bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allosteric regulation of switch-II controls K-Ras oncogenicity
Authors: Yang Moon Hee , Tran Timothy H. , Hunt Bethany , Agnor Rebecca , Johnson Christian W. , Waybright Timothy J. , Nowak Jonathan A. , Stephen Andrew G. , Simanshu Dhirendra K. , Haigis Kevin M. 
Published: September 2022

AbstractRas proteins are GTPases that regulate a wide range of cellular processes. The activity of Ras is dependent on its nucleotide-binding status, which is modulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Previously, we demonstrated that mutation of lysine 104 to glutamine (K104Q) attenuates the transforming capacity of oncogenic K-Ras by interrupting GEF induced nucleotide exchange. To assess the effect of this mutation in vivo, we used CRISPR/Cas9 to generate mouse models carrying the K104Q point mutation in wild-type and conditional K-RasLSL-G12D alleles. Consistent with our previous findings from in vitro studies, the oncogenic activity of K-RasG12D was significantly attenuated by mutation at K104 in vivo. These data demonstrate that lysine at position 104 is critical for the full oncogenic activity of mutant K-Ras and suggest that modification at K104, for example acetylation, may also regulate its activity. In addition, animals homozygous for K104Q were viable, fertile, and arose at Mendelian frequency, indicating that K104Q is not a complete loss of function mutation. Using biochemical and structural analysis, we found that the G12D and K104Q mutations cooperate to suppress GEF-mediated nucleotide exchange, explaining the preferential effect of K104Q on oncogenic K-Ras. Finally, we discovered an allosteric regulatory network consisting of K104 and residues including G75 on switch II (SWII) that is the key for regulating the stability of the α helix on SWII. In this allosteric network, K104-G75 interaction might be primary for keeping stabilization of SWII. Given the high frequency of KRAS mutations in human cancers, modulation of this network may provide a unique therapeutic approach.
Liquid-liquid phase separation of intrinsically disordered FG-Nups is driven by highly-dynamic hydrophobic FG-motifs
Authors: Dekker Maurice , van der Giessen Erik , Onck Patrick R. 
Published: September 2022

AbstractThe intrinsically disordered FG-Nups in the NPC central channel can undergo liquid-liquid phase sepration (LLPS) into liquid condensates that display NPC-like permeability barrier properties. Here we present LLPS characteristics of each of the disordered FG-Nups of the yeast NPC. Using molecular dynamics simulations at amino acid resolution, FG-Nup condensates are studied and the main physicochemical driving forces for FG-Nup LLPS are identified. We show that FG-motifs that are predominantly present in the disordered domain of FG-Nups act as highly-dynamic hydrophobic stickers that are essential for the formation of stable liquid-like condensates. Next to that, we study LLPS of an FG-Nup mixture that resembles the NPC stoichiometry and observe that an NPC condensate is formed containing multiple types of FG-Nups. We find that the LLPS of this NPC condensate is also driven by FG–FG interactions, similar to the homotypic FG-Nup condensates. Based on the observed LLPS behavior, we categorize the different FG-Nups of the yeast NPC into two classes: The GLFG-Nups located in the central channel of the NPC phase separate into liquid-like condensates, forming a high-density cohesive barrier that can exclude inert particles. The FG-Nups at the entry and exit of the NPC channel, containing no GLFG-motifs, do not phase separate and possibly form a repulsive barrier by entropically excluding inert particles.
CDKL5 regulates p62-mediated selective autophagy and host antiviral defense
Authors: Thinwa Josephine W. , Zou Zhongju , Parks Emily , Sebti Salwa , Hui Kelvin , Wei Yongjie , Singh Vibha , Urquhart Greg , Jewell Jenna L. , Pfeiffer Julie K. , Levine Beth , Reese Tiffany A. , Shiloh Michael U. 
Published: September 2022

