased, resulting in drastic reduction of an array of spermatogenic proteins and thus developmental arrest. Thus, DAZL is a master translational regulator essential for spermatogenesis.
Synthesis, SAR and Docking Studies of Substituted Aryl phenylthiazolyl phenylcarboxamide as PTP-1B Inhibitors
Authors: Varshney Kanika , Gupta Amit K. , Rawat Arun , Srivastava Rohit , Mishra Akansha , Saxena Mridula , Srivastava Arvind K. , Jain Sudha , Saxena Anil K.
Published: November 2018

Inspired by the potent PTP1B inhibitory activity reported in a novel series of substituted aryl thiazolyl phenylsulphonamides(I), sulfonyl moiety in the most active compound (I, R= OCH3, R1= CF3, 73.6% PTP1B inhibition) was replaced by benzoyl group (region B) to afford compoundIIwhich showed lesser activity (50.5% PTP1B inhibition). To optimize the activity, further structural modifications were done on compoundIIat region A, B and C to design and synthesize a series of 24 aryl phenylthiazolyl phenylcarboxamides for evaluation against PTP1B enzyme. Among these compounds six compounds showed good PTP1B inhibitory activity in the order of compound38 > 30 > 29 > 37 > 22 > 19. The lowest energy conformer of compound38at PTP1B active site shows favorable binding similar to known PTP1B binders and explains its selectivity towards PTP1B. Compound38also showed promising antihyperglycemic, antidyslipidemic and insulin resistant reversal activitiesin vivoin STZ model and db/db mice model. Altogether, the compound38present an excellent candidate for future PTP1B targeted drug discovery.
Modeling Attention Control Using A Convolutional Neural Network Designed After The Ventral Visual Pathway
Authors: Yu Chen-Ping , Liu Huidong , Samaras Dimitris , Zelinsky Gregory
Published: November 2018

Recently we proposed that people represent object categories using category-consistent features (CCFs), those features that occur both frequently and consistently across a categorys exemplars [70]. Here we designed a Convolutional Neural Network (CNN) after the primate ventral stream (VsNet) and used it to extract CCFs from 68 categories of objects spanning a three-level category hierarchy. We evaluated VsNet against people searching for the same targets from the same 68 categories. Not only did VsNet replicate our previous report of stronger attention guidance to subordinate-level targets, with its more powerful CNN-CCFs it was able to predict attention control to individual target categories–the more CNN-CCFs extracted for a category, the faster gaze was directed to the target. We also probed VsNet to determine where in its network of layers these attention control signals originate. We found that CCFs extracted from VsNet’s V1 layer contributed most to guiding attention to targets cued at the subordinate (e.g., police car) and basic (e.g., car) levels, but that guidance to superordinate-cued (e.g., vehicle) targets was strongest using CCFs from the CIT+AIT layer. We also identified the image patches eliciting the strongest filter responses from areas V4 and higher and found that they depicted representative parts of an object category (e.g., advertisements appearing on top of taxi cabs). Finally, we found that VsNet better predicted attention control than comparable CNN models, despite having fewer convolutional filters. This work shows that a brain-inspired CNN can predict goal-directed attention control by extracting and using category-consistent features.
PEDIA: Prioritization of Exome Data by Image Analysis
Authors: Hsieh Tzung-Chien , Mensah Martin Atta , Pantel Jean Tori , Peter Krawitz ,   the PEDIA consortium, Aguilar Dione , Bar Omri , Bayat Allan , Becerra-Solano Luis , Bentzen Heidi Beate , Biskup Saskia , Borisov Oleg , Braaten Oivind , Ciaccio Claudia , Coutelier Marie , Cremer Kirsten , Danyel Magdalena , Daschkey Svenja , David-Eden Hilda , Devriendt Koenraad , Dölken Sandra , Douzgou Sofia , Đukić Dejan , Ehmke Nadja , Fauth Christine , Fischer-Zirnsak Björn , Fleischer Nicole , Gabriel Heinz , Graul-Neumann Luitgard , Gripp Karen W. , Gurovich Yaron , Gusina Asya , Haddad Nechama , Hajjir Nurulhuda , Hanani Yair , Hertzberg Jakob , Konstanze Hoertnagel , Howell Janelle , Ivanovski Ivan , Kaindl Angela , Kamphans Tom , Kamphausen Susanne , Karimov Catherine , Kathom Hadil , Keryan Anna , Khalil Salma-Gamal , Knaus Alexej , Köhler Sebastian , Kornak Uwe , Lavrov Alexander , Leitheiser Maximilian , Lyon J. Gholson , Mangold Elisabeth , Marín Reina Purificación , Martinez Carrascal Antonio , Mitter Diana , Morlan Herrador Laura , Nadav Guy , Nöthen Markus , Orrico Alfredo , Ott Claus-Eric , Park Kristen , Peterlin Borut , Pölsler Laura , Raas-Rothschild Annick , Revencu Nicole , Ringmann Fagerberg Christina , Robinson Peter Nick , Rosnev Stanislav , Rudnik Sabine , Rudolf Gorazd , Schatz Ulrich , Schossig Anna , Schubach Max , Shanoon Or , Sheridan Eamonn , Smirin-Yosef Pola , Spielmann Malte , Suk Eun-Kyung , Sznajer Yves , Thiel Christian Thomas , Thiel Gundula , Verloes Alain , Vrecar Irena , Wahl Dagmar , Weber Ingrid , Winter Korina , Wiśniewska Marzena , Wollnik Bernd , Yeung Ming Wai , Zhao Max , Zhu Na , Zschocke Johannes , Mundlos Stefan , Horn Denise
Published: November 2018

Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. Here, we introduce an approach, driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features and the disease-causing mutations and simulated multiple exomes of different ethnic backgrounds. With the additional use of similarity scores from computer-assisted analysis of frontal photos, we were able to achieve a top-10-accuracy rate for the disease-causing gene of 99 %. As this performance is significantly higher than without the information from facial pattern recognition, we make gestalt scores available for prioritization via an API.
Hayai-Annotation Plants: an ultra-fast and comprehensive gene annotation system in plants
Authors: Ghelfi Andrea , Shirasawa Kenta , Hirakawa Hideki , Isobe Sachiko
Published: November 2018

Hayai-Annotation Plants is a browser-based interface for an ultra-fast and accurate gene annotation system for plant species using R. The pipeline combines the sequence-similarity searches, using USEARCH against UniProtKB (taxonomy Embryophyta), with a functional annotation step. Hayai-Annotation Plants provides five layers of annotation: 1) gene name; 2) gene ontology terms consisting of its three main domains (Biological Process, Molecular Function, and Cellular Component); 3) enzyme commission number; 4) protein existence level; 5) and evidence type. In regard to speed and accuracy, Hayai-Annotation Plants annotated Arabidopsis thaliana (Araport11, representative peptide sequences) within five minutes with an accuracy of 96.4 %.

Availability and Implementation

The software is implemented in R and runs on Macintosh and Linux systems. It is freely available at https://github.com/kdri-genomics/Hayai-Annotation-Plants under the GPLv3 license.
Fetal and trophoblast PI3Kp110α have distinct roles in regulating resource supply to the growing fetus
Authors: Lopez-Tello Jorge , Perez-Garcia Vicente , Khaira Jaspreet , Kusinski Laura C. , Cooper Wendy N. , Andreani Adam , Grant Imogen , de Liger Edurne Fernandez , Hemberger Myriam , Sandovici Ionel , Constancia Miguel , Sferruzzi-Perri Amanda N.
Published: November 2018

Previous studies suggest that the placental supply of nutrients to the fetus adapts according to fetal demand. However, the signaling events underlying placental adaptations remain largely unknown. Earlier work in mice has revealed that loss of the phosphoinositide 3-kinase p110α impairs feto-placental growth but placental nutrient supply is adaptively increased. Here we explore the role of p110α in the epiblast-derived (fetal) and trophoblast lineages of the conceptus in relation to feto-placental growth and placental development and transfer function. Using conditional gene manipulations to knock-down p110α either by ∼50% or ∼100% in the fetal lineages and/or trophoblast, this study shows that p110α in the fetus is essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110α also resulted in abnormal placental development, although fetuses were viable. However, in response to complete loss of trophoblast p110α, the placenta failed to transport sufficient amino acid to match fetal demands for growth. Using RNA-seq, we identified several genes downstream of p110α in the trophoblast that are important in adapting placental phenotype to support fetal growth. Further work using CRISPR/Cas9 genome targeting showed that loss of p110α differentially affects the expression of genes in trophoblast and embryonic stem cells. Our findings thus reveal important, but distinct roles for p110α signaling in the different compartments of the conceptus, which control fetal resource acquisition and ultimately affect healthy growth.

