bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategic Leadership Coaching supports Young Executives decision-making
Authors: Heyns-Nell Charlene , Williams Kimberley Clare , Hume David John , Howells Fleur Margaret 
Published: October 2021

ABSTRACTDecision-making is central to daily function for executives in any organisation. Strategic leadership coaching (SLC) is an effective way to support complex decision-making, yet empirical neuroscientific data to support is lacking. The purpose of this study was to investigate the effects of SLC on young executive’s cortical arousal and their neural circuitry activation during the completion of computerized tasks which require activation of decision-making circuitry. We hypothesised SLC would improve cortical arousal when engaged with decision-making tasks, specifically increased electroencephalography (EEG) relative alpha band activity and improved neural circuitry engagement, measured as increased amplitude of event-related potential wave components. This study included thirty-one young male executives, of which eighteen underwent 8 sessions of SLC over two months. EEG records were collected thrice from those who underwent SLC (prior, post, and two months post), and twice from the control group (two months apart). The EEG recording session included completion of two decision-making tasks, an Iowa gambling task and Stroop colour-word conflict task. Finding, SLC increased alpha band activity over left frontal and central electrodes, and increased right parietal N170 amplitude and left parietal P300 amplitude. These findings support our hypothesis, as SLC improved cognitive cortical resources (enhanced alpha) which in turn permitted greater efficiency within decision-making circuitry (increased wave component amplitudes). This study provides the first and necessary neurobiological evidence to support and develop this line of research in SLC, and other forms of coaching, as it adds significant value.
Probiotic-guided CAR-T cells for universal solid tumor targeting
Authors: Vincent Rosa L. , Gurbatri Candice R. , Redenti Andrew , Coker Courtney , Arpaia Nicholas , Danino Tal 
Published: October 2021

AbstractSynthetic biology enables the engineering of interactions between living medicines to overcome the specific limitations of any singular therapy. One major challenge of tumor-antigen targeting therapies like chimeric antigen receptor (CAR)-T cells is the identification of targetable antigens that are specifically and uniformly expressed on heterogenous solid tumors. In contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be readily engineered as antigen-independent platforms for therapeutic delivery. Bridging these approaches, we develop a platform of probiotic-guided CAR-T cells (ProCARs), in which T cells are engineered to sense synthetic antigens (SA) that are produced and released by tumor-colonizing probiotic bacteria. We demonstrate increased CAR-T cell activation and tumor-cell lysis when SAs anchor to components of the extracellular matrix. Moreover, we show that ProCARs are intratumorally activated by probiotically-delivered SAs, receive further stimulation from bacterial TLR agonists, and are safe and effective in multiple xenograft models. This approach repurposes tumor-colonizing bacteria as beacons that guide the activity of engineered T cells, and in turn builds the foundation for communities of living medicines.
Methylome inheritance and enhancer dememorization reset an epigenetic gate safeguarding embryonic programs
Authors: Wu Xiaotong , Zhang Hongmei , Zhang Bingjie , Zhang Yu , Wang Qiuyan , Shen Weimin , Wu Xi , Li Lijia , Xia Weikun , Nakamura Ryohei , Liu Bofeng , Liu Feng , Takeda Hiroyuki , Meng Anming , Xie Wei 
Published: October 2021

