bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autostent: A Semi-Automated Approach to Designing Customized 3D-Printed Oral Radiation Stents for Patients with Head and Neck Cancer
Authors: Agrawal Anshuman , Zaid Mohamed M. , Roach Millicent A. , Xiao Lianchun , Chambers Mark S. , Koay Eugene J. 
Published: September 2023

AbstractOral stents may reduce toxicities during radiation therapy for head and neck cancer (HNC). Although customized 3D-printed oral stents are more quickly fabricated and non-inferior (in terms of patient reported outcomes) compared to conventionally-fabricated stents, the design process is still relatively time-consuming, unstandardized, and requires experienced technicians. We hypothesized that semi-automating the 3D-printed stent design process can reduce design time and standardize the workflow. Using oral stent design principles established over decades by oral oncologists, we developed a customized computer program (Autostent) using MATLAB to semi-automate the design process. We then compared a previously described method utilizing non-automated computer-aided design with Autostent. Three users designed stents for four patients with HNC enrolled on a prospective observational study. These patients were selected based on differing dental anatomies, and each user designed stents for each patient thrice, using both the non- and semi-automated methods. The design time and stent volumes for the two methods were statistically analyzed. Semi-automation was found to significantly reduce the average design time by 23.6 minutes (51.2%, p=0.001), independent of user, dental anatomy, and trial number. Additionally, semi-automation reduced the average stent volume by 4.33 mL (12.9%, p=0.016, univariate analysis). While this was not statistically significant after accounting for the other experimental variables (p=0.40, multivariate analysis), semi-automation did reduce the variability in the stent volume across users (overall standard error of the mean reduced by 40%). Thus, the semi-automated workflow significantly reduced the design time and the variability in the stent volume across users compared to the non-automated workflow. This may lead to potential cost benefits, standardization of the device, and increased population-wide access to a device that could help reduce toxicities for HNC.
Quinoclamine inhibits Shiga toxin production in enterohemorrhagicEscherichia coli
Authors: Kar Oiti , Feng Hsiao-Cheng , Hirano Hiroyuki , Teng Ching-Hao , Osada Hiroyuki , Hashimoto Masayuki 
Published: September 2023

AbstractObjectivesEnterohemorrhagicEscherichia coli(EHEC) is responsible for the most severe symptoms ofE. coliinfections, including hemorrhagic colitis and hemorrhagic uremic syndrome. Shiga toxin 2 (Stx2) plays a significant role as a major virulence factor. The genes encoding Stx2 locate in lambda-like prophage on the EHEC genome. Consequently, Stx2 is expressed when production of the phage is induced by the SOS response. Antibiotic treatment is not recommended for curing the bacterial infection, because it is associated with severe hemorrhagic uremic syndrome. If Stx2 production is prevented, EHEC pathogenicity significantly decreases, and antibiotics may be available to treat the infection.MethodsWe conducted two independent screenings to identify Stx2 production inhibitors for libraries from the RIKEN Natural Product Depository (NPDepo); namely, screening of the Authentic Library, and two-round screening of the Pilot and Analog Libraries.ResultsThe screening of Authentic Library identified niclosamide as a Stx2 production inhibitor. Besides, two naphthoquinoids were identified after the two-round of screening of the Pilot and Analog Libraries. Niclosamide, and quinoclamine, which has structure shared in the two naphthoquinoids, prevented cell lysis via the phage production and ceased Stx2 production in EHEC. The SOS reporter assay indicated that quinoclamine prevented the SOS response inE. coli, whereas niclosamide did not.ConclusionsThese findings suggest that quinoclamine inhibited Stx2 production by preventing the SOS response, whereas niclosamide was involved in phage propagation following the SOS response. These compounds can be a potential therapeutic option to treat EHEC infections.
Characterising the Protein-Protein Interaction Between MDM2 and 14-3-3σ; Proof of Concept for Small Molecule Stabilisation
Authors: Ward Jake A. , Romartinez-Alonso Beatriz , Kay Danielle F. , Bellamy-Carter Jeddidiah , Thurairajah Bethany , Basran Jaswir , Kwon Hanna , Leney Aneika C. , Macip Salvador , Roversi Pietro , Muskett Frederick W. , Doveston Richard G. 
Published: September 2023

