bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the utility and attitudes toward molecular testing in neuro-oncology: a survey of the Society for Neuro-Oncology members
Authors: Fortin Ensign Shannon , Hrachova Maya , Chang Susan , Mrugala Maciej M
Published: February 2021

Background

Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. The aim of this study was to determine clinical practice patterns to acquire this information, interpret and utilize MT for patient care, and identify unmet needs in the practical clinical application of MT.

Methods

We conducted a voluntary online survey of providers within the Society for Neuro-Oncology (SNO) membership database between March and April 2019.

Results

We received 152 responses out of 2022 SNO members (7.5% of membership). 88.8% of respondents routinely order MT for newly diagnosed gliomas. Of those who do not, testing is preferentially performed in younger patients or those with midline tumors. 82.8% use MT in recurrent gliomas. Other common indications included: metastatic tumors, meningioma, and medulloblastoma. Many providers utilize more than one resource (36.0%), most frequently using in-house (41.8%) over commercially available panels. 78.1% used the results for clinical decision-making, with BRAF, EGFR, ALK, and H3K27 mutations most commonly directing treatment decisions. Approximately, half (48.5%) of respondents have molecular tumor boards at their institutions. Respondents would like to see SNO-endorsed guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials, and more educational programs on MT.

Conclusion

This survey was marked by several limitations including response rate and interpretation of MT. Among respondents, there is routine use of MT in Neuro-Oncology, however, there remains a need for increased guidance for providers to effectively incorporate the expanding genomic data resulting from MT into daily Neuro-Oncology practice.
Hepcidin and Ferritin Predict Microbial Etiology in Community-Acquired Pneumonia
Authors: Oppen Kjersti , Ueland Thor , Siljan William Ward , Skadberg Øyvind , Brede Cato , Lauritzen Trine , Aukrust Pål , Steinsvik Trude , Husebye Einar , Michelsen Annika E , Holter Jan Cato , Heggelund Lars
Published: February 2021

Background

Iron is crucial for survival and growth of microbes. Consequently, limiting iron availability is a human antimicrobial defense mechanism. We explored iron and iron-related proteins as potential biomarkers in community-acquired pneumonia and hypothesized that infection-induced changes in these potential biomarkers differ between groups of pathogens and could predict microbial etiology.

Methods

Blood samples from a prospective cohort of 267 patients with community-acquired pneumonia were analyzed for hepcidin, ferritin, iron, transferrin, and soluble transferrin receptor at admission, clinical stabilization, and a 6-week follow-up. A total of 111 patients with an established microbiological diagnosis confined to 1 microbial group (atypical bacterial, typical bacterial, or viral) were included in predictive analyses.

Results

High admission levels of ferritin predicted atypical bacterial versus typical bacterial etiology (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.18–4.32; P = .014). Furthermore, hepcidin and ferritin predicted atypical bacterial versus viral etiology (hepcidin: OR = 3.12, 95% CI = 1.34–7.28, P = .008; ferritin: OR = 2.38, 95% CI = 1.28–4.45, P = .006). The findings were independent of C-reactive protein and procalcitonin.

Conclusions

Hepcidin and ferritin are potential biomarkers of microbial etiology in community-acquired pneumonia.
Brassinosteroids repress the seed maturation program during the seed-to-seedling transition
Authors: Ruan Jiuxiao , Chen Huhui , Zhu Tao , Yu Yaoguang , Lei Yawen , Yuan Liangbing , Liu Jun , Wang Zhi-Yong , Kuang Jian-Fei , Lu Wang-Jin , Huang Shangzhi , Li Chenlong
Published: February 2021

In flowering plants, repression of the seed maturation program is essential for the transition from the seed to the vegetative phase, but the underlying mechanisms remain poorly understood. The B3-domain protein VIVIPAROUS1/ABSCISIC ACID-INSENSITIVE3-LIKE 1 (VAL1) is involved in repressing the seed maturation program. Here we uncovered a molecular network triggered by the plant hormone brassinosteroid (BR) that inhibits the seed maturation program during the seed-to-seedling transition in Arabidopsis (Arabidopsis thaliana). val1-2 mutant seedlings treated with a BR biosynthesis inhibitor form embryonic structures, whereas BR signaling gain-of-function mutations rescue the embryonic structure trait. Furthermore, the BR-activated transcription factors BRI1-EMS-SUPPRESSOR 1 and BRASSINAZOLE-RESISTANT 1 bind directly to the promoter of AGAMOUS-LIKE15 (AGL15), which encodes a transcription factor involved in activating the seed maturation program, and suppress its expression. Genetic analysis indicated that BR signaling is epistatic to AGL15 and represses the seed maturation program by downregulating AGL15. Finally, we showed that the BR-mediated pathway functions synergistically with the VAL1/2-mediated pathway to ensure the full repression of the seed maturation program. Together, our work uncovered a mechanism underlying the suppression of the seed maturation program, shedding light on how BR promotes seedling growth.
The inevitable sociality of money: the primacy of practical affirmation over conceptual consensus in the construction of Bitcoin’s economic value
Authors: Shaw Lynette
Published: February 2021