AbstractDrastic epigenetic reprogramming is essential to convert terminally-differentiated gametes to totipotent embryos. However, it remains puzzling why post-fertilization global DNA reprogramming occurs only in mammals but not in non-mammalian vertebrates. In zebrafish, global methylome inheritance is however accompanied by sweeping enhancer “dememorization” as they become fully methylated. By depleting maternal dnmt1 using oocyte microinjection in situ, we eliminated DNA methylation in zebrafish early embryos, which died around gastrulation with severe differentiation defects. Strikingly, methylation deficiency leads to extensive derepression of adult tissue-specific genes and CG-rich enhancers, which acquire ectopic TF binding and, unexpectedly, H3K4me3. By contrast, embryonic enhancers are generally CG-poor and evade DNA methylation repression. Hence, global DNA hypermethylation inheritance coupled with enhancer dememorization installs an epigenetic gate that safeguards embryonic programs and ensures temporally ordered gene expression. We propose that “enhancer dememorization” underlies and unifies distinct epigenetic reprogramming modes in early development between mammals and non-mammals.
Stably Accelerating Stiff Quantitative Systems Pharmacology Models: Continuous-Time Echo State Networks as Implicit Machine Learning
Authors: Anantharaman Ranjan , Abdelrehim Anas , Jain Anand , Pal Avik , Sharp Danny , Utkarsh  , Rackauckas Chris 
Published: October 2021

AbstractQuantitative systems pharmacology (QsP) may need to change in order to accommodate machine learning (ML), but ML may need to change to work for QsP. Here we investigate the use of neural network surrogates of stiff QsP models. This technique reduces and accelerates QsP models by training ML approximations on simulations. We describe how common neural network methodologies, such as residual neural networks, recurrent neural networks, and physics/biologically-informed neural networks, are fundamentally related to explicit solvers of ordinary differential equations (ODEs). Similar to how explicit ODE solvers are unstable on stiff QsP models, we demonstrate how these ML architectures see similar training instabilities. To address this issue, we showcase methods from scientific machine learning (SciML) which combine techniques from mechanistic modeling with traditional deep learning. We describe the continuous-time echo state network (CTESN) as the implicit analogue of ML architectures and showcase its ability to accurately train and predict on these stiff models where other methods fail. We demonstrate the CTESN’s ability to surrogatize a production QsP model, a >1,000 ODE chemical reaction system from the SBML Biomodels repository, and a reaction-diffusion partial differential equation. We showcase the ability to accelerate QsP simulations by up to 56x against the optimized DifferentialEquations.jl solvers while achieving <5% relative error in all of the examples. This shows how incorporating the numerical properties of QsP methods into ML can improve the intersection, and thus presents a potential method for accelerating repeated calculations such as global sensitivity analysis and virtual populations.
Universal Ontogenetic Growth without Fitted Parameters: Implications for Life History Invariants & Population Growth
Authors: Escala Andrés 
Published: October 2021

ABSTRACTSince the work of Von Bertalanffy (1957), several models have been proposed that relate the ontogenetic scaling of energy assimilation and metabolism to growth, which are able to describe ontogenetic growth trajectories for living organisms and collapse them onto a single universal curve (West et al. 2001; Barnavar et al. 2002). Nevertheless, all these ontogenetic growth models critically depend on fitting parameters and on the allometric scaling of the metabolic rate. Using a new metabolic rate relation (Escala 2019) applied to a Bertalanffy-type ontogenetic growth equation, we find that ontogenetic growth can also be described by a universal growth curve for all studied species, but without the aid of any fitting parameters (i.e., no fitting procedure is performed on individual growth curves). We find that the inverse of the heart frequency fH, rescaled by the ratio of the specific energies for biomass creation and metabolism, defines the characteristic timescale for ontogenetic growth. Moreover, our model also predicts a generation time and lifespan that explain the origin of several ‘Life History Invariants’ (Charnov 1993) and predict that the Malthusian parameter should be inversely proportional to both the generation time and lifespan, in agreement with the data in the literature (Duncan et al. 1997; Dillingham et. al 2016; Hatton et al 2019). In our formalism, several critical timescales and rates (lifespan, generation time and intrinsic population growth rate) are all proportional to the heart frequency fH, and thus, their allometric scaling relations come directly from the allometry of the heart frequency, which is typically fH∝ M−0.25under basal conditions.
Short-Term Dairy Elimination and Reintroduction Minimally Perturbs the Gut Microbiota in Self-Reported Lactose Intolerant Adults
Authors: Smith Courtney J. , Dethlefsen Les , Gardner Christopher , Nguyen Linda , Feldman Marcus , Costello Elizabeth K. , Kolodny Oren , Relman David A. 
Published: October 2021