AbstractMouse Double Minute 2 (MDM2) is a key negative regulator of the tumour suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of wild type p53. The 14-3-3 family of adaptor proteins are known to bind to MDM2 and the 14-3-3σ isoform controls MDM2 cellular localisation and stability to inhibit its activity. Therefore, small molecule stabilisation of the 14-3-3σ/MDM2 protein-protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. In this work we provide a detailed biophysical and structural characterisation of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. Each of the two phosphorylated stretches of MDM2 occupies one of the two binding grooves of a 14-3-3σ dimer, a novel model for binding of di-phosphorylated peptides to 14-3-3 proteins. In addition, we show that the 14-3-3σ/MDM2 interaction is amenable to small molecule stabilisation. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in stablisation of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilisers.
Prolonged delays in human microbiota transmission after a controlled antibiotic perturbation
Authors: Xue Katherine S. , Walton Sophie Jean , Goldman Doran A. , Morrison Maike L. , Verster Adrian J. , Parrott Autumn B. , Yu Feiqiao Brian , Neff Norma F. , Rosenberg Noah A. , Ross Benjamin D. , Petrov Dmitri A. , Huang Kerwyn Casey , Good Benjamin H. , Relman David A. 
Published: September 2023

AbstractHumans constantly encounter new microbes, but few become long-term residents of the adult gut microbiome. Classical theories predict that colonization is determined by the availability of open niches, but it remains unclear whether other ecological barriers limit commensal colonization in natural settings. To disentangle these effects, we used a controlled perturbation with the antibiotic ciprofloxacin to investigate the dynamics of gut microbiome transmission in 22 households of healthy, cohabiting adults. Colonization was rare in three-quarters of antibiotic-taking subjects, whose resident strains rapidly recovered in the week after antibiotics ended. In contrast, the remaining antibiotic-taking subjects exhibited lasting responses, with extensive species losses and transient expansions of potential opportunistic pathogens. These subjects experienced elevated rates of commensal colonization, but only after long delays: many new colonizers underwent sudden, correlated expansions months after the antibiotic perturbation. Furthermore, strains that had previously transmitted between cohabiting partners rarely recolonized after antibiotic disruptions, showing that colonization displays substantial historical contingency. This work demonstrates that there remain substantial ecological barriers to colonization even after major microbiome disruptions, suggesting that dispersal interactions and priority effects limit the pace of community change.
Nanoconnectivity: a quantitative approach to examine the structural complexity of the brain
Authors: Turégano-Lopez Marta , de las Pozas Félix , Santuy Andrea , Rodríguez José-Rodrigo , DeFelipe Javier , Merchán-Pérez Angel 
Published: September 2023

ABSTRACTUnraveling the highly complex connectivity at the synaptic level is critical for the understanding of brain function. However, investigating the structure of the brain is time consuming and technically demanding. We have developed and applied a tracing method that allows us to obtain a simplified or skeletonized version of all nerve fibers present within a given brain sample, without the need for full 3D reconstructions. Every tracing or “skeleton” is linked to its corresponding synaptic contacts, so the result is an intricate meshwork of axons and dendrites interconnected by a cloud of synaptic junctions. The tissue sample is obtained by volume electron microscopy (FIB-SEM) and tracing is performed by dedicated software. In addition, the software provides the length of each skeleton as well as the number and positions of its corresponding synapses. With this approach, we have identified clear as well as subtle quantitative differences between three brain regions (the stratum radiatum of the hippocampus and layers 1 and 3 of the somatosensory cortex). For example, we have found that axons and dendrites are densely packed in the neuropil of these three regions, reaching close to 8 kilometers of nerve fibers per cubic mm in layer 1. In all cases, the predominant fibers were excitatory axons, followed by spiny dendrites, inhibitory axons and smooth dendrites. Other examples include the fact that the excitatory axons in the stratum radiatum establish many more synapses per micron than the axons of the other regions, or the lack of correlation between the number of synapses established on the spines of a given dendrite and the number of synapses established on the dendritic shaft. Using this methodology, we obtain a set of quantitative parameters including the number and proportions of excitatory and inhibitory synapses; the numbers of dendrites and axons; the proportion of excitatory and inhibitory axons; the linear densities of synapses established on dendritic spines and dendritic shafts; the linear densities of synapses established by excitatory and inhibitory axons; and the lengths of the different types of dendrites and axons. Taken together, these data characterize each region, allowing us to compare them on a quantitative basis and to identify subtle traits and differences that would have escaped a qualitative analysis. With this strategy, we can achieve a better understanding of the structure and dynamics of the brain, and we are better equipped to explore how they change during both normal and pathological conditions.
Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10
Authors: López-Ayllón Blanca D. , Marín Silvia , Fernández Marco Fariñas , García-García Tránsito , Fernández-Rodríguez Raúl , Lucas-Rius Ana de , Redondo Natalia , Mendoza-García Laura , Foguet Carles , Grigas Juozas , Calvet Alba , Villalba José Manuel , Rodríguez Gómez María Josefa , Megías Diego , Mandracchia Biagio , Luque Daniel , Lozano Juan José , Calvo Cristina , Thomson Timothy M. , Garrido Juan J. , Cascante Marta , Montoya María 
Published: September 2023

