bluuebunny/crossref_metadata_2025 huggingface dataset:
Malignant granular cell tumor: Clinical features and long‐term survival
Authors: Moten Ambria S. , Zhao Huaqing , Wu Hong , Farma Jeffrey M.
Published: September 2018

Background

Malignant granular cell tumor GCT (mGCT) has not been well described. We sought to investigate associations between tumor characteristics, treatments and survival.

Methods

Patients diagnosed with mGCT years 1995‐2014 were identified using the Surveillance, Epidemiology and End Results database. Descriptive statistics regarding tumor and treatment characteristics were calculated. Chi‐square tests determined associations between tumor location and features. Survival analyses included Kaplan‐Meier functions and Cox proportional hazard ratios (HR).

Results

Of 113 patients included, median age was 54 years and 77.0% were female. Frequent tumor sites included soft tissues (36.3%), ovary/testis (16.8%), and skin (11.5%). Median tumor size was 4.0 cm. Metastases to regional lymph nodes (12.5%) and distant sites (11.4%) occurred. Treatments included surgery (85.0%), radiotherapy (12.4%) and chemotherapy (8.9%). Overall five and 10‐year cause‐specific survival was 74.3% and 65.2%, respectively. Survival was worse for patients with tumors >5 cm compared to those with tumors ≤5 cm (HR = 34.03; 95% confidence interval [CI]: 2.57‐450.17), and patients with metastasis (HR = 15.25; 95% CI: 1.19‐195.72) compared with those without metastasis. Patients who underwent surgery had superior survival than those who did not (HR = 0.13; 95% CI: 0.05‐0.34).

Conclusions

Particular tumor features and treatments are associated with superior survival. This information may be used to more accurately estimate prognosis.
Assessing tools for management of noncolorectal nonneuroendocrine liver metastases: External validation of a prognostic model
Authors: Tsang Melanie E. , Mahar Alyson L. , Martel Guillaume , Cleary Sean P. , Nanji Sulaiman , Ouellet Jean‐François , Hernandez‐Alejandro Roberto , Wei Alice C. , Hallet Julie ,   Members of the Canadian Noncolorectal Nonneuroendocrine Liver Metastases Study Group
Published: September 2018

Introduction

Selection criteria and benefits for resection of noncolorectal, nonneuroendocrine liver metastases (NCNNELM) remain debated. A prognostic score was developed by the Association Française de Chirurgie (AFC) for patient selection, but not validated. We performed a geographic external validation of this score.

Methods

Patients with resected NCNNELM from six institutions (2000–2014) were assigned risk groups based on the AFC score. Discrimination was evaluated by visually inspecting separation of overall survival (OS) curves among risk categories. The slope of the continuous score on OS and hazard ratios for risk categories were examined.

Results

Of 165 patients, 53 (32.1%) were low‐risk, 85 (51.5%) intermediate‐risk, and 27 (16.4%) high‐risk. The OS curves did not separate among risk groups: 5‐year OS were 60.1% (low), 57.1% (intermediate), and 55.6% (high). The parameter estimate (0.02) indicated lower discrimination than in the AFC cohort. Hazard ratios of 1.05 (0.63 to 1.70) for low vs intermediate, 0.87 (0.46 to 1.64) for low vs high, and 0.83 (0.46 to 1.49) for intermediate vs. high, demonstrated lack of discrimination in OS among risk groups.

Conclusion

While long‐term survival is achievable, discrimination of the AFC score is not maintained in a geographic external cohort of resected NCNNELM. It is not generalizable to this external population.
Shake No Bake: A Homemade Ultrasound Gel Recipe for Low‐Resource Settings
Authors: Cherukuri Anjuli R. , Lane Lucy , Guy Dave , Perusse Karina , Keating David P. , DeStigter Kristen K.
Published: September 2018

Commercially produced ultrasound coupling gel is often a scarce resource in rural regions of low‐income countries that use sonography as their main imaging modality and, when available, may be cost prohibitive. Various homemade gels were created and tested to assure image quality was not compromised. Glucomannan‐based gel and guar gum–based gel had superior physical properties in initial testing and showed no substantial difference compared with commercially available ultrasound gel on subject and phantom imaging and analysis (P > .05 using a 1‐tailed sign test). Neither gel required heating, attracted insects, damaged ultrasound transducers, stained samples of clothing, or had harmful effects to subjects.
How do genetically disabled adults view selective reproduction? Impairment, identity, and genetic screening
Authors: Boardman Felicity K , Hale Rachel
Published: September 2018

Background

Genomic medicine is rapidly evolving, particularly in the domain of reproduction. Population carrier screening for a range of disorders is becoming possible using whole genome/exome sequencing. However, very little is known about the views of genetically disabled adults toward selective reproduction.

