bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prefrontal Transcranial Direct Current Stimulation globally improves learning, but does not selectively potentiate the benefits of Targeted Memory Reactivation on awake memory consolidation
Authors: Gilson Médhi , Nitsche Michael A. , Peigneux Philippe 
Published: April 2020

AbstractTargeted Memory Reactivation (TMR) and transcranial Direct Current Stimulation (tDCS) can enhance memory consolidation. It is currently unknown whether TMR reinforced by simultaneous tDCS has superior efficacy. In this study, we investigated the complementary effect of TMR and bilateral tDCS on the consolidation of emotionally neutral and negative declarative memories. Participants learned neutral and negative word pairs. Each word pair was presented with an emotionally compatible sound. Following learning, participants spent a 20-minutes retention interval awake under 4 possible conditions: (1) TMR alone (i.e. replay of 50% of the associated sounds), (2) TMR combined with anodal stimulation of the left DLPFC, (3) TMR combined with anodal stimulation of the right DLPFC and (4) TMR with sham tDCS. Results evidenced selective memory enhancement for the replayed stimuli in the TMR-only and TMR-sham conditions, which confirms a specific effect of TMR on memory. However, memory was enhanced at higher levels for all learned items (irrespective of TMR) in the TMR-anodal right and TMR-anodal left tDCS conditions, suggesting that the beneficial effects of tDCS overshadow the specific effects of TMR. Emotionally negative memories were not modulated by tDCS hemispheric polarity. We conclude that electrical stimulation of the DLPFC during post-learning period globally benefits memory consolidation, but does not potentiate the specific benefits of TMR.
PLK1- and PLK4-mediated asymmetric mitotic centrosome size and positioning in the early zebrafish embryo
Authors: Rathbun LI , Aljiboury AA , Bai X , Manikas J , Amack JD , Bembenek JN , Hehnly H 
Published: April 2020

SUMMARYFactors that regulate mitotic spindle positioning have been elucidatedin vitro, however it remains unclear how a spindle is placed within the confines of extremely large cells. Our studies identified a uniquely large centrosome structure in the early zebrafish embryo (246.44±11.93μm2mitotic centrosome in a 126.86±0.35μm diameter cell), whereasC. eleganscentrosomes are notably smaller (6.75±0.28μm2mitotic centrosome in a 55.83±1.04μm diameter cell). During early embryonic cell divisions, cell size changes rapidly inC. elegansand zebrafish embryos. Notably, mitotic centrosome area scales closely with changing cell size compared to changes in spindle length for both organisms. One interesting difference between the two is that mitotic centrosomes are asymmetric in size across embryonic zebrafish spindles, with the larger mitotic centrosome being 2.14±0.13-fold larger in size than the smaller. The largest mitotic centrosome is placed towards the embryo center in a Polo-Like Kinase (PLK) 1 and PLK4 dependent manner 87.14±4.16% of the time. We propose a model in which uniquely large centrosomes direct spindle placement within the disproportionately large zebrafish embryo cells to orchestrate cell divisions during early embryogenesis.
The Narrowing of Dendrite Branches across Nodes follows a well-defined Scaling Law
Authors: Liao Maijia , Howard Jonathon 
Published: April 2020

AbstractThe systematic variation of diameters in branched networks has tantalized biologists since the discovery of da Vinci’s rule for trees. Da Vinci’s rule can be formulated as a power law with exponent two: the square of the mother branch’s diameter is equal to the sum of the squares of those of the daughters. Power laws, with different exponents, have been proposed for branching in circulatory systems and in neurons. The laws have been derived theoretically, based on optimality arguments, but, for the most part, have not been tested rigorously. In the case of neuronal dendrites, diameter changes across branch points have functional implications for the spread of electrical signals: for example, Rall’s law with an exponent of 3/2 maximizes propagation speeds of action potentials across branch points. Using a super-resolution method to measure the diameters of all dendrites in highly branchedDrosophilaClass IV sensory neurons, we have tested Rall’s law and shown it to be false. In its place, we have discovered a new diameter-scaling law: the cross-sectional area is proportional to the number of dendrite tips supported by the branch plus a constant, corresponding to a minimum dendrite diameter. The law accords with microtubules providing force and transport for dendrite tip growth. That the observed scaling differs from Rall’s law suggests that constraints imposed by cell biological mechanisms may impact electrical signaling in neurons. Our new scaling law generalizes to other branched processes such as the vasculature of plants and the circulatory system of animals.Significance StatementTo study the systematic variation of dendrite diameters, we have established a super-resolution method that allows us to resolve dendrite diameters inDrosophilaClass IV dendritic arborization neurons, a model cell for studying branching morphogenesis. Interestingly, they do not follow any of the known scaling laws. We propose a new scaling law that follows from two concepts: there is an incremental cross-sectional area needed to support each terminal branch, and there is a minimum branch diameter. The law is consistent with dendrite growing by tip extension and being supported by microtubule-based transport. If the law generalizes to other neurons, it may facilitate segmentation in connectomic studies.
A Live Attenuated Vaccine Model Confers Cross-Protective Immunity Against Different Species ofLeptospiraspp.
Authors: Wunder Elsio A. , Adhikarla Haritha , Hamond Camila , Owers Katharine A. , Liang Li , Rodrigues Camila B. , Bisht Vimla , Nally Jarlath E. , Alt David P. , Reis Mitermayer G. , Diggle Peter J. , Felgner Philip L. , Ko Albert I. 
Published: April 2020

ABSTRACTLeptospirosis is the leading zoonotic disease in terms of morbidity and mortality worldwide with a great health and economic impact in both humans and animals. Effective prevention is urgently needed as rapid urbanization, climate change and drivers of disease transmission continue to intensify. The key challenge has been developing a widely-applicable vaccine that protects against the 13 different pathogenic species and >300 serovars that can cause leptospirosis, providing a major public health benefit and opportunity to leverage One Health approaches. Live attenuated mutants that can boost immunity and induce protection are enticing vaccine candidates and poorly explored in the field. We evaluated a recently characterized motility-deficient mutant lacking the expression of a flagellar protein, FcpA. Although thefcpA-mutant has lost its ability to penetrate mucous membranes and cause disease, a transient bacteremia prior to clearance by the host immune response was observed. In two animal models, immunization with a single dose of thefcpA-mutant was sufficient to induce robust anti-protein antibodies response that promoted protection against infection with differentLeptospiraspp. species. Furthermore, characterization of the immune response identified a small repertoire of biologically relevant proteins that are highly conserved among pathogenicLeptospiraspecies and potential correlates of cross-protective immunity.
Implementation of single molecule FRET for visualizing intramolecular movement in CRISPR-Cas9
Authors: Narita Haruka , Ebata Hiroshi , Sakai Karibu , Minami Katsuhiko , Uemura Sotaro , Shima Tomohiro 
Published: April 2020

SHORT ABSTRACTThis paper summarizes how to visualize the flexible inter-domain movements of CRISPR-associated protein Cas9 using single molecule FRETLONG ABSTRACTThe CRISPR-associated protein Cas9 is widely used as a genome editing tool because of its ability to be programmed to cleave any DNA sequence that is followed by a protospacer adjacent motif. The continuing expansion of Cas9 technologies has stimulated studies regarding the molecular basis of the Cas9 catalytic process. Here we summarize methods for single molecule FRET (smFRET) to visualize the inter-domain movements of Cas9 protein. Our measurements and analysis demonstrate flexible and reversible movements of the Cas9 domains. Such flexible movements allow Cas9 to adopt transient conformations beyond those solved by crystal structures and play important roles in the Cas9 catalytic process. In addition to the smFRET measurement itself, to obtain precise results, it is necessary to validate Cas9 catalytic activity. Also, fluorescence anisotropy data are required to interpret smFRET data properly. Thus, in this paper, we describe the details of these important additional experiments for smFRET measurements.
The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations
Authors: Kim Jiyeon , Cai Feng , Ko Bookyung , Yang Chendong , Lee Hyun Min , Muhammad Nefertiti , Li Kailong , Haloul Mohamed , Gu Wen , Faubert Brandon , Kaushik Akash K. , Cai Ling , Kasiri Sahba , Marriam Ummay , Nham Kien , Girard Luc , Wang Hui , Sun Xiankai , Kim James , Minna John D. , Unsal-Kacmaz Keziban , DeBerardinis Ralph J. 
Published: April 2020

AbstractIn non–small cell lung cancer (NSCLC), concurrent mutations in the oncogeneKRASand the tumor suppressorSTK11encoding the kinase LKB1 result in aggressive tumors prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant (KL) cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analyzed tumor metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards an activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KL mutant tumors. KL cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2). GFPT2 inhibition selectively reduced KL cell growth in culture and xenografts. Our results define a new metabolic vulnerability in KL tumors and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.
Distinct CD8+T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome
Authors: Kwon Hyunwoo , Chung Dongjun , Kaneko Satoshi , Li Anqi , Zhou Lei , Riesenberg Brian , Song No-Joon , Sundi Debasish , Li Xue , Li Zihai 
Published: April 2020

AbstractMen and women show striking yet unexplained discrepancies in incidence, clinical presentation, and therapeutic response across different types of infectious/autoimmune diseases and malignancies1,2. For instance, bladder cancer shows a 4-fold male-biased incidence that persists after adjustment for known risk factors3,4. Here, we utilize murine bladder cancer models to establish that male-biased tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex differences exist in early fate decisions by intratumoral CD8+T cells following their activation. While female CD8+T cells retain their effector function, male counterparts readily adopt a Tcf1lowTim3−progenitor state that becomes exhausted over tumor progression. Human cancers show an analogous male-biased frequency of exhausted CD8+T cells. Mechanistically, we describe an opposing interplay between CD8+T cell intrinsic androgen and type I interferon5,6signaling in Tcf1/Tcf7regulation and formation of the progenitor exhausted T cell subset. Consistent with female-biased interferon response7, testosterone-dependent stimulation of Tcf1/Tcf7and resistance to interferon occurs to a greater magnitude in male CD8+T cells. Male-biased predisposition for CD8+T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder tumors is less common in males and carries implications for therapeutic efficacy of immune checkpoint inhibitors8,9.
Insight into biogeochemical models from Scale Transition Theory: A dimensionless, scale-free approach
Authors: Wilson Chris H. , Gerber Stefan 
Published: April 2020

AbstractLeading an effective response to the accelerating crisis of anthropogenic climate change will require improved understanding of global carbon cycling. A critical source of uncertainty in Earth Systems Models (ESMs) is the role of microbes in mediating both the formation and decomposition of soil organic matter, and hence in determining patterns of CO2 efflux. Traditionally, ESMs model carbon turnover as a first order process impacted primarily by abiotic factors, whereas contemporary biogeochemical models often explicitly represent the microbial biomass and enzyme pools as the active agents of decomposition. However, the combination of non-linear microbial kinetics and ecological heterogeneity across space guarantees that upscaled dyamics will violate mean-field assumptions via Jensen’s Inequality. Violations of mean-field assumptions mean that parameter estimates from models fit to upscaled data (e.g. eddy covariance towers) are likely systematically biased. Here we present a generic mathematical analysis of upscaled michaelis-menten kinetics, grounded in Scale Transition Theory. We advance the framework by providing solutions in dimensionless form, and illustrate how this approach facilitates qualitative insight into the significance of this scale transition, and argue that it will facilitate future cross site intercomparisons of scale transition effects from flux data. We also discuss the critical terms that need to be constrained in order to unbias parameter estimates.
FOXO regulates neuromuscular junction homeostasis duringDrosophilaaging
Authors: Birnbaum Allison , Chang Kai , Bai Hua 
Published: April 2020

AbstractThe transcription factor FOXO is a known regulator of lifespan extension and tissue homeostasis. It has been linked to the maintenance of neuronal processes across many species, and has been shown to promote youthful characteristics by regulating cytoskeletal flexibility and synaptic plasticity at the neuromuscular junction (NMJ). However, the role of FOXO in aging neuromuscular junction function has yet to be determined. We profiled adult Drosophila FOXO-null mutant abdominal ventral longitudinal muscles and found that young mutants exhibited morphological profiles similar to those of aged wild-type flies, such as larger bouton areas and shorter terminal branches. We also observed changes to the axonal cytoskeleton and an accumulation of late endosomes in FOXO null mutants and motor neuron-specific FOXO knockdown flies, similar to those of aged wild-types. Motor neuron-specific overexpression of FOXO can delay age-dependent changes to NMJ morphology, suggesting FOXO is responsible for maintaining NMJ integrity during aging. Through genetic screening, we identify several downstream factors mediated through FOXO-regulated NMJ homeostasis, including genes involved in the p38-MAPK pathway. Interestingly, the phosphorylation of p38 and ERK were increased in the motor neuron-specific FOXO knockdown flies, suggesting FOXO acts as a suppressor of MAPK activation. Our work reveals that FOXO is a key regulator for NMJ homeostasis, and it maintains NMJ integrity by repressing MAPK signaling during aging.
High-frequency phase-switching ofmodBmethylase is associated with phenotypic ceftriaxone susceptibility inNeisseria gonorrhoeae
Authors: Brynildsrud Ola B , Osnes Magnus N , Ma Kevin C , Grad Yonatan H , Koomey Michael , Caugant Dominique A , Eldholm Vegard 
Published: April 2020