ABSTRACTAntiviral signaling, immune response and cell metabolism in human body are dysregulated by SARS-CoV-2, the causative agent of the COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While all four ORFs caused mitochondrial fragmentation and altered mitochondrial function, only ORF3a and ORF9c induced a marked structural alteration in mitochondrial cristae. ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes. In contrast, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes for proteins with critical mitochondrial functions and morphology. Genome-Scale Metabolic Models predicted common and private metabolic flux reprogramming, notably a depressed amino acid metabolism, and an enhanced metabolism of specific lipids distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.One-Sentence SummaryMitochondria and metabolic alterations induced by SARS- CoV-2 accessory proteins ORF3a, ORF9b, ORF9c, ORF10 in pulmonary cells unravel new targets of intervention.
Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition
Authors: Vollger Mitchell R. , Korlach Jonas , Eldred Kiara C. , Swanson Elliott , Underwood Jason G. , Cheng Yong-Han H. , Ranchalis Jane , Mao Yizi , Blue Elizabeth E. , Schwarze Ulrike , Munson Katherine M. , Saunders Christopher T. , Wenger Aaron M. , Allworth Aimee , Chanprasert Sirisak , Duerden Brittney L. , Glass Ian , Horike-Pyne Martha , Kim Michelle , Leppig Kathleen A. , McLaughlin Ian J. , Ogawa Jessica , Rosenthal Elisabeth A. , Sheppeard Sam , Sherman Stephanie M. , Strohbehn Samuel , Yuen Amy L. ,   University of Washington Center for Mendelian Genomics (UW-CMG),   Undiagnosed Diseases Network (UDN), Reh Thomas A. , Byers Peter H. , Bamshad Michael J. , Hisama Fuki M. , Jarvik Gail P. , Sancak Yasemin , Dipple Katrina M. , Stergachis Andrew B. 
Published: September 2023

AbstractResolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploidde novogenome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA,PDK3,MAB21L1, andRB1) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four ‘omes’ to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.
Rolling the evolutionary dice:Neisseriacommensals as proxies for elucidating the underpinnings of antibiotic resistance mechanisms and evolution in human pathogens
Authors: Frost Kelly M. , Charron-Smith Sierra L. , Cotsonas Terence C. , Dimartino Daniel C. , Eisenhart Rachel C. , Everingham Eric T. , Holland Elle C. , Imtiaz Kainat , Kornowicz Cory J. , Lenhard Lydia E. , Lynch Liz H. , Moore Nadia P. , Phadke Kavya , Reed Makayla L. , Smith Samantha R. , Ward Liza L. , Wadsworth Crista B. 
Published: September 2023

ABSTRACTSpecies within the genusNeisseriaare especially adept at sharing adaptive allelic variation across species’ boundaries, with commensal species repeatedly transferring resistance to their pathogenic relativeN. gonorrhoeae. However, resistance in commensalNeisseriais infrequently characterized at both the phenotypic and genotypic levels, limiting our ability to predict novel and potentially transferable resistance mechanisms that ultimately may become important clinically. Unique evolutionary starting places of eachNeisseriaspecies will have distinct genomic backgrounds, which may ultimately control the fate of evolving populations in response to selection, as epistatic and additive interactions may coerce lineages along divergent evolutionary trajectories. However alternatively, similar genetic content present across species due to shared ancestry may constrain the adaptive solutions that exist. Thus, identifying the paths to resistance across commensals may aid in characterizing theNeisseriaresistome – or the reservoir of alleles within the genus, as well as its depth. Here, we usein vitroevolution of four commensal species to investigate the potential for and repeatability of resistance evolution to two antimicrobials, the macrolide azithromycin and the β-lactam penicillin. After 20 days of selection, commensals evolved elevated minimum inhibitory concentrations (MICs) to penicillin and azithromycin in 11/16 and 12/16 cases respectively. Almost all cases of resistance emergence converged on mutations within ribosomal components or themtrRCDEefflux pump for azithromycin-based selection, andmtrRCDEorpenAfor penicillin selection; thus, supporting constrained adaptive solutions despite divergent evolutionary starting points across the genus for these particular drugs. However, continuing to explore the paths to resistance across different experimental conditions and genomic backgrounds, which could shunt evolution down alternative evolutionary trajectories, will ultimately flesh out the fullNeisseriaresistome.
Statistical critical reactive maintenance characterisation for digital twin implementation in universities
Authors: Campos Fialho Beatriz , Codinhoto Ricardo , Minto Fabricio Márcio 
Published: September 2023

