bluuebunny/crossref_metadata_2025_split huggingface dataset:
Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi
Authors: Kalogriopoulos Nicholas A. , Lopez-Sanchez Inmaculada , Lin Changsheng , Ngo Tony , Midde Krishna , Roy Suchismita , Aznar Nicolas , Murray Fiona , Garcia-Marcos Mikel , Kufareva Irina , Ghassemian Majid , Ghosh Pradipta 
Published: August 2020

AbstractThe molecular mechanisms by which receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major signaling hubs in eukaryotes, independently relay signals across the plasma membrane have been extensively characterized. How these hubs crosstalk has been a long-standing question, but answers remain elusive. Using linear-ion-trap mass spectrometry in combination with biochemical, cellular, and computational approaches, we unravel a mechanism of activation of heterotrimeric G proteins by RTKs and chart the key steps that mediate such activation. Upon growth factor stimulation, the guanine-nucleotide exchange modulator, GIV, dissociates Gαi•βγ trimers, scaffolds monomeric Gαi with RTKs, and facilitates the phosphorylation on two tyrosines located within the inter-domain cleft of Gαi. Phosphorylation triggers the activation of Gαi and inhibits second messengers (cAMP). Tumor-associated mutants reveal how constitutive activation of this pathway impacts cell’s decision to ‘go’vs. ‘grow’. These insights define a tyrosine-based G protein signaling paradigm and reveal its importance in eukaryotes.Significance StatementGrowth factors and heterotrimeric G proteins are two of the most widely studied signaling pathways in eukaryotes; their crosstalk shapes some of the most fundamental cellular responses in both health and disease. Although mechanisms by which G protein pathways transactivate growth factor RTKs has been well-defined, how the reverse may happen is less understood. This study defines the key steps and cellular consequences of a fundamental mechanism of signal crosstalk that enables RTKs to transactivate heterotrimeric G protein, Gαi. Mutations found in tumors shed light on how derailing this mechanism impacts tumor cell behavior. Thus, findings not only show how cells integrate extracellular signalsviapathway crosstalk, but also demonstrate the relevance of this pathway in cancers.
Protein kinase D1 phosphorylates CBX8 to facilitate the disassociation of PRC1 complex from p16 promoter and promotes cell senescence
Authors: Su Yuanyuan , Liang Yao , Xu Chenzhong , Zhang Na , Liu Doudou , Li Guodong , Tong Tanjun , Chen Jun 
Published: August 2020

AbstractThe Polycomb group (PcG) protein chromobox 8 (CBX8) is the subunit of Polycomb repressive complex 1 (PRC1) and recognizes the trimethylation of histone H3 on Lysine 27 (H3K27me3), and coordinates with PRC2 complex to function as epigenetic gene silencer. CBX8 plays a key role in cell proliferation, stem cell biology, cell senescence, and cancer development. However, our knowledge of CBX8 post-translational modifications remains elusive. Here, we report that protein kinase D1 (PKD1) interacts and phosphorylates CBX8 at Ser256 and Ser311 in an evolutionarily conserved motif. We found that PKD1 activation triggered by serum stimulation, Nocodazole treatment and oncogene Ras-induced cell senescence (Ras OIS) all promotes CBX8 S256/311 phosphorylation. PKD1-mediated CBX8 S256/311 phosphorylation impairs PRC1 complex integrity by reducing the binding of CBX8 to other PRC1 components BMI1 and RING1B, decreases the monoubiquitination of histone H2AK119, and results in CBX8 dissociation from its target INK4a/ARF locus and the de-repression of p16, and thus ultimately facilitates cellular senescence. CBX8 S256/311 phosphorylation also compromises hepatocellular cancer cells proliferation and migration. Collectively, these results suggest that PKD1-mediated CBX8 S256/311 phosphorylation is a key mechanism governing CBX8 function, including cell senescence and cancer cell proliferation.Financial supportThis work was supported by grants from Ministry of Science and Technology of the People’s Republic of China (2018YFC2000102), and from National Natural Science Foundation of China (31871382 and 81571369).
Global inequity in scientific names and who they honor
Authors: DuBay Shane , Palmer Droguett Daniela H. , Piland Natalia C. 
Published: August 2020

