bluuebunny/crossref_metadata_2025_split huggingface dataset:
Important anatomical, age-related, and species considerations regarding ocular fibulin-3 (EFEMP1) analysis
Authors: Daniel Steffi , Hulleman John D. 
Published: September 2022

ABSTRACTPurposeFibulin-3 (F3) or EFEMP1 is a secreted extracellular matrix glycoprotein implicated in several ocular diseases. Little is known about the native biology of this protein. Thus, our study aims to determine expression and localization characteristics of F3 utilizing a range of mammalian species as well as F3-associated changes with age.MethodsGene expression analyses for fibulins as well as immunohistochemistry for F3 were conducted in ocular tissue from mice, pigs, non-human primates (NHPs), and humans (n = 3-5). Age-based F3 expression study along with changes in ECM remodeling enzymes was also evaluated in mice.ResultsWithin the mouse retina, F3 staining was consistent throughout the entirety of the retina (far-periphery, mid-periphery, and central), being enriched in the ganglion cell layer and inner nuclear layer (INL). However, in humans, the F3 staining pattern was quite unique; enriched in the RPE, INL, and outer nuclear layer (ONL) in the peripheral retina, but then shifting to predominantly outer plexiform layer (OPL) staining in the central retina and macula with waning RPE immunoreactivity approaching the fovea. We demonstrate that F3 expression in the mouse retina significantly increases with age, and the levels of extracellular F3 degrading enzymes produced by the RPE and retina (e.g., Mmp2 and Htra1) decrease with age.ConclusionsThese findings demonstrate that F3 has distinct species-dependent as well as ocular region-specific expression and localization patterns. We also show that F3 and ECM enzyme dynamics favor F3 accumulation in the retina and RPE with increasing age.
Red Palm Oil (RPO) May Enhance Chronic Inflammation Through Disturbance in Lipid Metabolism
Authors: Binyameen Ridwan Badmos , Akinola Franklin 
Published: September 2022

ABSTRACTSeveral studies have been published on lipid lowering effect of red palm oil (RPO) with little known about health impact of differential dosage. In this study, we examined lipid profile of hyperlipidemia-induced wistar rats fed with varying quantity of RPO supplementation (15ml/kg, 20ml/kg and 25ml/kg feed). A total of 30 male wistar rats were procured and randomly divided into five groups (A, B, C, D and E) with 6 rats in each group. Group C, D and E received 15 ml/kg, 20ml/kg and 25ml/kg of RPO respectively (thoroughly mixed with high fat diet). No force feeding or oral gavage procedures were employed. While rats in group A were fed with standard rat chow, group B animals fed on high fat diet only and neither of the two groups received RPO supplementation. Plasma concentration of total cholesterol (TC), triglycerides (TG), Albumin, low density lipoproteins (LDL-C), high density lipoproteins (HDL-C), and total proteins (TP) were assessed at the end of the experiment that lasted 4 weeks. In addition to the lipid lowering effect observed in RPO supplementation groups (C, D, E) compared to fatty diet fed only (group B) as widely reported in many studies, both the LDL-C and TG appeared to rise with more RPO supplementation. Findings also revealed the lipid lowering effect more pronounced on triglycerides than the low density lipoproteins. TP in group E was significantly higher compared to group A and B (P < 0.05) and RPO supplementation had a tendency to increase plasma TP.
Not getting in too deep: a practical deep learning approach to routine crystallisation image classification
Authors: Milne Jamie , Qian Chen , Hargreaves David , Wang Yinhai , Wilson Julie 
Published: September 2022

AbstractUsing a relatively small training set of ∼16 thousand images from macromolecular crystallisation experiments, we compare classification results obtained with four of the most widely-used convolutional deep-learning network architectures that can be implemented without the need for extensive computational resources. We show that the classifiers have different strengths that can be combined to provide an ensemble classifier achieving a classification accuracy comparable to that obtained by a large consortium initiative. We use eight classes to effectively rank the experimental outcomes, thereby providing detailed information that can be used with routine crystallography experiments to automatically identify crystal formation for drug discovery and pave the way for further exploration of the relationship between crystal formation and crystallisation conditions.Author summaryX-ray crystallography can provide structural information on the molecules that play important roles in cell function and allow interactions vital for drug design to be elucidated. However, the technique requires the molecules to be crystallised and obtaining sufficiently high-quality crystals can require hundreds of experiments under different conditions. Robots have been designed to perform the microscopic experiments with imaging systems to record the results over time but automated classification of all these images is becoming essential. In this work we compare different classifiers that can be used without the need for vast computational resources and show that an ensemble classifier which combines the different strengths of four deep-learning networks is able to correctly classify the experimental results into one of eight different categories 94% of the time.
Systematic analysis of in-source modifications of primary metabolites during flow-injection time-of-flight mass spectrometry
Authors: Farke Niklas , Schramm Thorben , Verhülsdonk Andreas , Link Hannes 
Published: September 2022