AbstractThe gonococcal adenine methylasesmodAandmodB, belonging to separate Type III restriction modification systems, are phase variable and could thus enable rapid adaptation to changing environments. However, the frequency of phase variation across transmission chains and the phenotypic impact of phase variation are largely unknown.Here we show that the repeat tracts enabling phase variation expand and contract at high rates in bothmodAandmodB. FormodB, multiple ON/OFF transition events were identified over the course of a single outbreak.A mixed effects model using population samples from Norway and a global meta-analysis collection indicates thatmodBin the OFF state is predictive of moderately decreased ceftriaxone susceptibility. Our findings suggest thatmodBorchestration of genome-wide 6-methyladenine modification controls the expression of genes modulating ceftriaxone susceptibility.ImportanceDespite significant progress, our current understanding of the genetic basis of antibiotic susceptibility remains incomplete. The gonococcal methylasemodBis phase variable, meaning that it can be switched ON or OFF via contraction or expansion of a repeat tract in the gene during replication. We find that transitions between the ON and OFF state occur at high frequency. Furthermore, isolates harbouringmodBin a configuration predicted to be inactive had decreased susceptibility to ceftriaxone, an antibiotic used to treat gonorrhea. This finding improves understanding of the genetic underpinnings of antibiotic resistance, but further work is needed to elucidate the mechanics and broader phenotypic effects of epigenetic modifications and transcription.
Parkinson’s disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM
Authors: Zhao Kun , Lim Yeh-Jun , Liu Zhenying , Long Houfang , Sun Yunpeng , Hu Jin-Jian , Zhao Chunyu , Tao Youqi , Zhang Xing , Li Dan , Li Yan-Mei , Liu Cong 
Published: April 2020

AbstractPost-translational modifications (PTMs) of α-synuclein (α-syn), e.g. phosphorylation, play an important role in modulating α-syn pathology in Parkinson’s disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. However, it is unclear how phosphorylation relates to α-syn pathology. Here, by combining chemical synthesis and bacterial expression, we obtained homogeneous α-syn fibrils with site-specific phosphorylation at Y39, which exhibits enhanced neuronal pathology in rat primary cortical neurons. We determined the cryo-EM structure of pY39 α-syn fibril, which reveals a new fold of α-syn with pY39 in the center of the fibril core forming electrostatic interaction network with eight charged residues in the N-terminal region of α-syn. This structure composed of residues 1-100 represents the largest α-syn fibril core determined so far. This work provides structural understanding on the pathology of pY39 α-syn fibril, and highlights the importance of PTMs in defining the polymorphism and pathology of amyloid fibrils in neurodegenerative diseases.
Creative Design Ltd.: the path to youth entrepreneurship
Authors: Chuang Ya-Hsueh , Kang Tsan-Ching , Chang Wen-Ching , Chen Po-Ju 
Published: April 2020

Learning outcomes
By the end of this session, students should be able to: explain what a business model is; summarize the case firm’s business strategy using the elements of business model canvas proposed by Alexander Osterwalder and practice how to apply the business model canvas to analyze the business model of a firm; understand how a firm can seize an opportunity for innovation; and discuss how the case firm navigated through problems that came up as it grew.

Case overview/synopsis
Creative Design was a start-up company in Taiwan. To fulfill a course requirement while she was still in school, the founder had formed a team and entered an entrepreneurship competition. They won the second runner up award in that competition and impressed some firms who enquired if they would be interested in doing corporate identity system (CIS) design. They discovered that without establishing a corporate structure their prospective clients would be unable to pay an invoice. As a consequence, the founder and one of the team members established Creative Design Ltd. This case discusses the challenge Creative Design faced at the end of 2012. Wonderland farmers’ association (WFA) wanted to market locally grown jasmine but did not know how to go about it. They reached out to the founder and her company for assistance. The case of WFA was uncharted territory. Creative Design already had extensive experience in CIS design, but it did not have any experience in handling agriculture products. In this case, they had to deal with the full supply chain from production to exhibition. The risk for this project was high but Creative Design accepted the case and became the first design firm offering a “total solution.” Currently, Creative Design works with all kinds of cases, from simple CIS designs to more complicated total solutions of various scales. The founder now has to contemplate if the design house should develop more total solution cases. Doing so would require recruiting more staff and the dilemma of balancing revenue and costs.

Complexity academic level
The case study is designed for the undergraduate and graduate students of the College of Management; the case can be adopted for the courses of management, innovation and entrepreneurship, etc.

Supplementary materials
Teaching Notes are available for educators only.

Subject code
CSS: 3 Entrepreneurship.