AbstractVirophagy, the selective autophagosomal engulfment and degradation of viral components, is crucial for antiviral immunity. However, the mechanisms leading to viral antigen recognition and autophagy induction remain poorly understood. Here, we identify a novel kinase, Cyclin-dependent kinase-like 5 (CDKL5), as an essential regulator of virophagy. Deletion of CDKL5 or abrogation of its kinase activity reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid proteins and cellular cytotoxicity. Mechanistically, through direct phosphorylation of the selective autophagy receptor p62, CDKL5 promoted formation of p62 inclusion bodies that bound capsid. Loss of CDKL5 disrupted the capsid-p62 interaction, and a p62 phosphomimetic mutant rescued the interaction. CDKL5 knockout mice demonstrated increased neuronal cell death after SINV infection and enhanced lethality after infection with several human viruses. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear toxic viral capsid aggregates during infection.
Antibiotic perseverance increases the risk of resistance development
Authors: Brandis Gerrit , Larsson Jimmy , Elf Johan 
Published: September 2022

AbstractThe rise of antibiotic-resistant bacterial infections poses a global threat. Antibiotic resistance development is generally studied in batch cultures which conceals the heterogeneity in cellular responses. Using single-cell imaging, we studied the growth response of Escherichia coli to sub-inhibitory and inhibitory concentrations of nine antibiotics. We found that the heterogeneity in growth increases more than what is expected from growth rate reduction for five out of the nine antibiotics tested. For two antibiotics (rifampicin and nitrofurantoin), we found that sub-populations were able to maintain growth at lethal antibiotic concentrations for up to 10 generations. This perseverance of growth increased the effective population size and led to an up to 40-fold increase in antibiotic resistance development in Gram-negative and Gram-positive species. We conclude that antibiotic perseverance is a common phenomenon across the bacterial kingdom that has the potential to impact antibiotic resistance development.
A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells
Authors: Heacock Mina L. , Abdulaziz Evana N. , Pan Xingxiu , Zuckerman Austin L. , Violante Sara , Yao Canglin , Cross Justin R. , Cracan Valentin 
Published: September 2022

ABSTRACTImpaired reduction/oxidation (redox) metabolism is a key contributor to the etiology of many diseases, including primary mitochondrial disorders, cancer, neurodegeneration, and aging. However, mechanistic studies of redox imbalance remain challenging due to limited strategies which can perturb cellular redox metabolism and model pathology in various cellular, tissue, or organismal backgrounds without creating additional and potentially confounding metabolic perturbations. To date, most studies involving impaired redox metabolism have focused on oxidative stress and reactive oxygen species (ROS) production; consequently, less is known about the settings where there is an overabundance of reducing equivalents, termed reductive stress. NADH reductive stress has been modeled using pharmacologic inhibition of the electron transport chain (ETC) and ethanol supplementation. Still, both these methods have significant drawbacks. Here, we introduce a soluble transhydrogenase from E. coli (EcSTH) as a novel genetically encoded tool to promote NADH overproduction in living cells. When expressed in mammalian cells, EcSTH, and a mitochondrially-targeted version (mitoEcSTH), can elevate the NADH/NAD+ ratio in a compartment-specific manner. Using this tool, we determine the metabolic and transcriptomic signatures of NADH reductive stress in mammalian cells. We also find that cellular responses to NADH reductive stress, including blunted proliferation, are dependent on cellular background and identify the metabolic reactions that sense changes in the cellular NADH/NAD+ balance. Collectively, our novel genetically encoded tool represents an orthogonal strategy to perturb redox metabolism and characterize the impact on normal physiology and disease states.
BLOod Test Trend for cancEr Detection (BLOTTED): protocol for an observational and prediction model development study using English primary care electronic health records data
Authors: Virdee Pradeep S. , Bankhead Clare , Koshiaris Constantinos , Drakesmith Cynthia Wright , Oke Jason , Withrow Diana , Swain Subhashisa , Collins Kiana , Chammas Lara , Tamm Andres , Zhu Tingting , Morris Eva , Holt Tim , Birks Jacqueline , Perera Rafael , Hobbs FD Richard , Nicholson Brian D. 
Published: September 2022

