bluuebunny/crossref_metadata_2025 huggingface dataset:
Early detection for autism spectrum disorder in young children
Authors: Zwaigenbaum Lonnie , Brian Jessica A , Ip Angie
Published: October 2019

Autism spectrum disorder (ASD) is a life-long neurodevelopmental disorder, characterized by impairments in social communication, repetitive, restricted patterns of behaviour, and unusual sensory sensitivities or interests. ASD significantly impacts the lives of children and their families. Currently, the estimated prevalence of ASD is 1 in 66 Canadians aged 5 to 17 years. General paediatricians, family physicians, and other health care professionals are, therefore, seeing more children with ASD in their practices. The timely diagnosis of ASD, and referral for intensive behavioural and educational interventions at the earliest age possible, may lead to better long-term outcomes by capitalizing on the brain’s neuroplasticity at younger ages. This statement provides clear, comprehensive, evidence-informed recommendations and tools to help community paediatricians and other primary care providers monitor for the earliest signs of ASD—an important step toward an accurate diagnosis and comprehensive needs assessment for intervention planning.
Le dépistage précoce du trouble du spectre de l’autisme chez les jeunes enfants
Authors: Zwaigenbaum Lonnie , Brian Jessica A , Ip Angie
Published: October 2019

Le trouble du spectre de l’autisme (TSA) est un trouble neurodéveloppemental permanent qui se caractérise par des déficits de la communication sociale, un mode répétitif et restreint des comportements et des sensibilités ou des intérêts sensoriels inhabituels. Le TSA a des répercussions importantes sur la vie des enfants et de leur famille. À l’heure actuelle, sa prévalence estimative est de un cas sur 66 enfants et adolescents canadiens dans le groupe d’âge des cinq à 17 ans. Les pédiatres généraux, les médecins de famille et les autres professionnels de la santé rencontrent donc plus d’enfants ayant un TSA qu’auparavant dans leur pratique. Le diagnostic rapide de ce trouble et l’orientation des cas vers des interventions comportementales et éducationnelles intensives dès le plus jeune âge peuvent favoriser un meilleur pronostic clinique à long terme grâce à la neuroplasticité du cerveau à un plus jeune âge. Le présent docu-ment de principes contient des recommandations et des outils clairs, détaillés et fondés sur des données probantes pour aider les pédiatres communautaires et les autres dispensateurs de soins de première ligne à surveiller les tout premiers signes de TSA, ce qui constitue une étape importante vers un diagnostic précis et une évaluation détaillée des besoins pour planifier les interventions.
Strength Exercise Has Different Effects on Pressure Pain Thresholds in Women with Endometriosis-Related Symptoms and Healthy Controls: A Quasi-experimental Study
Authors: Poli-Neto Omero Benedicto , Oliveira Arthur Marques Zecchin , Salata Mariana Cecchi , Cesar Rosa-e-Silva Julio , Machado Dalmo Roberto Lopes , Candido-dos-Reis Francisco Jose , Nogueira Antonio Alberto
Published: October 2019

Objective

To evaluate the influence of strength exercises on remote pain sensitivity in women with endometriosis-related symptoms.

Design

A quasi-experimental study.

Setting

University Hospital, a tertiary health unit.

Subjects

Twenty-one women with endometriosis-related symptoms and 21 healthy women provided written informed consent.

Methods

The participants performed weekly exercise sessions on an extensor chair for four consecutive weeks. An electronic algometer was used to measure the pressure pain thresholds on the nondominant forearm. Heart rate and blood pressure were measured using a digital device. All measurements were taken before, immediately after, and 10 and 20 minutes after the exercise series.

Results

Women with endometriosis-related symptoms had lower pain thresholds. Pressure pain thresholds increased immediately after exercise in healthy women, returning to baseline level 20 minutes after exercise. Women with endometriosis-related symptoms did not present significant pressure pain threshold alterations after exercise. However, they had a higher heart rate and systolic, diastolic, and average blood pressure than healthy women at all the timepoints. There were no consistent correlations between pressure pain thresholds and heart rate or blood pressure.

