bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Structural Logic of Dynamic Signaling in theEscherichia coliSerine Chemoreceptor
Authors: Reyes Georgina I. , Flack Caralyn E. , Parkinson John S. 
Published: July 2024

ABSTRACTThe experimental challenges posed by integral membrane proteins hinder molecular understanding of transmembrane signaling mechanisms. Here, we exploited protein crosslinking assays in living cells to follow conformational and dynamic stimulus signals in Tsr, theEscherichia coliserine chemoreceptor. Tsr mediates serine chemotaxis by integrating transmembrane serine-binding inputs with adaptational modifications of a methylation helix bundle to regulate a signaling kinase at the cytoplasmic tip of the receptor molecule. We created a series of cysteine replacements at Tsr residues adjacent to hydrophobic packing faces of the bundle helices and crosslinked them with a cell-permeable, bifunctional thiol-reagent. We identified an extensively crosslinked dynamic junction midway through the methylation helix bundle that seemed uniquely poised to respond to serine signals. We explored its role in mediating signaling shifts between different packing arrangements of the bundle helices by measuring crosslinking in receptor molecules with apposed pairs of cysteine reporters in each subunit and assessing their signaling behaviors with an in vivo kinase assay. In the absence of serine, the bundle helices evinced compact kinase-ON packing arrangements; in the presence of serine, the dynamic junction destabilized adjacent bundle segments and shifted the bundle to an expanded, less stable kinase-OFF helix-packing arrangement. An AlphaFold 3 model of kinase-active Tsr showed a prominent bulge and kink at the dynamic junction that might antagonize stable structure at the receptor tip. Serine stimuli probably inhibit kinase activity by shifting the bundle to a less stably-packed conformation that relaxes structural strain at the receptor tip, thereby freezing kinase activity.SIGNIFICANCEThis study used in vivo protein crosslinking to follow stimulus-induced signals through Tsr, a bacterial transmembrane receptor for chemotaxis to serine. Our experiments distinguished Tsr conformations that activate or inhibit its signaling kinase partner and showed how those signals reach the receptor’s kinase-controlling cytoplasmic tip. A dynamic junction in the Tsr molecule triggers stimulus responses by propagating a less stable helix-packing arrangement to flanking structural elements, thereby reducing structural stresses at the receptor tip. An AlphaFold model indicated that the dynamic junction might cause a structural distortion that destabilizes the receptor tip in the absence of a serine stimulus. This model and experimental approach could help to elucidate the signaling logic and mechanisms in other transmembrane chemoreceptor proteins.
Examining the Central Auditory Processing Using a Multi-Feature ERP Paradigm to Phonetic, Prosodic and Acoustic Features
Authors: Ioanna Zavogianni Maria , Kelić Maja , Honbolygó Ferenc 
Published: July 2024

AbstractPrevious studies have shown that multi-feature paradigms can be used for the investigation of the central auditory processing. In this study, we developed a speech multi-feature paradigm with phonetic, prosodic, and acoustic changes. Our aim was to examine the participants’ involuntary discrimination of the changes of speech sound features while they were watching a movie without any sound or subtitles. All five deviant conditions (vowel, consonant, stress, intensity, frequency) elicited statistically significant MMN ERP responses which varied in amplitude depending on the condition; stress was also connected with the occurrence of the LDN component. With vowel, consonant and stress among the conditions that received the most statistically significant ERPs, we could suggest that the current multi-feature paradigm can be used to successfully elicit the MMN ERP component and potentially to assess phonological processing in children and adults.
A postzygoticGNA13variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome
Authors: Masri Rana El , Iannuzzo Alberto , Kuentz Paul , Tacine Rachida , Vincent Marie , Barbarot Sébastien , Morice-Picard Fanny , Boralevi Franck , Oillarburu Naia , Mazereeuw-Hautier Juliette , Duffourd Yannis , Faivre Laurence , Sorlin Arthur , Vabres Pierre , Delon Jérôme 
Published: July 2024