Bitcoin went from being an obscure online project to a globally exchanged money valued at tens of thousands of dollars (USD) per unit. It has achieved this in spite of fundamental irreconcilabilities between the economic theories which spurred its creation and its own material basis. This article investigates how this happened using a computationally grounded analysis of 100 000s of messages from the early years of Bitcoin’s two main online communities. It will show how the continuing divergence in participants’ understandings of why Bitcoin possessed value ultimately gave way to an emerging focus on the social problem of adoption. In demonstrating this shift and accompanying promotion of activities that affirmed Bitcoin had value in practice, this article with argue that shared meaning in the form of practical affirmations of worth, rather than conceptual understandings of it, are key to communities’ ability to ‘bootstrap’ a money’s initial economic value.
From Paper to Webpage: Legislation during the British Regime in Palestine in the Israeli National Legislation Database
Authors: Ben-Or Gali , Barnai Daphna , Volberg Ayelet
Published: February 2021

The editorial team of the Israeli National Legislation Database endeavored to locate all the proclamations, ordinances, and ‘Orders in Council’ published from the beginning of the British military regime in Palestine to the last ‘hidden laws’ published in the waning days of the British Mandate. These documents complete the historical information on Israel state laws and shed light on the initial establishment of the legal and judicial system in Palestine, before the establishment of the State of Israel. In this paper, we describe the development of legislation under British regime, from 1917 to the establishment of the State of Israel in 1948. We introduce the three figures who played key roles in regulating the legislative system: Orme Bigland Clark, Norman Bentwich, and Sir Robert Harry Drayton, and describe the legislative process that was developed and the legislative procedures that prevailed at the time. The legal framework of this period, alongside the remaining Ottoman legislation, formed a solid basis for the legislative system and process for the Provisional State Council and subsequently, the Knesset.
The relation between individual-level factors and the implementation of classroom-based physical activity approaches among elementary school teachers
Authors: Walker Timothy J , Craig Derek W , Robertson Michael C , Szeszulski Jacob , Fernandez Maria E
Published: February 2021

Classroom-based physical activity approaches can improve students’ physical activity; however, their implementation remains a challenge. This study examined teacher-level factors associated with implementing two classroom-based physical activity approaches (active learning and physical activity breaks). We collected cross-sectional survey data from classroom teachers (n = 133) from 20 elementary schools in an urban Texas school district. Surveys included questions about theoretical constructs (e.g., knowledge, self-efficacy), personal characteristics (e.g., age, gender), and the implementation of active learning and physical activity breaks. We used linear regression models to assess associations between independent variables and implementation outcomes. We also assessed variable importance by examining the unique variance explained. Knowledge (b = .31, p = .001), outcome expectations (b = .18, p = .015), self-efficacy (b = .40, p ≤ .001), and support (b = .22, p = .028) were directly associated with active learning implementation. Teacher physical activity level (b = .29, p = .004) and grade level (third to fifth had lower levels than kindergarten to second grade, b = –.45, p = .022) were also associated with active learning implementation. In fully adjusted models, self-efficacy explained the most variance (≈5%) in active learning implementation compared to other variables. Knowledge (b = .18, p = 0.026), attitudes (b = .18, p = .019), self-efficacy (b = .15, p = .036), and teacher grade level (third to fifth had lower levels than kindergarten to second grade, b = –.80, p < .001) were associated with activity break implementation. In fully adjusted models, teacher grade level explained the most variance (≈13%) in activity break implementation compared to other variables. Results suggest multiple theoretical constructs and personal characteristics are important to target/consider when developing implementation strategies for classroom-based physical activity approaches. Additionally, self-efficacy and teacher grade level are two factors to prioritize.
Society of Behavioral Medicine (SBM) does not support “Public Charge Rule” changes affecting immigrants’ food security
Authors: Young Sabrina , Guadamuz Jenny , Fitzgibbon Marian , Buscemi Joanna , Odoms-Young Angela , Kong Angela
Published: February 2021