One Sentence Summary

Fetal and trophoblast p110α modify resource allocation
A Novel Class of Inferior Colliculus Principal Neurons Labeled in Vasoactive Intestinal Peptide-Cre Mice
Authors: Goyer David , Silveira Marina A. , George Alexander P. , Beebe Nichole L. , Edelbrock Ryan M. , Malinski Peter T. , Schofield Brett R. , Roberts Michael T.
Published: November 2018

Located in the midbrain, the inferior colliculus (IC) is the hub of the central auditory system. Although the IC plays important roles in speech processing, sound localization, and other auditory computations, the organization of the IC microcircuitry remains largely unknown. Using a multifaceted approach in mice, we have identified vasoactive intestinal peptide (VIP) neurons as a novel class of IC principal neurons. VIP neurons are glutamatergic stellate cells with sustained firing patterns. Their extensive axons project to long-range targets including the auditory thalamus, auditory brainstem, superior colliculus, and periaqueductal gray. Using optogenetic circuit mapping, we found that VIP neurons integrate input from the contralateral IC and the dorsal cochlear nucleus. The dorsal cochlear nucleus also drove feedforward inhibition to VIP neurons, indicating that inhibitory circuits within the IC shape the temporal integration of ascending inputs. Thus, VIP neurons are well-positioned to influence auditory computations in a number of brain regions.
Cholesterol-dependent enrichment of understudied erythrocytic stages of humanPlasmodiumparasites
Authors: Brown Audrey C. , Moore Christopher C. , Guler Jennifer L.
Published: November 2018

Plasmodiumprotozoan parasites undergo rounds of asexual replication inside human erythrocytes, progressing from ring stage, to trophozoites and schizonts, before egress and reinvasion. Given the discovery of ring-specific artemisinin tolerance and quiescence inPlasmodium falciparum, there is great urgency to better understand ring stage biology. However, the lack of an effective enrichment method has left rings and related parasite stages understudied compared to their late stage counterparts, which can be easily isolated due to their paramagnetic properties. Here, a method for separatingall Plasmodiuminfected erythrocytes from uninfected erythrocytes is presented. This approach takes advantage of streptolysin-O (SLO) to preferentially lyse uninfected erythrocytes as previously shown by Jackson,et al.Following lytic treatment, Percoll gradient centrifugation removes lysed cells, leaving an intact cell population enriched in infected erythrocytes. ThisSLO-Percoll (SLOPE) method is effective on stages from the entire erythrocytic cycle, including previously inaccessible forms such as circulating rings from malaria-infected patients and artemisinin-induced quiescent parasites. Furthermore, the utility of SLOPE is extended to multiple media formulations used for the propagation of two humanPlasmodiumspecies. The alteration of external cholesterol levels modulates SLOPE effectiveness, demonstrating the role of erythrocyte membrane cholesterol in lytic discrimination. Importantly, enrichment does not impact parasite viability, which establishes the non-toxic nature of SLOPE. Targeted metabolomics of SLOPE-enriched ring stage samples confirms the impact on treated samples; parasite-derived metabolites are increased and contaminating host material is reduced compared to non-enriched samples.