Conclusions

The strength exercise regimen used in this study increased pain thresholds in healthy women but not in women with endometriosis-related painful symptoms. The maintenance or even worsening of pain perception after exercise in women with persistent pain, such as those with endometriosis, may limit their adherence to a physical training program, which in turn could prevent them from experiencing the long-term beneficial effects of exercise.
Bridging the Gap? Police Volunteering and Community Policing in Scotland
Authors: Dickson Graeme
Published: October 2019

This article examines how far special constables can act as the ‘bridge’ between police services and local communities, within the context of Scottish policing. I consider the literature around the core concepts of community policing, the condition of community policing Scotland, and the role that volunteer police officers can play in enhancing local policing. Then, I draw upon the findings from qualitative interviews and observations of special constables in one division of Police Scotland, to explore the nature of the special constabulary as a potential resource in community and local policing. Finally, I consider these findings in relation to the ongoing discussions of special constables’ contribution to community policing, and how policing organizations might seek to enhance that contribution. This article, I believe, provides a unique contribution to the currently small but emerging field of research within police volunteerism, and brings the perspective of Scottish special constables to these discussions which have been primarily Anglo-centric.
Healthcare charging for migrants in the UK: awareness and experience of clinicians within sexual and reproductive health and HIV
Authors: Jones Bethan L , Finnerty Fionnuala , Richardson Daniel
Published: October 2019

Background

Forced migration is at record levels, leading many European countries to seek to limit immigration or control access to public services. The UK has introduced upfront healthcare charging for overseas patients, with exceptions for certain groups and services. Confusion over these regulations amongst healthcare professionals risks care being inappropriately delayed or denied. This is pertinent within sexual and reproductive health and HIV care where sensitivity and timely management are essential.

Methods

We conducted a survey exploring clinicians’ knowledge of healthcare charging regulations and terminology, their confidence and experience on this topic and their ability to evaluate case-based scenarios.

Results

Of 343 valid responses, 78% reported encountering refugees, asylum seekers or undocumented migrants in practice. Only 39% felt confident in their understanding of healthcare entitlements. Terminology was appropriately defined by 66%, but only 53% of case-based scenarios were answered correctly. About 71% reported needing further training in this area, and many comments indicated a desire for educational resources.

Conclusions

SRH and HIV professionals demonstrated limited knowledge of healthcare charging for migrants, despite working with these groups. This could undermine their ability to deliver appropriate advice and care to these potentially vulnerable patients. Training and support for these staff is essential.
How does information dependence affect public attitudes towards genetically modified technology in China?
Authors: Pang Zhenjing
Published: October 2019

This study presents a careful understanding of the impact of information dependence on public attitudes (PAs) towards genetically modified (GM) technology in China by employing a structural equation modelling approach. Results in this study provide further empirical evidence to support the point of view that PAs towards GM technology vary with their information dependence. Information evaluation is the reasoning mechanism between information dependence and the perception of risks and benefits, ultimately determining PAs towards GM technology. Empirical results can serve as the basis for risk communication, suggesting that the public sector, scientific institutions, scientists, and officials must be more active in sharing scientific knowledge about GM technology with the public by developing more open channels for the dissemination of authoritative information, and public education is also needed. On the other hand, the medias’ discourse system on GM technology should return to the scientific field for inspiring a rational attitude towards GM technology.
New insights into Sauropsid Papillomaviridae evolution and epizootiology: discovery of two novel papillomaviruses in native and invasive Island geckos
Authors: Agius Jessica E , Phalen David N , Rose Karrie , Eden John-Sebastian
Published: October 2019

Papillomaviruses cause persistent infections in skin and mucosal membranes and, in at least one species, are also be able to infect a tissue of mesenchymal origin. Infections may either be subclinical or induce proliferative lesions. Of the known papillomaviruses, the majority that have been characterized are from humans and other mammals. Currently, only fifteen complete bird and reptile papillomavirus genomes have been described, and they have been found in birds (n = 11), turtles (n = 2), and snakes (n = 2). Using next-generation sequencing technologies and virus-specific PCR, we have identified two novel papillomavirus genomes, Hemidactylus frenatus Papillomavirus 1 and 2 (HfrePV1, HfrePV2), in the widely distributed and highly invasive Asian house gecko (H.frenatus) and mute gecko (Gehyra mutilata) on Christmas Island and Cocos (Keeling) Islands. HfrePV1 was also detected in critically endangered Lister’s geckos (Lepidodactylus listeri) in their captive breeding colony on Christmas Island. Tissue-containing virus included epidermis, oral mucosa, and liver (HfrePV1) and epidermis, liver, and colon (HfrePV2). Concurrent infections were found in both H.frenatus and G.mutilata. Invasive mourning geckos (Lepidodactylus lugubris) (n = 4), Sri Lankan house geckos (Hemidactylus parvimaculatus) (n = 3), flat-tailed house geckos (Hemidactylus platyurus) (n = 4) from the Cocos Islands, and blue-tailed skinks (Cryptoblepharus egeriae) (n = 10) from Christmas Island were also screened but were not found to be infected. The novel HfrePV1 and HfrePV2 genomes were 7,378 bp and 7,380 bp in length, respectively, and each contained the early (E1, E2, and E7), and late (L1 and L2) open-reading frames. Phylogenetic analysis of the concatenated E1, E2, and L1 proteins from both papillomaviruses revealed that they clustered with, but were basal to, the Sauropsida clade containing bird and reptile viruses. This study sheds light on the evolution of papillomaviruses and the distribution of pathogens in a highly invasive species impacting endangered populations of geckos.
Dual role of cofilin in APP trafficking and amyloid‐β clearance
Authors: Liu Tian , Woo Jung‐A. A. , Yan Yan , LePochat Patrick , Bukhari Mohammed Zaheen , Kang David E.
Published: October 2019