AbstractBackgroundSimple blood tests can play an important role in identifying patients for cancer investigation. The current evidence base is limited almost entirely to tests used in isolation. However, recent evidence suggests combining multiple types of blood tests and investigating trends in blood test results over time could be more useful to select patients for further cancer investigation. Such trends could increase cancer yield and reduce unnecessary referrals. We aim to explore whether trends in blood test results are more useful than symptoms or single blood test results in selecting primary care patients for cancer investigation. We aim to develop clinical prediction models that incorporate trends in blood tests to identify risk of cancer.MethodsPrimary care electronic health records data from the English Clinical Practice Research Datalink Aurum primary care database will be accessed and linked to cancer registrations and secondary care datasets. Using a cohort study design, we will describe patterns in blood testing (Aim 1) and explore associations between covariates and trends in blood tests with cancer using mixed-effects, Cox, and joint models (Aim 2). To build the predictive models for risk of cancer, we will use multivariate joint modelling and machine-learning, incorporating simultaneous trends in multiple blood tests, together with other covariates (Aim 3). Model performance will be assessed using various performance measures, including c-statistic and calibration plots.DiscussionThese models will form decision rules to help general practitioners find patients who need referral for further investigation of cancer. This could increase cancer yield, reduce unnecessary referrals, and give more patients the opportunity for treatment and improved outcomes.
Targeting a broad spectrum of KRAS-mutant cancers by hyperactivation-induced cell death
Authors: Lilja Johanna , Kaivola Jasmin , Conway James R.W. , Vuorio Joni , Parkkola Hanna , Roivas Pekka , Varila Taru , Jacquemet Guillaume , Peuhu Emilia , Wang Emily , Pentikäinen Ulla , Posada Itziar Martinez D. , Hamidi Hellyeh , Najumudeen Arafat K. , Sansom Owen J. , Barsukov Igor L. , Abankwa Daniel , Vattulainen Ilpo , Salmi Marko , Ivaska Johanna 
Published: September 2022

AbstractThe KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where numerous different activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds overactive mutant forms to limit oncogenic KRAS signalling and maintain RAS- activity at an optimal level. Depletion of SHANK3 results in hyperactivation of KRAS/mitogen-activated protein kinase (MAPK) signalling, which in turn selectively induces MAPK/ERK-dependent cell death in KRAS-mutant cancers. Furthermore, targeting of this therapeutic vulnerability through nanobody- or RNA interference- mediated disruption of the SHANK3-KRAS interaction reduces tumour growth in vivo. Thus, inhibition of the SHANK3-KRAS interaction represents a new pan-KRAS-mutant compatible strategy for selective killing of KRAS- mutant cancer cells through excessive signalling.Graphical abstractSchematic model of SHANK3-controlled cell fate in KRAS-mutant cancers. SHANK3 directly interacts with KRAS and competes with RAF for KRAS binding to sustain oncogenic RAS-MAPK/ERK signalling at an optimal level (i.e. below toxic oncogenic signalling) in KRAS-mutant cancers. SHANK3 silencing (1) and inhibition of SHANK3-KRAS interaction (2) drive KRAS-mutant cells into cell death.
CFAP410 has a bimodular architecture with a conserved surface patch on its N-terminal LRR motif for binding interaction partners
Authors: Stadler Alexander , Gabriel Heloisa B. , De Liz Laryssa V. , Alonso-Gil Santiago , Deng Xuan , Crickley Robbie , Korbula Katharina , Huang Kaiyao , Žagrović Bojan , Vaughan Sue , Sunter Jack D. , Dong Gang 
Published: September 2022