AbstractOne of the outstanding questions regarding the human gut microbiota is how interventions designed to manipulate the microbiota may influence host phenotypic traits. Here, we employed a dietary intervention to probe this question in the context of lactose intolerance. To assess the effects of dairy elimination and reintroduction on the microbiota and host phenotype, we paired fecal 16S rRNA amplicon sequencing with a clinical assay for lactose intolerance, the hydrogen breath test. We studied 12 self-reported mildly lactose intolerant adults, each with tri-weekly collection of fecal samples over a 12-week study period (2 weeks baseline, 4 weeks of dairy elimination, 6 weeks of gradual milk reintroduction) and a hydrogen breath test before and after each phase. We found that although none of the subjects experienced a change in clinically defined status of lactose intolerant or tolerant, most subjects were qualitatively better able to tolerate dairy products with minimal symptoms at the end of the study compared to their baseline. Like clinical status, gut microbiota also resisted modification. Although the mean fraction of the genus Bifidobacterium, a group known to metabolize lactose, increased slightly with dairy reintroduction (from 0.0125 to 0.0206; Wilcoxon P = 0.068), the overall structure of each subject’s gut microbiota remained highly individualized and largely stable. Our study is small, but it suggests the possibility of qualitatively improved tolerance in the absence of change in clinically defined tolerance nor major change in the gut microbiota.
STAG2 promotes the myelination transcriptional program in oligodendrocytes
Authors: Cheng Ningyan , Kanchwala Mohammed , Evers Bret M. , Xing Chao , Yu Hongtao 
Published: October 2021

SUMMARYCohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelination-related genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelination-promoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.
Multiple nutritional and gut microbial factors associated with allergic rhinitis: the Hitachi Health Study
Authors: Sahoyama Yukari , Hamazato Fumiaki , Shiozawa Manabu , Nakagawa Tohru , Suda Wataru , Ogata Yusuke , Hachiya Tsuyoshi , Kawakami Eiryo , Hattori Masahira 
Published: October 2021

AbstractSeveral studies suggest the involvement of dietary habits and gut microbiome in allergic diseases. However, little is known about the nutritional and gut microbial factors associated with the risk of allergic rhinitis (AR). We recruited 186 apparently healthy workers with symptoms of AR and 106 controls at the Hitachi Health Care Center, Japan. The habitual consumption of 42 selected nutrients were examined using the brief-type self-administered diet history questionnaire. Faecal samples were collected and subjected to amplicon sequencing of the 16S ribosomal RNA gene hypervariable regions. Association analysis revealed that four nutrients (retinol, vitamin A, cryptoxanthin, and copper) were negatively associated with AR. Among 40 genera examined, relative abundance of Prevotella and Escherichia were associated with AR. Furthermore, significant statistical interactions were observed between retinol and Prevotella. The age- and sex-adjusted odds of AR were 25-fold lower in subjects with high retinol intake and high Prevotella abundance compared to subjects with low retinol intake and low Prevotella abundance. Our data provide insights into complex interplay between dietary nutrients, gut microbiome, and the development of AR.
RSV protects bystander cells against IAV infection by triggering secretion of type I and type III interferons
Authors: Czerkies Maciej , Kochańczyk Marek , Korwek Zbigniew , Prus Wiktor , Lipniacki Tomasz 
Published: October 2021