The accumulation of amyloid‐β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also via endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin‐severing protein, in actin dynamics and pathogen‐triggered endocytic processes. Moreover, the binding of Aβ42 oligomers to β1‐integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface β1‐integrin. However, a role for cofilin in APP processing and Aβ metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Aβ production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aβ deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin+/‐). However, the reduction of Aβ load in APP/PS1;cofilin+/‐ mice is paradoxically associated with significantly increased ionized calcium‐binding adaptor molecule 1‐positive microglial activation surrounding Aβ deposits. Primary microglia isolated from cofilin+/‐ mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aβ42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Aβ accumulation via dual and opposing endocytic mechanisms of promoting Aβ production in neurons and inhibiting Aβ clearance in microglia.—Liu, T., Woo, J.‐A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid‐β clearance. FASEB J. 33, 14234‐14247 (2019). www.fasebj.org
Vitamin D receptor (VDR) geneFokI,BsmI,ApaI andTaqI polymorphisms and osteoporosis risk: a meta-analysis
Authors: Yadav Upendra , Kumar Pradeep , Rai Vandana
Published: October 2019

Osteoporosis is a bone disease characterized by low bone density. The prevalence of osteoporosis varies between different populations and ethnic groups. Numerous studies have investigated the relationship between VDR gene polymorphisms and osteoporosis across ethnic populations. Present meta-analysis aims to comprehensively evaluate the influence of commonFokI,BsmI,ApaI andTaqI VDR gene polymorphisms and osteoporosis. PubMed, Google Scholar, Springer Link and Elsevier databases were searched for eligible studies and all statistical calculations were performed by Open Meta-Analyst software. Studies investigatedBsmI (65 studies; 6,880 case/ 8,049 control),ApaI (31 studies; 3,763 case/ 3,934 control),FokI (18 studies; 1,895 case/ 1,722 control), andTaqI (26 studies; 2,458 case/ 2,895 control) polymorphisms were included in the present meta-analysis. Results of meta-analysis revealed significant association between dominant model ofFokI (ORff+Ff vs. FF= 1.19, 95% CI= 1.04-1.36, p= 0.01, I2= 39.36%) in overall analysis and recessive model of Caucasian population ofTaqI polymorphism (ORTT+Tt vs. tt= 1.35, 95% CI= 1.11-1.63, p= 0.002, I2= 50.07%). While no such effect is found in any other genetic model in any other gene polymorphisms of the overall analyses or sub-group analyses. In conclusion, we found theFokI polymorphism is associated with osteoporosis in overall analysis, also theTaqI polymorphism is a risk factor for the Caucasian population.
Insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3) and breast cancer risk: observational and Mendelian randomization analyses
Authors: Murphy Neil , Knuppel Anika , Papadimitriou Nikos , Martin Richard M , Tsilidis Konstantinos K , Smith-Byrne Karl , Fensom Georgina , Perez-Cornago Aurora , Travis Ruth C , Key Timothy J , Gunter Marc J
Published: October 2019

Background

Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses to allow causal inference.

Patients and methods

We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206,263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6,711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGFBP-3 levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122,977 cases and 105,974 controls.

Results

In the UK Biobank, after a median follow-up of 7.1 years, 4,360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/L increment of IGF-1=1.11, 95%CI=1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/L increment in genetically-predicted IGF-1 concentration was associated with greater breast cancer risk (odds ratio [OR]=1.05, 95%CI=1.01-1.10; Pvalue=0.02), with a similar effect estimate for estrogen positive (ER+) tumors, but no effect found for estrogen negative (ER-) tumors. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (OR per 1-SD increment=1.00, 95%CI=0.97-1.04; Pvalue=0.98).

Conclusion

Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.

