bluuebunny/crossref_metadata_2025_split huggingface dataset:
Realization of phosphorylation hypothesis of sleep by mammalian CaMKIIβ
Authors: Tone Daisuke , Ode Koji L. , Zhang Qianhui , Fujishima Hiroshi , Yamada Rikuhiro G. , Nagashima Yoshiki , Matsumoto Katsuhiko , Wen Zhiqing , Yoshida Shota Y. , Mitani Tomoki T. , Ohno Rei-ichiro , Ukai-Tadenuma Maki , Garçon Junko Yoshida , Kaneko Mari , Shi Shoi , Ukai Hideki , Miyamichi Kazunari , Okada Takashi , Sumiyama Kenta , Kiyonari Hiroshi , Ueda Hiroki R. 
Published: October 2021

ABSTRACTThe reduced sleep duration observed inCamk2aandCamk2bknockout mice revealed the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII)α/CAMKIIβ as sleep-promoting kinases and lead to the phosphorylation hypothesis of sleep. However, the underlying mechanism of sleep regulation by kinases and protein phosphorylation is largely unknown. Here, we demonstrate that the phosphorylation states of CaMKIIβ regulates sleep duration and sleep needs. Importantly, the activation or inhibition of CaMKIIβ can increase or decrease sleep duration by almost two-fold, supporting the role of CaMKIIβ as a core sleep regulator in mammals. This sleep regulation depends on the kinase activity of CaMKIIβ in excitatory neurons. Furthermore, CaMKIIβ mutants mimicking different phosphorylation states can regulate various sleep steps including sleep induction, sleep maintenance, and sleep cancelation. Key CaMKIIβ residues responsible for the mode switch undergo ordered (auto-)phosphorylation. We thus propose that ordered multi-site phosphorylation of CaMKIIβ underlies multi-step sleep regulation in mammals.
SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy
Authors: Yang Ziwei , Han Yang , Ding Shilei , Finzi Andrés , Mothes Walther , Lu Maolin 
Published: October 2021

ABSTRACTSARS-CoV-2 variants of concern harbor mutations in the Spike (S) glycoprotein that confer more efficient transmission and dampen the efficacy of COVID-19 vaccines and antibody therapies. S mediates virus entry and is the primary target for antibody responses. Structural studies of soluble S variants have revealed an increased propensity towards conformations accessible to receptor human Angiotensin-Converting Enzyme 2 (hACE2). However, real-time observations of conformational dynamics that govern the structural equilibriums of the S variants have been lacking. Here, we report single-molecule Förster Resonance Energy Transfer (smFRET) studies of S variants containing critical mutations, including D614G and E484K, in the context of virus particles. Investigated variants predominantly occupied more open hACE2-accessible conformations, agreeing with previous structures of soluble trimers. Additionally, these S variants exhibited decelerated transitions in hACE2-accessible/bound states. Our finding of increased S kinetic stability in the open conformation provides a new perspective on SARS-CoV-2 adaptation to the human population.
Topological Constraints on Noise Propagation in Gene Regulatory Networks
Authors: Mahajan Tarun , Singh Abhyudai , Dar Roy D. 
Published: October 2021

AbstractGene expression, the production of protein from DNA and mRNA in the biological cell, is inherently stochastic. Cells with identical DNA exhibit fluctuations or ‘noise’ in gene expression. This noise propagates over gene regulatory networks (GRNs), which encode gene-gene interactions. The propagated ‘extrinsic’ noise interacts and combines with ‘intrinsic’ noise to affect biological decisions. Consequently, it is essential to understand how GRN topology affects total noise. Recently, uncertainty principles were established for noise propagation over GRN. In particular, in ring GRNs, exactly one node can have noise reduction below the intrinsic limit. We establish necessary and sufficient conditions for noise reduction in ring GRN. Specifically, for two- and three-node rings, an odd number of negative regulations is necessary for noise reduction. Further, sufficiency is ensured if sensitivities to input for feedforward and feedback regulations are bounded from below and above, respectively. These constraints are valid even if the ring GRN are regulated by an upstream gene. Finally, we use graph theory to decompose noise propagation in a general directed network over its strongly connected components. The combination of graph theory and stochastic processes may be a general framework for studying noise propagation.
White matter microstructural and morphometric alterations in autism: Implications for intellectual capabilities
Authors: Yeh Chun-Hung , Tseng Rung-Yu , Ni Hsing-Chang , Cocchi Luca , Chang Jung-Chi , Hsu Mei-Yun , Tu En-Nien , Wu Yu-Yu , Chou Tai-Li , Gau Susan Shur-Fen , Lin Hsiang-Yuan 
Published: October 2021