AbstractThe genetic bases of mosaic pigmentation disorders have increasingly been identified, but these conditions remain poorly characterised, and their pathophysiology is unclear. Here, we report in four unrelated patients that a recurrent postzygotic mutation inGNA13is responsible for a recognizable syndrome with hypomelanosis of Ito associated with developmental anomalies.GNA13encodes Gα13, a subunit of αβγ heterotrimeric G proteins coupled to specific transmembrane receptors known as G-protein coupled receptors. In-depth functional investigations revealed that this R200K mutation provides a gain of function to Gα13. Mechanistically, we show that this variant hyperactivates the RHOA/ROCK signalling pathway that consequently increases actin polymerisation and myosin light chains phosphorylation, and promotes melanocytes rounding. Our results also indicate that R200K Gα13hyperactivates the YAP signalling pathway. All these changes appear to affect cell migration and adhesion but not the proliferation. Our results suggest that hypopigmentation can result from a defect in melanosome transfer to keratinocytes due to cell shape alterations. These findings highlight the interaction between heterotrimeric G proteins and the RHOA pathway, and their role in melanocyte function.
Uncovering the multivariate genetic architecture of frailty with genomic structural equation modelling
Authors: Foote Isabelle F , Flint Jonny P , Fürtjes Anna E , Mullin Donncha S , Fisk John D , Karakach Tobias K , Rutenberg Andrew , Martin Nicholas G , Lupton Michelle K , Llewellyn David J , Ranson Janice M , Cox Simon R , Luciano Michelle , Rockwood Kenneth , Grotzinger Andrew D 
Published: July 2024

AbstractFrailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Therefore, we performed the first multivariate genome-wide association study of the latent genetic architecture between 30 frailty deficits, which identified 408 genomic risk loci. Our model included a general factor of genetic overlap across all deficits, plus six novel factors indexing shared genetic signal across specific groups of deficits. Follow-up analyses demonstrated the added clinical and etiological value of the six factors, including predicting frailty in external datasets, divergent genetic correlations with clinically relevant outcomes, and unique underlying biology linked to aging. This suggests nuanced models of frailty are key to understanding its causes and how it relates to worse health.
ASSESSING THE ACCESSIBILITY, AFFORDABILITY, AND ACCEPTABILITY OF REFRACTIVE SERVICES AS BARRIERS TO UPTAKE OF THESE SERVICES IN KAKAMEGA MUNICIPALITY, KENYA
Authors: Martin Kisenge Masinde , Naimah Ebrahim Khan 
Published: July 2024

ABSTRACTBackground informationRefractive errors and presbyopia remain a burden to the entire population. An estimated 76% of the 191 million blind people have preventable or treatable causes. Uncorrected Refractive Error (URE), the number one cause (51%) of moderate and severe vision impairment is easily preventable.AimThe study aimed to evaluate the accessibility, affordability, and acceptability of refractive services in Kakamega Municipality.MethodologyA population-based descriptive cross-sectional study was undertaken in Kakamega municipality using a cluster sampling method and descriptive data analysis.ResultsOut of 358 participants, 199 (55.6%) were male and 159 (44.4%) were female. The analysis shows affordability (18.3%) as the main reason for not using spectacles, followed by lack of quality care (3.4%), access to eye care (3.4%), awareness (2.5%), unpleasant past experiences (2.2%), importance not given to eye care issues (1.6%), lack of communication (0.9%), and disapproval from family members (0.9%). The study found that the affordable price range for spectacles varies between Kshs.5000 and less than Kshs.2000. More participants (38.0%) reported above Kshs.5000, while 29% indicated less Kshs.2000. The study found that affordability (p = 0.000), availability (p=0.004), and accessibility (p=0.005) of refractive services significantly influenced the uptake of these services.ConclusionThe study reveals that refractive services in Kakamega municipality are not easily accessible due to the lack of adequate services in government hospitals. Additionally, patients in the municipality struggle to afford spectacles due to the direct cost of spectacles and the lack of services in easily accessible public facilities.
Utilising the Palliative Prognostic Index in a mixed non-malignant and malignant patient group to determine prognosis. A general medicine tool for prognostication
Authors: Hawkins Joseph , Lester Megan 
Published: July 2024