Methods

Forty‐three in‐depth qualitative interviews were carried out with adults living with different types of genetic condition, recruited through support groups and clinics. Interviews covered participants’ experiences of their condition and their views toward genetic intervention in reproduction. Thematic analysis of the data using NVivo 11 was undertaken, and participants were assigned categories as either supporting, not‐supporting, or having ambivalent views toward selective reproduction.

Results

The majority of participants (65%) expressed either disapproval of, or held ambivalent views toward, selective reproduction. Key reasons for non‐support included regarding genetic impairment as part of personal identity and the prioritization of social and environmental barrier removal. Key reasons for support of selective reproduction included negative and externalizing attitudes toward genetic impairment and a belief in the importance of informed reproductive decision‐making.

Conclusion

The degree to which participants identified with their impairment, more so than how they valued it, was significant in determining attitudes toward selective reproduction. Those who supported genetic screening viewed their impairment as separate to themselves, while participants who considered their impairment as integral to their identity were most likely to report ambivalent or negative attitudes. Policymakers and stakeholders considering the role of genetic carrier screening panels might usefully engage with adults affected by heritable disease as well as disability identity politics when considering the acceptability and social impact of genetic screening programs.
Screening of known disease genes in congenital scoliosis
Authors: Takeda Kazuki , Kou Ikuyo , Mizumoto Shuji , Yamada Shuhei , Kawakami Noriaki , Nakajima Masahiro , Otomo Nao , Ogura Yoji , Miyake Noriko , Matsumoto Naomichi , Kotani Toshiaki , Sudo Hideki , Yonezawa Ikuho , Uno Koki , Taneichi Hiroshi , Watanabe Kei , Shigematsu Hideki , Sugawara Ryo , Taniguchi Yuki , Minami Shohei , Nakamura Masaya , Matsumoto Morio ,   Japan Early Onset Scoliosis Research Group, Watanabe Kota , Ikegawa Shiro
Published: September 2018

Background

Congenital scoliosis (CS) is defined as a lateral curvature of the spine due to the vertebral malformations and has an incidence of 0.5–1/1,000 births. We previously examined TBX6 in Japanese CS patients and revealed that approximately 10% of CS was caused by TBX6 mutations. However, the genetic cause of remaining CS is unknown.

Methods

We recruited 78 CS patients without TBX6 mutations and major comorbidities, and investigated the genes previously reported to be associated with CS and congenital vertebral malformations by whole‐exome sequencing.

Results

We identified the compound heterozygous missense variants in LFNG in one patient. No likely disease‐causing variants were identified in other patients, however. LFNG encodes a GlcNAc‐transferase. The LFNG variants showed loss of their enzyme function.

Conclusions

A LFNG mutation is reported in a case of spondylocostal dysostosis (SCD), a skeletal dysplasia with severe malformations of vertebra and rib. The CS patient with LFNG mutations had multiple vertebral malformations including hemivertebrae, butterfly vertebrae, and block vertebrae, and rib malformations. LFNG mutations may cause a spectrum of phenotypes including CS and SCD. The current list of known disease genes could explain only a small fraction of genetic cause of CS.
Predicting the Onset of Nonlinear Pharmacokinetics
Authors: Stein Andrew M. , Peletier Lambertus A.
Published: September 2018

When analyzing the pharmacokinetics (PK) of drugs, one is often faced with concentration C vs. time curves, which display a sharp transition at a critical concentration Ccrit. For C > Ccrit, the curve displays linear clearance and for C < Ccrit clearance increases in a nonlinear manner as C decreases. Often, it is important to choose a high enough dose such that PK remains linear in order to help ensure that continuous target engagement is achieved throughout the duration of therapy. In this article, we derive a simple expression for Ccrit for models involving linear and nonlinear (saturable) clearance, such as Michaelis‐Menten and target‐mediated drug disposition (TMDD) models.

Study Highlights
Design and field testing of a rover with an actively articulated suspension system in a Mars analog terrain
Authors: Cordes Florian , Kirchner Frank , Babu Ajish
Published: September 2018

This study presents the electromechanical design, the control approach, and the results of a field test campaign with the hybrid wheeled‐leg rover SherpaTT. The rover ranges in the 150 kg class and features an actively articulated suspension system comprising four legs with actively driven and steered wheels at each leg’s end. Five active degrees of freedom are present in each of the legs, resulting in 20 active degrees of freedom for the complete locomotion system. The control approach is based on force measurements at each wheel mounting point and roll–pitch measurements of the rover’s main body, allowing active adaption to sloping terrain, active shifting of the center of gravity within the rover’s support polygon, active roll–pitch influencing, and body‐ground clearance control. Exteroceptive sensors such as camera or laser range finder are not required for ground adaption. A purely reactive approach is used, rendering a planning algorithm for stability control or force distribution unnecessary and thus simplifying the control efforts. The control approach was tested within a 4‐week field deployment in the desert of Utah. The results presented in this paper substantiate the feasibility of the chosen approach: The main power requirement for locomotion is from the drive system, active adaption only plays a minor role in power consumption. Active force distribution between the wheels is successful in different footprints and terrain types and is not influenced by controlling the body’s roll–pitch angle in parallel to the force control. Slope‐climbing capabilities of the system were successfully tested in slopes of up to 28° inclination, covered with loose soil and duricrust. The main contribution of this study is the experimental validation of the actively articulated suspension of SherpaTT in conjunction with a reactive control approach. Consequently, hardware and software design as well as experimentation are part of this study.
Registration of three‐dimensional scanning LiDAR sensors: An evaluation of model‐based and model‐free methods
Authors: D’Adamo Timothy Andrew , Phillips Tyson Govan , McAree Peter Ross
Published: September 2018