Disclaimer

Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.
Liver cells and PBMC secrete Tumor-suppressive Plasma Extracellular Vesicles in Melanoma patients
Authors: Lee Jung-Hyun , Eberhardt Martin , Blume Katja , Vera Julio , Baur Andreas S.
Published: October 2019

Before and after surgery melanoma patients harbor elevated levels of extracellular vesicles in plasma (pEV), but their cellular origin is obscure. Here we suggest that these pEV are secreted in part by tumor cells, but particularly by liver and peripheral blood mononuclear cells (PBMC), which strongly suppressed tumor cell activity. As the cellular origin of pEV is difficult to determine, we mimicked the interaction of tumor cells with liver cells and PBMC in vitro, and compared newly secreted EV-associated miRNAs and protein factors with those detected in melanoma patient’s pEV. The results identified factors that could be associated either with tumor cell activity or the counteracting immune system and liver cells. Notably, the presence/absence of these factors correlated with the clinical stage and tumor relapse. Our study provides new insights into the innate immune defense against tumor cells and implies that residual tumor cells may be more active than previously thought.

Summary blurb

Plasma extracellular vesicles (pEV) in melanoma patients are a mix of cancer cell-suppressive vesicles from liver cells and PBMC, but derive also from residual cancer cells.
Amyloid damage to islet β-cells in type 2 diabetes: hypoxia or pseudo-hypoxia?
Authors: Bellotti Vittorio , Corazza Alessandra , Foglia Beatrice , Novo Erica , Simons J. Paul , Mangione P. Patrizia , Verona Guglielmo , Canetti Diana , Nocerino Paola , Obici Laura , Vanoli Alessandro , Paulli Marco , Giorgetti Sofia , Raimondi Sara , Al-Shawi Raya , Tennent Glenys A. , Taylor Graham W. , Gillmore Julian D. , Pepys Mark B. , Parola Maurizio
Published: October 2019

Aggregation of islet amyloid polypeptide (IAPP) and amyloid deposition in the islets of Langerhans may significantly contribute to the multifactorial pathogenic mechanisms leading to type 2 diabetes. A direct toxic effect on β-cells of oligomeric IAAP has been demonstrated in in vitro models, but the mechanism operating in vivo is still unclear. Mice models presenting amyloid deposition and glucose intolerance represent a good tool for exploring in vivo a putative mechanism of toxicity directly related to the physical expansion of the extracellular matrix by the amyloid fibrillar aggregates. Based on our hypothesis that deposition of amyloid may influence the oxygen perfusion, we have calculated that the mean distribution of oxygen partial pressure would drop by more than 50 % in the presence of amyloid deposits in the islet. This condition of hypoxia caused by the remodelling of the extracellular space may explain the metabolic abnormalities in the Langerhans islets, otherwise interpreted as pseudo-hypoxic response to IAPP oligomers.
Generation and Trapping of a Mesoderm Biased State of Human Pluripotency
Authors: Stavish Dylan , Böiers Charlotta , Price Christopher , Frith Thomas J R , Halliwell Jason , Barbaric Ivana , Brown John , Carr Jonathon , James Chela , Andrews Peter W , Enver Tariq
Published: October 2019

We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explored mesoderm lineage-bias within the human pluripotent stem cell compartment. We identified a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programs. Functionally these cells could initiate stem cell cultures and exhibited mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we could ‘trap’ and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal state on the differentiation trajectory, the plasticity of which is evidenced by their reacquisition of an unbiased state upon removal of differentiation cues. The use of ‘cross-antagonistic’ signalling to trap pluripotent stem cell intermediates with different lineage-bias may have general applicability in the efficient production of cells for regenerative medicine.
Losing Control: Sleep Deprivation Impairs the Suppression of Unwanted Thoughts
Authors: Harrington Marcus O. , Ashton Jennifer E. , Sankarasubramanian Subbulakshmi , Anderson Michael C. , Cairney Scott A.
Published: October 2019

Unwanted memories often enter conscious awareness when we confront reminders. People vary widely in their talents at suppressing such memory intrusions; however, the factors that govern suppression ability are poorly understood. We tested the hypothesis that successful memory control requires sleep. Following overnight sleep or total sleep deprivation, participants attempted to suppress intrusions of emotionally negative and neutral scenes when confronted with reminders. The sleep-deprived group experienced significantly more intrusions (unsuccessful suppressions) than the sleep group. Deficient control over intrusive thoughts had consequences: whereas in rested participants suppression reduced behavioural and psychophysiological indices of negative affect for aversive memories, it had no such salutary effect for sleep-deprived participants. Our findings raise the possibility that sleep deprivation disrupts prefrontal control over medial temporal lobe structures that support memory and emotion. These data point to an important role of sleep disturbance in maintaining and exacerbating psychiatric conditions characterised by persistent, unwanted thoughts.
Three criteria of intrinsically theoretical categories in biological system and classification of some medical plants
Authors: Zou Huabin
Published: October 2019