ABSTRACTObjectivesThis study tested the use of the Palliative Prognostic Index (PPI), an established cancer prognostic tool, in a general medicine group within an acute setting for non-selective adult palliative care. The PPI score ranges from 0 to 15, with scores <6 indicating a prognosis of over 6 weeks and scores >6 indicating under 3 weeks.MethodsData from 256 patients seen over three months by the Ashford and St Peter’s NHS Foundation Trust Palliative Care team were analysed. PPI scores were calculated and correlated with patient’s date of death (DoD) to evaluate predictive value. ASPH is a medium sized hospital in England with 500 adult beds.ResultsAmong 256 patients, 145 had cancer and 111 had non-malignant disease. Higher PPI scores correlated with more accurate prognostic predictions, with an overall prediction accuracy of 70%.ConclusionsThe study demonstrates the PPI tool’s value for mixed groups of non-malignant and malignant diseases. The ASPH population is representative of most UK areas, suggesting that the PPI tool can guide timely care decisions in general medical settings.
Destabilisation ofbamtranscripts terminates the mitotic phase ofDrosophilafemale germline differentiation
Authors: Samuels Tamsin J , Torley Elizabeth J , Naden Emily L , Blair Phoebe E , Hernandez Frometa Frankjel A , Karam Teixeira Felipe 
Published: July 2024

AbstractThe tight control of the mitotic phase of differentiation is crucial to prevent tumourigenesis while securing tissue homeostasis. In theDrosophilafemale germline, differentiation involves precisely four mitotic divisions, and accumulating evidence suggests thatbag-of-marbles(bam), the initiator of differentiation, is also involved in controlling the number of divisions. To test this hypothesis, we depleted Bam from differentiating cells and found a reduced number of mitotic divisions. We examined the regulation of Bam using RNA imaging methods and found that thebam39 UTR conveys instability to the transcript in the 8-cell cyst and early 16-cell cyst. We show that the RNA binding protein, Rbp9, is responsible for timingbammRNA decay. Rbp9 itself is part of a sequential cascade of RNA binding proteins activated downstream of Bam, and we show that it is regulated through a change in transcription start site, driven by Rbfox1. Altogether, we propose a model in which Bam expression at the dawn of differentiation initiates a series of events that eventually terminates the Bam expression domain.
PredIDR: Accurate prediction of protein intrinsic disorder regions using deep convolutional neural network
Authors: Han Kun-Sop , Yun Su-Jong , Kim Chol-Song , Ri Chol-Pyok , Del Conte Alessio , Piovesan Damiano 
Published: July 2024

AbstractThe involvement of protein intrinsic disorder in essential biological processes, it is well known in structural biology. However, experimental methods for detecting intrinsic structural disorder and directly measuring highly dynamic behavior of protein structure are limited. To address this issue, several computational methods to predict intrinsic disorder from protein sequences were developed and their performance is evaluated by the Critical Assessment of protein Intrinsic Disorder (CAID). In this paper, we describe a new computational method, PredIDR, which provides accurate prediction of intrinsically disordered regions in proteins, mimicking experimental X-ray missing residues. Indeed, missing residues in Protein Data Bank (PDB) were used as positive examples to train a deep convolutional neural network which produces two types of output for short and long regions. PredIDR took part in the second round of CAID and was as accurate as the top state-of-the-art IDR prediction methods. PredIDR can be freely used through the CAID Prediction Portal available athttps://caid.idpcentral.org/portalor downloaded as a Singularity container fromhttps://biocomputingup.it/shared/caid-predictors/.
MiCK: a database of gut microbial genes linked with chemoresistance in cancer patients
Authors: Shahzaib Muhammad , Manzoor Haseeb , Zubair Hasnain , Jabeen Farzana , Kayani Masood Ur Rehman 
Published: July 2024

