bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sorption of neuropsychopharmaca in microfluidic materials for in-vitro studies
Authors: Winkler Thomas E. , Herland Anna 
Published: May 2021

ABSTRACTSorption (i.e., ad- & ab-sorption) of small-molecule compounds to polydimethylsiloxane (PDMS) is widely acknowledged. However, studies to date have largely been conducted under atypical conditions for microfluidic applications (lack of perfusion, lack of biological fluids); especially considering the biological studies such as Organs-on-Chips where small-molecule sorption poses the largest concern. Here, we present the first study of small-molecule sorption under relevant conditions for microphysiological systems, focusing on a standard geometry for biological barrier studies that find application in pharmacokinetics. We specifically assess the sorption of a compound panel including 15 neuropsychopharmaca at in-vivo concentration levels. We consider devices constructed from PDMS as well as two material alternatives (off-stoichiometry thiol-ene-epoxy, or tape/polycarbonate laminates). Moreover, we study the much-neglected impact of peristaltic pump tubing, an essential component of the recirculating systems required to achieve in-vivo-like perfusion shear stresses. We find that choice of device material does not significantly impact sorption behavior in our barrier-on-chip-type system. Our PDMS observations in particular suggest that excessive compound sorption observed in prior studies is not sufficiently described by compound hydrophobicity or other suggested predictors. Critically, we show that sorption by peristaltic tubing, including the commonly-utilized PharMed BPT, dominates over device sorption even on an area-normalized basis, let alone at the typically much larger tubing surface areas. Our findings highlight the importance of validating compound dosages in Organ-on-Chip studies, as well as the need for considering tubing materials with equal or higher care than device materials.
Actin dynamics as a multiscale integrator of cellular guidance cues
Authors: Bull Abby L. , Campanello Leonard , Hourwitz Matt J. , Yang Qixin , Zhao Min , Fourkas John T. , Losert Wolfgang 
Published: May 2021

AbstractCells are able to integrate multiple, and potentially competing, cues to determine a migration direction. For instance, in wound healing, cells follow chemical signals or electric fields to reach the wound edge, regardless of any local guidance cues. To investigate this integration of guidance cues, we monitor the actin-polymerization dynamics of immune cells in response to cues on a subcellular scale (nanotopography) and on the cellular scale (electric fields, EFs). In the fast, amoeboid-type migration, commonly observed in immune cells, actin polymerization at the cell’s leading edge is the driver of motion. The excitable systems character of actin polymerization leads to self-propagating, two-dimensional wavefronts that enable persistent cell motion. We show that EFs guide these wavefronts, leading to turning of cells when the direction of the EF changes. When nanoridges promote one-dimensional (1D) waves of actin polymerization that move along the ridges (esotaxis), EF guidance along that direction is amplified. 1D actin waves cannot turn or change direction, so cells respond to a change in EF direction by generating new 1D actin waves. At the cellular scale, the emergent response is a turning of the cell. For nanoridges perpendicular to the direction of the EF, the 1D actin waves are guided by the nanotopography, but both the average location of new actin waves and the whole cell motion are guided by the EF. Thus, actin waves respond to each cue on its intrinsic length scale, allowing cells to exhibit versatile responses to the physical microenvironment.Significance StatementEffective cell migration requires the integration of multiple, and sometimes competing, guidance cues. For instance, in wound healing, immune cells are guided towards a wound edge by long-range electrical and chemical cues that may conflict with guidance cues from the local environment. How cells combine and respond to such cues is not well understood. We demonstrate that multiple guidance mechanisms can act simultaneously, but on different scales. Nanotopography, a local mechanical cue, guides individual waves of actin polymerization, thereby biasing the direction cell motion on the time scale of these waves. An external electric field applied at the same time biases the locations of new waves of actin polymerization, leading to overall directed migration over long distance scales.
Adenovirus transduction to express human ACE2 causes obesity-specific morbidity in mice, impeding studies on the effect of host nutritional status on SARS-CoV-2 pathogenesis
Authors: Rai Pallavi , Chuong Christina , LeRoith Tanya , Smyth James W , Panov Julia , Levi Moshe , Kehn-Hall Kylene , Duggal Nisha K. , Lucarelli James-Weger 
Published: May 2021

AbstractThe COVID-19 pandemic has paralyzed the global economy and resulted in millions of deaths globally. People with co-morbidities like obesity, diabetes and hypertension are at an increased risk for severe COVID-19 illness. This is of overwhelming concern because 42% of Americans are obese, 30% are pre-diabetic and 9.4% have clinical diabetes. Here, we investigated the effect of obesity on disease severity following SARS-CoV-2 infection using a well-established mouse model of diet-induced obesity. Diet-induced obese and lean control C57BL/6N mice, transduced for ACE2 expression using replication-defective adenovirus, were infected with SARS-CoV-2, and monitored for lung pathology, viral titers, and cytokine expression. No significant differences in tissue pathology, viral replication or cytokine expression were observed between lean and obese groups. Notably, significant weight loss was observed in obese mice treated with the adenovirus vector, independent of SARS-CoV-2 infection, suggesting an obesity-dependent morbidity induced by the vector. These data indicate that the adenovirus-transduced mouse model of SARS-CoV-2 infection is inadequate for performing nutrition studies, and caution should be used when interpreting resulting data.
aCPSF1 in synergy with terminator U-tract dictates archaeal transcription termination efficiency via the KH domains recognizing U-tract
Authors: Li Jie , Yue Lei , Zhang Wenting , Li Zhihua , Zhang Bing , Zhao Fangqing , Dong Xiuzhu 
Published: May 2021

AbstractRecently, aCPSF1 was reported to function as the long-sought global transcription termination factor of archaea, while the working mechanism remains elusive. This work, through analyzing transcript-3′end-sequencing data of Methanococcus maripaludis, found positive correlations of both the terminator uridine(U)-tract and aCPSF1 with hierarchical transcription termination efficiencies (TTEs) at the genome-wide level. In vitro assays determined that aCPSF1 specifically binds to the terminator U-tract with U-tract number-related binding abilities, and in vivo assays demonstrated the two are indispensable in dictating high TTEs, revealing that aCPSF1 and the terminator U-tract in synergy determine high TTEs. The N-terminal KH domains equip aCPSF1 of specific binding to terminator U-tract and the in vivo aCPSF1-terminator U-tract synergism; aCPSF1’s nuclease activity was also required for TTEs. aCPSF1 also functioned as back-up termination for transcripts with weak intrinsic terminator signals. aCPSF1 orthologs from Lokiarchaeota and Thaumarchaeota exhibited similar U-tract synergy in dictating TTEs. Therefore, aCPSF1 and the intrinsic U-rich terminator could work in a noteworthy two-in-one termination mode in Archaea, which could be widely employed by archaeal phyla; using one factor recognizing U-rich terminator signal and cleaving transcript 3′-end, the archaeal aCPSF1-dependent transcription termination could display a simplified archetypal mode of the eukaryotic RNA polymerase II termination machinery.
Simple methods for quantifying super-resolved cortical actin
Authors: Garlick Evelyn , Faulkner Emma L. , Briddon Stephen J. , Thomas Steven G. 
Published: May 2021

AbstractCortical actin plays a key role in cell movement and division, but has also been implicated in the organisation of cell surface receptors such as G protein-coupled receptors. The actin mesh proximal to the inner membrane forms small fenced regions, or ‘corrals’, in which receptors can be constrained. Quantification of the actin mesh at the nanoscale has largely been attempted in single molecule datasets and electron micrographs. This work describes the development and validation of workflows for analysis of super resolved fixed cortical actin images obtained by both Super Resolved Radial Fluctuations (SRRF) and expansion microscopy (ExM). SRRF analysis was used to show a significant increase in corral area when treating cells with the actin disrupting agent cytochalasin D (increase of 0.31µm2 ± 0.04 SEM), and ExM analysis allowed for the quantitation of actin filament densities. Thus this work allows complex actin networks to be quantified from super-resolved images and is amenable to both fixed and live cell imaging.
Evolutionary systems biology reveals patterns of rice adaptation to drought-prone agro-ecosystems
Authors: Groen Simon C. , Joly-Lopez Zoé , Platts Adrian E. , Natividad Mignon , Fresquez Zoë , Mauck William M. , Quintana Marinell R. , Cabral Carlo Leo U. , Torres Rolando O. , Satija Rahul , Purugganan Michael D. , Henry Amelia 
Published: May 2021

ABSTRACTRice was domesticated around 10,000 years ago and has developed into a staple for half of humanity. The crop evolved and is currently grown in stably wet and intermittently dry agro-ecosystems, but patterns of adaptation to differences in water availability remain poorly understood. While previous field studies have evaluated plant developmental adaptations to water deficit, adaptive variation in functional and hydraulic components, particularly in relation to gene expression, has received less attention. Here, we take an evolutionary systems biology approach to characterize adaptive drought resistance traits across roots and shoots. We find that rice harbors heritable variation in molecular, physiological, and morphological traits that is linked to higher fitness under drought. We identify modules of co-expressed genes that are associated with adaptive drought avoidance and tolerance mechanisms. These expression modules showed evidence of polygenic adaptation in rice subgroups harboring accessions that evolved in drought-prone agro-ecosystems. Fitness-linked expression patterns had predictive value and allowed us to identify the drought-adaptive nature of optimizing photosynthesis and interactions with arbuscular mycorrhizal fungi. Taken together, our study provides an unprecedented, integrative view of rice adaptation to water-limited field conditions.
Differences in nanoscale organization of DNase I hypersensitive and insensitive chromatin in single human cells
Authors: Brandstetter Katharina , Zülske Tilo , Ragoczy Tobias , Hörl David , Haugen Eric , Rynes Eric , Stamatoyannopoulos John A. , Leonhardt Heinrich , Wedemann Gero , Harz Hartmann 
Published: May 2021

AbstractMethodological advances in conformation capture techniques have fundamentally changed our understanding of chromatin architecture. However, the nanoscale organization of chromatin and its cell-to-cell variance are less studied. By using a combination of high throughput super-resolution microscopy and coarse-grained modelling we investigated properties of active and inactive chromatin in interphase nuclei. Using DNase I hypersensitivity as a criterion, we have selected prototypic active and inactive regions from ENCODE data that are representative for K-562 and more than 150 other cell types. By using oligoFISH and automated STED microscopy we systematically measured physical distances of the endpoints of 5kb DNA segments in these regions. These measurements result in high-resolution distance distributions which are right-tailed and range from very compact to almost elongated configurations of more than 200 nm length for both the active and inactive regions. Coarse-grained modeling of the respective DNA segments suggests that in regions with high DNase I hypersensitivity cell-to-cell differences in nucleosome occupancy determine the histogram shape. Simulations of the inactive region cannot sufficiently describe the compaction measured by microscopy, although internucleosomal interactions were elevated and the linker histone H1 was included in the model. These findings hint at further organizational mechanisms while the microscopy-based distance distribution indicates high cell-to-cell differences also in inactive chromatin regions. The analysis of the distance distributions suggests that direct enhancer-promoter contacts, which most models of enhancer action assume, happen for proximal regulatory elements in a probabilistic manner due to chromatin flexibility.
Antibody structure prediction using interpretable deep learning
Authors: Ruffolo Jeffrey A. , Sulam Jeremias , Gray Jeffrey J. 
Published: May 2021

AbstractTherapeutic antibodies make up a rapidly growing segment of the biologics market. However, rational design of antibodies is hindered by reliance on experimental methods for determining antibody structures. In recent years, deep learning methods have driven significant advances in general protein structure prediction. Here, we present DeepAb, a deep learning method for predicting accurate antibody FV structures from sequence. We evaluate DeepAb on two benchmark sets – one balanced for structural diversity and the other composed of clinical-stage therapeutic antibodies – and find that our method consistently outperforms the leading alternatives. Previous deep learning methods have operated as “black boxes” and offered few insights into their predictions. By introducing a directly interpretable attention mechanism, we show that our network attends to physically important residue pairs. For example, in prediction of one CDR H3 residue conformation, the network attends to proximal aromatics and a key hydrogen bonding interaction that constrain the loop conformation. Finally, we present a novel mutant scoring metric derived from network confidence and show that for a particular antibody, all eight of the top-ranked mutations improve binding affinity. These results suggest that this model will be useful for a broad range of antibody prediction and design tasks.SignificanceAccurate structure models are critical for understanding the properties of potential therapeutic antibodies. Conventional methods for protein structure determination require significant investments of time and resources and may fail. Although greatly improved, methods for general protein structure prediction still cannot consistently provide the accuracy necessary to understand or design antibodies. We present a deep learning method for antibody structure prediction and demonstrate improvement over alternatives on diverse, therapeutically relevant benchmarks. In addition to its improved accuracy, our method reveals interpretable outputs about specific amino acids and residue interactions that should facilitate design of novel therapeutic antibodies.
Use of waste foundry sand as fine aggregates for structural concrete – A review
Authors: M. Manjunatha , S.G.K. Rakshith 
Published: May 2021

Purpose
Waste foundry sand (WFS) is a by-product of the metal casting industries and is used for land filling purposes. Disposing of waste creates problems to environment and increases disposal values. To reduce environmental pollutions and solving disposal problems, several authors in worldwide are carried out research work by partial and complete replacing of natural sand with WFS in concrete mixtures. It is found that WFS can be used for production of structural grade concrete. The mechanical characteristics and flexural properties of RC beams has been reviewed in this paper. From this literature review, it has been noticed that there are improvements in concrete strength properties with WFS.

Design/methodology/approach
The results of various properties of concrete have been discussed in this review articles such as compressive strength, split tensile strength, flexural strength, modulus of elasticity, SEM micro-structures and flexural strength properties of RC beams.

Findings
From the literature review, it is found that there is gap of research on flexural behavior of reinforced concrete beam with WFS.

Originality/value
By using WFS effectively, the environmental pollutions and dumping of waste can be reduced. WFS can be successfully used in structural concrete members.
The impact of corporate bankruptcy on strategic management: using a textual analysis approach to analyze executives’ opinions
Authors: Nagel Raphael , Aviles Carmen 
Published: May 2021

Purpose
In the past decade, the development of the global economy, the change in organizational structures and the maturing of new technologies have led to considerable changes in business structures. Emergency situations, such as the recent COVID-19 pandemic, have led many companies to declare bankruptcy. In this context, the present study aims to analyze strategic opinions of company executives in a declaration of bankruptcy.

Design/methodology/approach
To this end, an innovative approach is applied to strategic management and business. First, the authors conducted 14 interviews with executives, and the interview data were transcribed. Second, using textual analysis and data mining techniques, the transcripts were analyzed to understand the importance of indicators identified as relevant in companies in a declaration of bankruptcy.

Findings
This resulted in identification of 10 relevant indicators perceived by executives to avoid or anticipate a state of bankruptcy, including innovation, business adaptability, room for improvement in production processes, time to react to situations of alarm, layoffs, support from public institutions, suppliers, international and national regulations, impact on the industry, credits and debts.

Originality/value
The paper concludes with a discussion of important theoretical and practical implications of these findings for the industry. Also, strategic management decision-making strategies are presented as a result of the innovative textual analysis approach used.
Non-sponsored brand-related user-generated content: effects and mechanisms of consumer engagement
Authors: Davcik Nebojsa S. , Langaro Daniela , Jevons Colin , Nascimento Rita 
Published: May 2021

Purpose
This study aims to investigate whether users’ engagement with a social media platform is affected as they engage in non-sponsored brand-related user-generated content (UGC). The concept of non-sponsored brand-related UGC encapsulates various social media patterns in which individuals choose how to consume, contribute or create brand-related content with no formal brand incentive or control.

Design/methodology/approach
The study focuses on the question of how users engage with non-sponsored brand-related UGC on Instagram and assesses the influence of UGC perceived value, using partial least squares variance-based structural equation modeling.

Findings
The research shows significant and positive effects of UGC on Instagram users’ intentions to engage with the platform and the influence of UGC perceived value on UGC uses. The findings deepen the understanding of the mechanisms underlying non-sponsored brand-related UGC in consumer engagement marketing, with significant implications for brand managers and the future development of Instagram and other social media platforms.

Originality/value
The UGC functional, social and emotional values are evaluated for their effects on generating the three distinct patterns of consumer online brand-related activities (consumer, contribute and create) in the non-sponsored brand-related UGC context.
Customer relationship and the operating performance following private placements
Authors: Teng Fei , Xia Xue , Xin Yu 
Published: May 2021

Purpose
Close relationship with major customers, by curtailing opportunistic behaviors during private placements (PPs) and guaranteeing the production and sales of products after, is expected to facilitate the realization of PP’s strategic goals. However, major customers, on the contrary, may impair PP’s performance because of their strong bargaining power. Based on the transaction cost theory and relational contract theory, this paper aims to investigate the impact of major customers on firms’ strategic development in the context of private placements. The mechanisms of such impact are analyzed from the prospect of economies of scale, supervision and the rip-off effect by major customers. Further, the moderating role of the customer relationship investment (CRI) is considered.

Design/methodology/approach
Using a sample of China’s non-financial A-share listed firms during 2010-2016, this paper empirically investigates the impact of customer relationships on firms’ operating performance following PPs. In the main regressions, the sales growth rate serves as the dependent variable to measure PP’s operating performance, while the customer concentration proxies for the closeness of customer relationship. This study captures the impact of customer relationships on PPs’ performance by looking at the coefficient of the interaction term of post PP dummy and customer concentration. In the additional tests, selling and management expenses along with entertainment and traveling expenditures are used to measure customer relationship investment.

Findings
Results show that major customers help improve PPs’ strategic performance. The more concentrated the customer portfolio is, the higher operating performance will be after the PPs. Such a relationship is stronger when CRI is at a higher level. However, CRI also incurs costs, which impairs the effect of major customers on net profit. Further research finds that the effect of major customers is more pronounced in situations of extensional PPs, with actively interactive customers and in non-state-owned firms. In addition, state-owned customers with strong bargaining power have impaired the role of customers in promoting PP’s operating performance.

Originality/value
This paper validates the role of customers in firms’ strategic development. The study not only contributes to the research on the economic consequences of customers but also adds to the evolving literature of factors affecting the performance of PPs. The findings of the study have important practical implications for both customer relationship management and the supervision of PPs.
Board Gender Diversity Codes, Quotas and Threats of Supranational Legislation: Impact on Director Characteristics and Corporate Outcomes
Authors: Martínez‐García Irma , Terjesen Siri , Gómez‐Ansón Silvia 
Published: May 2021

AbstractWe explore how a code, soft quota and a proposal for supranational law for board gender diversity affects women directors’ human capital characteristics and corporate outcomes with an unbalanced panel of 116 non‐financial firms and 1,321 firm‐year observations from 2003 to 2016 in Spain. Consistent with resource dependence theory, after a non‐punitive law is passed, boards seek to appoint more female directors who possess human capital attributes that will reduce uncertainty and bring necessary resources to firms. Compared with their pre‐law counterparts, the new female directors tend to have more human capital in terms of executive experience in non‐listed firms, and some non‐executive backgrounds, education and international experience; however, these new women directors generally possess less human capital than their male counterparts. Upper echelons theory suggests that board directors can meaningfully impact corporate outcomes. Overall, our results contradict upper echelons predictions about the impact of a regulation‐driven increase of women directors on corporate outcomes. Indeed, we find a lack of impact of the increase in women's presence on boards on corporate outcomes. Regarding policy, our findings substantially differ from those reported for countries with ‘hard law’ board gender quotas.