Importance

Malaria is caused by infection with protozoanPlasmodiumparasites and is responsible for over 400,000 deaths annually. The availability of effective antimalarial drugs is critical to the reduction of malaria-related mortality, yet widespread resistance highlights the need for the continued study ofPlasmodiumbiology. The SLOPE method is an accessible, scalable, rapid (30-40min), and non-toxic enrichment method that is broadly effective on many erythrocytic stages. This method is ideal for use upstream of a variety of sensitive analyses, which will increase experimental quality in virtually all areas of asexualPlasmodiumparasite research. Further, because the consumption of cholesterol is a common characteristic of other intracellular parasites (both bacteria and other protozoa), SLOPE holds potential for extension to other relevant pathogens.
TSD: A computational tool to study the complex structural variants using PacBio targeted sequencing data
Authors: Meng Guofeng , Tan Ying , Fan Yue , Wang Yan , Yang Guang , Fanning Gregory , Qiu Yang
Published: November 2018

The PacBio sequencing is a powerful approach to study the DNA or RNA sequences in a longer scope. It is especially useful in exploring the complex structural variants generated by random integration or multiple rearrangement of internal or external sequences. However, there is still no tool designed to uncover their structural organization in the host genome. Here, we present a tool, TSD, for complex structural variant discovery using PacBio targeted sequencing data. It allows researchers to identify and visualize the genomic structures of targeted sequences by unlimited splitting, alignment and assembly of long PacBio reads. Application to the sequencing data derived from an HBV integrated human cell line(PLC/PRF/5) indicated that TSD could recover the full profile of HBV integration events, especially for the regions with the complex human-HBV genome integrations and multiple HBV rearrangements. Compared to other long read analysis tools, TSD showed a better performance for detecting complex genomic structural variants. TSD is publicly available at: https://github.com/menggf/tsd
Pan-Cancer Repository of Validated Natural and Cryptic mRNA Splicing Mutations
Authors: Shirley Ben C. , Mucaki Eliseos J. , Rogan Peter K.
Published: November 2018

We present a major public resource of mRNA splicing mutations validated according to multiple lines of evidence of abnormal gene expression. Likely mutations present in all tumor types reported in the Cancer Genome Atlas (TCGA) were identified based on the comparative strengths of splice sites in tumor versus normal genomes and then validated by respectively comparing counts of splice junction spanning and abundance of transcript reads in RNA-Seq data from matched tissues and tumors lacking these mutations. The comprehensive resource features 351,423 of these validated mutations, the majority of which (69.1%) are not featured in the Single Nucleotide Polymorphism Database (dbSNP 150). There are 117,951 unique mutations which weaken or abolish natural splice sites, and 244,415 mutations which strengthen cryptic splice sites (10,943 affect both simultaneously). 27,803 novel or rare flagged variants (with <1% population frequency in dbSNP) were observed in multiple tumor tissue types. Single variants or chromosome ranges can be queried using a Global Alliance for Genomics and Health (GA4GH)-compliant web Beacon, Validated Splicing Mutations, either separately or in aggregate alongside other beacons through the public Beacon Network (http://www.beacon-network.org/#/search?beacon=cytognomix), as well as through our website (https://validsplicemut.cytognomix.com/).
Osteocyte death and bone overgrowth in mice lacking Fibroblast Growth Factor Receptors 1 and 2 in mature osteoblasts and osteocytes
Authors: McKenzie Jennifer , Smith Craig , Karuppaiah Kannan , Langberg Joshua , Silva Matthew J. , Ornitz David M.
Published: November 2018

Fibroblast Growth Factor (FGF) signaling pathways have well established roles in skeletal development, with essential functions in both chondrogenesis and osteogenesis. In mice, previous conditional knockout studies suggested distinct roles for FGF receptor 1 (FGFR1) signaling at different stages of osteogenesis and a role for FGFR2 in osteoblast maturation. However, the potential for redundancy among FGFRs and the mechanisms and consequences of stage-specific osteoblast lineage regulation were not addressed. Here, we conditionally inactivateFgfr1andFgfr2in mature osteoblasts with an Osteocalcin-Cre or Dentin matrix protein 1-CreER driver. We find that young mice lacking both receptors or only FGFR1 are phenotypically normal. However, after 6 weeks of age theseFgfr1/Fgfr2double- andFgfr1single-conditional knockout mice develop a high bone mass phenotype with increased periosteal apposition, increased endocortical woven bone with increased porosity, and biomechanical properties that reflect increased bone mass but impaired material properties. Histopathological and gene expression analyses show that this phenotype is preceded by a striking loss of osteocytes, and gradual activation of the Wnt/βCatenin signaling pathway. These data identify a role for FGFR1 signaling in mature osteoblasts/osteocytes that is required for osteocyte survival during postnatal bone growth.
Elucidating the H+coupled Zn2+transport mechanism of ZIP4; implications inAcrodermatitis Enteropathica
Authors: Hoch Eitan , Sekler Israel
Published: November 2018