AbstractWe observed the interference between two prevalent respiratory viruses, respiratory syncytial virus (RSV) and influenza A virus (IAV, H1N1), and characterized its molecular underpinnings in alveolar epithelial cells (A549). We found that RSV induces higher interferon (IFN) β production than IAV and that IFNβ priming confers higher protection against infection with IAV than with RSV. Consequently, we focused on the sequential infection scheme: RSV-then-IAV. Using the A549 WT, IFNAR1 KO, IFNLR1 KO, and IFNAR1–IFNLR1 double KO cell lines we found that both IFNβ and IFNλ are necessary for maximum protection against subsequent infection. Immunostaining revealed that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. Strikingly, the susceptible cells turned out to be those already compromised and efficiently expressing RSV, whereas the bystander, interferon-primed cells are resistant to IAV infection. Thus, the virus–virus exclusion at the cell population level is not realized through a direct competition for a shared ecological niche (single cell) but rather achieved with the involvement of specific cytokines induced within the host innate immune response.ImportanceThe influenza A virus (IAV) and the respiratory syncytial virus (RSV) are common recurrent respiratory infectants, which show a relatively high coincidence. We demonstrated that preinfection with RSV partitions the cell population into a subpopulation susceptible to subsequent infection with IAV and an IAV-proof subpopulation. The susceptible cells are those already compromised and efficiently expressing RSV, whereas the bystander cells are resistant to IAV infection. The cross-protective effect critically depends on IFNβ and IFNλ signaling and thus ensues when the proportion of cells preinfected with RSV is relatively low yet sufficient to trigger a pervasive antiviral state in bystander cells. Our study suggests that mild, but not severe, respiratory infections may have a short-lasting protective role against more dangerous respiratory viruses, including SARS-CoV-2.
Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle
Authors: Laiman Jessica , Loh Julie , Tang Wei-Chun , Chuang Mei-Chun , Liu Hui-Kang , Chen Bi-Chang , Chang Yi-Cheng , Chuang Lee-Ming , Liu Ya-Wen 
Published: October 2021

ABSTRACTTight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3α, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.
CD47 cross-dressing by extracellular vesicles expressing CD47 inhibits phagocytosis without transmitting cell death signals
Authors: Li Yang , Wu Yan , Federzoni Elena A. , Wang Xiaodan , Dharmawan Andre , Hu Xiaoyi , Wang Hui , Hawley Robert J. , Stevens Sean , Sykes Megan , Yang Yong-Guang 
Published: October 2021

AbstractTransgenic CD47 overexpression is an encouraging approach to ameliorating xenograft rejection and alloresponses to pluripotent stem cells, and the efficacy correlates with the level of CD47 expression. However, CD47, upon ligation, also transmits signals leading to cell dysfunction or death, raising a concern that overexpressing CD47 could be harmful. Here, we unveiled an alternative source of cell surface CD47. We showed that extracellular vesicles (EVs), including exosomes (Exos), released from normal or tumor cells overexpressing CD47 (transgenic or native) can induce efficient CD47 cross-dressing on pig or human cells. Like the autogenous CD47, CD47 cross-dressed on cell surfaces is capable of interacting with SIRPα to inhibit phagocytosis. However, ligation of the autogenous, but not cross-dressed, CD47 induced cell death. Thus, CD47 cross-dressing provides an alternative source of cell surface CD47 that may elicit its anti-phagocytic function without transmitting harmful signals to the cells. CD47 cross-dressing also suggests a previously unidentified mechanism for tumor-induced immunosuppression. Our findings should help to further optimize the CD47 transgenic approach that may improve outcomes by minimizing the harmful effects of CD47 overexpression.
Intercellular alignment of apical-basal polarity coordinates tissue homeostasis and growth
Authors: Gui Jinghua , Huang Yunxian , Myllymäki Satu-Marja , Mikkola Marja , Shimmi Osamu 
Published: October 2021