AbstractCancer remains a global health challenge, with significant morbidity and mortality rates. In 2020, cancer caused nearly 10 million deaths, making it the second leading cause of death worldwide. However, the emergence of chemoresistance becomes a major hurdle in successfully treating patients. Human gut microbes have been recognized for their role in modulating drug efficacy through their metabolites, ultimately leading to chemoresistance. The available databases are currently limited to knowledge regarding the interactions between gut microbiome and drugs. However, a database containing the human gut microbial gene sequences, and their effect on the efficacy of chemotherapy for cancer patients has not yet been reported. To address this challenge, we present the Microbial Chemoresistance Knowledgebase (MiCK), a comprehensive database cataloging microbial gene sequences associated with chemoresistance cancers. MiCK contains 1.6 million sequences of 29 gene types linked to chemoresistance and drug metabolism, curated manually from recent literature and sequence databases. The database supports efficient data retrieval and analysis, providing a user-friendly web interface for sequence search and download functionalities. MiCK aims to facilitate the understanding and mitigation of chemoresistance in cancers by serving as a valuable resource for researchers.Database URLhttps://microbialchemreskb.com/
Massively parallel genetic perturbation reveals the energetic architecture of an amyloid beta nucleation reaction
Authors: Arutyunyan Anna , Seuma Mireia , Faure Andre J. , Bolognesi Benedetta , Lehner Ben 
Published: July 2024

AbstractAmyloid protein aggregates are pathological hallmarks of more than fifty human diseases but how soluble proteins nucleate to form amyloids is poorly understood. Here we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid beta (Aβ42), the protein that aggregates in Alzheimer’s disease. In total, we quantify the nucleation rates of >140,000 variants of Aβ42. This allows us to accurately quantify the changes in reaction activation energy for all possible amino acid substitutions in a protein for the first time and, in addition, to quantify >600 energetic interactions between mutations. The data reveal the simple and interpretable genetic architecture of an amyloid nucleation reaction. Strikingly, strong energetic couplings are rare and identify a subset of structural contacts in mature fibrils. Together with the activation energy changes, this strongly suggests that the Aβ42 nucleation reaction transition state is structured in a short C-terminal region, providing a structural model for the reaction that may initiate Alzheimer’s disease. We believe this approach can be widely applied to probe the energetics and transition state structures of protein reactions.
Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin
Authors: Cortez-Romero Carlos R. , Lyu Jixing , Pillai Arvind S. , Laganowsky Arthur , Thornton Joseph W. 
Published: July 2024

ABSTRACTMany proteins form paralogous multimers – molecular complexes in which evolutionarily related proteins are arranged into specific quaternary structures. Little is known about the mechanisms by which they acquired their stoichiometry (the number of total subunits in the complex) and heterospecificity (the preference of subunits for their paralogs rather than other copies of the same protein). Here we use ancestral protein reconstruction and biochemical experiments to study historical increases in stoichiometry and specificity during the evolution of vertebrate hemoglobin (Hb), a α2β2heterotetramer that evolved from a homodimeric ancestor after a gene duplication. We show that the mechanisms for this evolutionary transition were simple. One hydrophobic substitution in subunit β after the gene duplication was sufficient to cause the ancestral dimer to homotetramerize with high affinity across a new interface. During this same interval, a single-residue deletion in subunit α at the older interface conferred specificity for the heterotetrameric form and thetrans-orientation of subunits within it. These sudden transitions in stoichiometry and specificity were possible because the interfaces in Hb are isologous – involving the same surface patch on interacting subunits, rotated 180° relative to each other. This architecture amplifies the impacts of individual mutations on stoichiometry and specificity, especially in higher-order complexes, and allows single substitutions to differentially affect heteromeric vs homomeric interactions. Our findings suggest that elaborate and specific symmetrical molecular complexes may often evolve via simple genetic and physical mechanisms.Significance statementMany molecular complexes are made up of proteins related by gene duplication, but how these assemblies evolve is poorly understood. Using ancestral protein reconstruction and biochemical experiments, we dissected how vertebrate hemoglobin, which comprises two copies each of two related proteins, acquired this architecture from a homodimeric ancestor. Each aspect of this transition – from dimer to tetramer and homomer to heteromer – had a simple genetic basis: a single-site amino acid change in each protein drove these changes in size and specificity. These transitions were possible because hemoglobin’s architecture is symmetric, which amplified the effect of small biochemical changes on the assembly of the complex. Many protein complexes are symmetrical, suggesting that they too may have evolved via simple genetic mechanisms.Classification: Major classification- Biological SciencesMinor classifications– Biochemistry/Evolution
Investigating the factors influencing ease of doing business in Gilan province
Authors: Miraskari Seyed Reza , Rezaei Pitenoei Yasser 
Published: July 2024