ABSTRACTBackgroundNeuroimage literature of autism spectrum disorder (ASD) has a moderate-to-high risk of bias, partially because those combined with intellectual impairment (II) and/or minimally verbal (MV) status are generally ignored. We aimed to provide more comprehensive insights into white matter alterations of ASD, inclusive of individuals with II (ASD-II-Only) or MV expression (ASD-MV).MethodsSixty-five participants with ASD (ASD-Whole; 16.6±5.9 years; comprising 34 intellectually able youth, ASD-IA, and 31 intellectually impaired youth, ASD-II, including 24 ASD-II-Only plus 7 ASD-MV) and 38 demographic-matched typically developing controls (TDC; 17.3±5.6 years) were scanned in accelerated diffusion-weighted MRI. Fixel-based analysis was undertaken to investigate the categorical differences in fiber density (FD), fiber cross-section (FC), and a combined index (FDC), and brain-symptom/cognition associations.ResultsASD-Whole had reduced FD in the anterior and posterior corpus callosum and left cerebellum Crus I, and smaller FDC in right cerebellum Crus II, compared to TDC. ASD-II, relative to TDC, showed almost identical alterations to those from ASD-Whole vs. TDC. ASD-II-Only had greater FD/FDC in the isthmus-splenium of callosum than ASD-MV. Autistic severity negatively correlated with FC in right Crus I. Non-verbal full-scale IQ positively correlated with FC/FDC in cerebellum VI. FD/FDC of the right dorsolateral prefrontal cortex showed a diagnosis-by-executive function interaction.LimitationsWe could not preclude the potential effects of age and sex from the ASD cohort, although statistical tests suggested that these factors were not influential. Our results could be confounded by variable psychiatric comorbidities and psychotropic medication uses in our ASD participants recruited from outpatient clinics, which is nevertheless closer to a real-world presentation of ASD. The outcomes related to ASD-MV were considered preliminaries due to the small sample size within this subgroup.Finally, our study design did not include intellectual impairment-only participants without ASD to disentangle the mixture of autistic and intellectual symptoms.ConclusionsASD-associated white matter alterations appear driven by individuals with II and potentially further by MV. Results suggest that changes in the corpus callosum and cerebellum are key for psychopathology and cognition associated with ASD. Our work highlights an essential to include understudied sub-populations on the spectrum in research.
The neurodevelopmental disorder-linked PHF14 complex that forms biomolecular condensates detects DNA damage and promotes repair
Authors: Käsper Eva-Lotta , Hwang In-Young , Grötsch Helga , Fung Herman Kar Ho , Sérandour Aurélien A. , Arecco Niccolò , Oellers Ronald , Poliński Patryk , Gomez-Monedero Almudena Garcia , Müller Christoph W. , Noh Kyung-Min 
Published: October 2021

AbstractNumerous chromatin-associated proteins have been linked to neurodevelopmental disorders, yet their molecular functions often remain elusive. PHF14, HMG20A, TCF20 and RAI1 are components of a putative chromatin-associated complex and have been implicated in neurological disorders. Here, we found that Phf14 knockout embryonic stem cells and neural progenitor cells exhibit impaired cell cycle progression and proliferation, inadequate protection of stalled replication forks, and decreased DNA repair. The PHF14 complex rapidly assembles at DNA damage sites and binds to DNA through HMG20A. The PHF14 complex forms DNA-containing phase separated droplets in vitro, where TCF20 facilitates droplet formation. Furthermore, TCF20 maintenance at DNA damage sites is destabilized upon pathological mutation. Our results suggest that the PHF14 complex contributes to DNA damage repair by sensing damaged sites and forming biomolecular condensates, thus supporting cell cycle progression, especially in neural progenitor cells whose spatiotemporal pool is critical for proper brain development.
Locus-Specific DNA Methylation Editing in Mammalian Cells using a CRISPR-Based System
Authors: Smith Jim , Banerjee Rakesh , Waly Reema , Urbano Arthur , Gimenez Gregory , Day Robert , Eccles Michael R. , Weeks Robert J. , Chatterjee Aniruddha 
Published: October 2021