In classical biology, different taxonomic categories are all decided based on empirical rules established on learning knowledge. In taxonomy, different classification systems are of diversified rules. One biology is often in different categories, although the concepts related to taxonomic categories are the same to each other. Whether there exist some absolute standards to classify biology, and to give unalterable results. This is of greatly scientific meaning. Common and variation, that is heredity and variation are the most elemental information in biology, and exist at multiply biology material levels. In this paper a generalized biological heredity and variation information theory was proposed based on previous works. Three typical heredity and variation models were analyzed by using this theory. They are unique asymmetric variation model, symmetric two variation model and extreme radial variation model. In the maximum information states, two biological constantsPg1= 0.69 andPg2=0.61 and a boundary similarity function were obtained. ThesePgandPgfunction can be defined as the three theoretically taxonomic category criteria of biological system. For 29 samples belonging to four kind plants, their chemical fingerprint — infrared (IR) fingerprint spectra (FPS) were analyzed depending on the theoretical criteria. The correct classification ratio was 96.6%. The results showed these samples could be ideally classified. A suggestion was proposed that biology should be absolutely classified relying on the three intrinsic theoretical criteria.
Detection of urinary metabolites of metabolic pathway disorders by using VTGE and LC-HRMS techniques
Authors: Kumar Ajay , Kothari Jainish , Bhatkar Devyani , Mitruka Manmohan , Pal Roshni , Sarode Sachin C. , Sharma Nilesh Kumar
Published: October 2019

Background

In recent, various human health disorders including cancer, diabetes, neurodegenerative and metabolic diseases are noticed among human populations. Currently, genetic and proteomic approaches are highly reported to detect metabolic disorders that also include inborn error of metabolisms. These existing detection methods are faced with cost issue and time consuming factors. Therefore, metabolites as biomarkers are one of potential avenues to detect metabolic disorders. Further, exploitation of urine as potential source of metabolite biomarkers, there are limitation in this area of research due to abundance of non-metabolite components such as proteins and nucleic acids. Hence, methods and processes are required to precisely fractionate metabolites from urine of inborn error of metabolism patients and then identified by analytical tools such as LC-HRMS and GC-MS.

Methods

Sterile filtered urine samples (750 µl) mixed with (250 µl) loading buffer were electrophoresed on VTGE that uses acrylamide gel (acrylamide:bisacrylamide, 30:1) as matrix of 15%. Further, vertical tube gel electrophoresis (VTGE) technique combined with LC-HR-MS to identify metabolites that are known as the biomarkers of metabolic disorders was carried out.

Results and Discussion

The authors provide evidence on the use of novel VTGE coupled with LC-HRMS to detect metabolites among metabolic disorders. Data suggest the applicability of VTGE coupled with LC-HRMS technique to detect metabolites such as 2-methyluridine, 2-Methylglutaric acid, 2-Methyl citric acid, 2-Hydroxyglutaric acid in case of metabolic disorders.

Conclusion

This preliminary work is suggested to be extended to large clinical samples to validate application of this method to detect metabolic disorders including inborn error of metabolisms.
An interactive retrieval system for clinical trial studies with context-dependent protocol elements
Authors: Park Junseok , Kim Kwangmin , Park Seongkuk , Hwang Woochang , Yoo Sunyong , Yi Gwan-su , Lee Doheon
Published: October 2019

A clinical trial protocol defines the procedures that should be performed during a clinical trial. Every clinical trial begins with the design of its protocol. While designing the protocol, most researchers refer to electronic databases and extract protocol elements using a keyword search. However, state-of-the-art retrieval systems only offer text-based searches for user-entered keywords. In this study, we present an interactive retrieval system with a context-dependent and protocol-element-selection function for successfully designing a clinical trial protocol. To do this, we first introduce a database for a protocol retrieval system constructed from individual protocol data extracted from 184,634 clinical trials and 13,210 frame structures of clinical trial protocols. The database contains various semantic information that enables the protocols to be filtered during the search operation. Based on the database, we developed a web application called the clinical trial protocol database system (CLIPS; available at https://corus.kaist.edu/clips), which enables an interactive search by utilizing protocol elements. CLIPS provides the options to select the next element according to the previous element in the form of a connected tree, thus enabling an interactive search for combinations of protocol elements. The validation results show that our method achieves better performance than existing databases in predicting phenotypic features.
Enabling community-based metrology for wood-degrading fungi
Authors: Perez Rolando , Luccioni Marina , Gaut Nathaniel , Stirling Finn , Kamakaka Rohinton , Adamala Katarzyna P. , Silver Pamela A. , Endy Drew
Published: October 2019