AbstractCilia and flagella associated protein 410 (CFAP410) is a protein localized at the basal body of cilia/flagella and plays essential roles in ciliogenesis. Multiple single amino acid mutations in CFAP410 have been identified in patients. However, the molecular mechanism for how the mutations cause these disorders remains poorly understood due to a lack of high-resolution structures of the protein. Our studies demonstrate that CFAP410 adopts a bimodular architecture. We have previously reported our structural studies on the C-terminal domain (CTD) of CFAP410 from various organisms. Here we report a 1.0-Å resolution crystal structure of the N-terminal domain (NTD) ofTrypanosoma bruceiCFAP410. We further examined how the disease-causing mutations in this domain may affect the folding and structural stability of CFAP410. Our results suggest that the single-residue mutations in the CFAP410-NTD cause human diseases by destabilizing the structure that subsequently disrupts its interaction with other partners.
Consumers attitude toward lack of food safety
Authors: Niewczas-Dobrowolska Magdalena 
Published: September 2022

PurposeFood safety is an important characteristic of food, because it influences health. Perception of food hazards is a complex issue. Consumers have different perceptions regarding the probability of a hazard occurring in different food groups. If a hazard appears in the food, it has severe consequences. This is not only because of the negative impact on health and life but also because of the entire economy and image of producers.Design/methodology/approachA survey using the Computer-Assisted Web Interviewing method was conducted in January 2020 in Poland with 2,000 respondents to collect information about consumers' perception of food safety and lack of food safety.FindingsIt was shown that this perception depends mainly on gender and the decisiveness on food purchase. The similarity of the country from which the hazard comes as well as the scientists' knowledge about the hazard influences hazard perception by consumers. If a hazard appears in food, it has serious consequences for consumers, food chain actors, public finance and so on. The occurrence of food hazards causes consumers to stop buying this food product.Originality/valueThis study provides interesting information about consumers' perception of the lack of food safety. These results can be used by food producers and food safety authorities. The results also provide input information for further research on the perception of food safety in various types of food products.
Country image effects after the Brexit crisis. A cross-cultural comparison
Authors: Aragonés-Jericó Cristina , Rodríguez-Santos Carmen , Vila-López Natalia , Küster-Boluda Inés 
Published: September 2022

Purpose
In the context of Brexit, this study aims to analyse whether the worsening of the UK’s image might have triggered: worse feelings towards the tourism workers and a decrease in the final intention to travel to the UK. This paper compares responses from high and low-context tourists to identify at which target the reactions are more intense.

Design/methodology/approach
Hypotheses were formulated in a general model based on the theory of reasoned action applied to Country Image in the tourism sector, comparing the model in high (150 responses) versus low-context (406 responses) scenarios. Structural equation modelling methodology was used.

Findings
The intention to travel to the UK worsens when two out of the three dimensions of country image worsen (aesthetical and functional) and also when feelings towards workers in this country worsen. Related to cross-cultural differences, the main effect on feelings towards workers comes from the normative dimension of the UK’s image, together with the aesthetic perception. Moreover, travellers’ intentions are influenced by functional and aesthetic perceptions of the country as well as feelings towards workers. High-context cultures showed a significantly stronger effect of the aesthetic dimension of the country on feelings towards workers.

Originality/value
This paper tries to advance the understanding of how feelings towards employees in the UK can determine future visits to this destination. In addition, some cultural differences may explain why low-context cultures are more affected by the worsening of the UK’s image after Brexit.
Do commodities hedge regional stock markets at the same effectiveness level? Evidence from MGARCH models
Authors: Zghal Rania , Melki Amel , Ghorbel Ahmed 
Published: September 2022

PurposeThis present work aims at looking into whether or not introducing commodities in international equity portfolios helps reduce the market risk and if hedging is carried out with the same effectiveness across different regional stock markets.Design/methodology/approachThe authors determine the optimal hedge ratios and hedging effectiveness of a number of commodity-hedged emerging and developed equity markets, using three versions of MGARCH model: DCC, ADCC and GO-GARCH. The authors also use a rolling window estimation procedure for the purpose of constructing out-of-sample one-step-ahead forecasts of dynamic conditional correlations and optimal hedge ratios.FindingsEmpirical results evince that commodities significantly display effective risk-reducing hedge instruments in short and long runs. The main finding is that commodities do not seem to hedge regional stock markets in the same way. They tend to provide evidence of a rather effective hedging regarding mainly the East European and Latin American stock markets.Originality/valueThe authors study whether commodities can hedge stock markets at regional context and if hedging effectiveness differ from one region to another.
Resonant leadership and organizational citizenship behavior: a moderated-mediation analysis of followers’ resilience
Authors: Tabche Ibrahim , Behery Mohamed H. , Bin Ahmad Kamarul Zaman 
Published: September 2022

PurposeThis paper aims to examine the relation between resonant leadership (RL) and organizational citizenship behaviors while testing for the mediation effects of followers’ resilience (FR) and gender as a moderating effect, all within the United Arab Emirates (UAE) business environment.Design/methodology/approachThe paper uses cross-sectional data collected through a questionnaire from 467 employees working at various organizations in the UAE. The data were analyzed using the Statistical Package for the Social Sciences (SPSS) software. The mediating and moderating effects were tested using Preacher and Hayes’s (2008) macro models.FindingsResults confirmed that RL positively affected employees’ organizational citizenship behaviors (OCBs). It also confirmed the mediating role of FR between RL and organizational citizenship behavior. Gender moderated the relation between RL and OCB but not between RL and FR.Practical implicationsManagers can use RL styles to improve workers’ resilience and OCB of employees, especially females.Originality/valueIt is important to understand the relation between such variables in times of crisis, such as the COVID-19 pandemic, where the relationship between the leadership style of the organizational managers and employees can greatly impact employees’ behaviors and organizational performance.
Improving information alignment and coordination in humanitarian supply chain through blockchain technology
Authors: Dubey Rameshwar , Gunasekaran Angappa , Foropon Cyril R.H. 
Published: September 2022

PurposeThe coordination among the various entities such as the military, government agencies, civilians, non-governmental agencies, and other commercial enterprises is one of the most challenging aspects of managing the humanitarian supply chain. Blockchain technology (BCT) can facilitate coordination, but the cost and other hindrances have limited their application in disaster relief operations. Despite some studies, the existing literature does not provide a nuanced understanding of the application of blockchain technology to improve information alignment and coordination. Motivated by some recent examples where blockchain technology has been used to trace and mobilize resources in the form of funds and materials from the origin to the destination, the authors develop a theoretical model grounded in the contingent resource-based view.Design/methodology/approachTo empirically validate the model and test the research hypotheses, the authors gathered cross-sectional data using a structured pre-tested questionnaire. In this study, the authors gathered our responses from international non-governmental organizations from twenty-four countries. The authors performed the statistical analyses using variance-based structural equation modeling (PLS-SEM) with the help of commercial software (WarpPLS 7.0).FindingsThe findings of the study offer some useful implications for theory and practice. The results obtained through statistical analyses suggest that the BCT significantly affects information alignment and coordination. However, contrary to popular beliefs the study suggests that intergroup leadership has no significant moderating effect on the paths joining BCT and information alignment/coordination. Moreover, the authors found that the control variable (interdependence) significantly affects the information alignment and coordination further, which opens the room for further investigation.Practical implicationsThe result of the study offers some useful guidance. Firstly, it suggests that humanitarian organizations should invest in BCT to improve information alignment and coordination which is one of the most complex tasks in front of humanitarian organizations. Secondly, intergroup leadership may not have desired influence on the effects of BCT on information alignment/coordination. However, the interdependence of the humanitarian organizations on each other may have a significant influence on the information alignment/coordination.Originality/valueThe study offers some useful implications for theory. For instance, how BCT influences information alignment and coordination was not well understood in the context of humanitarian settings. Hence, this study offers a nuanced understanding of technology-enabled coordination in humanitarian settings.