AbstractMaintaining apicobasal polarity (ABP) is crucial for epithelial integrity and homeostasis during tissue development. Although recent studies have greatly advanced our understanding of intracellular mechanisms underlying ABP establishment, it remains largely unknown how the ABP is regulated at the tissue level. Here, we address intercellular mechanisms coordinating ABP using the Drosophila wing imaginal disc. By studying Scribble, a key ABP determinant, we show that ABP is regulated through intercellular alignment, which takes place either progressively or regressively in a context-dependent manner. Cells expressing wild type scribble progressively restore ABP in scribble hypomorphic mutant cells. In contrast, cells with conditional scribble knockdown instigate the regressive loss of polarity in abutting wild type cells. Our data reveal that genetic and physical interactions between Scribble, Septate junction complex and α-Catenin appear to be key for sustaining intercellular network of ABP. Taken together, our findings indicate that the intercellular relay of the status of ABP contributes to the robustness of polarity across the tissue.
Annotation of glycolysis, gluconeogenesis, and trehaloneogenesis pathways provide insight into carbohydrate metabolism in the Asian citrus psyllid
Authors: Tamayo Blessy , Kercher Kyle , Vosburg Chad , Massimino Crissy , Jernigan Margaryta R. , Hasan Denisse L. , Harper Douglas , Mathew Anuja , Adkins Samuel , Shippy Teresa , Hosmani Prashant S. , Flores-Gonzalez Mirella , Panitz Naftali , Mueller Lukas A. , Hunter Wayne B. , Benoit Joshua B. , Brown Susan J. , D’Elia Tom , Saha Surya 
Published: October 2021

AbstractCitrus greening disease is caused by the pathogenCandidatusLiberibacter asiaticus, which is transmitted by the Asian citrus psyllid,Diaphorina citri. There is no curative treatment or significant prevention mechanism for this detrimental disease that causes continued economic losses from reduced citrus production. A high quality genome ofD. citriis being manually annotated to provide accurate gene models required to identify novel control targets and increase understanding of this pest. Here, we annotated genes involved in glycolysis, gluconeogenesis, and trehaloneogenesis in theD. citrigenome, as these are core metabolic pathways and suppression could reduce this pest. Specifically, twenty-five genes were identified and annotated in the glycolysis and gluconeogenesis pathways and seven genes for the trehaloneogenesis pathway. Comparative analysis showed that the glycolysis genes inD. citriare highly conserved compared to orthologs in other insect systems, but copy numbers vary inD. citri.Expression levels of the annotated gene models were analyzed and several enzymes in the glycolysis pathway showed high expression in the thorax. This is consistent with the primary use of glucose by flight muscles located in the thorax. A few of the genes annotated inD. citrihave been targeted for gene knockdown as a proof of concept, for RNAi therapeutics. Thus, manual annotation of these core metabolic pathways provides accurate genomic foundations for developing gene-targeting therapeutics to reduceD. citri.
Natural history of a mouse model of X-linked myotubular myopathy
Authors: Sarikaya Ege , Volpatti Jonathan , Sabha Nesrin , Maani Nika , Gonorazky Hernan D. , Celik Alper , Onofre-Oliveira Paula , Dowling James J. 
Published: October 2021

AbstractX-linked myotubular myopathy is a severe monogenetic disorder of the skeletal muscle caused by loss of expression/function mutations in theMTM1(myotubularin) gene. There is a growing understanding of the pathologic and molecular abnormalities associated with loss of MTM1, and emerging therapeutic strategies that are in the process of translation to patients. Much of these data have been uncovered through experimentation in pre-clinical animal models of the disease. The most widely used model is an Mtm1 gene knockout mouse line; this line faithfully recapitulates the salient genetic and pathologic features of the disease. Despite the advances in aspects of XLMTM, there remain many unknowns related to disease pathomechanisms and to understanding of MTM1’s function in normal muscle development, and a continued need for therapy identification and development. To address these barriers, and to lay the groundwork for future study, we performed a natural history study of the Mtm1 knockout mouse model of XLMTM. We show that certain molecular and pathologic changes precede overt phenotypic changes, while others, including abnormalities in triad structure, occur more coincident with muscle weakness in the mouse. In total, we provide a comprehensive longitudinal assessment of molecular and structural features of the murine XLMTM disease process.