AbstractAs a cornerstone of biodiversity science, Linnaean taxonomy has been used for almost 300 years to catalogue and organize our knowledge of the living world. In this system, the names of species themselves take on additional functions, such as describing features of the organism or honoring individuals. Here, we analyze the connections between bird species descriptions and who they honor from 1950 to 2019 within a context of global structures of power and access to science to interrogate how authority over the natural world is designated through Western scientific naming practices. We find that 95% of bird species described during this period occur in the Global South, but these species are disproportionately described by and named in honor of individuals from the Global North. We also find an increase through time in authors from the Global South, but Global North authors continue to disproportionately hold first author positions. Our findings show how research and labor in the Global South continue to be disproportionately translated into power and authority in the Global North, upholding and re-enacting imperialistic structures of domination. Addressing these inequities as a scientific community will require reflection and collective dialogue on the social foundations and impacts of our science.For working definitions of key terms, see Table 1. For a Spanish language version of the manuscript, see Supplement (para la versión en español, ver el Suplemento).
Probabilistic, entropy-maximizing control of large-scale neural synchronization
Authors: Menceloglu Melisa , Grabowecky Marcia , Suzuki Satoru 
Published: August 2020

AbstractOscillatory neural activity is dynamically controlled to coordinate perceptual, attentional and cognitive processes. On the macroscopic scale, this control is reflected in the U-shaped deviations of EEG spectral-power dynamics from stochastic dynamics, characterized by disproportionately elevated occurrences of the lowest and highest ranges of power. To understand the mechanisms that generate these low- and high-power states, we fit a simple mathematical model of synchronization of oscillatory activity to human EEG data. The results consistently indicated that the majority (~95%) of synchronization dynamics is controlled by slowly adjusting the probability of synchronization while maintaining maximum entropy within the timescale of a few seconds. This strategy appears to be universal as the results generalized across oscillation frequencies, EEG current sources, and participants (N = 52) whether they rested with their eyes closed, rested with their eyes open in a darkened room, or viewed a silent nature video. Given that precisely coordinated behavior requires tightly controlled oscillatory dynamics, the current results suggest that the large-scale spatial synchronization of oscillatory activity is controlled by the relatively slow, entropy-maximizing adjustments of synchronization probability (demonstrated here) in combination with temporally precise phase adjustments (e.g., phase resetting generated by sensorimotor interactions). Interestingly, we observed a modest but consistent spatial pattern of deviations from the maximum-entropy rule, potentially suggesting that the mid-central-posterior region serves as an “entropy dump” to facilitate the temporally precise control of spectral-power dynamics in the surrounding regions.
Resting State Functional Connectivity is Decreased Globally Across the C9orf72 Mutation Spectrum
Authors: Shoukry Rachel F Smallwood , Clark Michael G , Floeter Mary Kay 
Published: August 2020

AbstractA repeat expansion mutation in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or symptoms of both, and has been associated with gray and white matter changes in brain MRI scans. We used graph theory to examine the network properties of brain function at rest in a population of mixed-phenotype C9orf72 mutation carriers (C9+). Twenty-five C9+ subjects (presymptomatic, or diagnosed with ALS, behavioral variant FTD (bvFTD), or both ALS and FTD) and twenty-six healthy controls underwent resting state fMRI. When comparing all C9+ subjects with healthy controls, both global and connection-specific decreases in resting state connectivity were observed, with no substantial reorganization of network hubs. However, when analyzing subgroups of the symptomatic C9+ patients, those with bvFTD (with and without comorbid ALS) show remarkable reorganization of hubs compared to patients with ALS alone (without bvFTD), indicating that subcortical regions become more connected in the network relative to other regions. Additionally, network connectivity measures of the right hippocampus and bilateral thalami increased with increasing scores on the Frontal Behavioral Inventory, indicative of worsening behavioral impairment. These results indicate that while C9orf72 mutation carriers across the ALS-FTD spectrum have global decreased resting state brain connectivity, phenotype-specific effects can also be observed at more local network levels.
Cell-specific imputation of drug connectivity mapping with incomplete data
Authors: Sapashnik Diana , Newman Rebecca , Pietras Christopher Michael , Qu Fangfang , Kofman Lior , Boudreau Sean , Fried Inbar , Slonim Donna K. 
Published: August 2020