AbstractFlow-injection mass spectrometry (FI-MS) enables metabolomics studies with a very high sample-throughput. However, FI-MS is prone to in-source modifications of analytes because samples are directly injected into the electrospray ionization source of a mass spectrometer without prior chromatographic separation. Here, we spiked authentic standards of 160 primary metabolites individually into an Escherichia coli metabolite extract and measured the thus derived 160 spike-in samples by FI-MS. Our results demonstrate that FI-MS can capture a wide range of chemically divers analytes within 30 seconds measurement time. However, the data also revealed extensive in-source modifications. Across all 160 spike-in samples, we identified significant increases of 11,013 ion peaks in positive and negative mode combined. To explain these unknown m/z features, we connected them to the m/z feature of the (de-)protonated metabolite using information about mass differences and MS2 spectra. This resulted in networks that explained on average 49 % of all significant features. The networks showed that a single metabolite undergoes compound specific and often sequential in-source modifications like adductions, chemical reactions, and fragmentations. Our results show that FI-MS generates complex MS1 spectra, which leads to an overestimation of significant features, but neutral losses and MS2 spectra explain many of these features.HighlightsFI-MS enables measurements of chemically divers metabolites.Extensive in-source modifications during electrospray ionization are detected by FI-MS.A network approach explains 49 % of all recorded in-source modifications.
Piezo1-mediated spontaneous activity of satellite glia impacts DRG development
Authors: Brandt Jacob P. , Smith Cody J. 
Published: September 2022

ABSTRACTSpontaneous activity of neural cells is a hallmark of the developing nervous system. It is widely accepted that chemical signals, like neurotransmitters, contribute to spontaneous activity in the nervous system. Here we reveal an additional mechanism of spontaneous activity that is mechanosensitive in the peripheral nervous system (PNS) using intravital imaging of growing dorsal root ganglia (DRG) in zebrafish embryos. GCaMP6s imaging shows that developing DRG satellite glia contain distinct spontaneous Ca2+transients, classified into simultaneous, isolated and microdomains. Longitudinal analysis over days in development demonstrates that as DRG satellite glia become more synchronized, isolated Ca2+transients remain constant. Using a chemical screen, we identify that Ca2+transients in DRG glia are dependent on mechanical properties, which we confirmed using an experimental application of mechanical force. We find that isolated spontaneous Ca2+transients of the glia during development is altered by manipulation of mechanosensitive protein Piezo1, which is expressed in the developing ganglia. In contrast, simultaneous Ca2+transients of DRG satellite glia is not Piezo1-mediated, thus demonstrating that distinct mechanisms mediate subtypes of spontaneous Ca2+transients. Activating Piezo1 eventually impacts the cell abundance of DRG cells and behaviors that are driven by DRG neurons. Together, our results reveal mechanistically distinct subtypes of Ca2+transients in satellite glia and introduce mechanobiology as a critical component of spontaneous activity in the developing peripheral nervous system.
Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in Syrian hamsters
Authors: Abdelnabi Rana , Jochmans Dirk , Donckers Kim , Trüeb Bettina , Ebert Nadine , Weynand Birgit , Thiel Volker , Neyts Johan 
Published: September 2022

AbstractThe SARS-CoV-2 main protease (3CLpro) is one of the promising therapeutic target for the treatment of COVID-19. Nirmatrelvir is the only the 3CLpro inhibitor authorized for treatment of COVID-19 patients at high risk of hospitalization; other 3Lpro inhibitors are in development. We recently repored on the in vitro selection of a SARS-CoV2 3CLpro (L50F-E166A-L167F; short 3CLprores) virus that is cross-resistant with nirmatrelvir and yet other 3CLpro inhibitors. Here, we demonstrate that the resistant virus replicates efficiently in the lungs of intranassaly infected hamsters and that it causes a lung pathology that is comparable to that caused by the WT virus. Moreover, 3CLprores infected hamsters transmit the virus efficiently to co-housed non-infected contact hamsters. Fortunately, resistance to Nirmatrelvir does not readily develop (in the clinical setting) since the drug has a relatively high barrier to resistance. Yet, as we demonstrate, in case resistant viruses emerge, they may easily spread and impact therapeutic options for others. Therefore, the use of SARS-CoV-2 3CLpro protease inhibitors in combinations with drugs that have a different mechanism of action, may be considered to avoid the development of drug-resistant viruses in the future.
Concordance between male- and female-specific GWAS results helps define underlying genetic architecture of complex traits
Authors: Miller Anna K , Pan Calvin , Bartlett Jacquelaine , Lusis Aldons J , Crawford Dana C , Williams Scott M , Buchner David A 
Published: September 2022