Cellular Zn2+homeostasis is tightly regulated and primarily mediated by designated Zn2+transport proteins, namely ZnTs (SLC30) that shuttle Zn2+efflux, and ZIPs (SLC39) that mediate Zn2+influx. While the functional determinants of ZnT-mediated Zn2+efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3−or (II) H+coupled Zn2+transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3−failed to induce Zn2+influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+uptake. Furthermore, Zn2+uptake was coupled to enhanced H+influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+powered Zn2+co-transporter. We further illustrate how this functional mechanism is affected by genetic variants inSLC39A4that in turn lead toAcrodermatitis Enteropathica, a rare condition of Zn2+deficiency.
Application of UV-cured resin as embedding/mounting media for practical, time-saving otolith specimen preparation
Authors: Strüssmann Carlos Augusto , Miyoshi Kaho , Mitsui Shota
Published: November 2018

Otoliths are calcified structures located in the inner ears of fish, as in most vertebrates, that are responsible primarily for the perception of gravity, balance and movement, and secondarily of sound detection. Microstructural and chemical analyzes of the inner otolith growth layers, called increments, constitute powerful tools to estimate fish age and elucidate many life history and demographic traits of fish populations. Otolith analyzes often require the production of a thin cross section that includes in the same plane of view the otolith core and all microscopic layers formed from birth until the moment of collection (otolith edge). Here we report on the usefulness of UV-cured resins that have become recently popular among nail artists and hobbyists for otolith specimen preparation. We show that single-component UV-cured resins can replace successfully and advantageously the commonly used two-component Epoxy resins to obtain otolith cross sections suitable for both microstructural examination and chemical analysis by electron probe microanalysis. UV-cured resins provide on-demand, extremely rapid (minute-order) hardening and high transparency, while providing similar adhesion and mechanical support for the otoliths during processing and analysis as Epoxy resins. UV-cured resins may revolutionize otolith specimen preparation practically- and time-wise, and may be particularly useful in teaching and workshop situations in which time for otolith embedding is a constraint.
Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis
Authors: Ashouri Judith F. , Hsu Lih-Yun , Yu Steven , Rychkov Dmitry , Chen Yiling , Cheng Debra A. , Sirota Marina , Hansen Erik , Lattanza Lisa , Zikherman Julie , Weiss Arthur
Published: November 2018

How pathogenic CD4 T cells in Rheumatoid Arthritis (RA) develop remains poorly understood. We used Nur77—a marker of T cell antigen receptor (TCR) signaling—to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into IL-17 producing cells. The T cells with increased autoreactivity, nonetheless had diminishedex vivoinducible TCR signaling, perhaps reflective of adaptive inhibitory mechanisms induced by chronic auto-antigen exposurein vivo. The enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery, which might in part be attributable to a reduced amount of expression of suppressor of cytokine signaling 3 (SOCS3)—a key negative regulator of IL-6 signaling. As a result, the more autoreactive GFPhiCD4 T cells from SKGNur mice were hyper-responsive to IL-6 receptor signaling. Consistent with findings from SKGNur mice,SOCS3expression was similarly downregulated in RA synovium. This suggests that, despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6 which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA.

Significance Statement

How arthritis-causing T cells trigger rheumatoid arthritis (RA) is not understood since it is difficult to differentiate T cells activated by inflammation in arthritic joints from those activated through their TCR by self-antigens. We developed a model to identify and study antigen-specific T cell responses in arthritis. Nur77—a specific marker of TCR signaling—was used to identify antigen-activated CD4 T cells in the SKG arthritis model and patients with RA. Nur77 could distinguish highly arthritogenic and autoreactive T cells in SKG mice. The enhanced autoreactivity was associated with increased IL-6-receptor-signaling, likely contributing to their arthritogenicity. These data highlight a functional correlate between Nur77 expression, arthritogenic T cell populations, and heightened IL-6 sensitivity in SKG mice with translatable implications for human RA.