Registration, also know as extrinsic calibration, is the process of determining the position and orientation of a sensor relative to a known frame of reference. For ranging sensors such as light detection and ranging (LiDAR) used in field robotic applications, the quality of the registration determines the utility of the range measurements. This paper makes two contributions. The first is the introduction of a new method, termed maximum sum of evidence (MSoE) for registering three‐dimensional LiDAR sensors to moving platforms. This method is shown to produce more accurate registration solutions than two leading methods for these sensors, the adaptive structure registration filter (ASRF) and Rényi quadratic entropy (RQE). The second contribution of the paper is to study the accuracy of the MSoE registration against these two other approaches. One of these, like the MSoE, requires a truth model of the environment. The other, a model‐free method, seeks the registration that minimizes the RQE of a compound point cloud. The main finding of this investigation is that while the model‐based methods prove more accurate than the model‐free approach, the results of all three methods are fit for their intended field robotic applications. This leads us to conclude that registration based on RQE is preferable in many, if not all, field robotic applications for reasons of convenience, since a truth model of the environment is not required.
CCGD-ESCC: A Comprehensive Database for Genetic Variants Associated with Esophageal Squamous Cell Carcinoma in Chinese Population
Authors: Peng Linna , Cheng Sijin , Lin Yuan , Cui Qionghua , Luo Yingying , Chu Jiahui , Shao Mingming , Fan Wenyi , Chen Yamei , Lin Ai , Xi Yiyi , Sun Yanxia , Zhang Lei , Zhang Chao , Tan Wen , Gao Ge , Wu Chen , Lin Dongxin
Published: September 2018

Esophageal squamous-cell carcinoma (ESCC) is one of the most lethal malignancies in the world and occurs at particularly higher frequency in China. While several genome-wide association studies (GWAS) of germline variants and whole-genome or whole-exome sequencing studies of somatic mutations in ESCC have been published, there is no comprehensive database publically available for this cancer. Here, we developed the Chinese Cancer Genomic Database-Esophageal Squamous Cell Carcinoma (CCGD-ESCC) database, which contains the associations of 69,593 single nucleotide polymorphisms (SNPs) with ESCC risk in 2022 cases and 2039 controls, survival time of 1006 ESCC patients (survival GWAS) and gene expression (expression quantitative trait loci, eQTL) in 94 ESCC patients. Moreover, this database also provides the associations between 8833 somatic mutations and survival time in 675 ESCC patients. Our user-friendly database is a resource useful for biologists and oncologists not only in identifying the associations of genetic variants or somatic mutations with the development and progression of ESCC but also in studying the underlying mechanisms for tumorigenesis of the cancer. CCGD-ESCC is freely accessible at http://db.cbi.pku.edu.cn/ccgd/ESCCdb.
Dust spectrum and polarisation at 850 μm in the massive IRDC G035.39-00.33
Authors: Juvela Mika , Guillet Vincent , Liu Tie , Ristorcelli Isabelle , Pelkonen Veli-Matti , Alina Dana , Bronfman Leonardo , Eden David J. , Kim Kee Tae , Koch Patrick M. , Kwon Woojin , Lee Chang Won , Malinen Johanna , Micelotta Elisabetta , Montillaud Julien , Rawlings Mark G. , Sanhueza Patricio , Soam Archana , Traficante Alessio , Ysard Nathalie , Zhang Chuan-Peng
Published: September 2018

Context. The sub-millimetre polarisation of dust emission from star-forming clouds carries information on grain properties and on the effects that magnetic fields have on cloud evolution.

Aims. Using observations of a dense filamentary cloud G035.39-00.33, we aim to characterise the dust emission properties and the variations of the polarisation fraction.

Methods. JCMT SCUBA-2/POL-2 observations at 850 μm were combined with Planck 850 μm(353 GHz) data to map polarisation fraction at small and large scales. With previous total intensity SCUBA-2 observations (450 and 850 μm) and Herschel data, the column densities were determined via modified black-body fits and via radiative transfer modelling. Models were constructed to examine how the observed polarisation angles and fractions depend on potential magnetic field geometries and grain alignment processes.

