bluuebunny/crossref_metadata_2025_split huggingface dataset:
The enhancement of activity rescues the establishment ofMecp2null neuronal phenotypes
Authors: Scaramuzza Linda , De Rocco Giuseppina , Desiato Genni , Gigli Clementina Cobolli , Chiacchiaretta Martina , Mirabella Filippo , Pozzi Davide , De Simone Marco , Conforti Paola , Pagani Massimiliano , Benfenati Fabio , Cesca Fabrizia , Bedogni Francesco , Landsberger Nicoletta 
Published: April 2020

AbstractMecp2deficiency, the gene responsible for Rett syndrome (RTT), affects brain maturation by impairing neuronal activity, transcription and morphology. These three elements are physiologically linked in a feed-forward cycle where neuronal activity modulates transcription and morphology to further increase network maturity. We hypothesized that the reduced activity displayed by maturingMecp2null neurons during development could perturb such cycle, sustaining an improper transcriptional program that, ultimately, impairs neuronal maturation. Accordingly, we show that by enhancing activity within an early time window, Ampakine redirects,in vitro, the development of null neuronal networks towards more physiological routes. Similarly, the administration of the drug to newborn null offspring delays the progression of symptoms, significantly prolonging life span. Our data highlights the role of altered neuronal activity during the establishment ofMecp2null networks and the importance of such early defects to the typically poor maturity of RTT brain functions in adulthood. We propose the existence of an “early molecular phase” of Rett syndrome, a detailed description of which might disclose relevant targets for new rescue treatments.
Therapeutic Reversal of Chemically Induced Parkinson Disease by Converting Astrocytes into Nigral Neurons
Authors: Qian Hao , Hu Jing , Zhang Dongyang , Meng Fan , Zhang Xuan , Xue Yuanchao , Devaraj Neal K. , Dowdy Steven F. , Mobley William C. , Cleveland Don W. , Fu Xiang-Dong 
Published: April 2020

SUMMARYParkinson disease is characterized by loss of dopamine neurons in the substantia nigra. As with other neurodegenerative diseases, no disease-modifying treatments exist. While most treatment objectives aim to prevent neuronal loss or protect vulnerable neuronal circuits, an important alternative is to replace lost neurons to reconstruct disrupted circuits. Herein we report an efficient single-step conversion of isolated mouse and human astrocytes into functional neurons by depleting the RNA binding protein PTB. Applying this approach to mice with a chemically induced Parkinson’s phenotype, we provide evidence that disease manifestations can be potently reversed through converting astrocytes into new substantia nigral neurons, effectively restoring dopamine levels via reestablishing the nigrostriatal dopamine pathway. We further demonstrate similar disease reversal with a therapeutically feasible approach using antisense oligonucleotides to transiently suppress PTB. These findings identify a generalizable therapeutic strategy for treating neurodegenerative disorders through replacing lost neurons in the brain.
Post-transcriptional splicing can occur in a slow-moving zone around the gene
Authors: Coté Allison , O’Farrell Aoife , Dardani Ian , Dunagin Margaret , Coté Chris , Wan Yihan , Bayatpour Sareh , Drexler Heather L. , Alexander Katherine A. , Chen Fei , Wassie Asmamaw T. , Patel Rohan , Pham Kenneth , Boyden Edward S. , Berger Shelley , Phillips-Cremins Jennifer , Churchman L. Stirling , Raj Arjun 
Published: April 2020

AbstractSplicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription site proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.
A highly efficient protocol for transformingCuscuta reflexabased on artificially induced infection sites
Authors: Lachner Lena Anna-Maria , Galstyan Levon , Krause Kirsten 
Published: April 2020

ABSTRACTA current bottleneck in the functional analysis of the emerging parasitic model plantCuscutaand the exploitation of its recently sequenced genomes is the lack of efficient transformation tools. Here, we describe the development of a novel highly efficientAgrobacterium-mediated transformation protocol forCuscuta reflexabased on the parasitic structure referred to as adhesive disk. Both,Agrobacterium rhizogenesandAgrobacterium tumefacienscarrying binary transformation vectors with reporter fluorochromes yielded high numbers of transformation events. An overwhelming majority of transformed cells were observed in the cell layer below the adhesive disk’s epidermis, suggesting that these cells are particularly susceptible to infection. Co-transformation of these cells happens frequently whenAgrobacteriumstrains carrying different constructs are applied together. Explants containing transformed tissue expressed the fluorescent markers inin vitroculture for several weeks, offering a possibility for development of transformed cells into callus.ONE SENTENCE SUMMARYA protocol that yields high numbers of transformed cells in the adhesive disks ofCuscuta reflexaupon exposure to agrobacteria brings closer the vision of generating genetically modifiedCuscuta.
Precise, high-throughput production of multicellular spheroids with a bespoke 3D bioprinter
Authors: Utama Robert H. , Atapattu Lakmali , O’Mahony Aidan P. , Fife Christopher M. , Baek Jongho , Allard Théophile , O’Mahony Kieran J. , Ribeiro Julio , Gaus Katharina , Kavallaris Maria , Gooding J. Justin 
Published: April 2020

Abstract3Din vitrocancer models are important therapeutic and biological discovery tools, yet formation of multicellular spheroids in a throughput and highly controlled manner to achieve robust and statistically relevant data, remains challenging. Here, we developed an enabling technology consisting of a bespoke drop-on-demand 3D bioprinter capable of high-throughput printing of 96-well plates of spheroids. 3D-multicellular spheroids are embedded inside a tissue-like matrix with precise control over size and cell number. Application of 3D bioprinting for high-throughput drug screening was demonstrated with doxorubicin. Measurements showed that IC50values were sensitive to spheroid size, embedding and how spheroids conform to the embedding, revealing parameters shaping biological responses in these models. Our study demonstrates the potential of 3D bioprinting as a robust high-throughput platform to screen biological and therapeutic parameters.Significance StatementIn vitro3D cell cultures serve as more realistic models, compared to 2D cell culture, for understanding diverse biology and for drug discovery. Preparing 3D cell cultures with defined parameters is challenging, with significant failure rates when embedding 3D multicellular spheroids into extracellular mimics. Here, we report a new 3D bioprinter we developed in conjunction with bioinks to allow 3D-multicellular spheroids to be produced in a high-throughput manner. High-throughput production of embedded multicellular spheroids allowed entire drug-dose responses to be performed in 96-well plate format with statistically relevant numbers of data points. We have deconvoluted important parameters in drug responses including the impact of spheroid size and embedding in an extracellular matrix mimic on IC50values.
Efficient and Practical Sample Pooling for High-Throughput PCR Diagnosis of COVID-19
Authors: Shani-Narkiss Haran , Gilday Omri David , Yayon Nadav , Landau Itamar Daniel 
Published: April 2020

AbstractIn the global effort to combat the COVID-19 pandemic, governments and public health agencies are striving to rapidly increase the volume and rate of diagnostic testing. The most common form of testing today employs Polymerase Chain Reaction in order to identify the presence of viral RNA in individual patient samples one by one. This process has become one of the most significant bottlenecks to increased testing, especially due to reported shortages in the chemical reagents needed in the PCR reaction.Recent technical advances have enabled High-Throughput PCR, in which multiple samples are pooled into one tube. Such methods can be highly efficient, saving large amounts of time and reagents. However, their efficiency is highly dependent on the frequency of positive samples, which varies significantly across regions and even within regions as testing criterion and conditions change.Here, we present two possible optimized pooling strategies for diagnostic SARS-CoV-2 testing on large scales, both addressing dynamic conditions. In the first, we employ a simple information-theoretic heuristic to derive a highly efficient re-pooling protocol: an estimate of the target frequency determines the initial pool size, and any subsequent pools found positive are re-pooled at half-size and tested again. In the range of very rare target (<0.05), this approach can reduce the number of necessary tests dramatically, for example, achieving a reduction by a factor of 50 for a target frequency of 0.001. The second method is a simpler approach of optimized one-time pooling followed by individual tests on positive pools. We show that this approach is just as efficient for moderate target-product frequencies (0.05<0.2), for example, achieving a two-fold in the number of when the frequency of positive samples is 0.07.These strategies require little investment, and they offer a significant reduction in the amount of materials, equipment and time needed to test large numbers of samples. We show that both these pooling strategies are roughly comparable to the absolute upper-bound efficiency given by Shannon’s source coding theorem. We compare our strategies to the naïve way of testing and to alternative matrix-pooling methods. Most importantly, we offer straightforward, practical pooling instructions for laboratories that perform large scale PCR assays to diagnose SARS-CoV-2 viral particles. These two pooling strategies may offer ways to alleviate the bottleneck currently preventing massive expansion of SARS-CoV-2 testing around the world.
Proteomic and Metabolomic Characterization of COVID-19 Patient Sera
Authors: Shen Bo , Yi Xiao , Sun Yaoting , Bi Xiaojie , Du Juping , Zhang Chao , Quan Sheng , Zhang Fangfei , Sun Rui , Qian Liujia , Ge Weigang , Liu Wei , Liang Shuang , Chen Hao , Zhang Ying , Li Jun , Xu Jiaqin , He Zebao , Chen Baofu , Wang Jing , Yan Haixi , Zheng Yufen , Wang Donglian , Zhu Jiansheng , Kong Ziqing , Kang Zhouyang , Liang Xiao , Ding Xuan , Ruan Guan , Xiang Nan , Cai Xue , Gao Huanhuan , Li Lu , Li Sainan , Xiao Qi , Lu Tian , Zhu Yi , Liu Huafen , Chen Haixiao , Guo Tiannan 
Published: April 2020