ABSTRACTMotivationDrug repositioning allows expedited discovery of new applications for existing compounds, but re-screening vast compound libraries is often prohibitively expensive. “Connectivity mapping” is a process that links drugs to diseases by identifying compounds whose impact on expression in a collection of cells reverses the disease’s impact on expression in disease-relevant tissues. The high throughput LINCS project has expanded the universe of compounds and cell types for which data are available, but even with this effort, many potentially clinically useful combinations are missing. To evaluate the possibility of repurposing drugs this way despite missing data, we compared collaborative filtering with either neighborhood-based or SVD imputation methods to two naive approaches via cross-validation.ResultsMethods were evaluated for their ability to predict drug connectivity despite missing data. Predictions improved when cell type was taken into account. Neighborhood-based collaborative filtering was the most successful method, with the best improvements in non-immortalized primary cells. We also explored which classes of compounds are most and least reliant on cell type for accurate imputation, and we identified connections between related compounds even when many were not measured in the relevant cells. We conclude that even for cells in which drug responses have not been fully characterized, it is possible to identify unassayed drugs that reverse in those cells the expression signatures observed in disease.Contactdonna.slonim@tufts.edu
Mechanical stimulation of endocardial Purkinje fibres can trigger ventricular arrhythmias
Authors: White Ed , Walton Richard , Kaur Sarbjot , Power Amelia , Haïssaguerre Michel , Bernus Olivier , Ward Marie-Louise 
Published: August 2020

AbstractAcute ventricular dilation can evoke mechanically-induced arrhythmias, our study investigated whether Purkinje fibres (PFs) may play a role. Changes in left ventricular (LV) pressure and pseudo-ECGs were measured in isolated, Langendorff-perfused, male Wistar rat hearts in sinus rhythm. The LV endocardial surface was irrigated with experimental agents, via an indwelling catheter. Mechanically-induced arrhythmias were triggered by LV lumen inflation (100μl in 2s) via an indwelling balloon. Arrhythmias occurred as the LV volume was increased and spontaneously ceased within 20s of the onset of LV inflation. Arrhythmias were indexed as an increase in the standard deviation of all R-R intervals (SDRR), the number of ectopic activations and the period of these activations. Following 10s LV endocardial irrigation with Lugol’s solution (IK/I2) to chemically ablate surface PFs or with 0 Na+Tyrode, there was a statistically significant attenuation of mechanically-induced arrhythmias. Lugol’s reduced the mechanically-induced increase in SDRR (Tyrode pre-stretch 3.5±1.7ms to 113.8±15.1ms during stretch vs Lugol pre-stretch 3.3±0.5ms to 39.9±14.5ms during stretch n=8, P < 0.05). There was also a reduction in the number (21.2±2.0 to 1.5±0.7, P<0.001) and period (5.9±0.71s to 1.7±0.85s, P< 0.01) of ectopic activations. The experiment was repeated using LV lumen irrigation with either 1µM GsMTx4, a peptide that blocks stretch-activated channels or 50µM 9-Phenanthrol (9-Phen), a blocker of TRPM4 channels. GsMTx4 did not attenuate mechanically-activated arrhythmias while 9-Phen had a partial effect. 9-Phen statistically reduced the number and period of ectopic activations but did not attenuate the mechanically-induced increase in SDRR (n=6-11 for each intervention). In further studies,in situfocal mechanical stimulation of individual PFs, caused ectopic activations, in each of 4 sheep LV preparations (0.2±0.1 ectopics in 10s pre-mechanical stimulation vs 2.1±0.2 ectopics in 10s during mechanical stimulation, P<0.001). We interpret our observations in rat and sheep hearts as evidence for a role of PFs in the generation of some mechanically-induced arrhythmia.
Sedimentary factories and ecosystem change across the Permian-Triassic Critical Interval (P-TrCI) – insights from the Xiakou area (South China)
Authors: Pei Yu , Duda Jan-Peter , Reitner Joachim 
Published: August 2020