Purpose
Facilities management (FM) plays a key role in the performance of businesses to ensure the comfort of users and the sustainable use of natural resources over operation and maintenance. Nevertheless, reactive maintenance (RM) services are characterised by delays, waste and difficulties in prioritising services and identifying the root causes of failures; this is mostly caused by inefficient asset information and communication management. While linking building information modelling and the Internet of Things through a digital twin has demonstrated potential for improving FM practices, there is a lack of evidence regarding the process requirements involved in their implementation. This paper aims to address this challenge, as it is the first to statistically characterise RM services and processes to identify the most critical RM problems and scenarios for digital twin implementation. The statistical data analytics approach also constitutes a novel practical approach for a holistic analysis of RM occurrences.

Design/methodology/approach
The research strategy was based on multiple case studies, which adopted university campuses as objects for investigation. A detailed literature review of work to date and documental analysis assisted in generating data on the FM sector and RM services, where qualitative and statistical analyses were applied to approximately 300,000 individual work requests.

Findings
The work provides substantial evidence of a series of patterns across both cases that were not evidenced prior to this study: a concentration of requests within main campuses; a balanced distribution of requests per building, mechanical and electrical service categories; a predominance of low priority level services; a low rate of compliance in attending priority services; a cumulative impact on the overall picture of five problem subcategories (i.e. Building-Door, Mechanical-Plumbing, Electrical-Lighting, Mechanical-Heat/Cool/Ventilation and Electrical-Power); a predominance of problems in student accommodation facilities, circulations and offices; and a concentration of requests related to unlisted buildings. These new patterns form the basis for business cases where maintenance services and FM sectors can benefit from digital twins. It also provides a new methodological approach for assessing the impact of RM on businesses.

Practical implications
The findings provide new insights for owners and FM staff in determining the criticality of RM services, justifying investments and planning the digital transformation of services for a smarter provision.

Originality/value
This study represents a unique approach to FM and provides detailed evidence to identify novel RM patterns of critical service provision and activities within organisations for efficient digitalised data management over a building’s lifecycle.
Quality management research in Arab countries: current status and future directions
Authors: Yousef Darwish Abdulrahman 
Published: September 2023

PurposeThis study aims to review the current status of quality management (QM) research in Arab countries between 2001 and 2020.Design/methodology/approachThe study adopted the content analysis methodology, searching through various databases and search engines for relevant publications using several keywords. The selected publications were classified according to several criteria and the obtained results were presented in the form of frequencies and percentages.FindingsMost research publications regarding QM were journal articles. The number of publications has steadily increased between 2001 and 2020. Moreover, QM research largely uses the quantitative research design. Questionnaire surveys are widely used as a data collection method; basic statistical analysis techniques are commonly employed to analyze the data. There is a tendency toward empirical research versus conceptual research. A few journal articles were published in reputed peer-reviewed international journals with low citation. Overall, Arab scholars research on QM and related topics over the past two decades is not significant for the field considering the number of published papers, citations and the papers published in reputed peer-reviewed international journals.Research limitations/implicationsThis study has several limitations. First, it does not cover non-English information sources due to the overall lack of Arabic publication databases. Second, it uses a limited number of criteria to classify the selected publications. Third, it adopts the content analysis methodology to classify the selected publications. This method has several limitations, which may negatively affect the results. Nevertheless, the study offers several implications for research scholars, educators and practitioners.Originality/valueThis is the first study to attempt a comprehensive overview of the state of research on QM in Arab countries between 2001 and 2020 using the content analysis methodology.