Lignocellulosic biomass could support a greatly-expanded bioeconomy. Current strategies for using biomass typically rely on single-cell organisms and extensive ancillary equipment to produce precursors for downstream manufacturing processes. Alternative forms of bioproduction based on solid-state fermentation and wood-degrading fungi can enable more direct means of manufacture. However, such practices are oftenad hocand not readily reproducible. We sought to develop standard reference strains, substrates, measurements, and methods sufficient to begin to enable reliable reuse of mycological materials and products. Specifically, we show that a widely-available and globally-regularized consumer product (Pringles™) can support the growth of wood-degrading fungi, and that growth on Pringles™ can be correlated with growth on a fully-traceable and compositionally characterized substrate (NIST Reference Material 8492 Eastern Cottonwood Biomass). So established, five laboratories were able to compare measurements of wood-fungus performance via a simple radial extension growth rate assay. Reliable reuse of materials, measures, and methods is necessary to enable distributed bioproduction processes that can be adopted at all scales, from local to industrial.
Finding Hidden Treasures: A Child-Friendly Neural Test of Task-Following in Individuals Using Functional Transcranial Doppler Ultrasound
Authors: Petit Selene , Badcock Nicholas A. , Woolgar Alexandra
Published: October 2019

Despite growing interest in the mental life of individuals who cannot communicate verbally, objective and non-invasive tests of covert cognition are still sparse. In this study, we assessed the ability of neurotypical children to understand and follow task instructions by measuring neural responses through functional transcranial Doppler ultrasound (fTCD). We recorded blood flow velocity for the two brain hemispheres of twenty children (aged 9 to 12) while they performed either a language task or a visuospatial memory task, on identical visual stimuli. We extracted measures of neural lateralisation for the two tasks separately to investigate lateralisation, and we compared the left-minus-right pattern of activation across tasks to assess task-following. At the group level, we found that neural responses were left-lateralised when children performed the language task, and not when they performed the visuospatial task. However, with statistically robust analyses and controlled paradigms, significant lateralisation in individual children was less frequent than expected from the literature. Nonetheless, the pattern of hemispheric activation for the two tasks allowed us to confirm task-following in the group of participants, as well as in over half of the individuals. This provides a promising avenue for a covert and inexpensive test of children’s ability to covertly follow task instructions and perform different mental tasks on identical stimuli.
Epigenetic age provides insight into tissue origin in endometriosis
Authors: Leap Katie , Yotova Iveta , Horvath Steve , Martinez-Agosto Julian A
Published: October 2019

Background

Endometriosis is a common reproductive disease with a heterogeneous presentation. Classification attempts have thus far not offered insight into its cause or its symptoms. Endometriosis may result from the migration of shed endometrium to the peritoneal cavity. However, there are cases reported in girls without uteruses and men. While a non-retrograde menstruation origin of ectopic tissue is certain in these cases, we propose using DNA methylation age (DNAm age) to distinguish between retrograde and non-retrograde etiologies.

Methods

Using publicly available DNA methylation data and Horvath’s pan-tissue epigenetic clock, we compared DNAm age and epigenetic age acceleration (EAA) of ectopic lesions to eutopic endometrium of diseased and control endometrium. We examined EAA in cancer metastasis and teratomas to control for migration and developmental origin.

Results

Disease status does not change DNAm age of eutopic endometrium, but the effect of ectopic status was profound: −16.88 years (p = 4.82 × 10−7). There were no differences between EAA of primary/metastatic tumor pairs, suggesting that the observed effect is not due to migration. Immature or mature teratoma compartments decreased DNAm age by 9.44 and 7.40 years respectively, suggesting that developmental state correlates with DNAm age.

Conclusions

Ectopic endometriotic tissue exhibits decelerated DNAm age, similar to that observed in teratomas composed of multipotent tissue. The migration process does not change DNAm age and eutopic endometrium is concordant with chronological age regardless of disease status. We conclude that DNAm age of ectopic lesions can classify endometriosis into distinct subtypes that may be clinically relevant.
GPU-accelerated mesh-based Monte Carlo photon transport simulations
Authors: Fang Qianqian , Yan Shijie
Published: October 2019

The mesh-based Monte Carlo (MMC) algorithm is increasingly used as the gold-standard for developing new biophotonics modeling techniques in 3-D complex tissues, including both diffusion-based and various Monte Carlo (MC) based methods. Compared to multi-layered and voxel-based MCs, MMC can utilize tetrahedral meshes to gain improved anatomical accuracy, but also results in higher computational and memory demands. Previous attempts of accelerating MMC using graphics processing units (GPUs) have yielded limited performance improvement and are not publicly available. Here we report a highly efficient MMC – MMCL – using the OpenCL heterogeneous computing framework, and demonstrate a speedup ratio up to 420× compared to state-of-the-art single-threaded CPU simulations. The MMCL simulator supports almost all advanced features found in our widely disseminated MMC software, such as support for a dozen of complex source forms, wide-field detectors, boundary reflection, photon replay and storing a rich set of detected photon information. Furthermore, this tool supports a wide range of GPUs/CPUs across vendors and is freely available with full source codes and benchmark suites at http://mcx.space/#mmc.
Disrupted remapping of place cells and grid cells in knock-in model of Alzheimer’s disease
Authors: Jun Heechul , Soma Shogo , Saito Takashi , Saido Takaomi C , Igarashi Kei M
Published: October 2019