Federal nutrition assistance programs, especially the Supplemental Nutrition Assistance Program (SNAP), are an important safety net for households in the USA. Although few immigrant households are eligible for SNAP, those who need the program are less likely to participate than nonimmigrant households. Documented barriers to participation include language challenges and anti-immigrant rhetoric. However, previous research indicates that when immigrant households do participate in SNAP, their young children experience less food insecurity and the household as a whole makes fewer tradeoffs between food and other necessities. The Public Charge Rule limits ability to obtain a green card based on participation in public assistance programs. A recent change to this rule added programs to include some noncash programs, including SNAP. Although the vast majority of immigrants who are subject to the Public Charge Rule are not eligible for SNAP, misunderstanding of the rule and fear threaten to reduce SNAP enrollment and consequently increase food insecurity in immigrant families. Spillover effects may occur for families not targeted by changes in the Public Charge Rule as well as decreasing access to other safety net programs that are not impacted by the proposed changes, such as The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and school meals programs. In order to support the food security of immigrant families in the USA, we recommend that the Department of Homeland Security and the Department of State remove all non-cash safety net programs from the Public Charge Rule.
Levels and factors of social and physical distancing based on the Theory of Planned Behavior during the COVID-19 pandemic among Chinese adults
Authors: Yu Yanqiu , Lau Joseph Tak Fai , Lau Mason M C
Published: February 2021

Social and physical distancing is important in controlling the COVID-19 pandemic and it impacts people’s financial/social well-being tremendously. This study tested the application of the Theory of Planned Behaviors (TPB) to three types of social/physical distancing indicators (i.e., the number of close physical contacts on a single day in public venues, the frequencies of avoiding social gathering, and the levels of physical distancing in public venues). A population-based random telephone survey interviewed 300 Hong Kong Chinese adults in April 2020 when gatherings involving >4 people were banned. The participants on average made 15.3 close physical contacts (<1.5 m and for >3 min) in a day (5.0 in public transportation). About 80% practiced social distancing (avoided/reduced social gatherings) and physical distancing in public spaces (e.g., avoidance of going out, visiting crowded places, and gatherings of >4 people) but only 35.4% avoided using public transportations. Positive but not negative attitudes (inconvenience and lack of necessity), perceived behavioral control, and subjective norm were significantly associated with the three social/physical distancing outcomes. The data suggest that the levels of social/physical distancing were relatively high in the Hong Kong general population, and it, in general, supports the application of TPB to understand factors of social distancing for preventing COVID-19. Health promotion should take the findings into account. Furthermore, cross-cultural and time-series studies are warranted to compare the levels of social/physical distancing across countries and further explore their effectiveness in controlling the COVID-19 pandemic.
Probing the SAM Binding Site of SARS-CoV-2 nsp14 in vitro Using SAM Competitive Inhibitors Guides Developing Selective bi-substrate Inhibitors
Authors: Devkota Kanchan , Schapira Matthieu , Perveen Sumera , Yazdi Aliakbar Khalili , Li Fengling , Chau Irene , Ghiabi Pegah , Hajian Taraneh , Loppnau Peter , Bolotokova Albina , Satchell Karla J.F. , Wang Ke , Li Deyao , Liu Jing , Smil David , Luo Minkui , Jin Jian , Fish Paul V. , Brown Peter J. , Vedadi Masoud
Published: February 2021

The COVID-19 pandemic has clearly brought the healthcare systems world-wide to a breaking point along with devastating socioeconomic consequences. The SARS-CoV-2 virus which causes the disease uses RNA capping to evade the human immune system. Non-structural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small molecule inhibitors of nsp14 methyltransferase (MT) activity, we developed and employed a radiometric MT assay to screen a library of 161 in house synthesized S-adenosylmethionine (SAM) competitive methyltransferase inhibitors and SAM analogs. Among seven identified screening hits, SS148 inhibited nsp14 MT activity with an IC50value of 70 ± 6 nM and was selective against 20 human protein lysine methyltransferases indicating significant differences in SAM binding sites. Interestingly, DS0464 with IC50value of 1.1 ± 0.2 μM showed a bi-substrate competitive inhibitor mechanism of action. Modeling the binding of this compound to nsp14 suggests that the terminal phenyl group extends into the RNA binding site. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein methyltransferases. The structure-activity relationship provided by these compounds should guide the optimization of selective bi-substrate nsp14 inhibitors and may provide a path towards a novel class of antivirals against COVID-19, and possibly other coronaviruses.
Droplet and fibril formation of the functional amyloid Orb2
Authors: Ashami Kidist , Falk Alexander S. , Hurd Connor , Garg Samridhi , Cervantes Silvia A. , Rawat Anoop , Siemer Ansgar B
Published: February 2021

The functional amyloid Orb2 belongs to the cytoplasmic polyadenylation element binding (CPEB) protein family and plays an important role in long-term memory formation inDrosophila. The Orb2 domain structure combines RNA recognition motifs with low complexity sequences similar to many RNA binding proteins shown to form protein droplets via liquid-liquid phase separation (LLPS) in vivo and in vitro. This similarity suggests that Orb2 might also undergo LLPS. However, cellular Orb2 puncta have very little internal protein mobility and Orb2 forms fibrils inDrosophilabrains that are functionally active indicating that LLPS might not play a role for Orb2. In the present work, we reconcile these two views on Orb2 droplet formation. We show that soluble Orb2 can indeed phase separate into protein droplets. However, these droplets have either no or only an extremely short-lived liquid phase and appear maturated right after formation. For Orb2 fragments that lack the C-terminal RNA binding domain (RBD), droplet formation is a prerequisite for fibril formation of an otherwise stable monomeric Orb2 solution. Solid-state NMR shows that these fibrils have additional well ordered static domains beside the Gln/His-rich fibril core. Further, we find that full-length Orb2B, which is by far the major component of Orb2 fibrils in vivo, does not transition into cross-β fibrils but remains in the droplet phase. Together, our data suggest that phase separation might play a role in initiating the formation of functional Orb2 fibrils.
Individual variation in brain structural-cognition relationships in aging
Authors: Patel Raihaan , Mackay Clare E. , Jansen Michelle G. , Devenyi Gabriel A. , O’Donoghue M. Clare , Kivimäki Mika , Singh-Manoux Archana , Zsoldos Enikő , Ebmeier Klaus P. , Chakravarty M. Mallar , Suri Sana
Published: February 2021

The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ±4.9 years) and late-life (mean age = 67.7 ±4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ±4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive declineandmaintenance across diverse cognitive functions that are both positively and negatively associated with cortical structure.
Defining the transcriptional signature of esophageal-to-skin lineage conversion
Authors: Bejar Maria T. , Jimenez-Gomez Paula , Moutsopoulos Ilias , Colom Bartomeu , Han Seungmin , Calero-Nieto Fernando J , Göttgens Berthold , Mohorianu Irina , Simons Benjamin D. , Alcolea Maria P.
Published: February 2021

The ability of epithelial cells to rewire their cell fate program beyond their physiological repertoire has become a new paradigm in stem cell biology. This plasticity leaves behind the concept of strict stem cell hierarchies, opening up new exciting questions about its limits and underlying regulation. Here we developed a heterotypic 3D culture system to study the mechanisms modulating changes in the identity of adult esophageal epithelial cells. We demonstrate that, when exposed to the foreign stroma of adult skin, esophageal cells transition towards hair follicle identity and architecture. Heterotypic transplantation experiments recapitulated this cell fate conversion processin vivo. Single-cell RNA sequencing and histological analysis, capturing the temporality of this process, reveal that most esophageal cells switching towards skin identity remain in an intermediate state marked by a transient regenerative profile and a particularly strong hypoxic signature. Inhibition of HIF1a establishes the central role of this pathway in regulating epithelial cell plasticity, driving cells away from their transition state in favor of cell fate conversion.
Genetic diversification of persistentMycobacterium abscessuswithin Cystic Fibrosis patients
Authors: Lewin Astrid , Kamal Elisabeth , Semmler Torsten , Winter Katja , Kaiser Sandra , Schäfer Hubert , Mao Lei , Eschenhagen Patience , Grehn Claudia , Schwarz Carsten
Published: February 2021

Mycobacterium (M.) abscessusinfections in Cystic Fibrosis (CF) patients cause a deterioration of lung function. Treatment of these multidrug-resistant pathogens is associated with severe side-effects, while frequently unsuccessful. Insight onM. abscessusgenomic evolvement during chronic lung infection would be beneficial for improving treatment strategies. A longitudinal study enrolling 42 CF patients was performed at a CF center in Berlin, Germany, to elaborate phylogeny and genomic diversification of in-patientM. abscessus. Eleven of the 42 CF patients were infected withM. abscessus. Global human-transmissibleM. abscessuscluster strains were isolated from five of these 11 patients. Phylogenetic analysis of 88 genomes from isolates of the 11 patients excluded occurrence ofM. abscessustransmission among members of the study group. Genome sequencing and variant analysis of 30 isolates from 11 serial respiratory samples collected over four years from a chronically infected patient demonstrated accumulation of gene mutations. In total, 53 genes exhibiting non-synonymous variations were identified. Enrichment analysis emphasized genes involved in synthesis of glycopeptidolipids, genes from theembABC(arabinosyltransferase) operon,betA(glucose-methanol-choline oxidoreductase) andchoD(cholesterol oxidase). Genetic diversity evolved in a variety of virulence- and resistance-associated genes. The strategy ofM. abscessuspopulations in chronic lung infection is not clonal expansion of dominant variants, but to sustain simultaneously a wide range of genetic variants facilitating adaptation of the population to changing living conditions in the lung. Genomic diversification during chronic infection requires increased attention when new control strategies againstM. abscessusinfections are explored.
An Interpretable Deep Learning Approach for Biomarker Detection in LC-MS Proteomics Data
Authors: Iravani Sahar , Conrad Tim O.F.
Published: February 2021