Results. POL-2 data show clear changes in the magnetic field orientation. These are not in contradiction with the uniform orientation and almost constant polarisation fraction seen by Planck, because of the difference in the beam sizes and the POL-2 data being affected by spatial filtering. The filament has a peak column density of N(H2) ~ 7 × 1022 cm−2, a minimum dust temperature of T ~ 12 K, and a mass of ~4300 M⊙ for the area N(H2) > 5 × 1021 cm−2. The estimated average value of the dust opacity spectral index is β ~ 1.9. The ratio of sub-millimetre and J-band optical depths is τ (250 μm)∕τ (J) ~ 2.5 × 10−3, more than four times the typical values for diffuse medium. The polarisation fraction decreases as a function of column density to p ~ 1% in the central filament. Because of noise, the observed decrease of p(N) is significant only at N(H2) > 2 × 1022 cm−2. The observations suggest that the grain alignment is not constant. Although the data can be explained with a complete loss of alignment at densities above ~104 cm−3 or using the predictions of radiative torques alignment, the uncertainty of the field geometry and the spatial filtering of the SCUBA-2 data prevent strong conclusions.

Conclusions. The G035.39-00.33 filament shows strong signs of dust evolution and the low polarisation fraction is suggestive of a loss of polarised emission from its densest parts.
Road mortality of the eastern long-necked turtle (Chelodina longicollis) along the Murray River, Australia: an assessment using citizen science
Authors: Santori Claudia , Spencer Ricky-John , Van Dyke James U. , Thompson Michael B.
Published: September 2018

Turtles face a variety of threats (e.g. habitat destruction, introduced predators) that are pushing many species towards extinction. Vehicle collisions are one of the main causes of mortality of adult freshwater turtles. To conceptualise the level of threat that roads pose to Australians turtles, we analysed data gathered through the citizen science project TurtleSAT along the Murray River. We recorded 124 occurrences of turtle road mortality, which included all three local species (Chelodina expansa, Chelodina longicollis, and Emydura macquarii). Chelodina longicollis was the most commonly reported species killed on roads. We found that rain and time of year affect the likelihood of C. longicollis being killed on roads: increased turtle mortality is associated with rain events and is highest during the month of November, which coincides with their nesting season. Chelodina longicollis was most likely to be killed on the Hume Highway and roads around major urban centres; therefore, we recommend that governing bodies focus management practices and increase awareness at these locations. The degree of road mortality that we detected in this study requires mitigation, as it may contribute to the decline of C. longicollis along the Murray River.
Day-to-Day Home Blood Pressure Variability and Orthostatic Hypotension: The Nagahama Study
Authors: Tabara Yasuharu , Matsumoto Takeshi , Murase Kimihiko , Setoh Kazuya , Kawaguchi Takahisa , Nagashima Shunsuke , Kosugi Shinji , Nakayama Takeo , Wakamura Tomoko , Hirai Toyohiro , Chin Kazuo , Matsuda Fumihiko ,   Nagahama study group
Published: September 2018

BACKGROUND

The aim of this study is to clarify associations between orthostatic blood pressure (BP) change, as well as possible physiological factors, and day-to-day home BP variability, a promising risk factor for cardiovascular outcomes.

METHODS

Study participants were 6,465 community residents (age 58.3 years). Home BP was measured every morning and evening for 7 days. Orthostatic BP was calculated as the maximum difference between BP measured while sitting and remeasured after 1 and 3 minutes standing.

RESULTS

Frequency of individuals who showed orthostatic BP decline was as follows: systolic BP (SBP) change ≥−20 mm Hg: 2.6%, ≥−10 mm Hg: 14.1%. These subgroups showed larger home SBP variability (average real variability: 11.3 ± 5.3, 8.7 ± 3.9 mm Hg) when compared with orthostatic normotensives (7.6 ± 3.7 mm Hg) (all P < 0.001). Multiple linear regression analysis adjusted for major covariates, including seated BP, identified orthostatic BP drop as an independent determinant for morning BP variability (≥−20 mm Hg: β = 0.037, P = 0.003; ≥−10 mm Hg: β = 0.026, P = 0.036) but not for evening BP variability. Carotid hypertrophy was significantly associated with home BP variability (morning: β = 0.052, P = 0.001; evening: β = 0.065, P < 0.001) and showed a U-shaped association with orthostatic BP change. Plasma B-type natriuretic peptide level, a previously suggested factor for BP variability, did not show significant association with morning and evening BP variability.

CONCLUSION

Orthostatic BP decline was significantly associated with morning BP variability. Large artery atherosclerosis was a common risk factor.
The promise, problems and pitfalls of mass drug administration for malaria elimination: a qualitative study with scientists and policymakers
Authors: Kaehler Nils , Adhikari Bipin , Cheah Phaik Yeong , Day Nicholas P J , Paris Daniel H , Tanner Marcel , Pell Christopher
Published: September 2018

Background

The emergence of artemisinin resistance in the Greater Mekong Subregion (GMS) has prompted urgent containment measures. One possible approach is mass drug administration (MDA). This article explores attitudes towards and perceptions of MDA for malaria elimination among policymakers and leading malariologists.