PurposeThe ease of doing business (EODB) is a key factor in the development of investment, production and employment in a country. The purpose of this research is to identify the components of EODB in Gilan province in Northern Iran and rank these components from the perspective of economic operators.Design/methodology/approachThis research uses a mixed methods design. In the qualitative phase, the components of EODB in Gilan province are identified through meta-synthesis with the participation of 10 experts. In the quantitative phase, structural equation modeling is used to rank these components from the perspective of 75 randomly selected economic operators from different economic sectors of Gilan province.FindingsAccording to the participants, the main factors influencing EODB in Gilan province are: (1) public services and infrastructure; (2) political stability and the government; (3) policies, laws and regulations and (4) security of property rights.Practical implicationsIdentifying factors conducive to the business environment can play an effective role in removing the barriers to achieving the goals of development programs, such as economic growth and reducing unemployment, poverty and inflation. Gilan province, in particular, is in a favorable condition in terms of climate and geography, with an abundance of young, specialized human resources, which can help remove barriers to improving the business environment and facilitate the use of these capacities. It must be noted that the labor force participation rate in Gilan province is 41.3%, indicating that 58.7% of the working age population is not working or actively looking for work, and removing EODB barriers can provide these people with incentives for economic participation.Originality/valueThe results suggest that creating a stable, transparent, anti-rent, predictable and reliable business environment will allow for increasing investment, production and employment across the province, and that controlling the inflation caused by increased production will make it possible to achieve maximum productivity and economic development.
“They kill us mentally”: exploring microaggression towards LGBTQIA+ employees in Indian workplaces
Authors: Maji Sucharita , Rajeev Devu 
Published: July 2024

PurposeThe current study aimed to (1) explore the prevalence and processes associated with microaggression, along with (2) the consequences of such instances on the queer employees’ life.Design/methodology/approachFor this purpose, semi-structured in-depth interviews were conducted on 29 LGBTQIA + persons (21–42 years). The qualitative data were analysed through the thematic analysis method (a hybrid of theoretical and inductive thematic analysis). Nadal and colleagues’ (2010) taxonomy on sexual orientation and transgender microaggression was used as a theoretical lens for detecting the acts of microaggression.FindingsThe result revealed eight themes: i.e. (1) overt discrimination (bullying and sexual harassment); (2) workplace discrimination; (3) environmental microaggressions; (4) interpersonal microaggressions; (5) mental health effects; (6) disclosure dilemma; (7) consequences on job-related functioning; and (8) policy changes. Microaggression was more common as compared to overt forms of aggression such as bullying. The study detected a serious lag in the implementation of queer-friendly policies in Indian organizations. Experiences of overt discrimination and microaggressions hinder the work performance and the psychological well-being of queer employees.Originality/valueLGBTQIA + microaggression is not explored in the Indian workplace context.