Analyzing mass spectrometry-based proteomics data with deep learning (DL) approaches poses several challenges due to the high dimensionality, low sample size, and high level of noise. Additionally, DL-based workflows are often hindered to be integrated into medical settings due to the lack of interpretable explanation. We present DLearnMS, a DL biomarker detection framework, to address these challenges on proteomics instances of liquid chromatography-mass spectrometry (LC-MS) - a well-established tool for quantifying complex protein mixtures. Our DLearnMS framework learns the clinical state of LC-MS data instances using convolutional neural networks. Based on the trained neural networks, we show how biomarkers can be identified using layer-wise relevance propagation. This enables detecting discriminating regions of the data and the design of more robust networks. One of the main advantages over other established methods is that no explicit preprocessing step is needed in our DLearnMS framework.

Our evaluation shows that DLearnMS outperforms conventional LC-MS biomarker detection approaches in identifying fewer false positive peaks while maintaining a comparable amount of true positives peaks.

Code availability

The code is available from the following GIT repository:https://github.com/SaharIravani/DlearnMS
Time series models for prediction of Leptospirosis in different climate zones in Sri Lanka
Authors: Warnasekara Janith , Agampodi SB , Abeynayake R
Published: February 2021

In tropical countries such as Sri Lanka, where leptospirosis—a deadly disease with a high mortality rate—is endemic, prediction is required for public health planning and resource allocation. Routinely collected meteorological data may offer an effective means of making such predictions. This study included monthly leptospirosis and meteorological data from January 2007 to April 2019 from Sri Lanka. Factor analysis was used first with rainfall data to classify districts into meteorological zones. We used a seasonal autoregressive integrated moving average (SARIMA) model for univariate predictions and autoregressive distributed lag (ARDL) model for multivariable analysis of leptospirosis with monthly average rainfall, temperature, relative humidity (RH), solar radiation (SR) and the number of rainy days/month (RD). Districts were classified into wet (WZ) and dry (DZ) zones and highlands (HL) based on the factor analysis of rainfall data. The WZ had the highest leptospirosis incidence; there was no difference in the incidence between the DZ and HL. Leptospirosis was fluctuated positively with rainfall, RH and RD, whereas temperature and SR were fluctuated negatively. ARIMA(1,0,0)(0,1,1)12, ARIMA(1,0,0)(1,1,1)12, and ARIMA(0,1,1)(0,1,1)12were the best univariate models for DZ, WZ, and HL, respectively. Despite its known association, rainfall was positively significant in the WZ only at lag 5 (P= 0.03) but was negatively associated at lag 2 and 3 (P= 0.04). RD was positively associated for all three zones. Temperature was positively associated at lag 0 for the WZ and HL (P< 0.009) and was negatively associated at lag 1 for the WZ (P= 0.01). There was no association with RH in contrast to previous studies. Based on altitude and rainfall data, meteorological variables could effectively predict the incidence of leptospirosis with different models for different climatic zones. These predictive models could be effectively used in public health planning purposes.
Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo
Authors: Saenz Steven A. , Local Andrea , Carr Tiffany , Shakya Arvind , Koul Shivsmriti , Hu Haiqing , Chourb Lisa , Stedman Justin , Malley Jenna , D’Agostino Laura Akullian , Shanmugasundaram Veerabahu , Malona John , Schwartz Eric , Beebe Lisa , Clements Meghan , Rajaraman Ganesh , Cho John , Jiang Lan , Dubrovskiy Alex , Kreilein Matt , Shimanovich Roman , Hamann Lawrence G. , Escoubet Laure , Ellis J. Michael
Published: February 2021

Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenancein vitroand Th17-dependent inflammation and associated gene expressionin vivo, in a dose-dependent manner. Finally, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids.
Juvenile Huntington’s Disease and Other PolyQ diseases, Update on Neurodevelopmental Character and Comparative Bioinformatic Review of Transcriptomic Data
Authors: Świtońska-Kurkowska Karolina , Krist Bart , Delimata Joanna Maria , Figiel Maciej
Published: February 2021

Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington’s disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.
Genetic manipulation using hepatocyte-targeting adeno-associated viral vectors has minimal off-target effects
Authors: Kiourtis Christos , Wilczynska Ania , Nixon Colin , Clark William , May Stephanie , Bird Thomas G
Published: February 2021

Mice are a widely used pre-clinical model system in large part due to their potential for genetic manipulation. The ability to manipulate gene expression in specific cells under temporal control is a powerful experimental tool. The liver is central to metabolic homeostasis and a site of many diseases, making the targeting of hepatocytes attractive. Adeno-Associated Virus 8 (AAV8) vectors are valuable instruments for the manipulation of hepatocellular gene expression. However, their off-target effects in mice have not been thoroughly explored. Here, we sought to identify the short-term off-target effects of AAV8 administration in mice. To do this, we injected C57BL/6J Wild-Type mice with either recombinant AAV8 vectors expressing Cre recombinase or empty AAV8 vectors and characterised the changes in general health and in liver physiology, histology and transcriptomics compared to uninjected controls over 1 week. We observed an acute and transient reduction in homeostatic liver proliferation together with induction of the DNA damage marker γH2AX following AAV8 administration. The latter was enhanced upon Cre recombinase expression by the vector. Furthermore, we observed transcriptional changes in genes involved in circadian rhythm and response to infection. Notably, there were no additional transcriptomic changes upon expression of Cre recombinase by the AAV8 vector. Overall, there was no evidence of liver injury, dysfunction or leukocyte infiltration following AAV8 infection. These data support the use of AAV8-based Cre recombinase delivery as a specific tool for hepatocellular gene manipulation with minimal effects on murine physiology but highlight the off target effects of these systems.

Summary statement

This paper provides a comprehensive characterisation of the short-term effects of administration of Adeno-Associated Virus 8 on murine physiology, liver histology and liver transcriptome.
The molecular infrastructure of glutamatergic synapses in the mammalian forebrain
Authors: Peukes J. , Lovatt C. , Leistner C. , Boulanger J. , Morado D. R. , Fuller M. J. G. , Kukulski W. , Zhu F. , Komiyama N. H. , Briggs J. A. G. , Grant S. G. N. , Frank R.
Published: February 2021

Glutamatergic synapses form the vast majority of connections within neuronal circuits, but how these subcellular structures are molecularly organized within the mammalian brain is poorly understood. Conventional electron microscopy using chemically fixed, metal-stained tissue has identified a proteinaceous, membrane-associated thickening called the ‘postsynaptic density’ (PSD). Here, we combined mouse genetics and cryo-electron tomography to determine the 3D molecular architecture of fresh isolated and anatomically intact synapses in the adult forebrain. The native glutamatergic synapse did not consistently show a high density of proteins at the postsynaptic membrane thought to be characteristic of the PSD. Instead, a ‘synaptoplasm’ consisting of cytoskeletal elements, macromolecular complexes and membrane-bound organelles extended throughout the pre- and post-synaptic compartments. Snapshots of active processes gave insights into membrane remodeling processes. Clusters of 4-60 ionotropic glutamate receptors were positioned inside and outside the synaptic cleft. Together, these information-rich tomographic maps present a detailed molecular framework for the coordinated activity of synapses in the adult mammalian brain.
A photoswitchable GPCR-based opsin for presynaptic silencing
Authors: Copits Bryan A. , O’Neill Patrick R. , Gowrishankar Raaj , Yoo Judy J. , Meshik Xenia , Parker Kyle E. , Spangler Skylar M. , Vasquez Alexis M. , Elerding Abigail J. , Stander M. Christine , Kalyanaraman Vani , Vogt Sherri K. , Samineni Vijay K. , Gautam N. , Sunahara Roger K. , Gereau Robert W. , Bruchas Michael R.
Published: February 2021

Optical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, rapid and reversible synaptic inhibition has been far more difficult to achieve. Instead of relying on unpredictable ion manipulations or slow photoactivatable toxins at axon terminals, we took a different approach to leverage the natural ability of inhibitory presynaptic GPCRs to silence synaptic transmission. Here we characterize parapinopsin (PPO), a photoswitchable non-visual opsin from lamprey pineal gland that couples to Gi/o-signaling cascades. PPO can be rapidly activated by pulsed blue light, switched off with amber light, and is effective for repeated or prolonged inhibition. We developed viral vectors for cell-specific expression of PPO, which traffics very effectively in numerous neuron types. At presynaptic terminals, PPO can silence glutamate release and suppress dopamine-dependent reward and cocaine place preference behaviorsin vivo. PPO immediately fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition, and has broader utility for achieving spatiotemporal control of inhibitory GPCR signaling cascades in other biological and pharmacological applications.
Precision Diffusion Imaging
Authors: Seider Nicole A , Adeyemo Babatunde , Miller Ryland , Newbold Dillan J , Hampton Jacqueline M , Scheidter Kristen M , Rutlin Jerrel , Laumann Timothy O , Roland Jarod L , Montez David F , Van Andrew N , Zheng Annie , Marek Scott , Kay Benjamin P , Bretthorst G Larry , Schlaggar Bradley L , Greene Deanna J , Wang Yong , Petersen Steven E , Gordon Evan M , Snyder Abraham Z , Shimony Joshua S , Dosenbach Nico U F
Published: February 2021

Diffusion tensor imaging (DTI) aims to non-invasively characterize the anatomy and integrity of the brain’s white matter fibers. To establish individual-specific precision approaches for DTI, we defined its reliability and accuracy as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927-1442 diffusion weighted images [DWIs] per individual). DTI methods that allow for crossing fibers (BedpostX [BPX], Q-Ball Imaging [QBI]) estimated excess fibers when insufficient data was present and when the data did not match the model priors. To reduce such overfitting, we developed a novel crossing-fiber diffusion imaging method, Bayesian Multi-tensor Model-selection (BaMM), that is designed for high-quality repeated sampling data sets. BaMM was robust to overfitting, showing high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, the choice of diffusion imaging analysis method is important for the success of individual-specific diffusion imaging. Importantly, for potential clinical applications of individual-specific precision DTI, such as deep brain stimulation (DBS), other forms of neuromodulation or neurosurgical planning, the data quantities required to achieve DTI reliability are lower than for functional MRI measures.
Effect of membrane cholesterol on dynamical properties of solvent molecules
Authors: Rahmaninejad Hadi , Vaughan Darin D.
Published: February 2021

Membrane lipid composition is a critical feature of cell function, where cholesterol is a major lipid sterol component that influences the membranes physical and electrical properties. The effects of cholesterol on transport properties between adjacent to the cells, especially in junctions formed between cells is not completely understood. These junctions where substances transport and signaling is critical may be affected by modifying the cholesterol composition of the membrane in these junctional regions. Here we show how the cholesterol content in a membrane can regulate these phenomena by changing their effect on transport into and through regions between cell membranes in close proximity. Through geometric and electrostatic effects interaction with substrates, the properties of the fluid between membranes are shown to potentially enforce concentration gradients of dissolved compounds that may be biologically significant.
Supportive employment practices: perspectives of autistic employees
Authors: Hedley Darren , Spoor Jennifer R. , Cai Ru Ying , Uljarevic Mirko , Bury Simon , Gal Eynat , Moss Simon , Richdale Amanda , Bartram Timothy , Dissanayake Cheryl
Published: February 2021

Purpose

Employment can make an important contribution to individual well-being, for example, by providing people with a sense of purpose; however, autistic individuals face significant barriers to entering the workforce. This is reflected in high levels of underemployment and unemployment, with an estimated 80% of autistic people unemployed worldwide. This is higher than both other disability groups and people without disabilities. Research is needed to identify strategies that facilitate the sustained employment of autistic adults. This study aims to examine the perspectives of autistic individuals participating in a specialized employment program within the information and communication technology sector.

Design/methodology/approach

Three focus groups were conducted with nine adults on the autism spectrum. Data were analyzed using an inductive approach according to established guidelines, which included coding and categorizing data into themes.

Findings

Focus group analysis revealed four themes: trainees’ previous work experiences; expectations of the employment program; recruitment and selection processes; and training and transition. Several factors associated with the changes to the recruitment and selection process were found to benefit the autistic employees.

Originality/value

Few studies have characterized the work experiences of adults on the autism spectrum. Tailored employment processes that challenge traditional human resource management practices can increase the participation of autistic individuals in the workforce. Strategies for promoting the success of these programs are discussed.
A moderated mediation model of idiosyncratic deals and innovative performance of R&D employees: roles of vitality
Authors: Huang Yufang , Chen Xin
Published: February 2021

Purpose

As personalized work arrangements, idiosyncratic deals can activate employees’ energy and thus affect their innovative performance. The purpose of this study was to examine whether employee vitality mediates the relationships between two different types of idiosyncratic deals and the innovative performance of employees and whether the mediating effects are moderated by employees’ age.

Design/methodology/approach

Matched data were collected from 620 employees and their direct supervisors who work in two large Chinese technology R&D organizations.