Methods

Thirty-two semistructured interviews (SSI) were conducted with policymakers (n=17) and principal investigators (n=15) selected based on their involvement in malaria prevention, control and elimination in the GMS. Interviews were audio recorded and transcribed for qualitative content (thematic) analysis using NVivo (QSR International, Doncaster, Victoria, Australia).

Results

Researchers and policymakers described reluctance and consequently delays to pilot MDA for malaria elimination. Most policymakers and some researchers reported concerns around the evidence base, citing a lack of data on its effectiveness and appropriate target populations. There were also worries about promoting resistance. Other issues included a previous lack of support from the World Health Organization, past MDAs, the remoteness of target populations and challenges explaining the rationale for MDA.

Conclusions

The complex rationale for MDA for malaria elimination, mistaking pilot studies for implementation, past experiences with MDA, difficulties in selecting appropriate sites and the WHO’s lack of clear backing undermined the support for MDA for malaria elimination.
Assessment of eHealth behaviors in national surveys: a systematic review of instruments
Authors: Hong Y Alicia , Cho Jinmyoung
Published: September 2018

Objectives

To conduct a systematic review of instruments used in national surveys of eHealth behaviors.

Materials and Methods

Major databases and websites of federal agencies were searched with pre-determined inclusion and exclusion criteria. National surveys with measures of eHealth behaviors were identified. The survey instruments were retrieved, and their measures of eHealth behaviors were categorized and critiqued.

Results

We located 13 national surveys containing eHealth behavior assessment questions that were administered from 1999 to 2017. Most surveys were conducted annually or biennially and typically covered topics on searching health information, obtaining social support, communicating with healthcare providers, and buying medicine online; recent surveys included items related to personal health management and use of mobile tools. There were redundant measures of searching health information online but insufficient measures of use of mobile apps, social media, and wearable devices.

Discussion

Future assessment of eHealth behaviors should reflect the growing varieties of behaviors enabled by technology development and reflect the current mobile ownership patterns in diverse social groups. More studies also need to include longitudinal surveys, integrative and standardized measures, and better designs to allow data linkage and comparison.

Conclusion

The existing survey instruments covering eHealth behaviors are rather limited compared to fast technological progress. We call for more national surveys on eHealth behaviors that are more responsive to technology development; we also advocate for more analysis and dissemination of existing national data on eHealth behaviors for evidence-based health policies.
Potential application of phage therapy for prophylactic treatment against Pseudomonasaeruginosabiofilm Infections
Authors: Gurkar Aditi , Balasubramanian Deepak , Manur Jayasheela , Mathee Kalai
Published: September 2018

The majority of the microbial activity in humans is in the form of biofilms, i.e., an exopolysaccharide-enclosed bacterial mass. Unlike planktonic cells and the cells on the surface of the biofilm, the biofilm-embedded cells are more resistant to the effects of the antibiotics and the host cellular defense mechanisms. A combination of biofilm growth and inherent resistance prevents effective antibiotic treatment ofPseudomonas aeruginosainfections including those in patients with cystic fibrosis. Antibiotic resistance has led to an increasing interest in alternative modalities of treatment. Thus, phages that multiplyin situand in the presence of susceptible hosts can be used as natural, self-limiting, and profoundly penetrating antibacterial agents. The objective of this study is to identify active phages against a collection ofP. aeruginosaisolates (PCOR strains) including the prototype PAO1 and the isogenic constitutively alginate-producing PDO300 strains. These PCOR strains were tested against six phages (P105, P134, P140, P168, P175B, and P182). The analysis shows 69 % of the PCOR isolates are sensitive and the rest are resistant to all six phages. These phages were then tested for their ability to inhibit biofilm formation using a modified biofilm assay. The analysis demonstrated that the sensitive strains showed increased resistance, but none of the susceptible strains from the initial screening were resistant. Using the minimum biofilm eradication concentration (MBEC) assay for biofilm formation, the biofilm eradication ability of the phages was tested. The data showed that a higher volume of phage was required to eradicate preformed biofilms than the amount required to prevent colonization of planktonic cells. This data supports the idea of phage therapy more as a prophylactic treatment.
A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes
Authors: Gershlick David C. , Ishida Morié , Jones Julie R. , Bellomo Allison , Bonifacino Juan S. , Everman David B.
Published: September 2018

GARP and EARP are related heterotetrameric protein complexes that associate with the cytosolic face of thetrans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a six-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino-acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully-assembled GARP and EARP complexes. Likely because of this deficiency, the patient’s fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient’s fibroblasts exhibit swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of GARP/EARP function in cellular and organismal physiology.
HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy
Authors: Sazonovs Aleksejs , Kennedy Nick , Moutsianas Loukas , Heap Graham A. , Rice Daniel L. , Reppell Mark , Bewshea Claire , Walker Gareth , Perry Mandy H. , McDonald Timothy J. , Lees Charlie , Cummings Fraser , Parkes Miles , Mansfield John , Barrett Jeffrey C. , McGovern Dermot , Goodhand James , Anderson Carl A. , Ahmad Tariq ,   PANTS consortium
Published: September 2018

Background

Anti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.

Methods

The PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.

Findings

The Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).

Interpretation

HLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.
Limited significance of the in situ proximity ligation assay
Authors: Alsemarz Azam , Lasko Paul , Fagotto François
Published: September 2018

In situ proximity ligation assay (isPLA) is an increasingly popular technique that aims at detecting the close proximity of two molecules in fixed samples using two primary antibodies. The maximal distance between the antibodies required for producing a signal is 40 nm, which is lower than optical resolution and approaches the macromolecular scale. Therefore, isPLA may provide refined positional information, and is commonly used as supporting evidence for direct or indirect protein-protein interaction. However, we show here that this method is inherently prone to false interpretations, yielding positive and seemingly ‘specific’ signals even for totally unrelated antigens. We discuss the difficulty to produce adequate specificity controls. We conclude that isPLA data should be considered with extreme caution.
Left mid-ventral temporal cortex interacts with early visual cortex and the anterior temporal lobe to support word individuation
Authors: Boring Matthew J. , Hirshorn Elizabeth A. , Li Yuanning , Ward Michael J. , Mark Richardson R. , Fiez Julie A. , Ghuman Avniel Singh
Published: September 2018

The left mid-ventral temporal cortex (lmVTC) plays a dynamic role in reading. In this study we investigated the neural interactions that influence lmVTC dynamics and the lexical information these interactions are dependent on. We monitored activity with either intracranial electroencephalography or magnetoencephalography while participants viewed real words, pseudowords, consonant strings, and false fonts. A coarse level representation in early lmVTC activity allowed for decoding of visually dissimilar real words, pseudowords, and false fonts. Functional interactions between anterior ventral temporal regions, possibly containing stored knowledge about words, and low-order visual regions occurred after this initial stage of processing and was followed by the individuation of orthographically similar real words in lmVTC, but not similar pseudowords, letter strings, or false fonts. These results suggest that the individuation of real word representations in lmVTC is catalyzed by stored knowledge about word forms that emerges from network-level interactions with anterior regions of the temporal lobe.
Hydrodynamics of the frontal strike in aquatic snakes: drag, added mass and the possible consequences for prey capture success
Authors: Segall Marion , Herrel Anthony , Godoy-Diana Ramiro
Published: September 2018

Natural selection favors organisms that are the most successful in fitness-related behaviors such as foraging. Secondary adaptations pose the problem of re-adapting an already ‘optimized’ phenotype to new constraints. When animals forage underwater, they face strong physical constraints, particularly when capturing prey. Successful prey capture requires a predator to be fast and to generate a high acceleration. This involves two main constraints due to the surrounding fluid: drag and added mass. Both constraints are related to the shape of the animal. We experimentally explore the relationship between shape and performance in the context of an aquatic snake strike. As a model, we use two different 3D- printed snake heads representing typical shapes of aquatically-foraging and non-aquatically- foraging snakes, and frontal strike kinematics based on in vivo observations. By using direct force measurements, we compare the drag and added mass faced by the aquatic and non- aquatic snake models during a strike. Our results show that both drag and added mass are optimized in aquatic snakes. Using flow field measurements with particle image velocimetry, we examine the fluid dynamical mechanisms that could be behind the reduction of hydrodynamic constraints observed for the aquatic snake head shape, which makes it well suited to capture prey under water.

Summary statement

The present work explores the functional implications of head shape 15 in a group of aquatic predators using a fluid mechanics approach.
Male-Specific Protein Disulphide Isomerase Function is Essential forPlasmodiumFertilization and Transmission
Authors: Angrisano Fiona , Sala Katarzyna A. , Tapanelli Sofia , Christophides George K. , Blagborough Andrew M.
Published: September 2018

Inhibiting transmission ofPlasmodiumis an essential strategy in malaria eradication, and the biological process of gamete fusion during fertilization is a proven target for this approach. The lack of knowledge of the mechanisms underlying fertilization have been a hindrance in the development of transmission-blocking interventions. Here we describe a protein disulphide isomerase essential for malarial transmission (PDI-Trans/PBANKA_0820300) to the mosquito. We show thatPDI-Transactivity is male-specific, surface expressed, essential for fertilization/transmission, and exhibits disulphide isomerase activity which is up-regulated post-gamete activation. We demonstrate thatPDI-Transis a viable anti-malarial drug and vaccine target blocking malarial transmission with the use of the PDI inhibitor bacitracin (98.21%/92.48% reduction in intensity/prevalence), and anti-PDI-Transpeptide antibodies (66.22%/33.16% reduction in intensity/prevalence). To our knowledge, these results provide the first primary evidence that protein disulphide isomerase function is essential for malarial transmission, and emphasize the potential of anti-PDI agents to act as anti-malarials, facilitating the future development of novel transmission-blocking compounds or vaccines.
Evolution of the highly repetitive PEVK region of titin across mammals
Authors: Muenzen Kathleen , Monroy Jenna , Finseth Findley R.
Published: September 2018

The protein titin plays a key role in vertebrate muscle where it acts like a giant molecular spring. Despite its importance and conservation over vertebrate evolution, a lack of high quality annotations in non-model species makes comparative evolutionary studies of titin challenging. The PEVK region of titin—named for its high proportion of Pro-Glu-Val-Lys amino acids—is particularly difficult to annotate due to its abundance of alternatively spliced isoforms and short, highly repetitive exons. To understand PEVK evolution across mammals, we first developed a bioinformatics tool, PEVK_Finder, to annotate PEVK exons from genomic sequences of titin and then applied it to a diverse set of mammals. PEVK_Finder consistently outperforms standard annotation tools across a broad range of conditions and improves annotations of the PEVK region in non-model mammalian species. We find that the PEVK region can be divided into two subregions (PEVK-N, PEVK-C) with distinct patterns of evolutionary constraint and divergence. The bipartite nature of the PEVK region has implications for titin diversification. In the PEVK-N region, certain exons are conserved and may be essential, but natural selection also acts on particular codons. This region is also rich in glutamate and may contribute to actin binding. In the PEVK-C, exons are more homogenous and length variation of the PEVK region may provide the raw material for evolutionary adaptation in titin function. Taken together, we find that the very complexity that makes titin a challenge for annotation tools may also promote evolutionary adaptation.
Music Reveals Medial Prefrontal Cortex Sensitive Period in Childhood
Authors: Gabard-Durnam Laurel J. , Hensch Takao K. , Tottenham Nim
Published: September 2018

An outstanding issue in our understanding of human brain development is whether sensitive periods exist for higher-order processes (e.g., emotion regulation) that depend on the prefrontal cortex. Evidence from rodent models suggests that there is a sensitive period before puberty when acoustic stimuli, like music, shape medial prefrontal cortex (mPFC) responses that regulate affect in the context of acute stress in adulthood. The present study examined whether a homologous sensitive period for the mPFC occurs during human childhood. In the context of acute stress, adult behavioral preferences were observed only for music experienced during childhood, not preschool or adolescent periods. Childhood music increased mPFC activation and modulated connectivity with the amygdala, which was associated with enhanced emotion regulation and lowered autonomic arousal. Moreover, the timing of this sensitive period could be moved by early-life stress. These findings indicate that childhood is a sensitive period for mPFC encoding of regulatory stimuli.

Sensitive periods are developmental moments of heightened neuroplasticity when experiences shape brain function and behavior with lasting effects (1). They are fundamental to human cortical ontogeny, and yet, the timing and nature of sensitive periods for human prefrontal cortex functions remain unknown (2–8). In the rodent, Yang and colleagues have shown that the medial prefrontal cortex (mPFC) exhibits a sensitive period during the prepubertal juvenile period, with heightened responsivity to complex auditory stimuli (i.e., music) (9). Specifically, initial exposure to music during the open (juvenile) sensitive period or a pharmacologically re-opened sensitive period in adulthood was followed by that music uniquely producing a behavioral preference in adulthood, increasing mPFC activity, and reducing anxiety-like behavior. This finding and others converging on the same prepubertal period of plasticity in the rodent (9, 10) may have important implications for human development; the complementary prepubertal period in humans (i.e., school-age childhood) also exhibits developmentally-unique mPFC circuitry phenotypes (11–17) that make childhood a strong candidate for a human mPFC sensitive period. Here, we used Billboard music chart data to identify age-specific exposures to pop songs to test whether music shapes human mPFC responses during a childhood sensitive period as in the rodent. To parallel the approach used in the rodent, we examined whether (i) music experienced during childhood uniquely produced a behavioral preference under stress, (ii) childhood music enhanced emotion regulation behaviorally and physiologically, (iii) mPFC activity was enhanced by childhood music, and mPFC circuitry mediated emotion regulation benefits of childhood music, and (iv) whether the timing of this putative sensitive period could be shifted by early adversity.
Extraction-Free Whole Transcriptome Gene Expression Analysis of FFPE Sections and Histology-Directed Subareas of Tissue
Authors: Trejo Christy L , Babić Miloš , Imler Elliot , Gonzalez Migdalia , Bibikov Sergei , Shepard Peter J , VanSteenhouse Harper C , Yeakley Joanne M , Seligmann Bruce E
Published: September 2018

We describe the use of a ligation-based targeted whole transcriptome expression profiling assay, TempO-Seq™, to profile formalin-fixed paraffin-embedded (FFPE) tissue, including H&E stained FFPE tissue, by directly lysing tissue scraped from slides without extracting RNA or converting the RNA to cDNA. The correlation of measured gene expression changes in unfixed and fixed samples using blocks prepared from a pellet of a single cell type was R2 = 0.97, demonstrating that no significant artifacts were introduced by fixation. Fixed and fresh samples prepared in an equivalent manner produced comparable sequencing depth results (+/-20%), with similar %CV (11.5 and 12.7%, respectively), indicating no significant loss of measurable RNA due to fixation. The sensitivity of the TempO-Seq assay was the same whether the tissue section was fixed or not. The assay performance was equivalent for human, mouse, or rat whole transcriptome. The results from 10 mm2 and 2 mm2 areas of tissue obtained from 5 μm thick sections were equivalent, thus demonstrating high sensitivity and ability to profile focal areas of histology within a section. Replicate reproducibility of separate areas of tissue ranged from R2 = 0.83 (lung) to 0.96 (liver) depending on the tissue type, with an average correlation of R2 = 0.90 across nine tissue types. The average %CVs were 16.8% for genes expressed at greater than 200 counts, and 20.3% for genes greater than 50 counts. Tissue specific differences in gene expression were identified and agreed with the literature. There was negligible impact on assay performance using FFPE tissues that had been archived for up to 30 years. Similarly, there was negligible impact of H&E staining, facilitating accurate visualization for scraping and assay of small focal areas of specific histology within a section.
Spatial Gradient of Microstructural Changes in Normal-Appearing White Matter in Tracts Affected by White Matter Hyperintensities in Older Age
Authors: Muñoz Maniega Susana , Meijboom Rozanna , Chappell Francesca M. , Valdés Hernández Maria C. , Starr John M. , Bastin Mark E. , Deary Ian J. , Wardlaw Joanna M.
Published: September 2018

Brain white matter hyperintensities (WMH), common in older adults, may contribute to cortical disconnection and cognitive dysfunction. The presence of WMH within white matter (WM) tracts indicates underlying microstructural WM changes that may also affect the normal-appearing WM (NAWM) of a tract. We performed an exploratory study using diffusion magnetic resonance imaging of 52 healthy participants from the Lothian Birth Cohort 1936 (age 72.2 ± 0.7 years) selected to include a range of WMH burden, to quantify microstructural changes of tracts intersecting WMH. We reconstructed tracts using automated tractography and identified intersections with WMH. Tissue volumes and water diffusion tensor parameters (mean diffusivity (MD) and fractional anisotropy (FA)) were established for tract-WMH and tract-NAWM. MD and FA were also measured for tract-NAWM at 2 mm incremental distances from the tract-WMH edge, and from the edge of nearby, non-intersecting, WMH. We observed microstructural changes in tract-WMH suggestive of tissue damage. Tract-NAWM also showed a spatial gradient of FA and MD abnormalities, which diminished with distance from the tract-WMH. Nearby WMH lesions, not directly crossed by the tract, also affected tract microstructure with a similar pattern. Additionally, both FA and MD changes in tract-NAWM were predicted by FA and MD changes respectively in tract-WMH. FA was also predicted by tract-WMH overlap volume, whereas MD was better predicted by whole-brain WMH load. These results suggest that tract-NAWM microstructure is affected by the pathological process underlying WMH, when WMH are either within or near to the tract. The changes in NAWM tract tissue may indicate future lesion progression and may play an important role in cognitive ageing.
Translation of upstream open reading frames in a model of neuronal differentiation
Authors: Rodriguez C.M. , Chun S.Y. , Mills R.E. , Tod P.K.
Published: September 2018

Upstream open reading frames (uORFs) initiate translation within mRNA 5’ leaders, and have the potential to alter main coding sequence (CDS) translation on transcripts in which they reside. Ribosome profiling (RP) studies suggest that translating ribosomes are pervasive within 5’ leaders across model systems. However, the significance of this observation remains unclear. To explore a role for uORF usage in neuronal differentiation, we performed RP on undifferentiated and differentiated human neuroblastoma cells. Using a spectral coherence algorithm (SPECtre), we identify 4,954 uORFs across 31% of all neuroblastoma transcripts. These uORFs predominantly utilize non-AUG initiation codons and exhibit translational efficiencies (TE) comparable to annotated coding regions. Usage of both AUG initiated uORFs and a conserved and consistently translated subset of non-AUG initiated uORFs correlates with repressed CDS translation. Ribosomal protein transcripts are enriched in uORFs, and select uORFs on such transcripts were validated for expression. With neuronal differentiation, we observed an overall positive correlation between translational shifts in uORF/CDS pairs. However, a subset of transcripts exhibit inverse shifts in translation of uORF/CDS pairs. These uORFs are enriched in AUG initiation sites, non-overlapping, and shorter in length.

Cumulatively, CDSs downstream of uORFs characterized by persistent translation show smaller shifts in TE with neuronal differentiation relative to CDSs without a predicted uORF, suggesting that fluctuations in CDS translation are buffered by uORF translation. In sum, this work provides insights into the dynamic relationships and potential regulatory functions of uORF/CDS pairs in a model of neuronal differentiation.