AbstractA better understanding of genetic architecture will help translate genetic data into improved precision-based medicine and clinical care. Towards this end, we explored the use of sex-stratified analyses for several traits in the Hybrid Mouse Diversity Panel (HMDP) and UK Biobank to better determine trait polygenicity and identify contributing loci. This was accomplished by comparing the direction of allelic effects in males and females in sex-stratified analyses under the hypothesis that loci that are not associated with a trait should have equal chances of trending in the same direction of effect. Instead, we found that even for most alleles that do not meet nominal levels of statistical significance, the direction of effect in the two sexes was highly concordant. Results were consistent with hundreds of loci regulating each mouse trait and thousands of loci regulating each human trait, including traits for which no statistically significant loci were identified using conventional approaches. We also found evidence of likely spurious widespread epistasis. Collectively, these findings demonstrate the importance of stratifying by sex to discover novel associating loci, suggest a new method for identifying biologically rather than statistically significant associations, and caution that widespread marginal effects can lead to phantom epistasis.
Drug-combination wide association studies of cancer
Authors: Lalagkas Panagiotis Nikolaos , Melamed Rachel Dania 
Published: September 2022

AbstractBackgroundCombinations of common drugs may, when taken together, have unexpected effects on cancer. It is not feasible to test for all combination drug effects in clinical trials, but in the real world, drugs are frequently taken in combination. Then, there may be undiscovered effects protecting users from cancer–or increasing their risk. By analyzing massive health claims data containing numerous people exposed to drug combinations, we have an opportunity to evaluate the association of drug combinations with cancer risk. Discovering these effects can not only contribute to prevention of cancer, but also suggest new uses for combinations to prevent or treat cancer.MethodOur approach emulates a randomized trial where one arm would have been assigned to take a particular drug alone, while the other arm takes it together with a second drug. Because discovery of associations from observational data is prone to spurious results due to confounding, we develop strategies to distinguish confounding from biomedically relevant findings.ResultsThis tactic allows us to systematically assess effects across over 9,000 drug combinations, on all common cancers. Through multiple sensitivity analyses we identify a robustly supported beneficial drug combination that may synergistically impact lipid levels to reduce risk of cancer.ConclusionsThis study demonstrates the importance of considering confounding factors in drug-wide studies. But, we also show that our method is able to uncover associations with robust support.ImpactSearching for combinations of factors impacting cancer is crucial, but these effects can only be systematically discovered through observational data analysis.
A “grappling hook” interaction balances self-assembly and chaperone activity of Nucleophosmin 1
Authors: Saluri Mihkel , Leppert Axel , Gese Genis Valentin , Sahin Cagla , Lama Dilraj , Kaldmäe Margit , Chen Gefei , Elofsson Arne , Allison Timothy M. , Arsenian-Henriksson Marie , Johansson Jan , Lane David P. , Hällberg B. Martin , Landreh Michael 
Published: September 2022

AbstractHow the self-assembly of partially disordered proteins generates functional compartments in the cytoplasm and particularly in the nucleus is poorly understood. Nucleophosmin 1 (NPM1) is an abundant nucleolar protein that forms large oligomers which provide the scaffold for ribosome assembly but also prevent protein aggregation as part of the cellular stress response. Examining the relationship between the self-assembly and chaperone activity of NPM1, we find that oligomerization of full-length NPM1 modulates its ability to retard amyloid formation in vitro. Machine learning and cryo-electron microscopy reveal fuzzy interactions between the disordered region and the C-terminal nucleotide-binding domain that cross-link NPM1 pentamers into oligomers. Ribosomal peptides mediate in a tighter association within the oligomers, reducing their capacity to prevent amyloid formation. We conclude that NPM1 uses a “grappling hook” interaction to form a network-like structure whose chaperone activity is tuned by basic proteins, suggesting a regulatory mechanism for the nucleolar stress response.
Wage equation misrepresents gay wage discrimination: overlooked evidence from Russia
Authors: Alexeev Sergey 
Published: September 2022