AbstractDNA methylation is a key epigenetic modification implicated in the pathogenesis of numerous human diseases, including cancer development and metastasis. Gene promoter methylation changes are widely associated with transcriptional deregulation and disease progression. The advent of CRISPR-based technologies has provided a powerful toolkit for locus-specific manipulation of the epigenome. Here, we describe a comprehensive global workflow for the design and application of a dCas9-SunTag-based tool for editing a DNA methylation locus in human melanoma cells, alongside protocols for downstream techniques used to evaluate subsequent methylation and gene expression changes in methylation-edited cells. Using transient system delivery, we demonstrate both highly efficacious methylation and demethylation of the EBF3 promoter, a putative epigenetic driver of melanoma metastasis, achieving up to 304.00% gain of methylation and 99.99% relative demethylation, respectively. Further, we employ a novel, targeted screening approach to confirm minimal off-target activity and high on-target specificity of our editing sys-tem within our target locus.
Control of protein activity by photoinduced spin polarized charge reorganization
Authors: Ghosh Shirsendu , Banerjee-Ghosh Koyel , Levy Dorit , Scheerer David , Riven Inbal , Shin Jieun , Gray Harry B. , Naaman Ron , Haran Gilad 
Published: October 2021

AbstractConsiderable electric fields are present within living cells, and the role of bioelectricity has been well established at the organismal level. Yet little is known about electric-field effects on protein function. Here we use phototriggered charge injection from a site-specifically attached ruthenium photosensitizer to directly demonstrate the effects of charge redistribution within a protein. We find that binding of an antibody to phosphoglycerate kinase (PGK) is increased two folds under illumination. Remarkably, illumination is found to suppress the enzymatic activity of PGK by a factor as large as three. These responses are sensitive to the photosensitizer position on the protein. Surprisingly, left (but not right) circularly polarized light elicits these responses, indicating that the electrons involved in the observed dynamics are spin polarized, due to spin filtration by protein chiral structures. Our results directly establish the contribution of electrical polarization as an allosteric signal within proteins. Future experiments with phototriggered charge injection will allow delineation of charge rearrangement pathways within proteins and will further depict their effects on protein function.Significance StatementThe role of well-placed charges within proteins in mediating biological functions, from protein-protein association to enzyme kinetics, is well documented. Here we go beyond this static picture and show that charge motions can exert significant effects on protein function. Injecting charge from a photosensitizer, we demonstrate a three-fold decrease in enzymatic activity and a two-fold increase of antibody-antigen binding. These effects depend on the specific position of the photosensitizer on the protein. Our results point to charge reorganization as a form of allostery that complements known allosteric mechanisms such as conformational changes and dynamics.
G2 stem cells orchestrate time-directed, long-range coordination of calcium signaling during skin epidermal regeneration
Authors: Moore Jessica L , Gao Feng , Matte-Martone Catherine , Du Shuangshuang , Lathrop Elizabeth , Ganesan Smirthy , Shao Lin , Bhaskar Dhananjay , Cox Andy , Hendry Caroline , Rieck Bastian , Krishnaswamy Smita , Greco Valentina 
Published: October 2021