Patients with Alzheimer’s disease (AD) frequently suffer from spatial memory impairment and wandering behavior, but brain circuits causing such symptoms remain largely unclear. In healthy brains, spatially-tuned hippocampal place cells and entorhinal grid cells represent distinct spike patterns in different environments, a circuit function called “remapping” that underlies pattern separation of spatial memory. We investigated whether knock-in expression of mutated amyloid precursor protein deteriorates the remapping of place cells and grid cells. We found that the remapping of CA1 place cells was disrupted although their spatial tuning was only mildly diminished. Grid cells in the medial entorhinal cortex (MEC) were impaired, sending severely disrupted remapping signals to the hippocampus. Furthermore, fast gamma oscillations were disrupted in both CA1 and MEC, resulting in impaired fast gamma coupling in the MEC→CA1 circuit. These results point to the link between grid cell impairment and remapping disruption as a circuit mechanism causing spatial memory impairment in AD.
Epigenetic Effects of Assisted Reproductive Technology in Human Offspring
Authors: Chen Wei , Peng Yong , Ma Xinyi , Kong Siming , Tang Shuangyan , Wei Yuan , Zhao Yangyu , Zhang Wenxin , Wang Yang , Yan Liying , Qiao Jie
Published: October 2019

The births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the potential for elevated risks of ART-related disorders persists in adult life, and the underlying epigenetic mechanisms are largely uncharacterized. Here, we recruited 100 nuclear families and profiled the DNA methylomes, genome-wide histone modifications and transcriptomes to clarify the inherent extra risks attributable to specific ART procedures. We discovered that IVF-ET seemed to introduce less disturbance into the infant epigenome than IVF-FET or ICSI-ET did. Furthermore, we noted approximately half of the DNA methylomic changes in ART-conceived offspring could be explained by parental background biases. Through removal of the parental effect, we confirmed that ARTper sewould introduce minor DNA methylation changes locally. More importantly, we found that ART-induced epigenomic alterations were highly enriched in the processes which might contribute to increased incidence of preeclampsia during pregnancy and metabolic syndrome in offspring. Overall, our study provides an epigenetic basis for the potential long-term health risks in ART-conceived offspring that reinforces the need to review all methods of human ART.
Human periventricular nodular heterotopia shows several interictal epileptic patterns, associated with hyperexcitability of neuronal firing
Authors: Frazzini Valerio , Whitmarsh Stephen , Lehongre Katia , Yger Pierre , Lemarechal Jean-Didier , Matching Bertrand , Adam Claude , Hasboun Dominique , Lambrecq Virginie , Navarro Vincent
Published: October 2019

Periventricular nodular heterotopia (PNH) is a malformation of cortical development that frequently causes drug-resistant epilepsy. The epileptogenicity of ectopic neurons in PNH as well as their role in generating interictal and ictal activity is still a matter of debate. We report the firstin vivomicroelectrode recording of heterotopic neurons in humans. Highly consistent interictal patterns (IPs) were identified within the nodules: 1) Periodic Discharges PLUS Fast activity (PD+F), Sporadic discharges PLUS Fast activity (SD+F), and 3) epileptic spikes (ES). Neuronal firing rates were significantly modulated during all IPs, suggesting that multiple IPs were generated by the same local neuronal populations. Furthermore, firing rates closely followed IP morphologies. Among the different IPs, SD+FA pattern was found only in the three nodules that were actively involved in seizure generation, but was never observed in the nodule that did not take part in ictal discharges. On the contrary, PD+F and ES were identified in all nodules. Units that were modulated during the IPs were also found to participate in seizures, increasing their firing rate at seizure onset and maintaining an elevated rate during the seizures. Together, nodules in PNH are highly epileptogenic, and show several IPs that provide promising pathognomonic signatures of PNH. Furthermore, our results show that PNH nodules may well initiate seizures.