SUMMARYSevere COVID-19 patients account for most of the mortality of this disease. Early detection and effective treatment of severe patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model correctly classified severe patients with an accuracy of 93.5%, and was further validated using ten independent patients, seven of which were correctly classified. We identified molecular changes in the sera of COVID-19 patients implicating dysregulation of macrophage, platelet degranulation and complement system pathways, and massive metabolic suppression. This study shows that it is possible to predict progression to severe COVID-19 disease using serum protein and metabolite biomarkers. Our data also uncovered molecular pathophysiology of COVID-19 with potential for developing anti-viral therapies.
A Simulated Single Ventilator / Dual Patient Ventilation Strategy for Acute Respiratory Distress Syndrome During the COVID-19 Pandemic
Authors: Solís-Lemus José A. , Costar Edward , Doorly Denis , Kerrigan Eric C. , Kennedy Caroline H. , Tait Frances , Niederer Steven , Vincent Peter E. , Williams Steven E. 
Published: April 2020

AbstractThe potential for acute shortages of ventilators at the peak of the Covid-19 pandemic has raised the possibility of needing to support two patients from a single ventilator. To provide a system for understanding and prototyping designs we have developed a mathematical model of two patients supported by a mechanical ventilator. We propose a standard setup where we simulate the introduction of T-splitters to supply air to two patients and a modified setup where we introduce a variable resistance in each inhalation pathway and one-way valves in each exhalation pathway. Using the standard setup, we demonstrate that ventilating two patients with mismatched lung compliances from a single ventilator will lead to clinically-significant reductions in tidal volume in the patient with the lowest respiratory compliance. Using the modified setup, we demonstrate that it could be possible to achieve the same tidal volumes in two patients with mismatched lung compliances, and we show that the tidal volume of one patient can be manipulated independently of the other. The results indicate that, with appropriate modifications, two patients could be supported from a single ventilator with independent control of tidal volumes.
Organisational plasticity: can we really model human–agent behaviours?
Authors: Richards Dale 
Published: April 2020

PurposeThe ability for an organisation to adapt and respond to external pressures is a beneficial activity towards optimising efficiency and increasing the likelihood of achieving set goals. It can also be suggested that this very ability to adapt to one's surroundings is one of the key factors of resilience. The nature of dynamically responding to sudden change and then to return to a state that is efficient may be termed as possessing the characteristic of plasticity. Uses of agent-based systems in assisting in organisational processes may have a hand in facilitating an organisations' plasticity, and computational modelling has often been used to try and predict both agent and human behaviour. Such models also promise the ability to examine the dynamics of organisational plasticity through the direct manipulation of key factors. This paper discusses the use of such models in application to organisational plasticity and in particular the relevance to human behaviour and perception of agent-based modelling. The uses of analogies for explaining organisational plasticity is also discussed, with particular discussion around the use of modelling. When the authors consider the means by which the authors can adopt theories to explain this type of behaviour, models tend to focus on aspects of predictability. This in turn loses a degree of realism when we consider the complex nature of human behaviour, and more so that of human–agent behaviour.Design/methodology/approachThe methodology and approach used for this paper is reflected in the review of the literature and research.FindingsThe use of human–agent behaviour models in organisational plasticity is discussed in this paper.Originality/valueThe originality of this paper is based on the importance of considering the human–agent-based models. When compared to agent-based model approaches, analogy is used as a narrative in this paper.
Effect of the initial conditions on a one-dimensional model of small-amplitude wave propagation in shallow water
Authors: Ramos J.I. , García López Carmen María 
Published: April 2020

Purpose
The purpose of this paper is to determine both analytically and numerically the solution to a new one-dimensional equation for the propagation of small-amplitude waves in shallow waters that accounts for linear and nonlinear drift, diffusive attenuation, viscosity and dispersion, its dependence on the initial conditions, and its linear stability.

Design/methodology/approach
An implicit, finite difference method valid for both parabolic and second-order hyperbolic equations has been used to solve the equation in a truncated domain for five different initial conditions, a nil initial first-order time derivative and relaxation times linearly proportional to the viscosity coefficient.

Findings
A fast transition that depends on the coefficient of the linear drift, the diffusive attenuation and the power of the nonlinear drift are found for initial conditions corresponding to the exact solution of the generalized regularized long-wave equation. For initial Gaussian, rectangular and triangular conditions, the wave’s amplitude and speed increase as both the amplitude and the width of these conditions increase and decrease, respectively; wide initial conditions evolve into a narrow leading traveling wave of the pulse type and a train of slower oscillatory secondary ones. For the same initial mass and amplitude, rectangular initial conditions result in larger amplitude and velocity waves of the pulse type than Gaussian and triangular ones. The wave’s kinetic, potential and stretching energies undergo large changes in an initial layer whose thickness is on the order of the diffusive attenuation coefficient.

Originality/value
A new, one-dimensional equation for the propagation of small-amplitude waves in shallow waters is proposed and studied analytically and numerically. The equation may also be used to study the displacement of porous media subject to seismic effects, the dispersion of sound in tunnels, the attenuation of sound because of viscosity and/or heat and mass diffusion, the dynamics of second-order, viscoelastic fluids, etc., by appropriate choices of the parameters that appear in it.
Social capital, labour market status and wages: some evidence from Spain
Authors: Caparrós Ruiz Antonio 
Published: April 2020

PurposeThis article analyses the social capital's influence on the Spanish labour market. In particular, this study examines to what extent the social capital increases the likelihood of being employed, taking into account different labour market status, and diverse dimensions of the social capital. Focusing on wage earners, it is also analysed whether network structures in Spain influence on the wage earnings.Design/methodology/approachThe methodology applied to analyse the labour market status is a multinomial logit model. For the analysis of wages, it is specified a wage model with sample selection bias. In both cases, social capital indicators are included as regressors.FindingsThe results show that social participation exerts a positive influence on the probability of being self-employed, and lowers the likelihood of being unemployed. Moreover, it is verified that the interaction with family members or close friends influence positively on wages.Research limitations/implicationsFurther research should emphasise how employers assess the workers' competences associated with the social capital.Practical implicationsThe findings provide knowledge to policymakers useful to increase the role of social participation in the labour market.Social implicationsThe importance of social network as an instrument for the job search must be enhanced.Originality/valueThis article overcomes some drawbacks associated with the analysis of social capital from an aggregate perspective. Furthermore, social capital indicators are obtained using the Categorical Principal Components Analysis (CATPCA), which is unprecedented in the economic literature.
No leader is an island: contextual antecedents to line managers' constructive and destructive leadership during an organizational intervention
Authors: Lundmark Robert , Nielsen Karina , Hasson Henna , von Thiele Schwarz Ulrica , Tafvelin Susanne 
Published: April 2020

PurposeLine managers can make or break organizational interventions, yet little is known about what makes them turn in either direction. As leadership does not occur in a vacuum, it has been suggested that the organizational context plays an important role. Building on the intervention and leadership literature, we examine if span of control and employee readiness for change are related to line managers' leadership during an organizational intervention.Design/methodology/approachLeadership is studied in terms of intervention-specific constructive, as well as passive and active forms of destructive, leadership behaviors. As a sample, we use employees (N = 172) from 37 groups working at a process industry plant. Multilevel analyses over two time points, with both survey and organizational register data were used to analyze the data.FindingsThe results revealed that span of control was negatively related to constructive leadership and positively related to passive destructive leadership during the intervention. Employee readiness for change was positively related to constructive leadership, and negatively related to both passive and active destructive leadership.Practical implicationsOur findings suggest that contextual factors need to be assessed and considered if we want line managers to engage in constructive rather than destructive leadership during interventions.Originality/valueThe present study is the first to address line managers' making or breaking of organizational interventions by examining the influence of context on both their destructive and constructive leadership.
The effects of social ties on innovation behavior and new product performance in emerging economies: evidence from Turkey
Authors: Yeniaras Volkan , Kaya Ilker , Ashill Nick 
Published: April 2020

PurposeThe purpose of this paper is to offer a theoretical and empirical understanding of how social ties affect innovation behavior and new product performance in Turkey, which is an emerging economy where high levels of economic and political uncertainties exist.The authors examine whether innovation behavior binds the political and business ties of the firm to new product performance. They also examine if these effects are contingent on variations in the institutional environment and market environment.Design/methodology/approachStructural equation modeling and mediation analyses were used on a sample of 344 small- and medium-sized enterprises in Istanbul.FindingsBusiness ties are positively related to exploratory innovation behavior and political ties hamper such behavior. The authors also show that government support hinders firms’ disruptive innovation while encouraging incremental innovation behavior. The authors further demonstrate that the positive and indirect relation of business ties to new product performance through exploratory and exploitative innovation is largely insensitive to changes in market and institutional environments. Political ties are negatively (positively) and indirectly related to new product performance through exploratory (exploitative) innovation.Practical implicationsManagers should choose the form of their personal interactions (political and/or business) based on the type of innovation that is being pursued. Additionally, managers should consider both the institutional environment and the market environment as important contingencies in their decision of whether to invest resources in developing social ties to build innovation behavior.Originality/valueThe authors offer a deeper perspective of how social ties in emerging economies affect new product performance by considering exploratory and exploitative innovation behavior as mediating mechanisms. These mediating effects are conditional on institutional and market environments.