AbstractSkin epidermal homeostasis is maintained via constant regeneration by stem cells, which must communicate to balance their self-renewal and differentiation. A key molecular pathway, Ca2+ signaling has been implicated as a signal integrator in developing and wounded epithelial tissues[1, 2, 3, 4]. Yet how stem cells carry out this signaling across a regenerative tissue remains unknown due to significant challenges in studying signaling dynamics in live mice, limiting our understanding of the mechanisms of stem cell communication during homeostasis. To interpret high dimensional signals that have complex spatial and temporal patterns, we combined optimized imaging of Ca2+ signaling in thousands of epidermal stem cells in living mice with a new machine learning tool, Geometric Scattering Trajectory Homology (GSTH). Using a combination of signal processing, data geometry, and topology, GSTH captures patterns of signaling at multiple scales, either between direct or distant stem cell neighbors. Here we show that epidermal stem cells display dynamic intercellular Ca2+ signaling among neighborhoods of up to 10 cells that is surprisingly coordinated and directed through time across a pool of thousands of stem cells. We find that this collective coordination is an emergent property of the stem cell compartment, distinct from excitatory quiescent neuronal tissues. We demonstrate that cycling stem cells, specifically G2 cells, govern homeostatic patterns of Ca2+ signaling. Stem cells in different cell cycle stages dynamically regulate localization of the gap junction component Connexin43 (Cx43). Lastly, we uncouple global from local communication and identify Cx43 as the molecular mediator necessary for connectivity between local signaling neighborhoods. This work provides resolution in how stem cells at different stages of the cell cycle communicate and how that diversity of phases is essential for tissue wide communication and signaling flow during epidermal regeneration. Our approach provides a framework to investigate stem cell populations and their signaling dynamics, previously not possible.
Consequences of alanine-126 mutations in helix-3 on structure and functions of Rad6 E2 ubiquitin-conjugating enzymes
Authors: Shukla Prakash K. , Sinha Dhiraj , Leng Andrew M. , Bissell Jesse E. , Thatipamula Shravya , Ganguly Rajarshi , Skalicky Jack J. , Shrieve Dennis C. , Chandrasekharan Mahesh B. 
Published: October 2021

AbstractRad6, an E2 ubiquitin-conjugating enzyme conserved from yeast to humans, functions in transcription, genome maintenance and proteostasis. The contributions of many conserved secondary structures of Rad6 and its human homologs UBE2A and UBE2B to their biological functions are not understood. A mutant RAD6 allele with a missense substitution at alanine-126 (A126) of helix-3 that causes defects in telomeric gene silencing, DNA repair and protein degradation was reported over two decades ago. Here, using a combination of genetics, biochemical, biophysical, and computational approaches, we discovered that helix-3 A126 mutations compromise the ability of Rad6 to ubiquitinate target proteins without disrupting interactions with partner E3 ubiquitin-ligases that are required for their various biological functions in vivo. Explaining the defective in vitro or in vivo ubiquitination activities, molecular dynamics simulations and NMR showed that helix-3 A126 mutations cause local disorder of the catalytic pocket of Rad6 in addition to disorganizing the global structure of the protein to decrease its stability in vivo. We also show that helix-3 A126 mutations deform the structures of UBE2A and UBE2B, the human Rad6 homologs, and compromise the in vitro ubiquitination activity and folding of UBE2B. In summary, our studies reveal that the conserved helix-3 is a crucial structural constituent that controls the organization of catalytic pockets, enzymatic activities, and biological functions of the Rad6-family E2 ubiquitin-conjugating enzymes.
Architect: a tool for producing high-quality metabolic models through improved enzyme annotation
Authors: Nursimulu Nirvana , Moses Alan M. , Parkinson John 
Published: October 2021

AbstractMotivationConstraints-based modeling is a powerful framework for understanding growth of organisms. Results from such simulation experiments can be affected at least in part by the quality of the metabolic models used. Reconstructing a metabolic network manually can produce a high-quality metabolic model but is a time-consuming task. At the same time, current methods for automating the process typically transfer metabolic function based on sequence similarity, a process known to produce many false positives.ResultsWe created Architect, a pipeline for automatic metabolic model reconstruction from protein sequences. First, it performs enzyme annotation through an ensemble approach, whereby a likelihood score is computed for an EC prediction based on predictions from existing tools; for this step, our method shows both increased precision and recall compared to individual tools. Next, Architect uses these annotations to construct a high-quality metabolic network which is then gap-filled based on likelihood scores from the ensemble approach. The resulting metabolic model is output in SBML format, suitable for constraints-based analyses. Through comparisons of enzyme annotations and curated metabolic models, we demonstrate improved performance of Architect over other state-of-the-art tools.AvailabilityCode for Architect is available at https://github.com/ParkinsonLab/Architect.Contactjohn.parkinson@utoronto.caSupplementary informationSupplementary data are available at Bioinformatics online.
Loss of KRASG12D feedback regulation involving splicing factor SRSF1 accelerates pancreatic cancer
Authors: Wan Ledong , Lin Kuan-Ting , Rahman Mohammad Alinoor , Wang Zhikai , Jensen Mads A. , Park Youngkyu , Tuveson David A. , Krainer Adrian R. 
Published: October 2021

AbstractThe gene encoding KRAS GTPase is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), triggering the formation of precursor lesions, i.e., acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). However, the majority of pancreatic cells from KC (LSL-KrasG12D/+; Pdx-1-Cre) mice expressing the KrasG12D mutation remain morphologically normal for a long time, suggesting the existence of compensatory feedback mechanisms that buffer aberrant KrasG12D signaling, and that additional steps are required for disrupting cell homeostasis and promoting transformation. Here we report a feedback mechanism in which the ubiquitously expressed splicing factor SRSF1—which is associated with cell transformation in multiple cell types—is downregulated in the majority of morphologically normal pancreas cells with the KrasG12D mutation. Conversely, increasing SRSF1 expression disrupts cell homeostasis by activating MAPK signaling, in part by regulating alternative splicing and mRNA stability of interleukin 1 receptor type 1 (Il1r1). This disruption in homeostasis in turn accelerates KrasG12D-mediated PDAC initiation and progression. Our results demonstrate the involvement of SRSF1 in the pancreatic-cell homeostatic response against the KrasG12D mutation, dysregulation of which facilitates PDAC initiation.One-Sentence SummarySplicing factor SRSF1 is involved in KRASG12D feedback regulation and pancreatic-cancer tumorigenesis.
Social ties, access to loans, and loan repayments in savings and loan associations: evidence from rural Tanzania
Authors: Pamuk Haki , van Asseldonk Marcel , Ruben Ruerd , Kweka Tumainiely , Wattel Cor , Hella Joseph Phillip 
Published: October 2021

PurposeInstitutional structures of rural savings and loan associations influence their performances. One of the guiding principles for defining clear group membership boundaries is by setting rules on who has access. Social ties is a prominent requirement for membership. The objective of the current study is to provide quantitative evidence on the role of social ties membership criteria for the performance of saving and loan associations.Design/methodology/approachA cross-sectional survey was conducted in July–August 2019 comprising 48 associations in 13 villages in the Iringa District of Tanzania. In the current study, the authors use two indicators to measure the social ties between members, namely social closed association (the association applies criteria to accept only members who are relatives, friends or from the same hamlet) and physical distance (the fraction of members from other villages).FindingsThe authors find that associations are diverse both in terms of social ties, physical distance and performance, even in a small homogeneous region like Iringa District. Providing loans more easily to members with social ties has a negative relationship with loan repayment rates. Associations applying the social closeness criteria experience higher default rates than those not applying. The default rates become even worse when the fraction of member members from other villages increases in the socially tied associations.Practical implicationsPhysically distant members are more likely to default as they perceive less social pressure in an association with socially tied members. Development practitioners and policy makers should integrate the potential implications.Originality/valueThe authors provide empirical evidence on the relevance of social ties on credit access and repayment in savings and loan associations, using a novel multi-level data on financial performance in the context of community-based finance organizations in rural areas.
Investment returns from reputation investing: do good firms provide good returns?
Authors: Beck Kristine L. , Chong James , Niendorf Bruce D. 
Published: October 2021

PurposeThis study aims to examine whether a good corporate reputation leads to superior investment returns. Theory and empirics provide support for the idea that a good corporate reputation improves firm value, but much of the previous research fails to consider the risk of the companies they study and relies only on accounting measures of performance such as return on assets. A complete picture of the relationship between corporate reputation and shareholder value should include risk-adjusted returns and correlation with benchmark returns.Design/methodology/approachThe Harris Poll Reputation Quotient (RQ), based on the reputations of the 100 most visible companies, suggests that companies with a “solid reputation” are more likely to be attractive investments. The authors construct portfolios using deciles and the RQ categories, rebalancing annually as RQ rankings are updated. Returns are adjusted for risk using Jensen's alpha, the information ratio, the Sharpe ratio, Modigliani and Modigliani's M2 measure, and Muralidhar's M3 measure.FindingsThe results indicate that choosing a portfolio based on the highest RQ-ranked firms does outperform the market on a risk-adjusted basis, and that the relationship between rankings and time-weighted returns is roughly monotonic. The authors also observe that corporate reputation is persistent, and that the best and worst most-visible firms are more likely to be privately held.Originality/valueThis research adds to the literature by including both market-based return measures and risk in the examination of the relationship between corporate reputation and financial performance.