Highlights

Firstin vivomicroelectrode description of local epileptic activities in human PNH

Recordings revealed multiple microscopic epileptic interictal patterns

Firing rates ofalldetected units were significantly modulated duringallinterictal patterns

Seizures recruited the same units that are involved in interictal activity
Desmosomal coupling in apoptotic cell extrusion
Authors: Thomas Minnah , Ladoux Benoit , Toyama Yusuke
Published: October 2019

The mechanical coupling of epithelia enables coordination of tissue functions and collective tissue movements during different developmental and physiological processes. This coupling is ensured by cell-cell junctions, including adherens junctions (AJs) and desmosomal junctions (DJs) [1, 2]. During apoptosis, or programmed cell death, a dead cell is expelled from the tissue by coordinated processes between the dying cell and its neighbors. Apoptotic cell extrusion is driven by actomyosin cable formation and its contraction, and lamellipodial crawling of the neighboring cells (Fig. S1A-A’’, Movie S1) [3–6]. Throughout cell extrusion, the mechanical coupling of epithelia needs to be maintained in order to preserve tissue homeostasis [3]. Although much is known about the regulation of AJs in apoptotic cell extrusion [6–9], the role and dynamics of DJs during this process remains poorly understood. Here, we show that DJs stay intact throughout and are crucial for apoptotic cell extrusion. Pre-existing DJs between the apoptotic cell and neighboring non-dying cells remain intact even during the formation of de novo DJs between non-dying cells, suggesting that the neighboring cells possess two DJs in the middle of apoptotic cell extrusion. We further found that an actomyosin cable formed in the vicinity of DJs upon apoptosis, and subsequently deviated from DJs during its constriction. Interestingly, the departure of the actomyosin cable from DJs coincided with the timing when DJs lost their straightness, suggesting a release of junctional tension at DJs, and a mechanical coupling between DJs and actomyosin contractility. The depletion of desmoplakin, which links desmosomes and intermediate filaments, resulted in defective apical contraction and an inability to form de novo DJs, leading to a failure of apoptotic cell extrusion. Our study provides a framework to explain how desmosomes play pivotal roles in maintaining epithelial sheet integrity during apoptotic cell extrusion.
Meniscal and ligament modifications in spontaneous and post-traumatic mouse models of osteoarthritis
Authors: Ramos-Mucci Lorenzo , Javaheri Behzad , van ‘t Hof Rob , Bou-Gharios George , Pitsillides Andrew A , Comerford Eithne , Poulet Blandine
Published: October 2019

Osteoarthritis (OA) is a whole joint disease that affects all joint tissues, with changes in the articular cartilage (AC), subchondral bone and synovium. Pathologies in menisci and ligaments, however, are rarely analysed, although both are known to play vital roles in the mechanical stability of the joint. The aim of our study was to describe the pathological changes in menisci and ligament during disease development in murine spontaneous and post-traumatic surgically-induced OA and to quantify tissue mineralisation in the joint space using µCT imaging during OA progression.

Knees of Str/ort mice (spontaneous OA model; 26-40wks) and C57CBA F1 mice following destabilisation of medial meniscus (DMM) surgery (post-traumatic OA model; 8wks after DMM), were used to assess histological meniscal and ligament pathologies. Joint space mineralised tissue volume was quantified by µCT.

Meniscal pathological changes in Str/ort mouse knees were associated with articular cartilage lesion severity. These meniscal changes included ossification, hyperplasia, cell hypertrophy, collagen type II deposition and SOX9 expression in the fibrous region near the attachment to the knee joint capsule. Anterior cruciate ligaments exhibited extracellular matrix changes and chondrogenesis particularly at the tibial attachment site, and ossification was seen in collateral ligaments. Similar changes were confirmed in the post-traumatic DMM model. µCT analysis showed increased joint space mineralised tissue volume with OA progression in both the post-traumatic and spontaneous OA models.

Modifications in meniscal and ligament mineralisation and chondrogenesis are seen with overt AC degeneration in murine OA. Although the aetiology and the consequences of such changes remain unknown, they will influence stability and load transmission of the joint and may therefore contribute to OA progression. In addition, these changes may have important roles in movement restriction and pain, which represent major human clinical symptoms of OA. Description of such soft tissue changes, in addition to AC degradation, should be an important aspect of future studies in mouse models in order to furnish a more complete understanding of OA pathogenesis.

Summary statement

This manuscript describes histological changes in mouse knee joints in two models of osteoarthritis and correlates joint space mineralised tissue volume measured by µCT with disease severity.
Blood and Tissue Biomarker Analysis in Dogs with Osteosarcoma Treated with Palliative Radiation and Intra-Tumoral Autologous Natural Killer Cell Transfer
Authors: Judge Sean J. , Yanagisawa Mio , Sturgill Ian R. , Bateni Sarah B. , Gingrich Alicia A. , Foltz Jennifer A. , Lee Dean A. , Modiano Jaime F. , Monjazeb Arta M. , Culp William T. N. , Rebhun Robert B. , Murphy William J. , Kent Michael S. , Canter Robert J.
Published: October 2019

Background

We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects.

Methods

Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival.

Results

Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17 – 19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P=0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta).

Conclusions

Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance.