bluuebunny/crossref_metadata_2025_split huggingface dataset:
AlzGPS: A Genome-wide Positioning Systems Platform to Catalyze Multi-omics for Alzheimer’s Therapeutic Discovery
Authors: Zhou Yadi , Fang Jiansong , Bekris Lynn , Kim Young Heon , Pieper Andrew A. , Leverenz James B. , Cummings Jeffrey , Cheng Feixiong 
Published: September 2020

AbstractBackgroundOver15 million family members and caregivers have expended $220 billion for care of patients with AD and other dementias, and the attrition rate for AD clinical trials (2002-2012) is estimated at 99.6%. While recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, no effective disease-modifying or preventive therapies, for AD have emerged in the past two decades. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor.MethodsIn this study, we developed AlzGPS (Genome-widePositioningSystems platform forAlzheimer’s Therapeutic Discovery,https://alzgps.lerner.ccf.org), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and effective prevention and treatment of AD.ResultsVia AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecules’ profiles underlying AD pathogenesis (e.g., early vs. late stage and tau vs. amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we identified repurposable drugs from ∼3,000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated 300 literature references for highly repurposable drugs; (5) we included information from over 200 ongoing AD clinicals noting drug mechanisms and primary drug targets, and linking them to our integrated multi-omics view for targets and network analyses results for the drugs; (6) we implemented a highly interactive web-interface for database browsing and network visualization.ConclusionsNetwork visualization enabled by the AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for data sets-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, the AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.
Development of an MRI Compatible Nasal Drug Delivery Method: Probing Nicotine Addiction Dynamics
Authors: Mujica-Parodi Lilianne R. , Kumar Rajat , Wenke Michael , Amgalan Anar , Lithen Andrew , Govindarajan Sindhuja T. , Makaryus Rany , Benveniste Helene , Strey Helmut H. 
Published: September 2020

AbstractBackgroundSubstance abuse is a fundamentally dynamic disease, characterized by repeated oscillation between craving, drug self-administration, reward, and satiety. To model nicotine addiction as a control system, an MR-compatible nicotine delivery system is needed to elicit cyclical cravings.MethodUsing a concentric nebulizer, inserted into one nostril, we delivered each dose—each equivalent to a single cigarette puff—using a syringe pump by nebulizing the nicotine solution using pressurized medical air. A control mechanism permits dual modes: one delivers puffs on a fixed interval programmed by researchers; with the other, subjects press a button to self-administer each nicotine dose. Subjects were therefore able to intuitively “smoke” the equivalent of a cigarette, one “puff” at a time. We dosed each “puff” such that one cigarette would be equal, in nicotine content, to 10 puffs.ResultsWe tested the viability of this delivery method for studying the brain’s response to nicotine addiction in three steps. First, we established the pharmacokinetics of nicotine delivery, using a dosing scheme designed to gradually achieve saturation, as with a cigarette. Second, we lengthened the time between micro-doses to elicit craving cycles, using both fixed-interval and subject-driven behavior. Finally, we confirmed that the fixed-interval protocol reliably activates brain circuits linked to addiction.ConclusionOur MR-compatible nasal delivery method enables the measurement of neural circuit responses to drug doses on a single-subject level, allowing the development of data-driven predictive models to quantify individual dysregulations of the reward control circuit causing addiction.
Origins of 1/f-like tissue oxygenation fluctuations in the murine cortex
Authors: Zhang Qingguang , Gheres Kyle W. , Drew Patrick J. 
Published: September 2020

AbstractThe concentration of oxygen in the brain spontaneously fluctuates, and the power distribution in these fluctuations has 1/f-like dynamics. Though these oscillations have been interpreted as being driven by neural activity, the origins of these 1/f-like oscillations is not well understood. Here, to gain insight of the origin of the 1/f-like oxygen fluctuations, we investigated the dynamics of tissue oxygenation and neural activity in awake behaving mice. We found that oxygen signal recorded from the cortex of mice had 1/f-like spectra. However, band-limited power in the local field potential, did not show corresponding 1/f-like fluctuations. When local neural activity was suppressed, the 1/f-like fluctuations in oxygen concentration persisted. Two-photon measurements of erythrocyte spacing fluctuations (‘stalls’) and mathematical modelling show that stochastic fluctuations in erythrocyte flow and stalling could underlie 1/f-like dynamics in oxygenation. These results show discrete nature of erythrocytes and their irregular flow, rather than neural activity, could drive 1/f-like fluctuations in tissue oxygenation.
Measuring competitive exclusion in non-small cell lung cancer
Authors: Farrokhian Nathan , Maltas Jeff , Dinh Mina , Durmaz Arda , Ellsworth Patrick , Hitomi Masahiro , McClure Erin , Marusyk Andriy , Kaznatcheev Artem , Scott Jacob G 
Published: September 2020

ABSTRACTTherapeutic strategies for tumor control have traditionally assumed that maximizing reduction in tumor volume correlates with clinical efficacy. Unfortunately, this rapid decrease in tumor burden is almost invariably followed by the emergence of therapeutic resistance. Evolutionary based treatment strategies attempt to delay resistance via judicious treatments that maintain a significant treatable subpopulation. While these strategies have shown promise in recent clinical trials, they often rely on biological conjecture and intuition to derive parameters. In this study we experimentally measure the frequency-dependent interactions between a gefitinib resistant non-small cell lung cancer (NSCLC) population and its sensitive ancestor via the evolutionary game assay. We show that cost of resistance is insufficient to accurately predict competitive exclusion and that frequency-dependent growth rate measurements are required. In addition, we show that frequency-dependent growth rate changes may ultimately result in a safe harbor for resistant populations to safely accumulate, even those with significant cost of resistance. Using frequency-dependent growth rate data we then show that gefitinib treatment results in competitive exclusion of the ancestor, while absence of treatment results in a likely, but not guaranteed exclusion of the resistant strain. Finally, using our empirically derived growth rates to constrain simulations, we demonstrate that incorporating ecological growth effects can dramatically change the predicted time to sensitive strain extinction. In addition, we show that higher drug concentrations may not lead to the optimal reduction in tumor burden. Taken together, these results highlight the potential importance of frequency-dependent growth rate data for understanding competing populations, both in the laboratory and the clinic.
Dual GRIN lens two-photon endoscopy for high-speed volumetric and deep brain imaging
Authors: Chien Yu-Feng , Lin Jyun-Yi , Yeh Po-Ting , Hsu Kuo-Jen , Tsai Yu-Hsuan , Chen Shih-Kuo , Chu Shi-Wei 
Published: September 2020

AbstractStudying neural connections and activitiesin vivois fundamental to understanding brain functions. Given the cm-size brain and three-dimensional neural circuit dynamics, deep-tissue, high-speed volumetric imaging is highly desirable for brain study. With sub-micrometer spatial resolution, intrinsic optical sectioning, and deep-tissue penetration capability, two-photon microscopy (2PM) has found a niche in neuroscience. However, current 2PM typically relies on slow axial scan for volumetric imaging, and the maximal penetration depth is only about 1 mm. Here, we demonstrate that by integrating two gradient-index (GRIN) lenses into 2PM, both penetration depth and volume-imaging rate can be significantly improved. Specifically, an 8-mm long GRIN lens allows imaging relay through a whole mouse brain, while a tunable acoustic gradient-index (TAG) lens provides sub-second volume rate via 100 kHz ∼ 1 MHz axial scan. This technique enables the study of calcium dynamics in cm-deep brain regions with sub-cellular and sub-second spatiotemporal resolution, paving the way for interrogating deep-brain functional connectome.
Shared associations identify causal relationships between gene expression and immune cell phenotypes
Authors: Gasperi Christiane , Chun Sung , Sunyaev Shamil R. , Cotsapas Chris 
Published: September 2020

AbstractGenetic mapping studies have identified thousands of associations between common variants and hundreds of human traits. Translating these associations into mechanisms is complicated by two factors: they fall into gene regulatory regions; and they are rarely mapped to one causal variant. One way around these limitations is to find groups of traits that share associations, using this genetic link to infer a biological connection. Here, we assess how many trait associations in the same locus are due to the same genetic variant, and thus shared; and if these shared associations are due to causal relationships between traits. We find that only a subset of traits share associations, with most due to causal relationships rather than pleiotropy. We therefore suggest that simply observing overlapping associations at a genetic locus is insufficient to infer causality; direct evidence of shared associations is required to support mechanistic hypotheses in genetic studies of complex traits.
High-Quality Genomes of Nanopore Sequencing by Homologous Polishing
Authors: Huang Yao-Ting , Liu Po-Yu , Shih Pei-Wen 
Published: September 2020

AbstractNanopore sequencing has been widely used for reconstruction of a variety of microbial genomes. Owing to the higher error rate, the assembled genome requires further error correction. Existing methods erase many of these errors via deep neural network trained from Nanopore reads. However, quite a few systematic errors are still left on the genome. This paper proposed a new model trained from homologous sequences extracted from closely-related genomes, which provides valuable features missed in Nanopore reads. The developed program (called Homopolish) outperforms the state-of-the-art Racon/Medaka and MarginPolish/HELEN pipelines in metagenomic and isolates of bacteria, viruses and fungi. When Homopolish is combined with Medaka or with HELEN, the genomes quality can exceed Q50 on R9.4 flowcells. The genome quality can be also improved on R10.3 flowcells (Q50-Q90). We proved that Nanopore-only sequencing can now produce high-quality genomes without the need of Illumina hybrid sequencing.
MYC overrides HIF to regulate proliferating primary cell metabolism in hypoxia
Authors: Copeland Courtney A. , Olenchock Benjamin A. , Ziehr David R. , McGarrity Sarah , Leahy Kevin , Young Jamey D. , Loscalzo Joseph , Oldham William M. 
Published: September 2020

ABSTRACTHypoxia requires metabolic adaptations to sustain energetically demanding cellular activities. While the metabolic consequences of hypoxia have been studied extensively in cancer cell models, comparatively little is known about the metabolic response of primary cells to hypoxia. We performed metabolic flux analyses of proliferating human lung fibroblasts and pulmonary artery smooth muscle cells in hypoxia. Unexpectedly, hypoxia decreased glycolytic flux despite activation of hypoxia-inducible factor (HIF) and increased glycolytic enzyme expression. Pharmacologic activation of HIF with the prolyl hydroxylase (PHD) inhibitor molidustat in normoxia did increase glycolytic flux, but hypoxia abrogated this effect. Multi-omic profiling revealed distinct molecular responses to hypoxia and pharmacologic PHD inhibition and suggested a critical role for MYC in modulating the HIF response in hypoxia. MYC knockdown in hypoxia increased lactate efflux, while MYC overexpression in normoxia blunted the effects of molidustat treatment. Together, these data suggest that other factors, notably MYC, supersede the anticipated effects of HIF-dependent up-regulation of glycolytic gene expression on glycolytic flux in hypoxic proliferating primary cells.
The influence of leadership styles on new product development performance: the moderating effect of product innovativeness
Authors: Darawong Chonlatis 
Published: September 2020

PurposeThis article aims to examine the impact of leadership styles on new product development (NPD) and how product innovativeness of NPD projects moderates this impact. The results reveal the implications of different product innovativeness for leaders of NPD projects in achieving successful outcomes.Design/methodology/approachData were collected through a questionnaire survey of NPD team members who were involved in NPD. Participants were employees from different departments, including research and development (R&D), quality control (QC), production and marketing. These individuals worked in innovative manufacturing industries such as automotive and auto parts and electronics.FindingsResults show that transformational leadership has a significantly positive effect on new product success and NPD speed, whereas transactional leadership has a significantly negative effect on both outcomes. Furthermore, the positive impact of transformational leadership on new product success for high innovativeness is stronger than for low innovativeness. In addition, the negative impact of transactional leadership on both new product success and speed for high innovativeness is stronger than for low innovativeness.Research limitations/implicationsFirst, the sample size was fairly small because of limited access to middle-level management and low willingness to share information involving the firms' production. Second, since both transformational and transactional leaderships are multidimensional, each dimension may affect performance in different ways. Third, the respondents were mainly from a single department which could omit varying perspectives.Practical implicationsThe research findings provide recommendations on how different leadership styles support team members to effectively perform NPD tasks in either high or low innovativeness.Originality/valueThis study extends the theory of leadership by providing a holistic understanding of how leadership styles affect NPD performance. It also extends the understanding of how the impact of two different leadership styles on NPD performance is moderated by product innovativeness.
When is entrepreneurial orientation beneficial for new product performance? The roles of ambidexterity and market turbulence
Authors: Huang Shuangfa , Pickernell David , Battisti Martina , Soetanto Danny , Huang Qihai 
Published: September 2020

PurposeEntrepreneurial orientation (EO) is an exploratory orientation because its dimensions such as innovativeness, proactiveness and risk-taking are the essence of exploration that entails uncertain returns. While literature suggests firms might need to counterbalance and complement EO with another orientation for organisational success, research on this area remains limited. Drawing on organisational learning theory, the purpose of this article is to explore whether and how the EO dimensions and organisational ambidexterity complement each other to enhance new product performance. More specifically, the authors explore the configurations of innovativeness, proactiveness, risk-taking and ambidexterity for superior new product performance under different levels of market turbulence.Design/methodology/approachBased on a configurational perspective, the authors applied fuzzy set qualitative comparative analysis (fsQCA) on a sample of 88 small and medium-sized firms from the UK. Using fsQCA allows the authors to uncover the potential complementary role between the EO dimensions and ambidexterity for superior new product performance.FindingsThe results of this paper reveal three configurations that are sufficient to produce superior new product performance. The results suggest that the EO dimensions and ambidexterity can complement each other to enhance new product performance. Further, under the turbulent market environment, the EO dimensions are also sufficient to produce superior new product performance.Originality/valueBy adopting a configurational perspective using fsQCA, the study provides a more holistic understanding of how the EO dimensions work together to influence new product performance. It also contributes to the literature by uncovering the complementary role of the EO dimensions and ambidexterity in shaping new product performance.
Leadership and competition in the age of public and private school markets
Authors: Reimann Carolin Julia , Schwarz Judith , Koinzer Thomas 
Published: September 2020

PurposeThe article deals with competition between primary schools in Berlin. The focus is on the perception of competition and the process of student selection – despite school law restrictions for primary state schools. The aim is to find out whether and in what way primary school leaders perceive a competitive situation and how they act in view of second-order competition.Design/methodology/approachBerlin primary school leaders' statements were analyzed, which were collected and evaluated using quantitative and qualitative methods.FindingsResults show that schools with a good reputation are more likely to benefit from competition because a good reputation may increase the demand for spots at that school and may enable the school to select “desirable” students. State school leaders are more limited in their actions, while private school principals are more autonomous and are better able to make a match between a school's orientation and families' ideas.Research limitations/implicationsThe study is limited by its small sample size, yet it provides a basis for further research and gives much needed attention to selection processes at primary schools in Germany.Originality/valueThis is one of a few studies looking at the perspectives of primary school leaders regarding the competitive situation and in particular the selection of students.
Candle under a bushel: communicating environmental performance to improve firm performance
Authors: Nutsugah Francis Fonyee , Anning-Dorson Thomas , Braimah Stephen Mahama , Tweneboah-Koduah Ernest Yaw 
Published: September 2020

PurposeThis study answers the question: “does the communication of environmental performance transmit positive overall firm performance?” The authors examine the influence of a company's environmental performance (EP) on its overall firm performance (FP) and the mediating role of integrated marketing communication (IMC) on the EP-FP relationship.Design/methodology/approachA survey of firms from the extractive, manufacturing and hospitality sectors of an emerging economy was used in testing our hypothesized relationships. Partial least square structural equation modelling (PLS-SEM) was used in analysing the data from 194 firms.FindingsThe study found that EP negatively and significantly influences FP directly. However, the introduction of IMC into the direct relationship changes this effect. IMC was, therefore, found to have a partial and complementary mediation effect on the relationship between EP and FP.Practical implicationsThe negative influence of EP on FP found explains the reluctance of companies towards environmental protection. However, if companies can utilize their communication capacity well enough in creating the necessary awareness among their stakeholder audiences, a positive relationship is created between EP and FP.Originality/valueThe benefits of EP to companies and how companies can turn their EP into gains were not clearly established in the literature. The current study has explained one of the boundary conditions that convert EP, which appears to be a cost to the firm, into a positive influence on FP. This study has, therefore, established the mechanism through which EP affects FP.
National systems of entrepreneurship: goals of sustainability
Authors: Raposo Mario , Fernandes Cristina I. , Veiga Pedro M. 
Published: September 2020

PurposeNational systems of entrepreneurship (NSE) broadly act as a means of allocating resources driven by the constant search for opportunities at the individual level through the launching of new businesses and firms with such activities, and their results are governed by the specific institutional characteristics of each country. In contrast to the institutional emphasis on innovation systems, in which such institutions establish and regulate actions, institutions are only able to regulate those who act with the results stemming from such individual actions, the core driver of national entrepreneurship systems.Design/methodology/approachGiven the challenges faced by companies and societies in general over mitigating climate change, support for sustainable entrepreneurship is fundamental. However, there has to be any study of the impact of national entrepreneurship systems on sustainability. This research therefore analyses the impact of national entrepreneurship systems on the sustainability of countries.FindingsThe authors conclude that those countries deploying higher level national entrepreneurship systems return better results in terms of their sustainability.Originality/valueThe authors, thus, seek to contribute towards the academic throughout deepening the knowledge prevailing on the relationship between entrepreneurship and sustainability. The authors also seek to enable managers, entrepreneurs and politicians to grasp how entrepreneurship is a systemic factor, and it is at this level that it may make its greatest contribution to bringing about sustainability.
Novel small‐insertion mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis
Authors: Lv Hongli , Li Ming , Cheng Ruhong 
Published: September 2020

AbstractAutosomal recessive woolly hair/hypotrichosis (ARWH/H) is a rare form of congenital alopecia, which can be caused by mutations in lipase H (LIPH), lysophosphatidic acid receptor 6 (LPAR6/P2RY5) or keratin 25 (KRT25) genes. We present a 32‐year‐old woman with typical clinical features of ARWH. Hair microscopy was performed to observe differences between the patient’s hair and a normal sample. Next‐generation sequencing was used to detect pathogenic mutations. Sanger sequencing was used to further confirm the mutations. Abnormal hair appearance was found by hair microscopy. A novel frame‐shift mutation (NM_139248: c.686delinsGTAGAACCCAACCTGGCT: p.Asp229fs37X) and a reported mutation (NM_139248: exon6:c.T736A: p.C246S) in LIPH were identified in the patient. All reported mutations related to ARWH of various races were reviewed. Our study provides further evidence of the similarity of ARWH between the Chinese and Japanese population. A novel small‐insertion mutation also expands the LIPH mutation spectrum.