PurposeOnly data from developed countries were used to estimate the sexual orientation difference in wages. This paper is the first, which aims to identify the wage discrimination of gay men in Russia – a country where institutional discrimination and ignorance against gay men are known to present.Design/methodology/approachGays are identified as men who reported having sex with other men in several waves of the national household survey. A wage equation is used to estimate the gay wage penalty. Extending the wage equation to implement a difference-in-difference design, the paper also evaluates the effect of the gay-propaganda law of 2013 on gay wages.FindingsNo wage discrimination is identified. The law also has no adverse effect on gay wages.Practical implicationsCross-country comparison and theoretical generalizations are premature, and better identification strategies are needed to understand sexual orientation differences.Social implicationsPolicymakers should be aware that in both discriminatory and equitable environments, there may be hidden inequality even if researchers do not detect it.Originality/valueThe findings are implausible and add to existing evidence that gay discrimination measured with wage equation suffers from endogeneity and should be interpreted with caution. Particular caution should be exercised in cross-sectional and time-series comparisons, as a tendency to report the orientation honestly and unobserved confounders vary by location and time.
The impact of perceived organizational support on professional commitment: a moderation of burnout and mediation of well-being
Authors: Ilyas Sehrish , Abid Ghulam , Ashfaq Fouzia 
Published: September 2022

PurposeIn today’s challenging world, achieving professional commitment among healthcare workers is becoming the need of time. Drawing on self-determination theory, the current study examines how and under which boundary conditions perceived organizational support affects professional commitment.Design/methodology/approachData was collected from doctors and nurses employed in public and private sector hospitals by employing a split-questionnaire design.FindingsThe authors’ study findings demonstrate that perceived organizational support has a positive and indirect effect on the professional commitment of nurses and doctors via mediating the role of subjective well-being. The authors also found that these findings depend on healthcare workers’ burnout levels. The positive relationship between perceived organizational support and subjective well-being is attenuated by burnout syndrome.Practical implicationsThe current study poses implications for policymakers and administrators of healthcare institutions as well as to develop a supportive culture to evoke more professional commitment among healthcare workers. Implications for nursing managers and policymakers are discussed in light of the study findings.Originality/valueHealthcare institutions are increasingly paying attention to raising the professional commitment of their workforce, especially in the wake of a crisis like the COVID-19 outbreak. The current study will add to the body of literature on nursing management, healthcare studies and organizational psychology in the South Asian context by explaining the relationship between POS and professional commitment, drawing on self-determination theory.
The role of adaptive reuse in historic urban landscapes towards cities of inclusion. The case of acre
Authors: Yarza Pérez Ana Jayone , Verbakel Els 
Published: September 2022

PurposeCities are facing challenges that dramatically affect their social and physical landscapes, leading to the increase of urban segregation and polarization. One response to these challenges is adaptive reuse, yet, in heterogeneous communities, these adaptations are often a source of conflict, because local actions often lack an integrative approach, leading to further exclusion. In this paper the authors explore the potential of adaptive reuse of urban heritage as a planning tool to support inclusiveness and heterogeneity.Design/methodology/approachThe city of Acre is used as a case study, where different scenarios for urban heritage are proposed and tested among stakeholders through interviews. These aim to explore how adaptive reuse processes can lead to the inclusion or exclusion of certain groups and how design interventions in historic urban landscapes challenge the way the current disconnected historic and urban layers interact.FindingsThe paper presents the commonalities and differences between the interviewees' perceptions on Acre's functioning, their idea of inclusiveness and other aspects related to urban design. Moreover, it highlights the existing conflicts of interest, value prioritization and the adequacy of the proposed scenarios, serving as a way to verify the accuracy of the scenario building process.Originality/valueTesting an urban design tool related to adaptive reuse of urban heritage in a real and extreme case, based on the guidelines of the Historic Urban Landscape Recommendation; and critically analysing the sources of conflict and value systems to address inclusion in heterogenous settings.
Diaspora diplomacy and modes of engagement: the case of Romanian Diaspora in the UK
Authors: Moise Raluca 
Published: September 2022

PurposeThe current study aims to map the existent modes of engagement used by both individual and organisational actors of Romanian diaspora community in the UK to build public legitimacy and social value in the host society. This study focuses on two main questions: (1) What are the forms of engagement by which diaspora members enact their role as diplomats for ethnic diaspora communities? (2) What is the nature of their communication practices that sustain these forms of diasporic engagement?Design/methodology/approachThis study is based on an analysis of online public documents extracted from different websites, blogs and public social media accounts, complemented by primary data. The research design is a multi-levelled case study.FindingsThe main findings are that Romanian diaspora in the UK develops a specific model of diplomacy, focused on cultural and political forms of engagement. Firstly, equality and belonging are two key dimensions that clearly define this diasporic community diplomatic actions and practices. Secondly, the communication that fosters its networked and associative features has shifted towards a more democratic and strategic model.Originality/valueThis paper has multiple original points. Firstly, it deepens the understanding of diaspora diplomacy, connecting the concept with strategic communication. Secondly, the identification and theorisation of specific forms of engagement of diasporic communities reflects a process which is yet underdeveloped in both types of literature. Findings may be instrumental in providing strategies for relationship building, cultivation and the engagement efforts of the UK institutions regarding immigrant integration.