AbstractThe Permian-Triassic mass extinction included a potentially catastrophic decline of biodiversity, but ecosystem change across this event remains poorly characterized. Here we reconstruct sedimentary factories and ecosystem change across the Permian-Triassic Critical Interval (P-TrCI) in the Xiakou area (South China). Six microfacies (MF) were classified. The succession begins with a eukaryote-controlled carbonate factory (MF-1) that passes upward into an organomineralization-dominated carbonate factory (MF-2–3). Organic-rich marls atop these units reflect carbonate factory collapse (MF-4). Organomineralization-driven carbonate formation restarts prior to the Permian-Triassic boundary (MF-5) and subsequently develops into a mixed carbonate factory where organomineralization and biomineralization are almost equally important (MF-6). MF-1 reflects oxygenated shallow water environments. In contrast, MF-2–6 were all deposited in somewhat deeper environments, some of which episodically exhibited elevated salinities, oxygen depletion, and, possibly, euxinic conditions. Our results demonstrate that distinct changes in carbonate production styles, biodiversity, and environmental conditions are not synchronous at Xiakou. Furthermore, the Xiakou record is strikingly different to that of other localities, even from the same area (e.g., the Global Stratotype Section and Point section at Meishan). Together, these findings highlight the enormous complexity of the P-TrCI and calls simplified views of the Permian-Triassic mass extinction into question.
Ebselen Reacts with SARS Coronavirus-2 Main Protease Crystals
Authors: Malla Tek Narsingh , Pandey Suraj , Poudyal Ishwor , Feliz Denisse , Noda Moraima , Phillips George , Stojkovic Emina , Schmidt Marius 
Published: August 2020

AbstractThe SARS coronavirus 2 main protease 3CLpro tailor cuts various essential virus proteins out of long poly-protein translated from the virus RNA. If the 3CLpro is inhibited, the functional virus proteins cannot form and the virus cannot replicate and assemble. Any compound that inhibits the 3CLpro is therefore a potential drug to end the pandemic. Here we show that the diffraction power of 3CLpro crystals is effectively destroyed by Ebselen. It appears that Ebselen may be a widely available, relatively cost effective way to eliminate the SARS coronavirus 2.
Mutant-selective Degradation by BRAF-targeting PROTACs
Authors: Alabi Shanique , Jaime-Figueroa Saul , Yao Zhan , Gao Yijun , Hines John , Samarasinghe Kusal T.G. , Vogt Lea , Rosen Neal , Crews Craig M. 
Published: August 2020

AbstractOver 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we successfully achieve sub-nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable using degradation-based therapies by targeting mutant BRAF-driven cancers while sparing BRAFWT and thus expanding the therapeutic window using a new anti-tumor drug modality.
Influenza A virus NS1 protein binds as a dimer to the RNA-free PABP1 but not to the PABP1•Poly(A) RNA Complex
Authors: de Rozières Cyrus M , Joseph Simpson 
Published: August 2020

AbstractInfluenza A virus (IAV) is a highly contagious human pathogen responsible for nearly half a million deaths each year. Non-structural protein 1 (NS1) is a crucial protein expressed by IAV to evade the host immune system. Additionally, NS1 has been proposed to stimulate translation because of its ability to bind poly(A) binding protein 1 (PABP1) and eukaryotic initiation factor 4G (eIF4G). We analyzed the interaction of NS1 with PABP1 using quantitative techniques. Our studies show that NS1 binds as a homodimer to PABP1, and this interaction is conserved across different IAV strains. Unexpectedly, NS1 does not bind to PABP1 that is bound to poly(A) RNA. Instead, NS1 only binds to PABP1 free of RNA, suggesting that translation stimulation does not occur by NS1 interacting with the PABP1 molecule attached to the mRNA 3’-poly(A) tail. We propose that NS1 binds to the eIF4G complex at the 5’-end of the mRNA and recruits the RNA-free PABP1, which may stimulate translation initiation by promoting the association of the ribosomal subunits.
Discovery and biosynthesis of clostyrylpyrones from the obligate anaerobeClostridium roseum
Authors: Li Jeffrey S , Du Yongle , Gu Di , Cai Wenlong , Green Allison , Ng Samuel , Leung Alexander , Del Rio Flores Antonio , Zhang Wenjun 
Published: August 2020

ABSTRACTAnaerobic bacteria are a promising new source for natural product discovery. Examination of extracts from the obligate anaerobeClostridium roseumled to discovery of a new family of natural products, the clostyrylpyrones. The polyketide synthase-based biosynthetic mechanism of clostyrylpyrones is further proposed based on bioinformatic, gene knockout, biochemical analysis and heterologous expression studies.
A DNA-origami nuclear pore mimic reveals nuclear entry mechanisms of HIV-1 capsid
Authors: Shen Qi , Xu Chaoyi , Jang Sooin , Xiong Qiancheng , Devarkar Swapnil C. , Tian Taoran , Bedwell Gregory J. , Tripler Therese N. , Hu Yingxia , Yuan Shuai , Temple Joshua , Shi Jiong , Aiken Christopher , Engelman Alan N. , Perilla Juan R. , Lusk C. Patrick , Lin Chenxiang , Xiong Yong 
Published: August 2020

SummaryThe capsid of human immunodeficiency virus 1 (HIV-1) plays a pivotal role in viral nuclear import, but the mechanism by which the viral core passages the nuclear pore complex (NPC) is poorly understood. Here, we use DNA-origami mimics of the NPC, termed NuPODs (NucleoPorins Organized by DNA), to reveal the mechanistic underpinnings of HIV-1 capsid nuclear entry. We found that trimeric interface formed via three capsid protein hexamers is targeted by a triple-arginine (RRR) motif but not the canonical phenylalanine-glycine (FG) motif of NUP153. As NUP153 is located on the nuclear face of the NPC, this result implies that the assembled capsid must cross the NPCin vivo. This hypothesis is corroborated by our observations of tubular capsid assemblies penetrating through NUP153 NuPODs. NUP153 prefers to bind highly curved capsid assemblies including those found at the tips of viral cores, thereby facilitating capsid insertion into the NPC. Furthermore, a balance of capsid stabilization by NUP153 and deformation by CPSF6, along with other cellular factors, may allow for the intact capsid to pass NPCs of various sizes. The NuPOD system serves as a unique tool for unraveling the previously elusive mechanisms of nuclear import of HIV-1 and other viruses.
The COVID-19 Early Detection in Doctors and Healthcare Workers (CEDiD) Study: study protocol for a prospective observational trial
Authors: Zargaran Alexander , Radenkovic Dina , Trengrove Chelsea , Arbane Gill , El-Boghdadly Kariem , Martinez-Nunez Rocio , Greenough Anne 
Published: August 2020

AbstractBackgroundThe global COVID-19 pandemic has caused worldwide disruption with its exponential spread mandating national and international lockdown measures. Hospital-associated transmission has been identified as a major factor in the perpetuation of COVID-19, with healthcare workers at high-risk of becoming infected with SARS-CoV-2 and representing important vectors for spread, but not routinely having their clinical observations monitored or being tested for COVID-19.MethodsA single-center, prospective observational study of 60 healthcare workers will explore how many healthcare workers in high-risk areas develop COVID-19 infection over a thirty day period. High-risk areas are defined as COVID positive wards, the intensive care unit or the accident and emergency department. Healthcare workers (HCWs) will be recruited and have daily self-administered nasopharyngeal SARS-CoV-2 PCR tests. They will also be provided with a wearable medical device to measure their clinical observations during non-working hours, and be asked to complete a daily self-reported symptom questionnaire over the study period. Statistical analysis will assess the proportion of healthcare workers who develop COVID-19 infection as a primary objective, with secondary objectives exploring what symptoms are developed, time-to-event, and deviations in clinical observations.DiscussionAt present clinical observations, symptoms and COVID-19 PCR swabs are not routinely undertaken for healthcare workers. If the CEDiD (COVID-19 Early Detection in Doctors and Healthcare Workers) study is successful, it will provide useful information for workforce decisions in reducing hospital-associated transmission of COVID-19. The data will help in determining whether there are early warning signs for development of COVID-19 infections amongst healthcare workers and may contribute to the evidence base advocating for more regular testing of healthcare workers’ observations, symptoms and COVID-19 status.Trial registrationClinicalTrials.gov,NCT04363489. Registered on 27thJuly 2020