Findings

Results indicate that two different types of i-deals (task and work responsibilities i-deals and flexibility i-deals) are positively related to the innovative performance of employees and that vitality mediates those relationships. Further, chronological age enhances the positive relationship between task and work responsibilities i-deals and vitality, and it enhances the indirect effect that task and work responsibilities i-deals relate to the innovative performance of employees through vitality. However, the results of this study indicate that the moderating effect of chronological age on flexibility i-deals and vitality, as well as the moderated mediation effects of vitality on the relationship between flexibility i-deals and the innovative performance of employees, did not meet the standard for significance.

Originality/value

Based on the cognitive evaluation theory, this study explores more deeply the mechanism by which task and work responsibilities i-deals and flexibility i-deals activate employees’ energy and thus influence their innovative performance. In addition, this study comprehensively considers the moderating effect of chronological age, an important demographic variable, on the mechanism of idiosyncratic deals.
Assessing the hotel service robot interaction on tourists' behaviour: the role of anthropomorphism
Authors: Jia Jing Wen , Chung Namho , Hwang Jooyoung
Published: February 2021

Purpose

The main purpose of this study is to investigate the impact of service robots on hotel visitors' behaviour and to verify the role of anthropomorphism(human likeness) in customer satisfaction with robots.

Design/methodology/approach

An online survey of 381 respondents was conducted, divided into three types of robots according to the level of anthropomorphism. The research model was thoroughly tested using the PLS-SEM method. Research model was tested thoroughly using the PLS-SEM method.

Findings

This study found that user satisfaction with service robots in a hotel had a positive impact on user satisfaction, attitude towards the hotel and room purchase intention. Moreover, our results showed that users were most likely to accept medium-human likeness robots and least likely to accept high–human likeness robots.

Originality/value

This study proposes influencing factors to be considered when researching hotel service robots, as well as practical suggestions for any hotel intending to use or currently using a service robot.
Measuring productivity of dairy industry companies: an approach with data envelopment analysis
Authors: Ruales Guzmán Bertha Viviana , Rodríguez Lozano Gloria Isabel , Castellanos Domínguez Oscar Fernando
Published: February 2021

Purpose

This research had two main objectives: To measure the productivity of companies in the Colombian dairy industry and to identify efficient decision-making units (DMUs) that can be used as work sample in future case studies.

Design/methodology/approach

In the measurement of productivity, financial variables were considered for a sample of 19 DMUs. Efficient companies were identified through the data envelopment analysis (DEAs) methodology with the VRS model oriented to inputs and outputs. The input variables analyzed were “current asset,” “property, plant and equipment,” “non-current liability” and “equity,” while the output variables were “revenue” and “profit.”

Findings

Findings revealed that seven DMUs are efficient in the input and output orientation and that companies of different sizes and with or without quality certifications are efficient in the sample analyzed. Additionally, the benchmark efficient DMUs were identified for each of the non-efficient DMUs.

Research limitations/implications

The implications for the research include the contribution to the theory, on the one hand, with the analysis of the current state of the literature on the use of DEA in the food sector, and on the other, with the use of DEA to measure the productivity of Colombian dairy industry companies and with the identification of a sample of efficient units that can be analyzed in future case studies.

Originality/value

This article is novel and pioneering because it measures for the first time the productivity of DMUs of the Colombian dairy industry, in addition to including the current state of the literature on the application of the DEA methodology in the food sector. These findings contribute to the consolidation of the theory and also provide inputs for researchers, practitioners, managers, and policy makers.
Contextualising risk: the unfolding information work and practices of people during the COVID-19 pandemic
Authors: Lloyd Annemaree , Hicks Alison
Published: February 2021

Purpose

The aim of this study is to investigate people's information practices as the SARS-CoV-2 virus took hold in the UK. Of particular interest is how people transition into newly created pandemic information environments and the ways information literacy practices come into view.

Design/methodology/approach

The qualitative research design comprised one-to-one in-depth interviews conducted virtually towards the end of the UK's first lockdown phase in May–July 2020. Data were coded and analysed by the researchers using constant comparative and situated analysis techniques.

Findings

Transition into new pandemic information environments was shaped by an unfolding phase, an intensification phase and a stable phase. Information literacy emerged as a form of safeguarding as participants engaged in information activities designed to mitigate health, legal, financial and well-being risks produced by the pandemic.

Research limitations/implications

Time constraints meant that the sample from the first phase of this study skewed female.

Practical implications

Findings establish foundational knowledge for public health and information professionals tasked with shaping public communication during times of crisis.

Social implications

This paper contributes to understandings of the role that information and information literacy play within global and long-term crises.

Originality/value

This is one of the first studies to explore information practices during the COVID-19 pandemic.